Terrence Blaschke

All Publications

• Introduction to the Theme "Development of New Drugs: Moving from the Bench to Bedside and Improved Patient Care". Annual review of pharmacology and toxicology Blaschke, T. F., Insel, P. A., Amara, S. G., Meyer, U. A. 2022

  Abstract

  Investigations in pharmacology and toxicology range from molecular studies to clinical care. Studies in basic and clinical pharmacology and in preclinical and clinical toxicology are all essential in bringing new knowledge and new drugs into clinical use. The 30 reviews in Volume 63 of the Annual Review of Pharmacology and Toxicology explore topics across this spectrum. Examples include "Zebrafish as a Mainstream Model for In Vivo Systems Pharmacology and Toxicology" and "Artificial Intelligence and Machine Learning for Lead-to-Candidate Decision-Making and Beyond." Other reviews discuss components important for drug discovery and development and the use of pharmaceuticals in a variety of diseases. Air pollution continues to increase globally; accordingly, "Air Pollution-Related Neurotoxicity Across the Life Span" is a timely and forward-thinking review. Volume 63 also explores the use of contemporary technologies such as electronic health records, pharmacogenetics, and new drug delivery systems that help enhance and improve the utility of new therapies. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 63 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  View details for DOI 10.1146/annurev-pharmtox-091222-022612

  View details for PubMedID 36270297

• The World Health Organization Prequalification Program and Clinical Pharmacology in 2030. Clinical pharmacology and therapeutics Blaschke, T. F., Lumpkin, M., Hartman, D. 2019

  View details for DOI 10.1002/cpt.1680

  View details for PubMedID 31773722

• Wirelessly observed therapy compared to directly observed therapy to confirm and support tuberculosis treatment adherence: A randomized controlled trial. PLoS medicine Browne, S. H., Umlauf, A. n., Tucker, A. J., Low, J. n., Moser, K. n., Gonzalez Garcia, J. n., Peloquin, C. A., Blaschke, T. n., Vaida, F. n., Benson, C. A. 2019; 16 (10): e1002891

  Abstract

  Excellent adherence to tuberculosis (TB) treatment is critical to cure TB and avoid the emergence of resistance. Wirelessly observed therapy (WOT) is a novel patient self-management system consisting of an edible ingestion sensor (IS), external wearable patch, and paired mobile device that can detect and digitally record medication ingestions. Our study determined the accuracy of ingestion detection in clinical and home settings using WOT and subsequently compared, in a randomized control trial (RCT), confirmed daily adherence to medication in persons using WOT or directly observed therapy (DOT) during TB treatment.We evaluated WOT in persons with active Mycobacterium tuberculosis complex disease using IS-enabled combination isoniazid 150 mg/rifampin 300 mg (IS-Rifamate). Seventy-seven participants with drug-susceptible TB in the continuation phase of treatment, prescribed daily isoniazid 300 mg and rifampin 600 mg, used IS-Rifamate. The primary endpoints of the trial were determination of the positive detection accuracy (PDA) of WOT, defined as the percentage of ingestions detected by WOT administered under direct observation, and subsequently the proportion of prescribed doses confirmed by WOT compared to DOT. Initially participants received DOT and WOT simultaneously for 2-3 weeks to allow calculation of WOT PDA, and the 95% confidence interval (CI) was estimated using the bootstrap method with 10,000 samples. Sixty-one participants subsequently participated in an RCT to compare the proportion of prescribed doses confirmed by WOT and DOT. Participants were randomized 2:1 to receive WOT or maximal in-person DOT. In the WOT arm, if ingestions were not remotely confirmed, the participant was contacted within 24 hours by text or cell phone to provide support. The number of doses confirmed was collected, and nonparametric methods were used for group and individual comparisons to estimate the proportions of confirmed doses in each randomized arm with 95% CIs. Sensitivity analyses, not prespecified in the trial registration, were also performed, removing all nonworking (weekend and public holiday) and held-dose days. Participants, recruited from San Diego (SD) and Orange County (OC) Divisions of TB Control and Refugee Health, were 43.1 (range 18-80) years old, 57% male, 42% Asian, and 39% white with 49% Hispanic ethnicity. The PDA of WOT was 99.3% (CI 98.1; 100). Intent-to-treat (ITT) analysis within the RCT showed WOT confirmed 93% versus 63% DOT (p < 0.001) of daily doses prescribed. Secondary analysis removing all nonworking days (weekends and public holidays) and held doses from each arm showed WOT confirmed 95.6% versus 92.7% (p = 0.31); WOT was non-inferior to DOT (difference 2.8% CI [-1.8%, 9.1%]). One hundred percent of participants preferred using WOT. WOT associated adverse events were <10%, consisting of minor skin rash and pruritus associated with the patch. WOT provided longitudinal digital reporting in near real time, supporting patient self-management and allowing rapid remote identification of those who needed more support to maintain adherence. This study was conducted during the continuation phase of TB treatment, limiting its generalizability to the entire TB treatment course.In terms of accuracy, WOT was equivalent to DOT. WOT was superior to DOT in supporting confirmed daily adherence to TB medications during the continuation phase of TB treatment and was overwhelmingly preferred by participants. WOT should be tested in high-burden TB settings, where it may substantially support low- and middle-income country (LMIC) TB programs.ClinicalTrials.gov NCT01960257.

  View details for DOI 10.1371/journal.pmed.1002891

  View details for PubMedID 31584944

• A systematic evaluation of effect of adherence patterns on the sample size and power of a clinical study. CPT: pharmacometrics & systems pharmacology Mallayasamy, S., Chaturvedula, A., Blaschke, T., Fossler, M. J. 2018

  Abstract

  The objective of our study was to evaluate the effect of adherence patterns on the sample size and power of a clinical trial. Simulations from a population pharmacokinetic (PK)-pharmacodynamic (PD) model linked to an adherence model were used. Four types of drug characteristics such as long (~35 hr) and short (~12 hr) half-life in combination with earlier or delayed time to reach steady-state PD endpoints were studied. Adherence patterns were simulated using Markov chains. Our results clearly demonstrate the significant impact of varying levels and patterns of non-adherence on the sample size and power of a study. For drugs with short-half-lives the evidence to support efficacy could be diluted by various patterns of non-adherence that would make its efficacy indistinguishable from the response to placebo. Prospectively utilizing clinical trial simulations with thorough incorporation of various adherence patterns would provide valuable information when designing a trial.

  View details for PubMedID 30291680

• Introduction to the Theme "New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development" ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 58 Insel, P. A., Amara, S. G., Blaschke, T. F., Meyer, U. A., Insel, P. A. 2018; 58: 33–36

  Abstract

  The theme "New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development" links 13 articles in this volume of the Annual Review of Pharmacology and Toxicology (ARPT). The engaging prefatory articles by Arthur Cho and Robert Lefkowitz set the stage for this theme and for the reviews that insightfully describe new approaches that advance research and discovery in pharmacology and toxicology. Examples include the progress being made in developing Organs-on-Chips/microphysiological systems and human induced pluripotent stem cell-derived cells to aid in understanding cell and tissue pharmacokinetics, action, and toxicity; the recognition of the importance of circadian rhythm, the microbiome, and epigenetics in drug and toxicant responses; and the application of results from new types of patient-derived information to create personalized/precision medicine, including therapeutics for pain, which may perhaps provide help in dealing with the opioid epidemic in the United States. Such new information energizes discovery efforts in pharmacology and toxicology that seek to improve the efficacy and safety of drugs in patients and to minimize the consequences of exposure to toxins.

  View details for PubMedID 29058990

• Improving antiretroviral therapy adherence in resource-limited settings at scale: a discussion of interventions and recommendations JOURNAL OF THE INTERNATIONAL AIDS SOCIETY Haberer, J. E., Sabin, L., Amico, K. R., Orrell, C., Galarraga, O., Tsai, A. C., Vreeman, R. C., Wilson, I., Sam-Agudu, N. A., Blaschke, T. F., Vrijens, B., Mellins, C. A., Remien, R. H., Weiser, S. D., Lowenthal, E., Stirratt, M. J., Sow, P. S., Thomas, B., Ford, N., Mills, E., Lester, R., Nachega, J. B., Bwana, B. M., Ssewamala, F., Mbuagbaw, L., Munderi, P., Geng, E., Bangsberg, D. R. 2017; 20

  Abstract

  Successful population-level antiretroviral therapy (ART) adherence will be necessary to realize both the clinical and prevention benefits of antiretroviral scale-up and, ultimately, the end of AIDS. Although many people living with HIV are adhering well, others struggle and most are likely to experience challenges in adherence that may threaten virologic suppression at some point during lifelong therapy. Despite the importance of ART adherence, supportive interventions have generally not been implemented at scale. The objective of this review is to summarize the recommendations of clinical, research, and public health experts for scalable ART adherence interventions in resource-limited settings.In July 2015, the Bill and Melinda Gates Foundation convened a meeting to discuss the most promising ART adherence interventions for use at scale in resource-limited settings. This article summarizes that discussion with recent updates. It is not a systematic review, but rather provides practical considerations for programme implementation based on evidence from individual studies, systematic reviews, meta-analyses, and the World Health Organization Consolidated Guidelines for HIV, which include evidence from randomized controlled trials in low- and middle-income countries. Interventions are categorized broadly as education and counselling; information and communication technology-enhanced solutions; healthcare delivery restructuring; and economic incentives and social protection interventions. Each category is discussed, including descriptions of interventions, current evidence for effectiveness, and what appears promising for the near future. Approaches to intervention implementation and impact assessment are then described.The evidence base is promising for currently available, effective, and scalable ART adherence interventions for resource-limited settings. Numerous interventions build on existing health care infrastructure and leverage available resources. Those most widely studied and implemented to date involve peer counselling, adherence clubs, and short message service (SMS). Many additional interventions could have an important impact on ART adherence with further development, including standardized counselling through multi-media technology, electronic dose monitoring, decentralized and differentiated models of care, and livelihood interventions. Optimal targeting and tailoring of interventions will require improved adherence measurement.The opportunity exists today to address and resolve many of the challenges to effective ART adherence, so that they do not limit the potential of ART to help bring about the end of AIDS.

  View details for DOI 10.7448/IAS.20.1.21371

  View details for Web of Science ID 000397570700002

  View details for PubMedID 28364569

• Improving antiretroviral therapy adherence in resource-limited settings at scale: a discussion of interventions and recommendations. Journal of the International AIDS Society Haberer, J. E., Sabin, L., Amico, K. R., Orrell, C., Galárraga, O., Tsai, A. C., Vreeman, R. C., Wilson, I., Sam-Agudu, N. A., Blaschke, T. F., Vrijens, B., Mellins, C. A., Remien, R. H., Weiser, S. D., Lowenthal, E., Stirratt, M. J., Sow, P. S., Thomas, B., Ford, N., Mills, E., Lester, R., Nachega, J. B., Bwana, B. M., Ssewamala, F., Mbuagbaw, L., Munderi, P., Geng, E., Bangsberg, D. R. 2017; 20 (1): 21371

  Abstract

  Introduction: Successful population-level antiretroviral therapy (ART) adherence will be necessary to realize both the clinical and prevention benefits of antiretroviral scale-up and, ultimately, the end of AIDS. Although many people living with HIV are adhering well, others struggle and most are likely to experience challenges in adherence that may threaten virologic suppression at some point during lifelong therapy. Despite the importance of ART adherence, supportive interventions have generally not been implemented at scale. The objective of this review is to summarize the recommendations of clinical, research, and public health experts for scalable ART adherence interventions in resource-limited settings. Methods: In July 2015, the Bill and Melinda Gates Foundation convened a meeting to discuss the most promising ART adherence interventions for use at scale in resource-limited settings. This article summarizes that discussion with recent updates. It is not a systematic review, but rather provides practical considerations for programme implementation based on evidence from individual studies, systematic reviews, meta-analyses, and the World Health Organization Consolidated Guidelines for HIV, which include evidence from randomized controlled trials in low- and middle-income countries. Interventions are categorized broadly as education and counselling; information and communication technology-enhanced solutions; healthcare delivery restructuring; and economic incentives and social protection interventions. Each category is discussed, including descriptions of interventions, current evidence for effectiveness, and what appears promising for the near future. Approaches to intervention implementation and impact assessment are then described. Results and discussion: The evidence base is promising for currently available, effective, and scalable ART adherence interventions for resource-limited settings. Numerous interventions build on existing health care infrastructure and leverage available resources. Those most widely studied and implemented to date involve peer counselling, adherence clubs, and short message service (SMS). Many additional interventions could have an important impact on ART adherence with further development, including standardized counselling through multi-media technology, electronic dose monitoring, decentralized and differentiated models of care, and livelihood interventions. Optimal targeting and tailoring of interventions will require improved adherence measurement. Conclusions: The opportunity exists today to address and resolve many of the challenges to effective ART adherence, so that they do not limit the potential of ART to help bring about the end of AIDS.

  View details for DOI 10.7448/IAS.20.1.21371

  View details for PubMedID 28630651

  View details for PubMedCentralID PMC5467606

• Poor medication adherence in clinical trials: consequences and solutions. Nature reviews. Drug discovery Breckenridge, A., Aronson, J. K., Blaschke, T. F., Hartman, D., Peck, C. C., Vrijens, B. 2017; 16 (3): 149-150

  Abstract

  Poor adherence to medicines in clinical trials can undermine the value of the trials; for example, by compromising estimates of the benefits and risks of a medicine. In this article, we highlight such consequences and also discuss approaches to tackle this problem.

  View details for DOI 10.1038/nrd.2017.1

  View details for PubMedID 28154411

• Adherence to Medications: Insights Arising from Studies on the Unreliable Link Between Prescribed and Actual Drug Dosing Histories ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 52 Blaschke, T. F., Osterberg, L., Vrijens, B., Urquhart, J. 2012; 52: 275-?

  Abstract

  Satisfactory adherence to aptly prescribed medications is essential for good outcomes of patient care and reliable evaluation of competing modes of drug treatment. The measure of satisfactory adherence is a dosing history that includes timely initiation of dosing plus punctual and persistent execution of the dosing regimen throughout the specified duration of treatment. Standardized terminology for initiation, execution, and persistence of drug dosing is essential for clarity of communication and scientific progress. Electronic methods for compiling drug dosing histories are now the recognized standard for quantifying adherence, the parameters of which support model-based, continuous projections of drug actions and concentrations in plasma that are confirmable by intermittent, direct measurements at single time points. The frequency of inadequate adherence is usually underestimated by pre-electronic methods and thus is clinically unrecognized as a frequent cause of failed treatment or underestimated effectiveness. Intermittent lapses in dosing are potential sources of toxicity through hazardous rebound effects or recurrent first-dose effects.

  View details for DOI 10.1146/annurev-pharmtox-011711-113247

  View details for Web of Science ID 000301839600014

  View details for PubMedID 21942628

• Global Challenges for Clinical Pharmacology in the Developing World CLINICAL PHARMACOLOGY & THERAPEUTICS Blaschke, T. F. 2009; 85 (6): 579-581

  Abstract

  The increasing burden of HIV care threatens to overwhelm health-care providers and systems in the developing world. Clinical pharmacologists, applying the training that they possess in regulatory science, rational prescribing, and teaching therapeutics, could improve the delivery of care in that setting. However, the shortage of clinical pharmacologists and the emigration of health-care providers limit the ability to take advantage of this approach. Possible solutions are outlined in this Commentary.

  View details for DOI 10.1038/clpt.2009.54

  View details for Web of Science ID 000266290000010

  View details for PubMedID 19451910

• Adherence to medication. New England journal of medicine Osterberg, L., Blaschke, T. 2005; 353 (5): 487-497

  View details for PubMedID 16079372

• Drug therapy - Adherence to medication NEW ENGLAND JOURNAL OF MEDICINE Osterberg, L., Blaschke, T. 2005; 353 (5): 487-497

  View details for Web of Science ID 000230939000008

• The disposition of saquinavir in normal and P-glycoprotein deficient mice, rats, and in cultured cells DRUG METABOLISM AND DISPOSITION Washington, C. B., Wiltshire, H. R., Man, M., Moy, T., Harris, S. R., Worth, E., Weigl, P., Liang, Z. M., Hall, D., Marriott, L., Blaschke, T. F. 2000; 28 (9): 1058-1062

  Abstract

  Protease inhibitors are very effective in treating patients infected with HIV. However, many drugs in this class penetrate poorly into the central nervous system (CNS) and may permit this site to be a sanctuary from which resistant virus can emerge. Previous studies have shown that the protease inhibitor saquinavir (SQV) interacts with the multidrug transport system, P-glycoprotein (P-gp), expressed in epithelial cells in the gut mucosa and at the blood-brain barrier, and thus might affect both the oral absorption and the penetration of SQV into the CNS. To determine whether SQV is a substrate for P-gp, its uptake was determined in cancer cells, which do (Dx5) and do not (MES-SA) express P-gp. The distribution of SQV between brain tissue and plasma was also investigated in rats and in normal and P-gp-deficient mdr1a(-/-) mice. The distribution ratio of SQV in plasma:brain:cerebrospinal fluid was approximately 100:10:0.2 in rats. The accumulation of SQV was enhanced in MES-SA cells (P-gp-negative) versus Dx5 cells (P-gp-positive). Bolus i.v. injection of [(14)C]SQV (2 and 5 mg/kg) into mdr1a(-/-) and normal mice (n = 3 or 4) resulted in 3-fold higher radioactivity in brains from mdr1a(-/-) mice. Similarly, oral administration of [(14)C]SQV (500 mg/kg) resulted in a 5-fold increase in systemic exposure and a 10-fold increase in brain levels in mdr1a(-/-) mice. These data demonstrate that saquinavir is a substrate for P-gp and that this transport system may play a role in limiting oral absorption and CNS exposure to this protease inhibitor.

  View details for Web of Science ID 000088860600009

  View details for PubMedID 10950849

• Nicotine impairs endothelium-dependent dilatation in human veins in vivo CLINICAL PHARMACOLOGY & THERAPEUTICS Chalon, S., Moreno, H., Benowitz, N. L., Hoffman, B. B., Blaschke, T. F. 2000; 67 (4): 391-397

  Abstract

  Cigarette smoking is associated with impaired endothelium-dependent dilatation in human veins and arteries. An in vivo study in animals suggests that nicotine may contribute to this abnormality. We tested the hypothesis that local administration of nicotine at a dose reproducing the plasma concentration observed during smoking would impair endothelium-dependent vasodilatation in human veins in vivo.We studied 11 healthy nonsmokers with the dorsal hand vein compliance technique. After 70% to 80% preconstriction with phenylephrine, endothelium-dependent venous relaxation was assessed by infusion of bradykinin (1 to 278 ng/min), a potent vasodilator acting primarily in this model through endothelial release of nitric oxide and prostanoids. Sodium nitroprusside (0.0001 to 3166 ng/min) was used to test endothelium-independent relaxation. Dose-response curves were constructed before and during nicotine coinfusion at a rate of 40 ng/min, reproducing a plasma concentration of 15 ng/mL.After a 10-minute preinfusion, nicotine administration was associated with a loss in sensitivity to bradykinin (P < .001). After 30 and 60 minutes of preinfusion with nicotine, the venorelaxant effect of bradykinin was further reduced (P < .001). A similar inhibition of the response to bradykinin by nicotine persisted in the presence of indomethacin (INN, indomethacin). Coinfusion of nicotine did not attenuate sodium nitroprusside-induced venodiiation.The results show that acute local exposure to nicotine in vivo is associated with an impaired response to endothelium-derived nitric oxide in human veins. This finding may provide further insight into the pathophysiology of smoking-induced endothelial dysfunction.

  View details for Web of Science ID 000086783100010

  View details for PubMedID 10801248

• A Markov mixed effect regression model for drug compliance STATISTICS IN MEDICINE GIRARD, P., Blaschke, T. F., Kastrissios, H., Sheiner, L. B. 1998; 17 (20): 2313-2333

  Abstract

  Patient compliance (adherence) with prescribed medication is often erratic, while clinical outcomes are causally linked to actual, rather than nominal medication dosage. We propose here a hierarchical Markov model for patient compliance. At the first stage, conditional upon individual random effects and a set of individual-specific nominal daily dose times, we assume that (i) the subject-specific probability of taking zero, one, or more than one dose associated with a given nominal dose time depends on the value of certain covariates, and on the number of doses associated with the immediate previous time, but is independent of any other previous or future dosing events (the Markov hypothesis); and (ii) the set of 'errors' between actual dose times associated with each nominal time is multivariate normally distributed, conditional on covariates and the number of such actual dose times, as in (i). At the second stage, a multivariate normal distribution is assumed for the individual random effects. We fit this model by maximum likelihood to data collected over three months using an electronic system for recording actual dose times in HIV-positive patients assigned to a regimen of zidovudine thrice daily. Beyond its value for describing and quantifying compliance behaviour, as illustrated here, the model may prove useful for explanatory analyses of clinical trials.

  View details for Web of Science ID 000076548100003

  View details for PubMedID 9819830

• Patient compliance and drug failure in protease inhibitor monotherapy JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Vanhove, G. F., Schapiro, J. M., Winters, M. A., Merigan, T. C., Blaschke, T. F. 1996; 276 (24): 1955-1956

  View details for Web of Science ID A1996VY68900024

  View details for PubMedID 8971062

• Clinical and epidemiological correlates of treatment change in patients with NMOSD: insights from the CIRCLES cohort. Journal of neurology Gholizadeh, S., Exuzides, A., Lewis, K. E., Palmer, C., Waltz, M., Rose, J. W., Jolley, A. M., Behne, J. M., Behne, M. K., Blaschke, T. F., Smith, T. J., Sinnott, J., Cook, L. J., Yeaman, M. R., Guthy-Jackson Charitable Foundation CIRCLES Study Group, Aguerre, I., Amezcua, L., Chitnis, T., Lewis, J. C., Engel, C., Han, M. H., Klawiter, E. C., Kocsik, A., Kruse-Hoyer, M., Levine, L., Levy, M., Marcille, M., Mealy, M. A., Moore, S., Mullin, D. S., Nelson, K. E., Onomichi, K. B., Planchon, S. M., Pruitt, A., Repovic, P., Riley, C. S., Rimler, Z., Russo, A. W., Ocampo, C. T., Tomczak, A. J. 2022

  Abstract

  OBJECTIVE: Neuromyelitis optica spectrum disorders (NMOSD) represent rare autoimmune diseases of the central nervous system largely targeting optic nerve(s) and spinal cord. The present analysis used real-world data to identify clinical and epidemiological correlates of treatment change in patients with NMOSD.METHODS: CIRCLES is a longitudinal, observational study of NMOSD conducted at 15 centers across North America. Patients with≥60days of follow-up and receiving on-study maintenance treatment were evaluated. The mean annual relapse rate (ARR) was estimated using negative binomial models; the likelihood of treatment change was estimated using Cox proportional hazards models. Relapses were included as time-varying covariates to estimate the relationship to treatment change.RESULTS: Of 542 patients included, 171 (31.5%) experienced≥1 relapse on the study and 133 patients (24.5%) had≥1 change in the treatment regimen. Two categories of variables significantly correlated with the likelihood of treatment change: (1) relapse: any on-study relapse (hazard ratio [HR]=2.91; p<0.001), relapse phenotypes (HR range=2.15-5.49; p<0.001), and pre-study ARR>0.75 (HR 2.28; p<0.001); 2) disease phenotype: brain syndrome only vs transverse myelitis involvement at onset (HR 2.44; p=0.008), disease duration<1 vs>5years (HR 1.66; p=0.028), or autoimmune comorbidity (HR 1.55; p=0.015). A subset of these factors significantly correlated with shorter time to first rituximab discontinuation.CONCLUSIONS: In CIRCLES, relapse patterns and disease phenotype significantly correlated with changes in the maintenance treatment regimen. Such findings may facilitate the identification of patients with NMOSD who are likely to benefit from treatment change to reduce relapse risk or disease burden and enhance the quality of life.

  View details for DOI 10.1007/s00415-022-11529-6

  View details for PubMedID 36565348

• Supporting the Art: Medication Adherence Patterns in Persons Prescribed Ingestible Sensor-enabled Oral Pre-Exposure Prophylaxis to Prevent Human Immunodeficiency Virus (HIV) Infection. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Browne, S. H., Vaida, F., Umlauf, A., Tucker, A. J., Blaschke, T. F., Benson, C. A. 2022

  Abstract

  Timely, accurate adherence data may support oral pre-exposure prophylaxis (PrEP) success and inform prophylaxis choice. We evaluated a Food and Drug Administration (FDA)-approved digital health feedback system (DHFS) with ingestible-sensor-enabled (IS) tenofovir-disoproxil-fumarate plus emtricitabine (Truvada®) in persons starting oral PrEP.Human immunodeficiency virus (HIV)-negative adults were prescribed IS-Truvada® with DHFS for 12 weeks to observe medication taking behavior. Baseline demographics, urine toxicology, and self-report questionnaires were obtained. Positive detection accuracy and adverse events were computed as percentages, with Kaplan Meier Estimate for persistence-of-use. In participants persisting ≥28 days, adherence patterns (taking and timing) were analyzed, and mixed-effects logistic regression modeled characteristics associated with treatment adherence.Seventy-one participants were enrolled, mean age 37.6 years (range 18-69), 90.1% male, 77.5% White, 33.8% Hispanic, 95.8% housed, and 74.6% employed. Sixty-three participants (88.7%) persisted ≥28 days, generating 4987 observation days, average 79.2 (29-105). Total confirmed doses were 86.2% (95% confidence interval [CI] 82.5, 89.4), decreasing over time, odds ratio (OR) 0.899 (95% CI .876, .923) per week, P < .001; 79.4% (95% CI 66.7%, 87.3%) of participants had ≥80% adherence. Pattern analysis showed days without confirmed doses clustered (P = .003); regular dose timing was higher among participants with ≥80% confirmed doses (0.828, 95% CI .796 to .859) than among those with <80% (0.542, 95% CI95 .405 to .679) P < .001. In multi-predictor models, better adherence was associated with older age, OR 1.060 (95% CI 1.033, 1.091) per year, P < .001; negative vs positive methamphetamine screen, OR 5.051 (95% CI 2.252, 11.494), P < .001.DHFS with IS-Truvada® distinguished adherent persons from those potentially at risk of prophylactic failure. Ongoing methamphetamine substance use may impact oral PrEP success.

  View details for DOI 10.1093/cid/ciac280

  View details for PubMedID 36484300

• Demographic and Relapse Correlates of Treatment Change in NMOSD Patients: Analysis of the CIRCLES Study Gholizadeh, S., Exuzides, A., Lewis, K., Palmer, C., Waltz, M., Rose, J., Jolley, A., Behne, J., Behne, M., Blaschke, T., Smith, T., Yeaman, M., Sinnott, J., Cook, L. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for Web of Science ID 000729283600246

• Correlates of Rituximab Discontinuation in Patients with NMOSD: a CIRCLES Cohort Analysis Exuzides, A., Gholizadeh, S., Lewis, K., Palmer, C., Waltz, M., Rose, J., Jolley, A., Behne, J., Behne, M., Blaschke, T., Smith, T., Cook, L., Sinnott, J., Yeaman, M. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for Web of Science ID 000729283600245

• Relapse Profile Correlates with Treatment Change in NMOSD Patients of the CIRCLES Cohort Exuzides, A., Gholizadeh, S., Sinnott, J., Lewis, K., Palmer, C., Waltz, M., Rose, J., Jolley, A., Behne, J., Behne, M., Blaschke, T., Smith, T., Cook, L., Yeaman, M. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for Web of Science ID 000729283600240

• Introduction to the Theme "Old and New Toxicology: Interfaces with Pharmacology". Annual review of pharmacology and toxicology Costa, M. n., Blaschke, T. F., Amara, S. G., Meyer, U. A., Insel, P. A. 2021; 61: 1–7

  Abstract

  The theme of Volume 61 is "Old and New Toxicology: Interfaces with Pharmacology." Old toxicology is exemplified by the authors of the autobiographical articles: B.M. Olivera's work on toxins and venoms from cone snails and P. Taylor's studies of acetylcholinesterase and the nicotinic cholinergic receptor, which serve as sites of action for numerous pesticides and venoms. Other articles in this volume focus on new understanding and new types of toxicology, including (a) arsenic toxicity, which is an ancient poison that, through evolution, has caused most multicellular organisms to express an active arsenic methyltransferase to methylate arsenite, which accelerates the excretion of arsenic from the body; (b) small molecules that react with lipid dicarbonyls, which are now considered the most toxic oxidative stress end products; (c) immune checkpoint inhibitors (ICIs), which have revolutionized cancer therapy but have numerous immune-related adverse events, including cardiovascular complications; (d) autoimmunity caused by the environment; (e) idiosyncratic drug-induced liver disease, which together with the toxicity of ICIs represents new toxicology interfacing with pharmacology; and (f) sex differences in the development of cardiovascular disease, with men more susceptible than women to vascular inflammation that initiates and perpetuates disease. These articles and others in Volume 61 reflect the interface and close integration of pharmacology and toxicology that began long ago but continues today.

  View details for DOI 10.1146/annurev-pharmtox-092220-033032

  View details for PubMedID 33411582

• Introduction to the Theme "New Insights, Strategies, and Therapeutics for Common Diseases". Annual review of pharmacology and toxicology Insel, P. A., Blaschke, T. F., Amara, S. G., Meyer, U. A. 2021

  Abstract

  The reviews in Volume 62 of the Annual Review of Pharmacology and Toxicology (ARPT) cover a diverse range of topics. A theme that encompasses many of these reviews is their relevance to common diseases and disorders, including type 2 diabetes, heart failure, cancer, tuberculosis, Alzheimer's disease, neurodegenerative disorders, and Down syndrome. Other reviews highlight important aspects of therapeutics, including placebos and patient-centric approaches to drug formulation. The reviews with this thematic focus, as well as other reviews in this volume, emphasize new mechanistic insights, experimental and therapeutic strategies, and novel insights regarding topics in the disciplines of pharmacology and toxicology. As the editors of ARPT, we believe that these reviews help advance those disciplines and, even more importantly, have the potential to improve the health care of the world's population. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  View details for DOI 10.1146/annurev-pharmtox-091421-094627

  View details for PubMedID 34606327

• Scientific considerations for global drug development. Science translational medicine Wilson, J. L., Cheung, K. W., Lin, L., Green, E. A., Porras, A. I., Zou, L., Mukanga, D., Akpa, P. A., Darko, D. M., Yuan, R., Ding, S., Johnson, W. C., Lee, H. A., Cooke, E., Peck, C. C., Kern, S. E., Hartman, D., Hayashi, Y., Marks, P. W., Altman, R. B., Lumpkin, M. M., Giacomini, K. M., Blaschke, T. F. 2020; 12 (554)

  Abstract

  Requiring regional or in-country confirmatory clinical trials before approval of drugs already approved elsewhere delays access to medicines in low- and middle-income countries and raises drug costs. Here, we discuss the scientific and technological advances that may reduce the need for in-country or in-region clinical trials for drugs approved in other countries and limitations of these advances that could necessitate in-region clinical studies.

  View details for DOI 10.1126/scitranslmed.aax2550

  View details for PubMedID 32727913

• Correlates of Anti-AQP4 Autoantibody Serostatus Among NMOSD Participants in the CIRCLES Study Cook, L., Alvey, J., Rose, J., Jolley, A., Kuhn, R., Marron, B., Behne, M., Sheard, J., Behne, J., Blaschke, T. F., Smith, T. J., Yeaman, M. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058005019

• Comparative Immune Cell and Cytokine Phenotyping in Neuromyelitis Optica Spectrum Disorder Patients from the CIRCLES Cohort O'Connor, K., Sharma, A., Cotzomi, E., Jiang, R., Cook, L., Alvey, J., Blaschke, T., Sheard, J., Behne, J., Smith, T., Yeaman, M. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058006302

• Introduction to the Theme "Ion Channels and Neuropharmacology: From the Past to the Future". Annual review of pharmacology and toxicology Dolphin, A. C., Insel, P. A., Blaschke, T. F., Meyer, U. A. 2020; 60: 1–6

  Abstract

  "Ion Channels and Neuropharmacology: From the Past to the Future" is the main theme of articles in Volume 60 of the Annual Review of Pharmacology and Toxicology. Reviews in this volume discuss a wide spectrum of therapeutically relevant ion channels and GPCRs with a particular emphasis on structural studies that elucidate drug binding sites and mechanisms of action. The regulation of ion channels by second messengers, including Ca2+ and cyclic AMP, and lipid mediators is also highly relevant to several of the ion channels discussed, including KCNQ channels, HCN channels, L-type Ca2+ channels, and AMPA receptors, as well as the aquaporin channels. Molecular identification of exactly where drugs bind in the structure not only elucidates their mechanism of action but also aids future structure-based drug discovery efforts to focus on relevant pharmacophores. The ion channels discussed here are targets for multiple nervous system diseases, including epilepsy and neuropathic pain. This theme complements several previous themes, including "New Therapeutic Targets," "New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development," and "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology."

  View details for DOI 10.1146/annurev-pharmtox-082719-110050

  View details for PubMedID 31914892

• Towards consensus on correct interpretation of protein binding in plasma and other biological matrices for COVID-19 therapeutic development. Clinical pharmacology and therapeutics Boffito, M. n., Back, D. J., Flexner, C. n., Sjö, P. n., Blaschke, T. F., Horby, P. W., Cattaneo, D. n., Acosta, E. P., Anderson, P. n., Owen, A. n. 2020

  Abstract

  The urgent global public health need presented by SARS-CoV-2 has brought scientists from diverse backgrounds together in an unprecedented international effort to rapidly identify interventions. There is a pressing need to apply clinical pharmacology principles and this has already been recognised by several other groups. However, one area that warrants additional specific consideration relates to plasma and tissue protein binding that broadly influences pharmacokinetics and pharmacodynamics. The principles of free drug theory have been forged and applied across drug development but are not currently being routinely applied for SARS-CoV-2 antiviral drugs. Consideration of protein binding is of critical importance to candidate selection but requires correct interpretation, in a drug-specific manner, to avoid either under- or over-interpretation of its consequences. This manuscript represents a consensus from international researchers seeking to apply historical knowledge, which has underpinned highly successful antiviral drug development for other viruses such as HIV and HCV for decades.

  View details for DOI 10.1002/cpt.2099

  View details for PubMedID 33113246

• Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD. Neurology(R) neuroimmunology & neuroinflammation Cook, L. J., Rose, J. W., Alvey, J. S., Jolley, A. M., Kuhn, R., Marron, B., Pederson, M., Enriquez, R., Yearley, J., McKechnie, S., Han, M. H., Tomczak, A. J., Levy, M., Mealy, M. A., Coleman, J., Bennett, J. L., Johnson, R., Barnes-Garcia, M., Traboulsee, A. L., Carruthers, R. L., Lee, L. E., Schubert, J. J., McMullen, K., Kister, I., Rimler, Z., Reid, A., Sicotte, N. L., Planchon, S. M., Cohen, J. A., Ivancic, D., Sedlak, J. L., Sand, I. K., Repovic, P., Amezcua, L., Pruitt, A., Amundson, E., Chitnis, T., Mullin, D. S., Klawiter, E. C., Russo, A. W., Riley, C. S., Onomichi, K. B., Levine, L., Nelson, K. E., Nealon, N. M., Engel, C., Kruse-Hoyer, M., Marcille, M., Tornes, L., Rumpf, A., Greer, A., Kenneally Behne, M., Rodriguez, R. R., Behne, D. W., Blackway, D. W., Coords, B., Blaschke, T. F., Sheard, J., Smith, T. J., Behne, J. M., Yeaman, M. R., Guthy-Jackson Charitable Foundation International Clinical Consortium (GJCF-ICC) 2019; 6 (5): e583

  Abstract

  Objective: To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment.Methods: To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks.Results: As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female.Conclusions: Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD.

  View details for DOI 10.1212/NXI.0000000000000583

  View details for PubMedID 31355319

• Neuromyelitis optica spectrum disorder: Patient experience and quality of life. Neurology(R) neuroimmunology & neuroinflammation Beekman, J., Keisler, A., Pedraza, O., Haramura, M., Gianella-Borradori, A., Katz, E., Ratchford, J. N., Barron, G., Cook, L. J., Behne, J. M., Blaschke, T. F., Smith, T. J., Yeaman, M. R. 2019; 6 (4): e580

  Abstract

  Objective: To gain insights into NMOSD disease impact, which may negatively affect QoL of patients, their families, and social network.Methods: The current study used validated instruments to assess physical, emotional, and socioeconomic burden of NMOSD on QoL among 193 patients.Results: A majority of patients reported an initial diagnosis of a disease other than NMOSD. Overall, two-thirds of patients reported NMOSD as having a strong negative impact on physical health (Short Form-36 [SF-36] score 27.1 ± 39.1), whereas emotional well-being was relatively unimpaired on average (SF-36 score 54.0 ± 44.9). A subset of patients reported having the highest category of emotional health despite worse physical health or financial burden, suggesting psychological resilience. Pain (r = 0.61) and bowel/bladder dysfunction (r = 0.41) imposed the greatest negative physical impact on overall QoL. In turn, ability to work correlated inversely with worsened health (r = -0.68). Increased pain, reduced sexual function, inability to work, and reduced QoL had greatest negative impacts on emotional well-being. Dissatisfaction with treatment options and economic burden correlated inversely with QoL.Conclusions: Collectively, the current findings advance the understanding of physical, emotional, social, and financial tolls imposed by NMOSD. These insights offer potential ways to enhance QoL by managing pain, enhancing family and social networks, and facilitating active employment.

  View details for DOI 10.1212/NXI.0000000000000580

  View details for PubMedID 31355316

• Introduction to the Theme "New Therapeutic Targets". Annual review of pharmacology and toxicology Insel, P. A., Amara, S. G., Blaschke, T. F., Meyer, U. A. 2019; 59: 15–20

  Abstract

  "New Therapeutic Targets" is the theme of articles in the Annual Review of Pharmacology and Toxicology, Volume 59. Reviews in this volume discuss targets for a variety of conditions in need of new therapies, including type 2 diabetes, heart failure with preserved ejection fraction, obesity, thyroid-associated ophthalmopathy, tinnitus, multiple sclerosis, Parkinson's disease and other neurodegenerative diseases, pain, depression, post-traumatic stress disorder, muscle wasting diseases, cancer, and anemia associated with chronic renal disease. Numerous articles in this volume focus on the identification, validation, and utility of novel therapeutic targets, in particular, ones that involve new or unexpected molecular entities. This theme complements several previous themes, including "New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development," "Precision Medicine and Prediction in Pharmacology," and "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology."

  View details for PubMedID 30625286

• Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD. Neurology(R) neuroimmunology & neuroinflammation Cook, L. J., Rose, J. W., Alvey, J. S., Jolley, A. M., Kuhn, R. n., Marron, B. n., Pederson, M. n., Enriquez, R. n., Yearley, J. n., McKechnie, S. n., Han, M. H., Tomczak, A. J., Levy, M. n., Mealy, M. A., Coleman, J. n., Bennett, J. L., Johnson, R. n., Barnes-Garcia, M. n., Traboulsee, A. L., Carruthers, R. L., Lee, L. E., Schubert, J. J., McMullen, K. n., Kister, I. n., Rimler, Z. n., Reid, A. n., Sicotte, N. L., Planchon, S. M., Cohen, J. A., Ivancic, D. n., Sedlak, J. L., Sand, I. K., Repovic, P. n., Amezcua, L. n., Pruitt, A. n., Amundson, E. n., Chitnis, T. n., Mullin, D. S., Klawiter, E. C., Russo, A. W., Riley, C. S., Onomichi, K. B., Levine, L. n., Nelson, K. E., Nealon, N. M., Engel, C. n., Kruse-Hoyer, M. n., Marcille, M. n., Tornes, L. n., Rumpf, A. n., Greer, A. n., Kenneally Behne, M. n., Rodriguez, R. R., Behne, D. W., Blackway, D. W., Coords, B. n., Blaschke, T. F., Sheard, J. n., Smith, T. J., Behne, J. M., Yeaman, M. R. 2019; 6 (5)

  Abstract

  To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment.To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks.As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female.Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD.

  View details for DOI 10.1212/NXI.0000000000000583

  View details for PubMedID 31454765

• Usability of a Medication Event Reminder Monitor System (MERM) by Providers and Patients to Improve Adherence in the Management of Tuberculosis. International journal of environmental research and public health Liu, X., Blaschke, T., Thomas, B., De Geest, S., Jiang, S., Gao, Y., Li, X., Buono, E. W., Buchanan, S., Zhang, Z., Huan, S. 2017; 14 (10)

  Abstract

  Poor initiation and implementation and premature discontinuation of anti-tuberculous therapy, all forms of nonadherence, are major reasons for treatment failure, the development of drug-resistant tuberculosis, and transmission to other non-infected individuals. Directly Observed Therapy (DOT) has been the worldwide standard, but implementation of DOT is burdensome for providers and patients, especially in resource-limited settings, where most of the burden of active TB is located. Among the alternatives to DOT is electronic monitoring (EM) of drug dosing histories. Here we report a usability study of a newly-designed, modular electronic monitor product, called the MERM (Medication Event and Reminder Monitor), that is compatible with TB medication formats and supply chains in resource-limited settings. This study, done in a rural setting in China, showed that the use of the MERM for EM of TB medications was associated with a high degree of user performance, acceptability, and satisfaction among both TB patients and medical staff. Based on these data, EM is becoming the standard of care for drug-susceptible TB patients in China and scaled implementations in several other countries with high TB burden have begun. In addition, the MERM is being used in MDR-TB patients and in clinical trials involving patients with TB/HIV and latent TB.

  View details for DOI 10.3390/ijerph14101115

  View details for PubMedID 28946683

  View details for PubMedCentralID PMC5664616

• Introduction to the Theme "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology" ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 57 Insel, P. A., Amara, S. G., Blaschke, T. F., Meyer, U. A. 2017; 57: 13-17

  Abstract

  Major advances in scientific discovery and insights can result from the development and use of new techniques, as exemplified by the work of Solomon Snyder, who writes a prefatory article in this volume. The Editors have chosen "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology" as the Theme for a number of articles in this volume. These include ones that review the development and use of new experimental tools and approaches (e.g., nanobodies and techniques to explore protein-protein interactions), new types of therapeutics (e.g., aptamers and antisense oligonucleotides), and systems pharmacology, which assembles (big) data derived from omics studies together with information regarding drugs and patients. The application of these new methods and therapeutic approaches has the potential to have a major impact on basic and clinical research in pharmacology and toxicology as well as on patient care.

  View details for DOI 10.1146/annurev-pharmtox-091616-023708

  View details for Web of Science ID 000396044800002

• Introduction to the Theme "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology". Annual review of pharmacology and toxicology Insel, P. A., Amara, S. G., Blaschke, T. F., Meyer, U. A. 2016: -?

  Abstract

  Major advances in scientific discovery and insights can result from the development and use of new techniques, as exemplified by the work of Solomon Snyder, who writes a prefatory article in this volume. The Editors have chosen "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology" as the Theme for a number of articles in this volume. These include ones that review the development and use of new experimental tools and approaches (e.g., nanobodies and techniques to explore protein-protein interactions), new types of therapeutics (e.g., aptamers and antisense oligonucleotides), and systems pharmacology, which assembles (big) data derived from omics studies together with information regarding drugs and patients. The application of these new methods and therapeutic approaches has the potential to have a major impact on basic and clinical research in pharmacology and toxicology as well as on patient care.

  View details for PubMedID 27732830

• Introduction to the Theme "Cancer Pharmacology" ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 56 Insel, P. A., Amara, S. G., Blaschke, T. F., Meyer, U. A., Insel, P. A. 2016; 56: 19–22

  View details for PubMedID 26551200

• Introduction to the Theme "Precision Medicine and Prediction in Pharmacology" ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 55 Insel, P. A., Amara, S. G., Blaschke, T. F., Insel, P. A. 2015; 55: 11–14

  View details for DOI 10.1146/annurev-pharmtox-101714-123102

  View details for Web of Science ID 000348560500002

  View details for PubMedID 25562643

• Impact of Adherence and Anthropometric Characteristics on Nevirapine Pharmacokinetics and Exposure Among HIV-Infected Kenyan Children JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Vreeman, R. C., Nyandiko, W. M., Liechty, E. A., Busakhala, N., Bartelink, I. H., Savic, R. M., Scanlon, M. L., Ayaya, S. O., Blaschke, T. F. 2014; 67 (3): 277-286

  Abstract

  There are insufficient data on pediatric antiretroviral therapy (ART) pharmacokinetics (PK), particularly for children in low- and middle-income countries.We conducted a prospective nevirapine (NVP) PK study among HIV-infected Kenyan children aged 3-13 years initiating an NVP-based ART regimen. NVP dose timing was measured through medication event monitors. Participants underwent 2 inpatient assessments: 1 at 4-8 weeks after ART initiation and 1 at 3-4 months after ART initiation. Allometric scaling of oral clearance (CL)/bioavailability (F) and volume of distribution (Vd)/F values were computed. Nonlinear mixed-effects modeling using the first-order conditional estimation with interaction method was performed with covariates. The impact of adherence on time below minimum effective concentration was assessed in the final PK model using medication event monitors data and model-estimated individual parameters.Among 21 children enrolled, mean age was 5.4 years and 57% were female. CL/F was 1.67 L/h and Vd/F was 3.8 L for a median child weighing 15 kg. Participants' age had a significant impact on CL/F (P < 0.05), with an estimated decrease in CL of 6.2% for each 1-year increase in age. Total body water percentage was significantly associated with Vd/F (P < 0.001). No children had >10% of time below minimum effective concentration when the PK model assumed perfect adherence compared with 10 children when adherence data were used.Age and body composition were significantly associated with children's NVP PK parameters. ART adherence significantly impacted drug exposure over time, revealing subtherapeutic windows that may lead to viral resistance.

  View details for DOI 10.1097/QAI.0000000000000300

  View details for Web of Science ID 000344361400011

  View details for PubMedID 25140906

• Integrative Continuum: Accelerating Therapeutic Advances in Rare Autoimmune Diseases ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 52 Van Herle, K., Behne, J. M., Van Herle, A., Blaschke, T. F., Smith, T. J., Yeaman, M. R. 2012; 52: 523-547

  Abstract

  Autoimmune diseases are chronic, life threatening, and of burgeoning public health concern. They rank among the 10 most common causes of death in women, and some have incidence rates surpassing those of heart disease and cancer. Emerging information regarding molecular and cellular mechanisms affords opportunities for the discovery of novel therapeutic strategies or the repurposing of FDA-approved pharmacologic agents. Yet, obstacles to drug development amplify as an inverse function of the incidence of rare autoimmune disease; challenges include heterogeneous clinical presentation, paucity of definitive biomarkers, and poorly validated measures of therapeutic response. An integrative continuum model to address these challenges is being applied to neuromyelitis optica (NMO)-a potentially devastating neurodegenerative process that has had limited therapeutic options. This model links target discovery with pharmacologic application to accelerate improved clinical efficacy. The application of such innovative strategies may help researchers overcome barriers to therapeutic advances in NMO and other rare autoimmune diseases.

  View details for DOI 10.1146/annurev-pharmtox-010611-134628

  View details for Web of Science ID 000301839600025

  View details for PubMedID 22235861

• Understanding Forgiveness: Minding and Mining the Gaps Between Pharmacokinetics and Therapeutics CLINICAL PHARMACOLOGY & THERAPEUTICS Osterberg, L. G., Urquhart, J., Blaschke, T. F. 2010; 88 (4): 457-459

  Abstract

  The usual objective during long-term pharmacotherapy is, in large part, to maintain continuity of action of the prescribed drug(s). Continuity of action arises from the continuity of execution of a prescribed dosing regimen that is pharmacologically sound in dose quantity and interval between successive doses. Interruptions in dosing can interrupt drug action, but the consequences vary according to length of interruption, drug, drug formulation, length of the patient's prior exposure to the drug, and the disease being treated.

  View details for DOI 10.1038/clpt.2010.171

  View details for Web of Science ID 000282064000013

  View details for PubMedID 20856243

• Variable adherence to prescribed dosing regimens for protease inhibitors: scope and outcomes. Current opinion in HIV and AIDS Blaschke, T. F. 2008; 3 (6): 603-607

  Abstract

  It is generally accepted that a high degree of adherence to the dosing regimens of protease inhibitors is essential to avoid virological failure. It is also believed that once-daily dosing of protease inhibitors, by improving adherence, will lead to better outcomes. This review will discuss the patterns of adherence for once-daily and twice-daily regimens and illustrate how differences in these patterns might favor twice-daily regimens in some settings.Using electronic monitoring of more than 1800 patients enrolled in HIV clinical trials, the fraction of doses taken by patients on a once-daily regimen was about 10% higher than that taken by patients on a twice-daily regimen. However, patients on the twice-daily regimen were less likely to have their trough concentrations fall below a minimum effective concentration. In an outcome study that compared once-daily with twice-daily lopinavir/ritonavir, there was no difference in virological failure through 48 weeks, but patients with a viral load of more than 100 000 copies/ml had a greater probability of a sustained viral response on a twice-daily regimen.Although patients and providers strongly favor once-daily regimens, recent clinical and model-based studies suggest that twice-daily protease inhibitor containing regimens may yield better outcomes in some settings. Continued reinforcement of adherence is necessary to improve both the execution of the drug regimen as well as continuation (persistence) with antiretroviral therapy.

  View details for DOI 10.1097/COH.0b013e32831271c2

  View details for PubMedID 19373030

• Variable adherence to prescribed dosing regimens for protease inhibitors: scope and outcomes CURRENT OPINION IN HIV AND AIDS Blaschke, T. F. 2008; 3 (6): 603-607

  Abstract

  It is generally accepted that a high degree of adherence to the dosing regimens of protease inhibitors is essential to avoid virological failure. It is also believed that once-daily dosing of protease inhibitors, by improving adherence, will lead to better outcomes. This review will discuss the patterns of adherence for once-daily and twice-daily regimens and illustrate how differences in these patterns might favor twice-daily regimens in some settings.Using electronic monitoring of more than 1800 patients enrolled in HIV clinical trials, the fraction of doses taken by patients on a once-daily regimen was about 10% higher than that taken by patients on a twice-daily regimen. However, patients on the twice-daily regimen were less likely to have their trough concentrations fall below a minimum effective concentration. In an outcome study that compared once-daily with twice-daily lopinavir/ritonavir, there was no difference in virological failure through 48 weeks, but patients with a viral load of more than 100 000 copies/ml had a greater probability of a sustained viral response on a twice-daily regimen.Although patients and providers strongly favor once-daily regimens, recent clinical and model-based studies suggest that twice-daily protease inhibitor containing regimens may yield better outcomes in some settings. Continued reinforcement of adherence is necessary to improve both the execution of the drug regimen as well as continuation (persistence) with antiretroviral therapy.

  View details for DOI 10.1097/COH.0b013e32831271c2

  View details for Web of Science ID 000208418700001

• Increased vascular alpha1-adrenergic sensitivity in patients with renal failure: receiving recombinant erythropoeitin. American journal of therapeutics Abiose, A. K., Aronow, W. S., Moreno, H., Nair, C. K., Blaschke, T. F., Hoffman, B. B. 2007; 14 (5): 427-434

  Abstract

  End stage renal disease (ESRD) is associated with altered hemodynamic regulation as a result of the pathophysiology or treatment of renal failure. Hypertension, common among dialysis patients, is a recognized complication of recombinant human erythropoietin (rHuEPO) therapy. We determined vascular adrenergic and nitric-oxide-mediated responsiveness in 7 patients with established ESRD on rHuEPO treatment and in 13 healthy volunteers using the dorsal hand vein technique. Sensitivity to the alpha1-adrenergic selective agonist phenylephrine was significantly increased in patients with ESRD on rHuEPO. The mean dose of phenylephrine producing 50% venoconstriction (ED50) was 38 +/- 1.6 ng/min in patients with ESRD and 135 +/- 1.3 ng/min in healthy volunteers-almost a 4-fold increase in dose, P = 0.01. In contrast, maximal venodilation mediated by bradykinin, an endothelium-dependent vasodilator, was not different in the 2 groups. To determine whether rHuEPO has a direct vasoconstrictor effect, we studied venous responsiveness to local infusions of rHuEPO in healthy volunteers. Increasing concentrations of rHuEPO produced no vasoconstriction in hand veins of healthy volunteers. These results suggest that vascular responsiveness to alpha-adrenergic stimulation in patients with ESRD on rHuEPO is increased whereas bradykinin-mediated venodilation remains intact. This increase in vascular alpha-adrenergic responsiveness may contribute to the increased peripheral vascular resistance and hypertension seen in patients with ESRD on rHuEPO.

  View details for PubMedID 17890929

• Improving data reliability using a non-compliance detection method versus using pharmacokinetic criteria JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS Kshirsagar, S. A., Blaschke, T. F., Sheiner, L. B., Krygowski, M., Acosta, E. P., Verotta, D. 2007; 34 (1): 35-55

  Abstract

  Data from clinical trials present numerous problems for the data analyst. These include non-compliance with the prescribed dosing regimen and inaccurate recollection of dosing history by patients as well as mistakes in recording data. Several methods have been proposed to address these issues. One such technique by Lu et al. (Selecting reliable pharmacokinetic data for explanatory analyses of clinical trials in the presence of possible noncompliance. J. Pharmacokinet. Pharmacodyn. 28:343-362 (2001)) identifies occasions in pharmacokinetic (PK) data where the preceding dosing history is likely to be unreliable. We used this method, implemented in the software program NONMEM (beta) VI, to clean a dataset containing indinavir (IDV) plasma concentrations from HIV-1 infected patients. The data was also cleaned by inspection in Microsoft Excel using clinical PK criteria. A one-compartment model with first order absorption and elimination was fit to both sets of cleaned data. IDV population PK parameters obtained from these analyses were similar to those reported previously. It is established that IDV nephrotoxicity is related to high IDV exposure. However, no relationships were found between any PK parameters and nephrotoxicity in the "compliance cleaned" dataset. In the "PK cleaned" dataset, the oral clearance and apparent volume were lower by 9.1% and 6.6%, respectively in patients with any type of nephrotoxicity and the maximum IDV concentration (C(max)) was 12.1% higher. In patients suffering from nephrolithiasis in particular, C(max) was 15.5% higher. Accordingly, the use of the non-compliance detection method did not improve the reliability of our dataset over the usual method of applying clinical criteria. In fact, analyses on the compliance-cleaned dataset missed some exposure-toxicity relationships. Thus, automated methods must be tested rigorously with 'real life' datasets, used with caution, and always in conjunction with clinical reasoning to avoid overlooking a signal in noisy data.

  View details for DOI 10.1007/s10928-006-9032-2

  View details for Web of Science ID 000243465900004

  View details for PubMedID 17004125

• Characterization of nelfinavir binding to plasma proteins and the lack of drug displacement interactions HIV MEDICINE Motoya, T., Thevanayagam, L. N., Blaschke, T. F., Au, S., Stone, J. A., Jayewardene, A. L., Chi, J., Aweeka, F. T. 2006; 7 (2): 122-128

  Abstract

  To determine the characteristics of the binding of nelfinavir and active M8 to alpha1-acid glycoprotein (AAG) and human serum albumin (HSA), and to examine the displacement effects of drugs binding extensively to AAG (ritonavir and saquinavir) or to HSA (salicylic acid and valproic acid).Free drugs were separated by equilibrium dialysis after incubation with human plasma or purified plasma proteins and after co-incubation with potential displacers. Association constants were estimated from double-reciprocal plots of the data.Nelfinavir and M8 free fractions [fractions of unbound drug (fus)] were 0.42+/-0.08% (mean+/-standard deviation) and 0.64+/-0.07%, respectively. For the two analytes, respectively, association constants were 7.25 x 10(7)/m and 3.33 x 10(7)/m for AAG and 1.11 x 10(6)/m and 7.92 x 10(5)/m for HSA. Nelfinavir fu in an AAG solution was significantly (P < 0.01) increased by the addition of ritonavir or saquinavir, whereas it was unaltered by addition of these drugs to whole plasma. Similarly, fu in an HSA solution was significantly increased (P < 0.01) by the addition of salicylic acid or valproic acid, whereas there was no difference in the free fraction in plasma.The affinity of nelfinavir for human plasma proteins was higher than that of M8, and both nelfinavir and M8 showed higher affinity to AAG than to HSA. The free fraction of nelfinavir was not affected by drugs that bind extensively to AAG or albumin when these drugs were added to whole plasma in combination, suggesting a compensatory effect of alternate binding proteins.

  View details for Web of Science ID 000234739400007

  View details for PubMedID 16420257

• Adherence to medication - Reply NEW ENGLAND JOURNAL OF MEDICINE Osterberg, L., Blaschke, T. 2005; 353 (18): 1973-1974

  View details for Web of Science ID 000232972800024

• Sex differences in pharmacokinetics and pharmacodynamics ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY Gandhi, M., Aweeka, F., Greenblatt, R. M., Blaschke, T. F. 2004; 44: 499-523

  Abstract

  The importance of reviewing and studying sex-based differences in pharmacologic parameters is demonstrated by the increasing data on gender variation in drug efficacy and toxicity profiles. Sex-based differences in the four major factors that contribute to interindividual pharmacokinetic variability--bioavailability, distribution, metabolism, and elimination--are theorized to stem from variations between men and women in factors such as body weight, plasma volume, gastric emptying time, plasma protein levels, cytochrome P450 activity, drug transporter function, and excretion activity. Sex-determined variations in pharmacodynamics have traditionally been more difficult to study, but a number of recent studies have explored these differences. This review examines the biologic basis of differences in pharmacokinetics and pharmacodynamics between the sexes and summarizes studies that have addressed these differences. As an example, sex-based variation in the efficacy and toxicity of antiretroviral therapy in human immunodeficiency virus (HIV)-infected patients is explored more thoroughly to illustrate some of the factors underlying sex-based differences in drug therapy.

  View details for Web of Science ID 000189351000021

  View details for PubMedID 14744256

• Protein binding in antiretroviral therapies AIDS RESEARCH AND HUMAN RETROVIRUSES Boffito, M., Back, D. J., Blaschke, T. F., Rowland, M., Bertz, R. J., Gerber, J. G., Miller, V. 2003; 19 (9): 825-835

  Abstract

  There is marked variability in the extent to which the three classes of antiretroviral (ARV) drugs bind to plasma proteins (<5 to >99%). Protease inhibitors (PIs), with the exception of indinavir, are more than 90% protein bound, mainly to alpha1-acid glycoprotein (AAG). Efavirenz, a nonnucleoside reverse transcriptase inhibitor (NNRTI), is more than 99% bound, mainly to albumin. Nucleoside reverse transcriptase inhibitors (NRTIs) are not highly protein bound. The pharmacological activity of ARV drugs is dependent on unbound drug entering cells that harbor the human immunodeficiency virus (HIV). There has been concern that changes in protein binding could impact on antiviral activity and management. However, for PIs and NNRTIs, and for many drugs given orally, altered plasma binding would not be expected to influence the average exposure to unbound (active) drug after chronic oral dosing. Nevertheless, there will be a change in the relationship between total and unbound concentrations that will be important if, as part of therapeutic drug monitoring, the total rather than the unbound drug is measured. Measuring drug concentrations that are needed to inhibit different HIV strains (wild type and drug resistant) in vitro could also cause confusion because most methods employ bovine serum in the assay medium, and unbound concentrations are not directly measured. Estimating unbound drug concentrations in human plasma and in incubation media can be highly method dependent and thus may affect the calculated IC50 (the concentration of drug that results in 50% inhibition of viral replication). Because inhibitory quotients (IQs = C(trough)/IC50) are becoming part of pharmacokinetic/pharmacodynamic (PK/PD) analyses of clinical trial data, the strengths and weaknesses of the methods used for the determination of unbound drug concentration in plasma and in vitro systems--ultracentrifugation, ultrafiltration, and equilibrium dialysis--need to be understood. Consensus on standard procedures must be reached. In June 2002, a panel of experts assembled by the Forum for Collaborative HIV Research met in Washington, DC, to review the basic principles of protein binding of ARV drugs, and to discuss the impact that changes in plasma protein binding may have on the PKs and activity of ARV drugs as well as on therapeutic drug monitoring. The purpose of the meeting was to discuss the following topics: (1) basic principles of protein binding and how changes in binding can impact on drug PKs and drug exposure in vivo, (2) variability in plasma protein binding among patients taking ARV drugs, (3) the impact of HIV infection and concomitant diseases on the extent of plasma protein binding, (4) the likelihood of clinically relevant drug interactions at the level of plasma protein binding, (5) the evidence that measuring unbound concentrations of ARV drugs in the plasma of patients gives more meaningful information than total drug concentration and, therefore, should be considered in routine therapeutic drug monitoring of ARV agents, (6) optimal method(s) for measuring the unbound concentration of drugs in vitro (for IC50 determination) and in vivo, and (7) future studies that need to be considered to fully understand the importance of plasma protein binding in therapeutic drug monitoring. This report summarizes the topics discussed at this meeting. It guides the reader through the discussions that allowed the panel to formulate a series of statements regarding the significance of plasma protein binding of ARV drugs when studied in vitro and in vivo. The roundtable participants also identified research priorities that are important for understanding the sources of inter- and intraindividual variability in protein binding in patients. These include obtaining data on unbound as well as on total concentrations in PK studies; looking at variants of AAG and whether they differ in binding affinity; and emphasizing the importance of developing a standard procedure for drug susceptibility assays used to determine IC50 values.

  View details for Web of Science ID 000185675200012

  View details for PubMedID 14585213

• Effect of simultaneous versus staggered dosing on pharmacokinetic interactions of protease inhibitors CLINICAL PHARMACOLOGY & THERAPEUTICS Washington, C. B., Flexner, C., Sheiner, L. B., Rosenkranz, S. L., Segal, Y., Aberg, J. A., Blaschke, T. F. 2003; 73 (5): 406-416

  Abstract

  The aim of this study was to determine whether pharmacokinetic interactions between the protease inhibitors saquinavir soft gel, nelfinavir, and ritonavir are affected by the timing of administration.We used an open-label, 6-period, incomplete Latin square crossover study in 18 human immunodeficiency virus-negative subjects. Each received single oral doses of 2 of the 3 protease inhibitors during each of 6 periods. Single doses were given either simultaneously or separated by 4 hours. The order of the periods was balanced, and periods were separated by 2 days. We measured protease inhibitor concentrations over a 24-hour period by HPLC and estimated pharmacokinetic parameters by noncompartmental methods.Median saquinavir area under the curve (AUC) increased by 62-fold when ritonavir was coadministered, by 50-fold when ritonavir was given 4 hours earlier, and by 16-fold when saquinavir preceded ritonavir by 4 hours. Saquinavir AUC increased by 7-fold when nelfinavir was coadministered. Nelfinavir AUC increased by 2.5-fold with coadministration of ritonavir and by 1.8- and 2.1-fold when ritonavir was administered before nelfinavir and after nelfinavir, respectively. Ritonavir AUCs were unaffected by coadministration of the other drugs. The effect of ritonavir on the kinetics of saquinavir persisted for at least 48 hours after a single dose of ritonavir, suggesting the possibility of metabolic intermediates that form inhibitory complexes.Except for saquinavir followed by ritonavir, there is little difference in protease inhibitor exposure for simultaneous or staggered doses. The persistent effect of ritonavir suggests the possibility that lower doses and longer dosing intervals might be effective when ritonavir is used to boost concentrations of other protease inhibitors.

  View details for DOI 10.1016/S0009-9236(03)00006-7

  View details for Web of Science ID 000183174300004

  View details for PubMedID 12732841

• Model-based analysis of the pharmacokinetic interactions between ritonavir, nelfinavir, and saquinavir after simultaneous and staggered oral administration DRUG METABOLISM AND DISPOSITION Lu, J. F., Blaschke, T. F., Flexner, C., Rosenkranz, S. L., Sheiner, L. B. 2002; 30 (12): 1455-1461

  Abstract

  Eighteen healthy human immunodeficiency virus-negative subjects participated in an open-label, six-period, incomplete Latin-square crossover pharmacokinetic study. Each subject received two of the three possible pair-wise combinations of single-dose oral ritonavir (R) (400 mg), nelfinavir (N) (750 mg), and saquinavir (S) (800 mg), each pair on three occasions (simultaneous or staggered administration), each occasion at least 2 days after the last. A model-based analysis reveals the following major drug interactions under the conditions of this study: 1). R given simultaneously with S decreases S hepatic intrinsic clearance almost 50-fold relative to that predicted for S given alone and increases its gut bioavailability 90% (but decreases its rate of absorption 40%) relative to when N is given simultaneously; 2). N given simultaneously with S decreases S hepatic intrinsic clearance 10-fold relative to that predicted for S given alone; and 3) R inhibits S hepatic intrinsic clearance even after R plasma levels have become undetectable (>48 h after dosing), implying that R, when used as a pharmacokinetic enhancer, can be dosed less frequently than might be predicted from the duration of detectable systemic concentrations.

  View details for Web of Science ID 000179244200025

  View details for PubMedID 12433819

• Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047 AIDS Fichtenbaum, C. J., Gerber, J. G., Rosenkranz, S. L., Segal, Y., Aberg, J. A., Blaschke, T., Alston, B., Fang, F., Kosel, B., Aweeka, F. 2002; 16 (4): 569-577

  Abstract

  Lipid lowering therapy is used increasingly in persons with HIV infection in the absence of safety data or information on drug interactions with antiretroviral agents. The primary objectives of this study were to examine the effects of ritonavir (RTV) plus saquinavir soft-gel (SQVsgc) capsules on the pharmacokinetics of pravastatin, simvastatin, and atorvastatin, and the effect of pravastatin on the pharmacokinetics of nelfinavir (NFV) in order to determine clinically important drug-drug interactions.Randomized, open-label study in healthy, HIV seronegative adults at AIDS Clinical Trials Units across the USA.Three groups of subjects (arms 1, 2, and 3) received pravastatin, simvastatin or atorvastatin (40 mg daily each) from days 1-4 and 15-18. In these groups, RTV 400 mg and SQVsgc 400 mg twice daily were given from days 4-18. A fourth group (arm 4) received NFV 1250 mg twice daily from days 1-14 with pravastatin 40 mg daily added from days 15-18. Statin and NFV levels were measured by liquid chromatography/tandem mass spectrometry.Fifty-six subjects completed both pharmacokinetic study days. In arms 1-3, the median estimated area under the curves (AUC)(0-24) for the statins were: pravastatin (arm 1, n = 13), 151 and 75 ng.h/ml on days 4 and 18 (decline of 50% in presence of RTV/SQVsgc), respectively (P = 0.005); simvastatin (arm 2, n = 14), 17 and 548 ng.h/ml on days 4 and 18 (increase of 3059% in the presence of RTV/SQVsgc), respectively (P < 0.001); and total active atorvastatin (arm 3, n = 14), 167 and 289 ng.h/ml on days 4 and 18 (increase of 79% in the presence of RTV/SQVsgc), respectively (P < 0.001). In arm 4, the median estimated AUC(0-8) for NFV (24 319 versus 26 760 ng.h/ml; P = 0.58) and its active M8 metabolite (15 565 versus 14 571 ng.h/m; P = 0.63) were not statistically different from day 14 to day 18 (without or with pravastatin).Simvastatin should be avoided and atorvastatin may be used with caution in persons taking RTV and SQVsgc. Dose adjustment of pravastatin may be necessary with concomitant use of RTV and SQVsgc. Pravastatin does not alter the NFV pharmacokinetics, and thus appears to be safe for concomitant use.

  View details for Web of Science ID 000174367100008

  View details for PubMedID 11873000

• Determination of nelfinavir free drug concentrations in plasma by equilibrium dialysis and liquid chromatography tandem mass spectrometry: important factors for method optimization EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES Herforth, C., Stone, J. A., Jayewardene, A. L., Blaschke, T. F., Fang, F., Motoya, T., Aweeka, F. T. 2002; 15 (2): 185-195

  Abstract

  A method was developed and validated for measuring the free fraction of nelfinavir in plasma employing equilibrium dialysis for the separation of free (unbound) drug and liquid chromatography/tandem mass spectrometry for quantitation. Nelfinavir, widely used to treat HIV infection, is a highly bound HIV protease inhibitor with the fraction bound in plasma being greater than 98%. Thus variations in the free fraction may be clinically important when interpreting total drug concentrations. Optimization of the method was carried out considering the influence of sample matrix and physicochemical and absorptive properties of nelfinavir. Nelfinavir free fraction averaged 0.41 +/- 0.094, 0.43 +/- 0.087 and 0.41 +/- 0.063% at nelfinavir plasma concentrations of 1000, 2000 and 3000 ng/ml, respectively. Free nelfinavir concentrations were underestimated with this assay by approximately 25% because of unavoidable losses to adsorption. However, the adsorptive loss was reproducible and consistent across the concentration range of the assay. Within-day and between-day precisions ranged from 6.0 to 9.4% and 15.2 to 27.3%, respectively. The lower limit of quantitation of the unbound concentration of nelfinavir was 1.0 ng/ml, permitting analysis of samples with total concentrations of nelfinavir in plasma that are > or = 400 ng/ml. This developed method proves reproducible and sensitive and its application to patient plasma samples is also reported.

  View details for Web of Science ID 000174911100009

  View details for PubMedID 11849916

• Model-based analysis of the pharmacokinetic interactions between dual HIV protease inhibitions after simultaneous or staggered oral administration. Lu, J., Blaschke, T., Flexner, C., Rosenkranz, S., Sheiner, L. NATURE PUBLISHING GROUP. 2002: P15–P15

  View details for Web of Science ID 000174178600053

• Optimizing the science of drug development: Opportunities for better candidate selection and accelerated evaluation in humans JOURNAL OF CLINICAL PHARMACOLOGY Lesko, L. J., Rowland, M., Peck, C. C., Blaschke, T. F. 2000; 40 (8): 803-814

  Abstract

  Two international meetings were convened in 1998 to review the current science of drug development and the potential opportunities to optimize the evaluation of new drugs in humans. This report represents a synopsis of these meetings, and focuses on the current state of knowledge pertaining to drug development, future scientific and technical needs, and the relative merits of various strategies intended to accelerate the clinical development of drugs.

  View details for Web of Science ID 000088308500001

  View details for PubMedID 10934664

• Asymmetric dimethylarginine increases mononuclear cell adhesiveness in hypercholesterolemic humans ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Chan, J. R., Boger, R. H., Bode-Boger, S. M., Tangphao, O., Tsao, P. S., Blaschke, T. F., Cooke, J. P. 2000; 20 (4): 1040-1046

  Abstract

  Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is elevated in hypercholesterolemia. This study was designed to determine the role of ADMA in the increased mononuclear cell adhesiveness observed in human hypercholesterolemia. In patient studies, plasma ADMA levels were determined by high-performance liquid chromatography. Functional mononuclear leukocyte adhesion assays were performed in parallel, and flow cytometry was used to characterize bound monocytes and T lymphocytes. Hypercholesterolemic patients were then placed on an oral L-arginine regimen of 14 or 21 g/d and studied over 12 weeks. In cell culture studies, bovine aortic endothelial cells were incubated with varied concentrations of ADMA. Monocytoid cells were cocultured with these bovine aortic endothelial cells, and their adhesiveness was assessed by use of a binding assay. Flow cytometry was used to quantify adhesion molecule expression. Plasma ADMA levels and adhesiveness of mononuclear cells (specifically, monocytes and T lymphocytes) were elevated in hypercholesterolemic patients. Adhesiveness was inversely correlated with the plasma L-arginine/ADMA ratio. Oral administration of L-arginine normalized plasma L-arginine/ADMA ratios and attenuated monocyte and T-lymphocyte adhesiveness. ADMA had no direct effect on the adhesiveness of mononuclear cells. However, monocytes became hyperadhesive when cocultured with ADMA-exposed endothelial cells. In human hypercholesterolemia, the plasma L-arginine/ADMA ratio is inversely correlated with mononuclear cell adhesiveness. Restoration of the L-arginine/ADMA ratio to control levels normalizes mononuclear cell adhesiveness. Our studies suggest that the elaboration of endothelium-derived nitric oxide affects the behavior of circulating T lymphocytes and monocytes.

  View details for Web of Science ID 000086468300020

  View details for PubMedID 10764670

• Interactions of HIV protease inhibitors with a human organic cation transporter in a mammalian expression system DRUG METABOLISM AND DISPOSITION Zhang, L., Gorset, W., Washington, C. B., Blaschke, T. F., Kroetz, D. L., Giacomini, K. M. 2000; 28 (3): 329-334

  Abstract

  Recently, we cloned a human organic cation transporter, hOCT1, which is expressed primarily in the liver. hOCT1 plays an important role in the cellular uptake and elimination of various xenobiotics including therapeutically important drugs. HIV protease inhibitors are a new class of therapeutic agents. The purpose of this study was to elucidate the interactions of HIV protease inhibitors with hOCT1 and to determine whether hOCT1 is involved in the elimination of these compounds. We studied the interactions of HIV protease inhibitors with hOCT1 in a transiently transfected human cell line, HeLa. Uptake studies were carried out 40 h post-transfection using the radiolabeled model organic cation, [(14)C]tetraethylammonium (TEA), under different experimental conditions. In cis-inhibition studies, all of the HIV protease inhibitors tested, i.e., indinavir (IC(50) of 62 microM), nelfinavir (IC(50) of 22 microM), ritonavir (IC(50) of 5.2 microM), and saquinavir (IC(50) of 8.3 microM) inhibited TEA uptake in HeLa cells expressing hOCT1. However, none of the HIV protease inhibitors trans-stimulated [(14)C]TEA uptake, suggesting that they are poorly translocated by hOCT1. Nelfinavir, ritonavir, and saquinavir demonstrated an apparent "trans-inhibition" effect. No enhanced uptake of [(14)C]saquinavir was observed in hOCT1 DNA-transfected cells versus empty vector-transfected cells. These data suggest that HIV protease inhibitors are potent inhibitors, but poor substrates, of hOCT1. Some HIV protease inhibitors may potently inhibit the uptake and elimination of cationic drugs that are substrates for hOCT1, leading to potential drug-drug interactions. Other transporters, e.g., MDR1 and MRP1, in HIV-targeted cells may control the intracellular concentrations of HIV protease inhibitors.

  View details for Web of Science ID 000085396400013

  View details for PubMedID 10681378

• Efavirenz decreases saquinavir protein binding. Fang, F., Blaschke, T. F. NATURE PUBLISHING GROUP. 2000: 156–56

  View details for Web of Science ID 000085543200269

• Vascular reactivity in obstructive sleep apnea syndrome AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Duchna, H. W., Guilleminault, C., Stoohs, R. A., Faul, J. L., Moreno, H., Hoffman, B. B., Blaschke, T. F. 2000; 161 (1): 187-191

  Abstract

  The obstructive sleep apnea syndrome (OSAS) is associated with cardiovascular disease and systemic hypertension. Because systemic arterial blood pressure is proportional to venodilation and venous return to the heart, we hypothesized that altered vascular responsiveness might exist in the veins of subjects with OSAS. We therefore investigated venodilator responses in awake, normotensive subjects with and without OSAS, using the dorsal hand vein compliance technique. Dose-response curves to bradykinin and nitroglycerin were obtained from 12 subjects with OSAS and 12 matched control subjects. Maximal dilation (E(max)) to bradykinin was significantly lower in the OSAS group (62.1% +/- 26.1%) than in the control group (94.3% +/- 10.7%) (p < 0.005). Vasodilation to nitroglycerin tended to be lower in the OSAS group (78.6% +/- 31.8%) than the control group (100.3% +/- 12.9%), but this effect did not reach statistical significance. When six of the OSAS subjects were retested after 60 d of treatment with nasal continuous positive airway pressure (CPAP), E(max) to bradykinin rose from 60.3% +/- 20. 3% to 121.4% +/- 26.9% (p < 0.01). Vasodilation to nitroglycerin also increased, but this effect did not reach statistical significance. These results demonstrate that a blunted venodilatory responsiveness to bradykinin exists in OSAS. This effect appears to be reversible with nasal CPAP therapy.

  View details for Web of Science ID 000084820200032

  View details for PubMedID 10619819

• Heparin-induced vasodilation in human hand veins CLINICAL PHARMACOLOGY & THERAPEUTICS Tangphao, O., Chalon, S., Moreno, H. J., Abiose, A. K., Blaschke, T. F., Hoffman, B. B. 1999; 66 (3): 232-238

  Abstract

  To investigate whether heparin produces vasodilation in human veins and to explore the underlying mechanisms.Eleven healthy volunteers were studied with the dorsal hand vein compliance technique. Dose-response curves to heparin and enoxaparin were generated. Dose-response curves to heparin were also constructed before and after heparin was infused with the nitric oxide synthase inhibitor N(G)-monomethyl-l-arginine (L-NMMA) or combined histamine H1- and H2-receptor blockade.Heparin but not enoxaparin caused significant dose-dependent relaxation with an average apparent maximal response (at an infusion rate of 20 IU/min) of 47% +/- 23%. L-NMMA attenuated heparin-induced relaxation (P < .001). The combination of H1-and H2-receptor antagonists attenuated heparin-induced relaxation to a lesser extent (P < .05). Heparin-induced relaxation decreased by 52%, 73%, and 35% in the presence of L-NMMA, indomethacin (INN, indometacin) plus L-NMMA, and combined H1- and H2-receptor blockade, respectively.Heparin is an endothelium-dependent venodilator in humans. The mechanism of heparin-induced relaxation involves an increased availability of nitric oxide, possibly partially related to local release of histamine.

  View details for Web of Science ID 000082744100004

  View details for PubMedID 10511058

• Angiotensin-converting enzyme inhibition improves venous endothelial dysfunction in chronic smokers CLINICAL PHARMACOLOGY & THERAPEUTICS Chalon, S., Moreno, H., Hoffman, B. B., Blaschke, T. F. 1999; 65 (3): 295-303

  Abstract

  In arteries and veins smoking is associated with impaired nitric oxide-mediated relaxation to endothelium-dependent agonists such as bradykinin. We investigated whether acute local angiotensin-converting enzyme (ACE) inhibition, achieved by enalaprilat, could influence bradykinin-induced vasodilation in veins of smokers.We studied 7 smokers and 7 nonsmokers with the hand vein technique. After preconstriction with phenylephrine was performed, endothelium-dependent and independent relaxations were assessed by infusing bradykinin (1 to 278 ng/min) and sodium nitroprusside (0.0001 to 3166 ng/min), respectively. Dose-response curves were constructed before and during enalaprilat coinfusion (1 microg/min for 40 minutes).Smokers had impaired venodilation to bradykinin compared with nonsmokers (P < .01). Apparent maximal relaxation induced by bradykinin was 78%+/-9% in the control group and 48%+/-9% in smokers (mean +/- SD). ACE inhibition shifted the bradykinin dose-response curve to the left in both groups (P < .001) and was associated with a minimal increase in apparent maximal venodilation in nonsmokers (78%+/-9% to 83%+/-18%). In contrast, in smokers ACE inhibition augmented the magnitude of apparent maximal venodilation to values comparable to those observed in the control group (48%+/-9% to 102%+/-21%). In both groups the response to sodium nitroprusside was not affected by enalaprilat.This study shows that acute local ACE inhibition restores bradykinin-induced relaxation in smokers to values found in nonsmokers. This observation suggests that increased vascular metabolism of bradykinin exists in veins of smokers and that the vascular renin-angiotensin system may play a key role in smoking-induced endothelial dysfunction.

  View details for Web of Science ID 000079197500009

  View details for PubMedID 10096262

• Pharmacokinetics of intravenous and oral L-arginine in normal volunteers BRITISH JOURNAL OF CLINICAL PHARMACOLOGY Tangphao, O., Grossmann, M., Chalon, S., Hoffman, B. B., Blaschke, T. F. 1999; 47 (3): 261-266

  Abstract

  Recent studies in patients with cardiovascular diseases suggest potential for the use of orally administered L-arginine, the precursor of nitric oxide, as a therapeutic agent. This crossover study was designed to examine the pharmacokinetics of single i.v. and oral doses of L-arginine in healthy volunteers (n = 10).A preliminary control study (n = 12) was performed to assess the variation in plasma L-arginine concentrations when ingesting a normal diet. The observed variation was taken into account when interpreting the pharmacokinetic data obtained after exogenous administration.The mean baseline plasma concentration of L-arginine in the control study was 15.1+/-2.6 microg ml(-1). After intravenous administration (30 g over 30 min), the plasma concentration reached 1390+/-596 microg ml(-1). The disappearance of l-arginine appeared biphasic, with an initial rapid disappearance due to concentration-dependent renal clearance followed by a slower fall in plasma concentrations due to nonrenal elimination. The peak concentration after oral administration (10 g) was 50.0+/-13.4 microg ml(-1), occurring 1 h after administration. Renal elimination was not observed after oral administration of this dose. The absolute bioavailability of a single oral 10 g dose of L-arginine is approximately 20%.This study provides basic knowledge of L-arginine pharmacokinetics in healthy humans. Intravenous and oral administrations show at minimum a biphasic pattern. Further studies will assess whether a similar profile is observed when the drug is administered to patients.

  View details for Web of Science ID 000079405200005

  View details for PubMedID 10215749

• L-arginine and nitric oxide-related compounds in plasma: comparison of normal and arginine-free diets in a 24-h crossover study VASCULAR MEDICINE Tangphao, O., Chalon, S., Coulston, A. M., Moreno, H., Chan, J. R., Cooke, J. P., Hoffman, B. B., Blaschke, T. F. 1999; 4 (1): 27-32

  Abstract

  The amino acid L-arginine is the precursor of nitric oxide (NO), a powerful vasodilator with antiplatelet properties. The availability of L-arginine has been suggested to be a rate-limiting factor in the production of NO in conditions such as hypercholesterolemia. It was speculated that fluctuations in plasma concentrations of L-arginine during the day may be dependent upon dietary intake of the amino acid, or other variables, and might modify the elaboration of endogenous NO. Over a 24-h period, the plasma concentrations of L-arginine and NO-related compounds (NOx) were measured during an L-arginine and nitrate/nitrite-free diet (diet A) or a nitrate/nitrite-free diet with a fixed amount of L-arginine intake (3.8 g/d) (diet B) in eight healthy volunteers during a 2-day crossover study. Subjects were randomly selected to begin with diet A or diet B and consumed the other diet on the second day. During diet A, plasma L-arginine decreased significantly from 09.00 to 16.00 (21.4+/-2.0 to 11.9+/-1.1 microg/ml), rose slightly in the evening (to 16.6+/-1.7 microg/ml) and gradually increased during the night. During diet B, plasma L-arginine showed a peak after each meal (approximately 23 microg/ml). Plasma NOx concentrations measured by chemiluminescence did not show any circadian variation on either diet. Plasma L-arginine concentrations change during the day and are influenced by dietary intake. Importantly, plasma NOx do not seem to vary with this pattern in healthy individuals.

  View details for Web of Science ID 000081421400005

  View details for PubMedID 10355867

• Pharmacokinetics of L-arginine during chronic administration to patients with hypercholesterolaemia CLINICAL SCIENCE Tangphao, O., Chalon, S., Moreno, H., Hoffman, B. B., Blaschke, T. F. 1999; 96 (2): 199-207

  Abstract

  Acute administration of L-arginine, the precursor of endothelial nitric oxide, has been shown to improve endothelial function in hypercholesterolaemic rabbits and humans. Animal studies suggest that this beneficial effect, which is thought to be related to the increased availability of nitric oxide, may not be sustained during chronic oral administration. Pharmacokinetic alterations may contribute to this observation. The present study was designed to examine the disposition of L-arginine in hypercholesterolaemic subjects during long-term administration. Plasma L-arginine concentrations were determined by HPLC in 10 patients (eight women and two men; mean age 46+/-16 years) after an intravenous dose of 10 or 30 g and an oral dose of 5 or 7 g. Pharmacokinetic studies were performed at regular intervals (4 weeks) during a 12-week period of oral L-arginine administration (14-21 g/day). The average plasma L-arginine concentrations before (baseline) and during administration were 16.1+/-1.2 and 22.5+/-1.3 microg/ml respectively (P<0.05). Plasma concentrations of L-arginine remained above baseline throughout weeks 2-12. The L-arginine exposure, expressed as a normalized area-under-the-curve for 8 h (AUC0-8) after oral or intravenous doses during the first visit, was 894.4+/-118.7 and 1837. 8+/-157.0 units respectively. There were no significant changes in peak plasma L-arginine concentrations or in the AUC0-8 after oral and intravenous doses during subsequent visits (P>0.05). The mean non-renal clearance of L-arginine during the four visits remained constant. Knowledge of the pharmacokinetics of L-arginine may be useful in the design of clinical trials involving this agent, as well as in the interpretation of the pharmacodynamics of this important precursor of nitric oxide.

  View details for Web of Science ID 000078706000011

  View details for PubMedID 9918901

• Role of nitric oxide in isoprenaline and sodium nitroprusside-induced relaxation in human hand veins BRITISH JOURNAL OF CLINICAL PHARMACOLOGY Chalon, S., Tejura, B., Moreno, H., Urae, A., Blaschke, T. F., Hoffman, B. B. 1999; 47 (1): 91-98

  Abstract

  Recent reports, largely in animal models, have suggested that either inhibition of nitric oxide (NO) synthase or endothelium removal in arteries inhibits the response to isoprenaline, a beta-adrenoceptor agonist, and also enhances the response to sodium nitroprusside, a nitrovasodilator. This in vivo study was designed to determine whether N(G)-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthesis, influences relaxation of human hand veins mediated by isoprenaline or by sodium nitroprusside.Using the dorsal hand vein technique, full dose-response curves to bradykinin (0.27-278 ng min(-1), n=6), isoprenaline (2.12-271 ngmin(-1), n=8) and sodium nitroprusside (0.01-634 ng min(-1) n=7) were generated on separate occasions before and after L-NMMA co-infusion (50 microg min(-1)).In veins preconstricted with the alpha1-adrenoceptor-selective agonist phenylephrine, the three vasodilators induced maximal responses (Emax) of 119+/-35, 72+/-18 and 103+/-17%, respectively. L-NMMA inhibited relaxation to bradykinin by 64% (P=0.014) but did not influence relaxation induced by isoprenaline. The sensitivity to sodium nitroprusside was significantly enhanced by L-NMMA co-infusion (concentration shift of 2.3, P=0.031). CONCLUSIONS; We conclude that in human veins, spontaneously released NO does not play a major role in isoprenaline-induced relaxation. Our results also suggest that the effects of sodium nitroprusside in this vascular bed may be attenuated by endothelium-derived NO.

  View details for Web of Science ID 000078493800017

  View details for PubMedID 10073745

• Inhibition of angiotensin-converting enzyme in human hand veins CLINICAL PHARMACOLOGY & THERAPEUTICS Chalon, S., Bedarida, G. V., Moreno, H., Tejura, B., Urae, A., Hoffmann, B. B., Blaschke, T. F. 1999; 65 (1): 58-65

  Abstract

  Conversion of angiotensin I to angiotensin II likely occurs in human veins, supporting the existence of endothelial angiotensin-converting enzyme (ACE) activity in these vessels. Using the dorsal hand vein technique, we investigated the effects of 2 ACE inhibitors, captopril (single oral dose of 6.25 mg) and enalaprilat (local infusion of 1 microgram/min), on venous responsiveness in healthy subjects. Orally administered captopril induced a marked decrease in angiotensin I- but not angiotensin II-induced venoconstriction. This blunted response persisted for at least 4 hours. Enalaprilat and captopril increased the sensitivity to bradykinin, decreasing the dose producing half-maximal response (ED50) of bradykinin 18-fold and 5-fold, respectively, without changing the maximal venodilatory response. These results confirm that there is substantial rapid metabolism of angiotensin I in human veins and suggest that a single dose of locally infused angiotensin I can be used with the dorsal hand vein technique to assess the time-course effect of vascular ACE inhibition after oral administration. Our findings also extend previous in vitro observations in human veins by showing that these agents potentiate the venodilatory effects of bradykinin in vivo.

  View details for Web of Science ID 000078293300007

  View details for PubMedID 9951431

• The extent of non-adherence in a large AIDS clinical trial using plasma dideoxynucleoside concentrations as a marker 95th Annual Meeting of the American-Society-of-Clinical-Pharmacology Kastrissios, H., Suarez, J. R., Hammer, S., KATZENSTEIN, D., Blaschke, T. F. LIPPINCOTT WILLIAMS & WILKINS. 1998: 2305–11

  Abstract

  To assess adherence to study medications in an AIDS clinical trial, to evaluate whether study participants adhered to only one component of a multidrug regimen ('differential adherence'), and to determine whether there was evidence of non-uniform adherence to study medications among treatment groups.This was a substudy of AIDS Clinical Trials Group protocol 175, a large, double-blind, randomized study of monotherapy versus combination dideoxynucleoside therapy. Participants were required to adhere to a complex regimen of zidovudine, zalcitabine and didanosine, or their matching placebos.Between October 1992 and January 1994, study sites were selected at random, and a 1-week period was designated during which study participants attending routine clinic visits provided a blood sample and dosing history. Participants were not informed of the purpose of the substudy.Adherence was assessed using plasma drug concentrations and defined by the presence of detectable drug in a plasma sample obtained within a specified analysis window.Of 722 plasma samples analyzed, approximately 75% contained detectable concentrations of the assigned drugs and 5-14.5% contained no detectable drugs. Approximately 7 and 13% of samples from participants assigned to monotherapy arms contained non-prescribed dideoxynucleosides, and 14 and 19% assigned to combination therapies contained only one drug.Various non-adherence behaviors were observed, including patterns of underdosing and taking non-prescribed drugs. Non-adherence was moderate but uniform amongst the treatment groups and may have contributed to a marginal reduction in the power of the primary intent-to-treat analysis to detect differences in efficacy amongst the assigned treatments.

  View details for Web of Science ID 000077173000012

  View details for PubMedID 9863873

• Characterizing patterns of drug-taking behavior with a multiple drug regimen in an AIDS clinical trial 96th Annual Meeting of the American-Society-of-Clinical-Pharmacology Kastrissios, H., Suarez, J. R., KATZENSTEIN, D., GIRARD, P., Sheiner, L. B., Blaschke, T. F. LIPPINCOTT WILLIAMS & WILKINS. 1998: 2295–2303

  Abstract

  To characterize drug-taking behavior using continuous electronic monitoring in an AIDS clinical trial.This was a substudy of AIDS Clinical Trials Group (ACTG) protocol 175, a phase II/III study of dideoxynucleoside monotherapy versus combination therapy in asymptomatic HIV-positive subjects. Participants were required to comply with regimens containing zidovudine, zalcitabine and didanosine, or matching placebos; the total daily pill count was 16.For participants at two ACTG 175 sites, electronic devices were used to monitor drug-taking behavior of all study medications over a period of approximately 90 days.Four indices of drug-taking behavior were calculated and their distributions and relationship to the prescribed regimen were examined.Data from 41 subjects were analyzed. Of the prescribed doses of zidovudine, zalcitabine and didanosine, 88, 84 and 82%, respectively, were taken. Of these, 55, 66 and 79%, respectively, were taken at the prescribed dosing frequency. The median percentage of days on which participants failed to take any of the doses was 2-5%. There was a trend towards lower adherence in the combination therapy arms compared with those assigned to receive monotherapy. In this analysis, older patients demonstrated better adherence, although patient characteristics, in general, were poorly predictive of adherence.Drug-taking behavior for all three active study medications differed from that prescribed. One result of this erratic adherence was that study participants sustained little antiretroviral effect during more than 25% of the monitoring period.

  View details for Web of Science ID 000077173000011

  View details for PubMedID 9863872

• Asymmetric dimethylarginine (ADMA): A novel risk factor for endothelial dysfunction - Its role in hypercholesterolemia CIRCULATION Boger, R. H., Bode-Boger, S. M., Szuba, A., Tsao, P. S., Chan, J. R., Tangphao, O., Blaschke, T. F., Cooke, J. P. 1998; 98 (18): 1842-1847

  Abstract

  Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide (NO) synthase. Because endothelial NO elaboration is impaired in hypercholesterolemia, we investigated whether plasma concentrations of ADMA are elevated in young, clinically asymptomatic hypercholesterolemic adults. We further studied whether such elevation of ADMA levels was correlated with impaired endothelium-dependent, NO-mediated vasodilation and urinary nitrate excretion. In a randomized, double-blind, placebo-controlled study, we investigated whether these changes could be reversed with exogenous L-arginine.We measured plasma levels of L-arginine, ADMA, and symmetrical dimethylarginine (SDMA) by high-performance liquid chromatography in 49 hypercholesterolemic (HC) and 31 normocholesterolemic (NC) humans. In 8 HC subjects, endothelium-dependent forearm vasodilation was assessed before and after an intravenous infusion of L-arginine or placebo and compared with 8 NC control subjects. ADMA levels were significantly elevated by >100% (2.17+/-0.15 versus 1.03+/-0.09 micromol/L; P<0.05) in HC subjects compared with NC adults. L-Arginine levels were similar, resulting in a significantly decreased L-arginine/ADMA ratio in HC subjects (27.7+/-2.4 versus 55. 7+/-5.4; P<0.05). In 8 HC subjects, intravenous infusion of L-arginine significantly increased the L-arginine/ADMA ratio and normalized endothelium-dependent vasodilation and urinary nitrate excretion. ADMA levels were inversely correlated with endothelium-mediated vasodilation (R=0.762, P<0.01) and urinary nitrate excretion rates (R=0.534, P<0.01).We find that ADMA is elevated in young HC individuals. Elevation of ADMA is associated with impaired endothelium-dependent vasodilation and reduced urinary nitrate excretion. This abnormality is reversed by administration of L-arginine. ADMA may be a novel risk factor for endothelial dysfunction in humans.

  View details for Web of Science ID 000076718900005

  View details for PubMedID 9799202

• Interaction of anti-HIV protease inhibitors with the multidrug transporter P-glycoprotein (P-gp) in human cultured cells JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Washington, C. B., Duran, G. E., Man, M. C., Sikic, B. I., Blaschke, T. F. 1998; 19 (3): 203-209

  Abstract

  The anti-HIV protease inhibitors represent a new class of agents for treatment of HIV infection. Saquinavir, ritonavir, indinavir, and nelfinavir are the first drugs approved in this class and significantly reduce HIV RNA copy number with minimal adverse effects. They are all substrates of cytochrome P450 3A4, and are incompletely bioavailable. The drug transporting protein, P-glycoprotein (P-gp), which is highly expressed in the intestinal mucosa, could be responsible for the low oral bioavailability of these and other drugs which are substrates for this transporter. To determine whether these protease inhibitors are modulators of P-gp, we studied them in cell lines which do and do not express P-gp. Saquinavir, ritonavir and nelfinavir significantly inhibited the efflux of [3H]paclitaxel and [3H]vinblastine in P-gp-positive cells, resulting in an increase in intracellular accumulation of these drugs. However, similar concentrations of indinavir did not affect the accumulation of these anticancer agents. In photoaffinity labeling studies, saquinavir and ritonavir displaced [3H]azidopine, a substrate for P-gp, in a dose-dependent manner. These data suggest that saquinavir, ritonavir, and nelfinavir are inhibitors and possibly substrates of P-gp. Because saquinavir has a low bioavailability, its interaction with P-gp may be involved in limiting its absorption.

  View details for Web of Science ID 000076693700001

  View details for PubMedID 9803961

• Endothelial dysfunction in human hand veins is rapidly reversible after smoking cessation AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Moreno, H., Chalon, S., Urae, A., Tangphao, O., Abiose, A. K., Hoffman, B. B., Blaschke, T. F. 1998; 275 (3): H1040-H1045

  Abstract

  Cigarette smoking has been shown to impair endothelium-dependent dilation in arteries. We tested the hypothesis that cigarette smoking also impairs endothelium-dependent venodilation and evaluated changes in this response after smoking cessation in a time-course study using the dorsal hand vein technique. Dose-response curves were constructed in smokers and nonsmokers by infusing bradykinin (1-278 ng/min), an endothelium-dependent vasodilator, and nitroglycerin (0.006-1,583 ng/min), an endothelium-independent vasodilator, into hand veins preconstricted with the selective alpha1-adrenergic agonist phenylephrine. The maximal venodilation induced by bradykinin was 89 +/- 5% in controls (n = 16) and 61 +/- 7% in smokers (n = 18; P = 0.02). No difference in nitroglycerin-induced venodilation was observed between the two groups. Coinfusion of L-arginine (0.33 mg/min) markedly improved the bradykinin-induced venodilation in smokers (52 +/- 7 to 90 +/- 9%; P < 0.01). After acute smoking cessation (n = 7), restoration to normal bradykinin-induced venodilation was observed within 24 h, whereas no change in the response to a maximally effective dose of nitroglycerin (1,583 ng/min) was detected. In a human vein model appropriate for testing vascular functional alterations, this study demonstrates that smoking impairs endothelium-dependent venodilation in heavy smokers. Moreover, this endothelial dysfunction appears to be rapidly reversible after smoking cessation. This model may be useful in studies evaluating mechanisms of endothelial dysfunction and interventions to modify it.

  View details for Web of Science ID 000075620800038

  View details for PubMedID 9724311

• Diurnal variation of plasma L-arginine concentrations and the effect of dietary L-arginine intake. Tangphao, O., Coulston, A. M., Moreno, H., Chalon, S., Chan, J. R., Cooke, J. P., Blaschke, T. F., Hoffman, B. B. NATURE PUBLISHING GROUP. 1998: 178–78

  View details for Web of Science ID 000072420300166

• Exposure-response relationships for saquinavir, zidovudine, and zalcitabine in combination therapy ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Vanhove, G. F., Gries, J. M., Verotta, D., Sheiner, L. B., COOMBS, R., Collier, A. C., Blaschke, T. F. 1997; 41 (11): 2433-2438

  Abstract

  The relationship of CD4+ cell response, level of RNA in plasma, and quantitative peripheral blood mononuclear cell (PBMC) titer to apparent drug exposure was investigated by using data from AIDS Clinical Trial Group protocol 229, a multicenter randomized study. Patients received either saquinavir, zalcitabine, or a combination of both, along with open-label zidovudine. Approximately 100 patients were enrolled in each arm, and the primary study duration was 24 weeks. Individual drug exposure, the area under the concentration-time curve, was estimated by using population-based pharmacokinetic methods. Response was defined as the maximum increase in CD4+ cell count or the maximum decrease in RNA in plasma or PBMC titer adjusted for baseline CD4+ cell count, RNA in plasma, and PBMC titer, respectively. Regression of responses on exposure demonstrated an exposure effect for saquinavir which was significant for the maximum increase in CD4+ cell count and the decrease in RNA in plasma. For the PBMC titer, no significant relationship could be demonstrated but the results suggested a trend similar to that of the other response variables. For all three response variables, the slope of the saquinavir exposure response was greater with the triple combination (saquinavir, zidovudine, and zalcitabine) than with the combination of saquinavir and zidovudine, suggesting possible synergism between saquinavir and zalcitabine.

  View details for Web of Science ID A1997YE74500020

  View details for PubMedID 9371346

  View details for PubMedCentralID PMC164141

• Pharmacokinetics of saquinavir, zidovudine, and zalcitabine in combination therapy ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Vanhove, G. F., Kastrissios, H., Gries, J. M., Verotta, D., Park, K. S., Collier, A. C., Squires, K., Sheiner, L. B., Blaschke, T. F. 1997; 41 (11): 2428-2432

  Abstract

  We investigated the pharmacokinetics of zidovudine, zalcitabine, and saquinavir in AIDS Clinical Trial Group protocol 229. Patients received either saquinavir, zalcitabine, or a combination of both, together with zidovudine three times a day. Approximately 100 patients were enrolled in each treatment arm, and intensive pharmacokinetic studies were performed on about 25 patients per arm at weeks 1 and 12. We estimated the pharmacokinetic parameters of all three drugs by using parametric and nonparametric methods. The mean values of the pharmacokinetic parameters of zidovudine (clearance [CL]/bioavailability [F], 168 liters/h; volume of distribution [V]/F, 185 liters; half-life, 0.76 h) and zalcitabine (CL/F, 25 liters/h; V/F, 92.2 liters; half-life, 2.7 h) were similar to those reported previously. For saquinavir, the mean pharmacokinetic parameter estimates using parametric methods were as follows: maximum concentration of drug in serum [Cmax], 70.8 ng/ml; time to Cmax, 3.11 h; area under the curve, 809 ng x h/ml; CL/F, 989 liters/h; V/F, 1,503 liters; half-life, 1.38 h. For all three drugs, clearance decreased with age. Weight did not influence the clearance of zidovudine, but the clearance of zalcitabine and saquinavir increased with weight. There were no differences in pharmacokinetic parameters between study weeks and arms, suggesting that there is no change in kinetics with chronic administration and that there are no significant pharmacokinetic interactions among these three drugs.

  View details for Web of Science ID A1997YE74500019

  View details for PubMedID 9371345

• A semiparametric method for describing noisy population pharmacokinetic data JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS Park, K., Verotta, D., Blaschke, T. F., Sheiner, L. B. 1997; 25 (5): 615-642

  Abstract

  We propose a semiparametric method to estimate model-independent pharmacokinetic (PK) measures such as area under concentration-time, peak concentration and time to peak concentration (Tpeak), for noisy population PK data from a sparsely sampled prospectively designed trial. The method is developed within the mixed-effect model framework, for the single-dose and steady-state case. We describe individual concentration vs. time using a longitudinal spline, consisting of a template spline, common to all individuals, and an individual-specific distortion spline accounting for individual differences. We impose a number of constraints on the longitudinal spline, including (i) it has a decreasing tail, (ii) its typical Tpeak is near the modal Tpeak observed in the population data, and (iii) its value is zero at time zero (single dose), or the same nonzero value at the beginning and end of a dosing interval (steady state). We test our method using simulated data and compare its performance to that of a parametric and a nonparametric method. An actual data example is also shown. The performance of the method is as good or better than that of a standard nonparametric method, and when the analysis model is misspecified, the method is superior to a standard parametric one. Since it is often not apparent that an analysis model is correct, we propose this approach as a general method for analysis.

  View details for Web of Science ID 000074808900004

  View details for PubMedID 9679225

• Chloroquine-induced venodilation in human hand veins CLINICAL PHARMACOLOGY & THERAPEUTICS Abiose, A. K., Grossmann, M., Tangphao, O., Hoffman, B. B., Blaschke, T. F. 1997; 61 (6): 677-683

  Abstract

  Hypotension induced by parenteral administration of chloroquine is a common and serious adverse effect of this drug. Our aim was to investigate whether chloroquine produces venodilation in vivo and to explore the underlying mechanisms.Vascular effects of chloroquine were studied in healthy volunteers with use of the dorsal hand vein technique at the Geriatric Research Education and Clinical Center, Veterans Affairs Palo Alto Health Care System. We studied 22 healthy volunteers (19 men and three women). Venous responsiveness was determined with the dorsal hand vein technique, which measures the diameter of the vein.Chloroquine was found to produce a dose-dependent relaxation of hand veins preconstricted with the alpha 1-receptor selective agonist phenylephrine. The venodilatory response to chloroquine ranged from 15% +/- 19% at an infusion rate of 0.75 microgram/min to 61% +/- 24% at 48 microgram/min. Venodilation was attenuated by the nitric-oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) so that the dose of chloroquine required to produce 20% venodilation was increased from 3.7 micrograms/min to 15 micrograms/min (p < 0.01). In the presence of a combination of histamine receptor antagonists, there was also a diminution of the vasodilatory response to chloroquine from 72% +/- 5% to 44% +/- 5% at the infusion rate of 96 micrograms/min. The response was further reduced to 33% +/- 7% by the coinfusion of H1-/H2-receptor antagonists with L-NMMA.Chloroquine produces venodilation at infusion rates that achieve local concentrations likely similar to those observed systemically after clinically relevant intravenous doses. The date also suggest a role for nitric oxide and histamine release in mediating this response.

  View details for Web of Science ID A1997XG20900010

  View details for PubMedID 9209251

• Medication compliance as a feature in drug development ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY Kastrissios, H., Blaschke, T. F. 1997; 37: 451-475

  Abstract

  Well-designed clinical trials maximize the information that can be obtained regarding the clinical pharmacology of a drug and, in turn, can streamline and enhance the drug development process. Until recently, little emphasis has been placed on integrating the role of variability in individual patterns of drug-taking into the drug development process. With the use of electronic monitoring, the temporal relationship between an individual's pattern of dosing and the prescribed regimen may be examined, and individual drug exposure may be estimated based on the actual history of dosing. As a result, accurate estimation of exposure-response relationships (or surrogate markers of response) can be obtained. Considerations in the design of clinical trials must therefore be expanded to include appropriate methods to measure compliance, sufficient frequency of monitoring to allow the time course of response to be mapped, and the use of statistically valid methods of data analysis.

  View details for Web of Science ID A1997WV83500018

  View details for PubMedID 9131261

• Morphine-induced venodilation in humans CLINICAL PHARMACOLOGY & THERAPEUTICS Grossman, M., Abiose, A., Tangphao, O., Blaschke, T. F., Hoffman, B. B. 1996; 60 (5): 554-560

  Abstract

  Morphine has been extensively used in the treatment of pulmonary edema, and its action is believed to be mediated in part by its ability to produce peripheral venodilation. This study investigated whether opiates produce venodilation in human hand veins and explored the underlying mechanism(s). Fifteen healthy volunteers (11 men and four women) were studied with use of the dorsal hand vein compliance technique. After preconstriction with the selective alpha 1-adrenergic receptor agonist phenylephrine, dose-response curves were constructed to (1) opiate receptor agonists morphine (1 to 30 micrograms/min) or fentanyl (0.07 to 1 microgram/min), (2) a combination of morphine and the mu-opiate receptor antagonist naloxone, and (3) morphine and a combination of histamine (H1 and H2) receptor antagonists. Infusion of morphine caused venodilation in a dose-dependent manner, whereas fentanyl did not produce venodilation. Coinfusion of naloxone and morphine impaired the venodilation only slightly. Coinfusion of the H1- and H2-antagonists completely abolished the venodilatory effect of morphine. These results suggest that the venodilatory effect of morphine is mediated through histamine release and that mu-opiate receptors have little or no involvement in this process.

  View details for Web of Science ID A1996VV59700008

  View details for PubMedID 8941028

• A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. AIDS Clinical Trials Group Study 175 Study Team. New England journal of medicine Hammer, S. M., Katzenstein, D. A., Hughes, M. D., Gundacker, H., Schooley, R. T., Haubrich, R. H., Henry, W. K., Lederman, M. M., Phair, J. P., Niu, M., Hirsch, M. S., Merigan, T. C. 1996; 335 (15): 1081-1090

  Abstract

  This double-blind study evaluated treatment with either a single nucleoside or two nucleosides in adults infected with human immunodeficiency virus type 1 (HIV-1) whose CD4 cell counts were from 200 to 500 per cubic millimeter.We randomly assigned 2467 HIV-1--infected patients (43 percent without prior antiretroviral treatment) to one of four daily regimens: 600 mg of zidovudine; 600 mg of zidovudine plus 400 mg of didanosine; 600 mg of zidovudine plus 2.25 mg of zalcitabine; or 400 mg of didanosine. The primary end point was a > or = 50 percent decline in the CD4 cell count, development of the acquired immunodeficiency syndrome (AIDS), or death.Progression to the primary end point was more frequent with zidovudine alone (32 percent) than with zidovudine plus didanosine (18 percent; relative hazard ratio, 0.50; P<0.001), zidovudine plus zalcitabine (20 percent; relative hazard ratio, 0.54; P<0.001), or didanosine alone (22 percent; relative hazard ratio, 0.61; P<0.001). The relative hazard ratios for progression to an AIDS-defining event or death were 0.64 (P=0.005) for zidovudine plus didanosine, as compared with zidovudine alone, 0.77 (P=0.085) for zidovudine plus zalcitabine, and 0.69 (P=0.019) for didanosine alone. The relative hazard ratios for death were 0.55 (P=0.008), 0.71 (P=0.10), and 0.51 (P=0.003), respectively. For zidovudine plus zalcitabine, the benefits were limited to those without previous treatment.Treatment with zidovudine plus didanosine, zidovudine plus zalcitabine, or didanosine alone slows the progression of HIV disease and is superior to treatment with zidovudine alone. Antiretroviral therapy can improve survival in patients with 200 to 500 CD4 cells per cubic millimeter.

  View details for PubMedID 8813038

• A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter NEW ENGLAND JOURNAL OF MEDICINE Hammer, S. M., Katzenstein, D. A., Hughes, M. D., Gundacker, H., Schooley, R. T., Haubrich, R. H., Henry, W. K., Lederman, M. M., Phair, J. P., Niu, M., Hirsch, M. S., Merigan, T. C., Blaschke, T. F., Simpson, D., McLaren, C., ROONEY, J., Salgo, M. 1996; 335 (15): 1081-1090

  Abstract

  This double-blind study evaluated treatment with either a single nucleoside or two nucleosides in adults infected with human immunodeficiency virus type 1 (HIV-1) whose CD4 cell counts were from 200 to 500 per cubic millimeter.We randomly assigned 2467 HIV-1--infected patients (43 percent without prior antiretroviral treatment) to one of four daily regimens: 600 mg of zidovudine; 600 mg of zidovudine plus 400 mg of didanosine; 600 mg of zidovudine plus 2.25 mg of zalcitabine; or 400 mg of didanosine. The primary end point was a > or = 50 percent decline in the CD4 cell count, development of the acquired immunodeficiency syndrome (AIDS), or death.Progression to the primary end point was more frequent with zidovudine alone (32 percent) than with zidovudine plus didanosine (18 percent; relative hazard ratio, 0.50; P<0.001), zidovudine plus zalcitabine (20 percent; relative hazard ratio, 0.54; P<0.001), or didanosine alone (22 percent; relative hazard ratio, 0.61; P<0.001). The relative hazard ratios for progression to an AIDS-defining event or death were 0.64 (P=0.005) for zidovudine plus didanosine, as compared with zidovudine alone, 0.77 (P=0.085) for zidovudine plus zalcitabine, and 0.69 (P=0.019) for didanosine alone. The relative hazard ratios for death were 0.55 (P=0.008), 0.71 (P=0.10), and 0.51 (P=0.003), respectively. For zidovudine plus zalcitabine, the benefits were limited to those without previous treatment.Treatment with zidovudine plus didanosine, zidovudine plus zalcitabine, or didanosine alone slows the progression of HIV disease and is superior to treatment with zidovudine alone. Antiretroviral therapy can improve survival in patients with 200 to 500 CD4 cells per cubic millimeter.

  View details for Web of Science ID A1996VN39900001

• High-performance liquid chromatographic assay for the quantitation of L-arginine in human plasma ANALYTICAL CHEMISTRY Gopalakrishnan, V., Burton, P. J., Blaschke, T. F. 1996; 68 (19): 3520-3523

  Abstract

  L-Arginine is metabolized to nitric oxide by nitric oxide synthase, and abnormalities in nitric oxide production have been implicated in the pathogenesis of some diseases involving the vasculature. Thus, there has been interest in the effects of pharmacologic doses of L-arginine in patients with cardiovascular and renal diseases. To study the disposition of exogenous doses, an HPLC method was developed to analyze plasma samples for L-arginine. The assay involves precolumn derivatization of arginine with naphthalenedicarboxaldehyde and cyanide followed by HPLC with UV detection. Only a simple deproteinization of the plasma samples was required. The derivatized arginine was stable (less than 5% degradation in 20 h), facilitating batch sample processing and analysis in an autosampler. Calibration curves were generated in Ringer's lactate solution instead of plasma to correct for endogenous plasma L-arginine. Recovery in plasma, compared to Ringer's solution (n = 4), was 103%. Mean intraday assay precision (n = 6), expressed as coefficient of variation, was 3.4%. Interassay precision (n = 6) was 7%. The assay was applied for the quantitation of L-arginine in plasma samples from a normal subject who had been given a single oral (10 g) and a single intravenous dose (30 g) of exogenous L-arginine.

  View details for Web of Science ID A1996VK59000042

  View details for PubMedID 8843144

• Pharmacokinetics of high dose oral CCNU in bone marrow transplant patients CANCER CHEMOTHERAPY AND PHARMACOLOGY Kastrissios, H., Chao, N. J., Blaschke, T. F. 1996; 38 (5): 425-430

  Abstract

  CCNU (lomustine) and other nitrosourea compounds are rapidly metabolized to alkylating moieties, which are active against various malignancies. In humans, CCNU undergoes biotransformation to the geometric isomers of 4'-hydroxyCCNU. The pharmacokinetics of trans-and cis-4'-hydroxyCCNU were determined in five patients with Hodgkin's or non-Hodgkin's lymphoma receiving sequential doses of CCNU (15 mg/kg), etoposide (60 mg/kg) and cyclophosphamide (100 mg/kg) prior to autologous bone marrow transplantation.Plasma concentrations of the isomeric forms of the metabolites were determined by high-performance liquid chromatography. Data were analysed using noncompartmental pharmacokinetic methods.Formation of the trans-isomer predominated over that of the cis-isomer, with an average exposure ratio of 1.4 (range 1.0-2.1). Peak plasma concentrations occurred between 1 and 4.1 h postdosing and averaged 1.56 mg/l for the trans-isomer and 1.10 mg/l for cis isomer. Peak plasma concentrations and systemic exposures varied approximately six- and ninefold, respectively, reflecting significant interindividual variability in alkylating activity after high doses of CCNU. Plasma half-lives of the metabolites were 3.1 h (range 1.1-4.5 h) for the trans-isomer and 3.5 h (range 1.3-6.4 h) for the cis- isomer, and varied linearly with increasing patient body weight. There was no significant difference in plasma half-lives after high-dose CCNU administration observed in this study and those reported previously after the administration of substantially lower doses of CCNU.Despite linearity in the pharmacokinetics of the isomeric forms of 4'-hydroxyCCNU at high doses, large interindividual variability in exposure to the CCNU metabolites was observed. Potential saturation of metabolic pathways to the isomers at these doses may manifest as toxic symptoms since alkylating moieties formed directly from the parent, CCNU, may be associated with greater toxicity than those formed from the isomeric forms of the 4'-hydroxylated metabolite.

  View details for Web of Science ID A1996VC37000005

  View details for PubMedID 8765435

• Phase 1 study of combination therapy with L-697,661 and zidovudine JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY Schooley, R. T., Campbell, T. B., Kuritzkes, D. R., Blaschke, T., Stein, D. S., Rosandich, M. E., Phair, J., Pottage, J. C., Messari, F., Collier, A., Kahn, J., Ray, G., Curtis, S., Bakhtiari, M., Kessler, H., COOMBS, R., Corey, L., Volberding, P., Calandra, G., Massari, F. 1996; 12 (4): 363-370

  Abstract

  We performed a pilot study that examined the clinical and pharmacokinetic interactions between zidovudine (ZDV) and a pyridinone derivative, L-697-661. The results indicate that the drugs were well tolerated, with no important pharmacokinetic interactions, when administered concomitantly for as long as 8 weeks. Although the number of study participants was small, we noted rapid emergence of resistance to L-697,661 among ZDV-naive study subjects who were administered L-697,661 as monotherapy but did not observe isolates of human immunodeficiency virus type 1 (HIV-1) resistant to L-697,661 among those who were administered concomitant ZDV. These results suggest a potential interaction between development of resistance to L-697,661 and ZDV. Although the clinical development of L-697,661 has been halted, our results support the need for further studies to test whether specific interactions among antiretroviral agents administered in combination and the molecular target can delay the emergence of isolates that exhibit resistance to all drugs in the regimen.

  View details for Web of Science ID A1996UY96500006

• Phase 1 study of combination therapy with L-697,661 and zidovudine. The ACTG 184 Protocol Team. Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association Schooley, R. T., Campbell, T. B., Kuritzkes, D. R., Blaschke, T., Stein, D. S., Rosandich, M. E., Phair, J., Pottage, J. C., Messari, F., Collier, A., Kahn, J. 1996; 12 (4): 363-370

  Abstract

  We performed a pilot study that examined the clinical and pharmacokinetic interactions between zidovudine (ZDV) and a pyridinone derivative, L-697-661. The results indicate that the drugs were well tolerated, with no important pharmacokinetic interactions, when administered concomitantly for as long as 8 weeks. Although the number of study participants was small, we noted rapid emergence of resistance to L-697,661 among ZDV-naive study subjects who were administered L-697,661 as monotherapy but did not observe isolates of human immunodeficiency virus type 1 (HIV-1) resistant to L-697,661 among those who were administered concomitant ZDV. These results suggest a potential interaction between development of resistance to L-697,661 and ZDV. Although the clinical development of L-697,661 has been halted, our results support the need for further studies to test whether specific interactions among antiretroviral agents administered in combination and the molecular target can delay the emergence of isolates that exhibit resistance to all drugs in the regimen.

  View details for PubMedID 8673545

• Do we need full compliance data for population pharmacokinetic analysis? JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS GIRARD, P., Sheiner, L. B., Kastrissios, H., Blaschke, T. F. 1996; 24 (3): 265-282

  Abstract

  For population pharmacokinetic analysis of multiple oral doses one of the key issues is knowing as precisely as possible the dose inputs in order to fit a model to the input-output (dose-concentration) relationship. Recently developed electronic monitoring devices, placed on pill containers, permit precise records to be obtained over months, of the time/date opening of the container. Such records are reported to be the most reliable measurement of drug taking behavior for ambulatory patients. To investigate strategies for using and summarizing this new abundant information, a Markov chain process model was developed, that simulates compliance data from real data from electronically monitored patients, and data simulations and analyses were conducted. Results indicate that traditional population pharmacokinetic analysis methods that ignore actual dosing information tend to estimate biased clearance and volume and markedly overestimate random interindividual variability. The best dosing information summarization strategies consist of initially estimating population pharmacokinetic parameters, using no covariates and only a limited number of dose records, the latter chosen based on an a priori estimate of the half-life of the drug in the compartment of interest; then resummarizing the dose records using either population or individual posterior Bayes parameter estimates from the first population fit; and finally reestimating the population parameters using the newly summarized dose records. Such summarization strategies yield the same parameter estimates as using full dosing information records while reducing by at least 75% the CPU time needed for a population pharmacokinetic analysis.

  View details for Web of Science ID A1996VX87100001

  View details for PubMedID 8970015

• Introducing medical students to medication noncompliance CLINICAL PHARMACOLOGY & THERAPEUTICS Kastrissios, H., FLOWERS, N. T., Blaschke, T. F. 1996; 59 (5): 577-582

  Abstract

  Medical students were introduced to issues relating to medication noncompliance in a simulated clinical setting. Compliance with either a twice-a-day or a three-times-a-day regimen was monitored with use of electronic monitoring devices for a 2-week interval. Compliance with the twice-a-day regimen was higher than compliance with the three-times-a-day regimen, although the difference was not significantly different. Overall, 71% of the prescribed doses were taken by the medical student participants; however, only 46.5% of the doses were taken at the prescribed dosing frequency and 28.5% were taken at the prescribed intervals. The majority of students linked dose taking with routine daily activities and reported that their hectic lifestyles adversely influenced compliance. Similar factors might be expected to influence compliance in patient populations. The goal of this exercise was to demonstrate to future physicians the difficulties that patients have with compliance to prescribed medications.

  View details for Web of Science ID A1996UN14900010

  View details for PubMedID 8646829

• The clinical pharmacokinetics of rifabutin Symposium on Rifabutin - The Research Continues Blaschke, T. F., Skinner, M. H. UNIV CHICAGO PRESS. 1996: S15–S21

  Abstract

  Rifabutin is structurally similar to rifampin, but there are important pharmacokinetic differences between the two drugs. Rifabutin is more lipid soluble than is rifampin, resulting in more-extensive tissue uptake, a larger volume of distribution, lower maximum plasma concentrations, lower trough concentrations, a longer terminal half-life, and higher tissue-to-plasma drug concentration ratios. The oral bioavailability of rifabutin is low. Like rifampin, rifabutin induces its own metabolism during multiple dosing. Rifabutin is extensively metabolized. The two major metabolites of rifabutin contribute to its antimicrobial activity. Rifabutin induces hepatic metabolism but is not as potent an inducer as is rifampin. Rifabutin does not affect the pharmacokinetics of antiretroviral drugs that are excreted in the urine. Although rifabutin decreases plasma concentrations of zidovudine, this finding does not appear to be clinically relevant. When administered during rifabutin prophylaxis, fluconazole decreases the incidence of Mycobacterium avium complex bacteremia. The coadministration of clarithromycin and rifabutin results in increased plasma concentrations of rifabutin and decreased plasma concentrations of clarithromycin; however, the plasma concentration of clarithromycin's active metabolite is increased.

  View details for Web of Science ID A1996UC13700004

  View details for PubMedID 8785251

• Improved combined solid-phase extraction-RIA method for quantifying zalcitabine in plasma CLINICAL CHEMISTRY Kastrissios, H., Nakano, M., Burton, P., Blaschke, T. 1996; 42 (3): 465-466

  View details for Web of Science ID A1996TY85500024

  View details for PubMedID 8598115

• H-1-HISTAMINE AND H-2-HISTAMINE RECEPTOR-MEDIATED VASODILATION VARIES WITH AGING IN HUMANS CLINICAL PHARMACOLOGY & THERAPEUTICS BEDARIDA, G., Bushell, E., Blaschke, T. F., Hoffman, B. B. 1995; 58 (1): 73-80

  Abstract

  Aging is associated with alterations in the responses to several important vasoactive drugs. We have investigated histamine-mediated venodilation across the adult age range using the human hand vein compliance technique. Histamine produces dilation in human veins by activating both H1- and H2-receptors.Full dose-response curves to histamine were constructed in 16 healthy volunteers (mean age, 47 +/- 20 years; age range, 21 to 80 years) by infusing histamine (2 to 136 ng/min) into dorsal hand veins preconstricted with the alpha-adrenergic selective agonist phenylephrine.Histamine was an efficacious venodilator across the age range; the average maximal response (Emax) was 122 +/- 45% and the geometric mean ED50 (the dose producing half-maximal response) was 16.6 ng/min for all subjects. Dose-response curves to histamine were repeated after infusion of the H2-selective antagonist cimetidine at a dose sufficient to completely block the H2-mediated response (49 micrograms/min). Cimetidine did not inhibit the Emax in the elderly as much as it did in the young subjects. The Emax to histamine in the presence of cimetidine plotted against age showed a significant relationship (r = 0.62, p = 0.02).These results suggest that, although the overall histamine-induced venodilation is conserved in aging, there is a loss of the signal transduction pathway activated by way of H2-receptors but no loss in function of H1-receptors. Consequently, these results suggest differential changes in function of H1- versus H2-histamine receptors with aging. Because H1-receptors are coupled to endothelial-derived relaxing factor release and because H2-receptors activate cyclic adenosine monophosphate in smooth muscle, the results are compatible with hypothesis that there are specific changes in these signal transduction pathways with aging.

  View details for Web of Science ID A1995RL59000009

  View details for PubMedID 7628185

• A MULTIMODALITY APPROACH TO PREPARATION FOR CLINICAL MEDICINE ACADEMIC MEDICINE Jacobs, C., Moreno, B., Blaschke, T. 1995; 70 (5): 441-442

  View details for Web of Science ID A1995QZ28000046

  View details for PubMedID 7748409

• A NEW PREPARATORY REGIMEN FOR AUTOLOGOUS BONE-MARROW TRANSPLANTATION FOR PATIENTS WITH LYMPHOMA CANCER Chao, N. J., Kastrissios, H., Long, G. D., Negrin, R. S., Horning, S. J., Wong, R. M., Blaschke, T. F., Blume, K. G. 1995; 75 (6): 1354-1359

  Abstract

  This trial studied the feasibility and efficacy of a new preparatory regimen for autologous bone marrow transplantation for patients with advanced lymphoid malignancies.Twenty-one patients with Hodgkin's disease (n = 12) and non-Hodgkin's lymphoma (n = 9) were treated in this study. Lomustine was substituted for carmustine) in a dose-escalation study with an initial dose of 6 mg/kg and increasing by 3 mg/kg in groups of four patients. The preparatory regimen consisted of lomustine (6-15 mg/kg) orally on Day -6, etoposide (60 mg/kg) intravenously (i.v.) on Day -4, and cyclophosphamide (100 mg/kg) i.v. on Day -2. Peripheral blood progenitor cells and/or bone marrow were infused on Day 0.Lomustine was well tolerated in all patients with no significant toxicity specific to this drug. Engraftment was prompt: the time to achieving greater than or equal to 500 granulocytes/microliters was 12 days (range, 9-16 days) and the time to achieving greater than or equal to 25,000 platelets/microliters without transfusion support was 16 days (range, 9-22 days). Five patients experienced interstitial pneumonitis, three of whom had active or recent interstitial pneumonitis before bone marrow transplantation, and one who just completed mantle irradiation. Three patients died from this preparatory regimen, one of progressive interstitial pneumonitis, one of Legionella pneumonia, and one of multiorgan failure. Three patients with non-Hodgkin's lymphoma relapsed. Fourteen patients are currently alive and disease free to date. The actuarial are currently alive and disease free to date. The actuarial disease free survival was 57%, with a median follow-up of 23 months (range, 1-48 months).The preparatory regimen consisting of lomustine/etoposide/cyclophosphamide is active in treating patients with lymphomas. Further trials with high doses of lomustine are warranted.

  View details for PubMedID 7882286

• CLINICAL PHARMACOKINETICS OF RIFABUTIN CLINICAL PHARMACOKINETICS Skinner, M. H., Blaschke, T. F. 1995; 28 (2): 115-125

  Abstract

  The clinical effectiveness of rifabutin for prophylaxis of disseminated Mycobacterium avium complex infection has recently been demonstrated in HIV-positive patients with low CD4 counts. Rifabutin is a newly marketed, semisynthetic antimycobacterial agent similar to rifampicin (rifampin) in structure and activity. However, rifabutin has important pharmacokinetic differences compared with rifampicin. Rifabutin has relatively low oral bioavailability; about 20% after single dose administration. With long term administration rifabutin induces its own metabolism and the metabolism of some other drugs. The elimination half-life of rifabutin is long (45 hours) but, as a result of a very large volume of distribution (> 9 L/kg), average plasma concentrations remain relatively low after repeated administration of standard doses. In vitro rifabutin is more active against M. avium-intracellulare complex and at least as active against M. tuberculosis as rifampicin. In vivo the advantage of rifabutin is less apparent due to its lower plasma concentrations at equivalent doses. Adverse effects are unusual at the recommended oral dosage of 300 mg/day, but become common as the total daily dose approaches 1 g. Dose-limiting toxicity consists of a polyarthralgia/arthritis syndrome, possibly complicated by uveitis. More clinical studies are needed to establish the role of rifabutin in combination therapy for M. avium-intracellulare complex and other mycobacterial infections.

  View details for Web of Science ID A1995QE55200003

  View details for PubMedID 7736687

• EFFECT OF AGING ON BETA(2)-ADRENERGIC RECEPTOR-STIMULATED FLUX OF K+, PO4, FFA, AND GLYCEROL IN HUMAN FOREARMS JOURNAL OF APPLIED PHYSIOLOGY Ford, G. A., Dachman, W. D., Blaschke, T. F., Hoffman, B. B. 1995; 78 (1): 172-178

  Abstract

  beta-Adrenergic responses have been shown to decline with aging, particularly in the cardiovascular system. We infused terbutaline, a selective beta 2-adrenoceptor agonist, into the brachial artery of 10 young (mean age 25 yr, range 22-31 yr) and 9 elderly (mean age 73 yr, range 68-81 yr) healthy subjects to examine its effects on nutrient flux. Forearm K+, PO4, free fatty acid (FFA), and glycerol uptake were determined by measurement of forearm blood flow (using dye dilution) and brachial arterial and deep venous plasma substrate concentrations. Elderly subjects were less sensitive to terbutaline-mediated increases in forearm blood flow, net fluxes of K+, and glycerol but not net fluxes of FFA or PO4. The mean fitted slopes of each parameter vs. the log of the terbutaline concentration, a measure of forearm beta-adrenergic sensitivity, for young and elderly groups were 4.9 +/- 1.7 (SD) vs. 2.4 +/- 2.3 for forearm blood flow (P < 0.05), 0.84 +/- 0.46 vs. 0.43 +/- 0.37 for K+ net flux (P < 0.05), -157 +/- 113 vs. -26 +/- 26 for glycerol net flux (P < 0.01), -336 +/- 429 vs. -44 +/- 457 for FFA net flux (P = 0.11), and 0.31 +/- 0.24 vs. 0.18 +/- 0.16 for PO4 net flux (P = 0.14). Terbutaline promoted net uptake of K+ into skeletal muscle less well in the elderly, although net PO4 flux was similar in the two groups. Terbutaline-stimulated vasodilation and net glycerol efflux but not FFA efflux were impaired with aging. These data demonstrate that heterogeneous changes in beta-adrenergic responses occur with aging.

  View details for Web of Science ID A1995QC30100025

  View details for PubMedID 7713808

• HISTAMINE-INDUCED VENODILATION IN HUMAN-BEINGS INVOLVES BOTH H-1 AND H-2-RECEPTOR SUBTYPES JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Dachman, W. D., BEDARIDA, G., Blaschke, T. F., Hoffman, B. B. 1994; 93 (3): 606-614

  Abstract

  Histamine is a potent vasodilatory substance released during anaphylaxis. The purpose of this study was to investigate the mechanism by which histamine produces venodilation in humans in vivo with the use of the dorsal hand-vein compliance technique. In healthy volunteers full dose-response curves were constructed by infusing histamine, before and after administration of an H1 or H2 antagonist or both antagonists, into dorsal hand veins preconstricted with the alpha-adrenergic agonist phenylephrine. In the presence of the H1 antagonist brompheniramine (530 ng/min), the maximal venodilatory response to histamine decreased from 128% +/- 57% to 78% +/- 15% (p < 0.05). In the presence of H2 antagonist cimetidine (49 micrograms/min), the maximal venodilatory response to histamine decreased from 120% +/- 33% to 48% +/- 26% (p < 0.01). Concurrent infusion of histamine with the combination of cimetidine and diphenhydramine resulted in almost complete abolishment of histamine-induced venodilation. Methylene blue (6.8 micrograms/min), an inhibitor of the action of endothelium-derived relaxing factor, decreased the vasodilatory response to histamine from 131% +/- 23% to 73% +/- 24% (p = 0.01). The results suggest that the venodilatory response of histamine is mediated through both H1 and H2 receptor subtypes and that this response is mediated in part by endothelium-derived relaxing factor.

  View details for Web of Science ID A1994ND14000007

  View details for PubMedID 8151062

• CHARACTERIZATION OF AN INHIBITOR OF NITRIC-OXIDE SYNTHASE IN HUMAN-HAND VEINS HORMONE AND METABOLIC RESEARCH Bedarida, G. V., Kim, D., BLASCHKE, I. F., Hoffman, B. B. 1994; 26 (2): 109-112

  Abstract

  The enzyme nitric oxide synthase mediates synthesis of nitric oxide (NO) from 1-arginine in endothelial cells. NO, also known as endothelium-dependent relaxing factor (EDRF), diffuses to smooth muscle cells where it leads to cGMP production and dilation. We characterized the potency, efficacy and time course of NG-monomethyl-l-arginine (l-NMMA) as an inhibitor of bradykinin-mediated, endothelium-dependent dilation using the human hand-vein compliance technique. We also compared the efficacy of l-NMMA with methylene blue, an inhibitor of guanylate cyclase, in blocking bradykinin-mediated vasodilation. l-NMMA potently inhibited bradykinin-induced venodilation with a log ED50 of 3.74 +/- 0.52 (geometric mean of 5.5 micrograms/min). Responses to bradykinin (0.27-555 ng/min) were tested in veins pre-constricted with the alpha-adrenergic agonist phenylephrine. l-NMMA (25 micrograms/min) decreased bradykinin's maximal venodilatory response from 90 +/- 22% to 39 +/- 15% (p < 0.05). Complete recovery of bradykinin venodilation was obtained within 155 minutes after stopping l-NMMA infusion, indicating that its effects were reversible. In another set of experiments we compared the efficacy of methylene blue to l-NMMA; methylene blue decreased bradykinin-mediated venodilatory response to 53 +/- 17%; when l-NMMA was added, the response was further decreased to 32 +/- 9% (p < 0.002). We conclude that l-NMMA is a very efficacious NO synthase inhibitor in human veins and it is likely functionally reversible.

  View details for Web of Science ID A1994MY29500008

  View details for PubMedID 7515369

• PERIPHERAL VASCULAR RESPONSIVENESS IN CIRRHOSIS Bedarida, G. V., Garcia, G., Blaschke, T. F., Hoffman, B. B. NATURE PUBLISHING GROUP. 1994: 186–86

  View details for Web of Science ID A1994MY42100252

• VENODILATION IN RAYNAUDS-DISEASE LANCET Bedarida, G. V., Kim, D., Blaschke, T. F., Hoffman, B. B. 1993; 342 (8885): 1451-1454

  Abstract

  The pathogenesis of Raynaud's disease is unclear; an enhanced response to catecholamines has been hypothesised to contribute to this vasospastic disorder. Impaired endothelium-dependent dilation occurs in other diseases associated with vasospasm, such as coronary atherosclerosis. We investigated both endothelium-dependent and endothelium-independent venodilatory function in Raynaud's disease using the hand-vein compliance technique. Full dose-response curves to noradrenaline were constructed in 10 subjects with primary Raynaud's disease and 10 age and sex matched control subjects. The two groups did not have a different response to noradrenaline. Mean (SD) log values of ED50s (the dose producing half maximum response) were 1.00 (0.59) (geometric mean 10 ng/min) in Raynaud's disease compared with 1.29 (0.66) (20 ng/min) in control subjects (p = 0.16). The efficacy of noradrenaline as a venoconstrictor was similar in the two groups: mean maximum dilation (Emax) to noradrenaline was 81 (14)% in the Raynaud's group and 89 (8)% in the control group (p = 0.08). Full dose-response curves to the endothelium-dependent dilator bradykinin were constructed. Emax to bradykinin was significantly lower in the Raynaud's group than in the control group (65 [21] vs 91 [29%], p = 0.02). ED50 values (doses producing half maximum response) for bradykinin were similar in the two groups. Maximum dilation with nitroprusside, a direct releaser of the vasodilator nitric oxide, was not diminished in the Raynaud's group (94 [23] vs 102 [15]% in controls, p = 0.26). These results suggest that endothelium-dependent venodilation is impaired in peripheral vessels in Raynaud's disease, possibly due to diminished release of nitric oxide, and may contribute to the pathogenesis of the disorder.

  View details for Web of Science ID A1993ML21700008

  View details for PubMedID 7902481

• RESPONSIVENESS TO BRADYKININ IN VEINS OF HYPERCHOLESTEROLEMIC HUMANS CIRCULATION Bedarida, G. V., Bushell, E., Haefeli, W. E., Blaschke, T. F., Hoffman, B. B. 1993; 88 (6): 2754-2761

  Abstract

  Hypercholesterolemia impairs endothelium-dependent dilation in arteries. We tested the hypothesis that hypercholesterolemia impairs endothelium-dependent vasodilation by an interaction between elevated plasma lipoproteins and a presumably normal endothelium using human veins in vivo; veins do not generally develop atherosclerosis and are appropriate for testing functional alterations.Full dose-response curves were constructed in 13 hypercholesterolemic and 12 normocholesterolemic subjects by infusing bradykinin (0.25 to 508 ng/min) into hand veins preconstricted with the alpha-adrenergic agonist phenylephrine. The maximal relaxation induced by bradykinin was 80 +/- 38% in the controls and 103 +/- 40% in subjects with hypercholesterolemia (P = .08). Responsiveness to bradykinin was also determined after infusion of indomethacin (5.4 micrograms/min), a cyclooxygenase inhibitor, to block the contribution of prostaglandins; maximal responsiveness was greater in hypercholesterolemic subjects (112 +/- 41%) than in controls (81 +/- 31%) (P = .03). Hypercholesterolemic subjects were more sensitive to bradykinin, with an ED50 of 4.2 ng/min versus 10.9 ng/min in controls (P = .05); a similarly increased sensitivity was found in the presence of indomethacin. The response to a maximally effective dose of nitroglycerin was greater in hypercholesterolemic subjects (142 +/- 31%) versus 106 +/- 28% in controls (P = .007). In five hypercholesterolemic subjects, treated with lovastatin to normalize serum cholesterol concentrations, maximal responsiveness to bradykinin decreased from 103 +/- 52% to 80 +/- 28%.These results demonstrate that hypercholesterolemia in humans does not impair endothelium-derived relaxing factor-mediated venodilation.

  View details for Web of Science ID A1993ML69900034

  View details for PubMedID 8252688

• ZIDOVUDINE RESPONSE RELATIONSHIPS IN EARLY HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION CLINICAL PHARMACOLOGY & THERAPEUTICS Sale, M., Sheiner, L. B., Volberding, P., Blaschke, T. F. 1993; 54 (5): 556-566

  Abstract

  To examine predictors of magnitude of CD4+ response to treatment of human immunodeficiency virus (HIV) infection with zidovudine.This was a post hoc analysis of randomized placebo-controlled clinical trial in a multicenter trial, 1423 asymptomatic HIV-positive subjects with CD4+ cell counts less than 500 mm-3 were given 500 mg/day zidovudine, 1500 mg/day zidovudine, or placebo. The main outcome measure was change in the CD4+ cell counts over time.This study suggests that earlier treatment with zidovudine results in a larger increment in the CD4+ cell count. In addition, the increment in CD4+ cell count is very long lived. However, drug exposure was not found to be a predictor of response to treatment in the dose range studied.A parametric model of disease progression can be estimated with use of data collected in a conventionally designed study. These parametric models may provide insight into the optimal use of drugs. This model suggests that zidovudine does not change the underlying course of HIV infection but simply delays the time course. The model also suggests that the magnitude of this delay is larger when treatment is begun earlier in the course of the disease.

  View details for Web of Science ID A1993MU53000011

  View details for PubMedID 7900949

• EFFECT OF AGING ON CHANGES IN PLASMA POTASSIUM DURING EXERCISE JOURNALS OF GERONTOLOGY Ford, G. A., Blaschke, T. F., Wiswell, R., Hoffman, B. B. 1993; 48 (4): M140-M145

  Abstract

  Exercising skeletal muscle releases large amounts of potassium into plasma. beta-adrenergic receptors enhance reuptake of potassium into muscle. Since beta-adrenergic responses decline with aging in many tissues, the elderly might be predisposed to hyperkalemia during exercise.Venous plasma potassium (K+) was measured during graded bicycle exercise (30 W initial workload with 3-minute 30 W increments) in 18 healthy young men (24.0 +/- 2.9 yrs; mean +/- SD), 18 healthy untrained elderly men (70.0 +/- 3.6 yrs), and 7 elderly master athletes (70.0 +/- 4.6 yrs). Subjects exercised to exhaustion.Exercise times and maximal oxygen uptake were: young (N = 14; 19.6 +/- 4.4 min, 42.1 +/- 3.8 ml/kg/min), elderly (N = 13; 11.7 +/- 1.9 min, 26.6 +/- 8.0 ml/kg/min), elderly master athletes (N = 6; 16.8 +/- 2.4 min, 40.2 +/- 10.2 ml/kg/min). The rate of increase in K+ was greater in both elderly (89 +/- 59 mumol/l/min) and elderly master athletes (88 +/- 26) compared with healthy young men (60 +/- 30), p < .05. Despite this greater rate of increase, the elderly group did not achieve higher maximal K+ concentrations than the young because of the much shorter duration of exercise in the elderly group. For subjects performing a maximal exercise test, the maximal increase in K+ was similar in the elderly (1.15 +/- 0.91), but significantly greater in elderly master athletes (1.70 +/- 0.31), compared with healthy young men (1.31 +/- 0.45).Changes in K+ during short-lasting exercise are similar in untrained healthy elderly men compared with healthy young men, but elderly master athletes have greater changes in K+ during exercise. The greater rate of increase in potassium in healthy and athletic subjects supports the hypothesis of an age-related impairment of the beta 2-adrenergic process that mediates potassium flux into skeletal muscle.

  View details for Web of Science ID A1993LL26100029

  View details for PubMedID 8315226

• GLUTATHIONE S-TRANSFERASE-MU POLYMORPHISM DOES NOT EXPLAIN VARIATION IN NITROGLYCERIN RESPONSIVENESS CLINICAL PHARMACOLOGY & THERAPEUTICS Haefeli, W. E., Srivastava, N., Kelsey, K. T., WIENCKE, J. K., Hoffman, B. B., Blaschke, T. F. 1993; 53 (4): 463-468

  Abstract

  To determine whether the considerable interindividual variability in nitroglycerin-induced venodilation in humans is related to the polymorphic expression of the mu class of glutathione S-transferase (GST mu). Recently vascular glutathione S-transferase (EC 2.5.1.18) of the mu-class (GST mu), a polymorphic group of enzymes present in only about 60% of the population, have been identified and shown in vitro to possess high metabolic activity toward nitroglycerin. Their clinical relevance is unknown.Dose-response relationships to nitroglycerin were constructed in vivo measuring changes in compliance of dorsal hand veins in 26 healthy volunteers during local infusion of small amounts of nitroglycerin. Polymerase chain reaction was applied to detect the deoxyribonucleic acid sequence that codes GST mu in whole blood samples.The GST mu isozyme was present in 15 subjects (58%) and deficient in 11 subjects. Values for mean maximum venodilation (Emax) and dose rates producing 50% of Emax (ED50) were not significantly different between the groups with or without GST mu. The respective values were 98% and 103% dilation for Emax and 9 and 16 ng/min for ED50. There was no gender difference in the venodilatory response to nitroglycerin.Subjects lacking GST mu can clearly respond normally to nitroglycerin, and the large interindividual variability in nitroglycerin potency is not related to the expression of this polymorphic enzyme. Intersubject variability is therefore more likely to be the result of differences in the presence or activity of other vascular enzymes or in steps further distal in the venodilatory cascade.

  View details for Web of Science ID A1993KY91100011

  View details for PubMedID 8477563

• PRIMUM-NON-NOCERE - VALUING OF THE RISK OF DRUG TOXICITY IN THERAPEUTIC DECISION-MAKING CLINICAL PHARMACOLOGY & THERAPEUTICS Lenert, L. A., Markowitz, D. R., Blaschke, T. F. 1993; 53 (3): 285-291

  View details for Web of Science ID A1993KU55300001

  View details for PubMedID 8453846

• MECHANISM OF BRADYKININ-INDUCED VENODILATION IN HUMANS JOURNAL OF CARDIOVASCULAR PHARMACOLOGY Dachman, W. D., Ford, G. A., Blaschke, T. F., Hoffman, B. B. 1993; 21 (2): 241-248

  Abstract

  Bradykinin, a nonapeptide, dilates vascular smooth muscle at least in part via endothelial cell-dependent mechanisms. The aim of this study was to examine the action of bradykinin in human veins in vivo. Utilizing the dorsal hand vein technique, dose-response curves to bradykinin (maximum dose = 513 ng/min) were constructed in veins preconstricted with the alpha-adrenergic agonist phenylephrine in healthy young volunteers. Bradykinin almost fully dilated the veins back to their baseline diameter. To determine if desensitization of bradykinin-mediated vasodilation occurs, two bradykinin dose-response curves were constructed with a short (10 min) interval between studies. The second dose-response curve showed a diminished response. The EMAX of the first curve was 97.8 +/- 47.4% dilation and the EMAX of the second curve was 64.3 +/- 28.0% dilation (p < 0.05). However, when the two curves were separated by 40 min, there was no loss of responsiveness. To investigate the mechanism by which bradykinin caused vasodilation, we used methylene blue to antagonize endothelium-derived relaxing factor, and indomethacin to block prostaglandin-dependent effects. Methylene blue partially antagonized the vasodilatory response to bradykinin, decreasing the EMAX by 50%. Indomethacin also partially antagonized the vasodilatory response, but to a lesser extent than did methylene blue. The vasodilatory response to bradykinin was not fully antagonized with concurrent infusion of both methylene blue and indomethacin. The mechanism of bradykinin-induced vasodilation involves both EDRF and prostacyclin, and possibly another, as yet unidentified, mediator as well.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1993KH73600009

  View details for PubMedID 7679158

• LACK OF ROLE OF ENDOTHELIUM-DERIVED RELAXING FACTOR IN EFFECTS OF ALPHA-ADRENERGIC AGONISTS IN CUTANEOUS VEINS IN HUMANS AMERICAN JOURNAL OF PHYSIOLOGY Haefeli, W. E., Srivastava, N., Kongpatanakul, S., Blaschke, T. F., Hoffman, B. B. 1993; 264 (2): H364-H369

  Abstract

  In some blood vessels, the alpha 2-adrenergic agonist clonidine simultaneously activates vasoconstrictive alpha-adrenoceptors on smooth muscle cells and endothelial alpha 2-adrenoceptors mediating release of endothelium-derived relaxing factor (EDRF), with the net vascular response representing a balance between these two counteracting pathways. To investigate whether clonidine's modest constrictor effect in human veins is due to simultaneous release of EDRF, the dorsal hand vein compliance technique was used to measure vascular responses in healthy volunteers. Clonidine-induced venoconstriction was not potentiated by methylene blue, an inhibitor of EDRF-mediated relaxation. After preconstriction with angiotensin II, clonidine did not cause venodilation but rather promoted further constriction, which could be reversed by the alpha 1-antagonist labetalol. However, in veins preconstricted with the full alpha 1-agonist phenylephrine, clonidine induced venodilation, suggesting that clonidine is a partial agonist at venous alpha 1-adrenoceptors. In conclusion, we found no evidence for endothelial alpha 2-adrenoceptor-mediated release of EDRF in human hand veins. The results further suggest that postjunctional alpha 1-adrenoceptors participate in clonidine-induced venoconstriction in humans.

  View details for Web of Science ID A1993KN68100011

  View details for PubMedID 8095374

• EVIDENCE FOR ACTIVATION OF THE SYMPATHETIC NERVOUS-SYSTEM BY RECOMBINANT HUMAN INTERLEUKIN-1-BETA IN HUMANS JOURNAL OF IMMUNOTHERAPY Haefeli, W. E., Bargetzi, M. J., STARNES, H. F., Blaschke, T. F., Hoffman, B. B. 1993; 13 (2): 136-140

  Abstract

  Administration of interleukin-1 beta (IL-1 beta) to humans initiates a cascade of metabolic, hematologic, and cardiovascular events. To investigate the role of the sympathetic nervous system in the early cardiovascular response to IL-1 beta in humans, we recorded the heart rate, blood pressure, and changes in hand vein compliance in five patients with malignant melanoma treated with a 30-min infusion of 10,000-20,000 U/kg of human recombinant IL-1 beta. All patients developed fever, chills, and marked hemodynamic changes. During or shortly after the infusion, a dramatic decrease in hand vein compliance occurred (vasoconstriction). At the time of maximum venoconstriction (35 min after the start of the IL-1 beta infusion), the mean heart rate and systolic blood pressure were significantly increased by 30 mm Hg and 31 beats/min, respectively. Venoconstriction always preceded the onset of chills by several minutes (mean of 7 min), was closely correlated with the heart rate, and could be reversed by local administration of the alpha-antagonist phentolamine, indicating involvement of catecholamines. Our study shows that cardiovascular responses that occur early after IL-1 beta administration in humans are most likely the result of adrenergic stimulation possibly through its effect on the central nervous system.

  View details for Web of Science ID A1993KJ60300009

  View details for PubMedID 8318499

• PHARMACOKINETICS OF ZIDOVUDINE ALONE AND IN COMBINATION WITH OXAZEPAM IN THE HIV INFECTED PATIENT JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY Mole, L., Israelski, D., BUBP, J., OHANLEY, P., Merigan, T., Blaschke, T. 1993; 6 (1): 56-60

  Abstract

  This three-phase study was designed to determine if a pharmacokinetic drug-drug interaction exists between zidovudine and oxazepam. Six individuals infected with human immunodeficiency virus (HIV) and receiving zidovudine at 500 mg daily, with normal renal and hepatic function, were enrolled. During phase I, zidovudine pharmacokinetics were studied after steady-state oral administration (100 mg every 4 h) and after a single dose (70 mg) of intravenous zidovudine. Phase II consisted of a single oral dose (30 mg) of oxazepam followed by a 48-h blood sampling period. Phase III began with 48 h of concomitant zidovudine, 100 mg orally every 4 h, and oxazepam, 15 mg orally every 8 h, followed by concomitant dosing of intravenous zidovudine and oral oxazepam. Zidovudine concentrations were determined by radioimmunoassay. Oxazepam concentrations were determined with use of a fluorescence polarization immunoassay. The calculated bioavailability was 0.61 for zidovudine alone and 0.75 when administered in combination with oxazepam (p = 0.16). Plasma half-life for oral zidovudine alone and in combination with oxazepam was 1.17 h versus 0.99 h, respectively (p = 0.25), and 1.38 h versus 1.15 h (p = 0.38) for intravenous zidovudine during single and combination therapy, respectively. Total body clearance of zidovudine was not significantly altered by oxazepam (93 L/h vs. 109 L/h, p = 0.16). The mean pharmacokinetic parameters determined for a single 30-mg dose of oxazepam for oral clearance, apparent volume of distribution, and plasma half-life were 9.8 L/h, 65.7 L, and 5.1 h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1993KE09500008

  View details for PubMedID 8417175

• COMPARISON OF VASODILATORY RESPONSES TO NITROGLYCERIN AND ITS DINITRATE METABOLITES IN HUMAN VEINS CLINICAL PHARMACOLOGY & THERAPEUTICS Haefeli, W. E., Gumbleton, M., Benet, L. Z., Hoffman, B. B., Blaschke, T. F. 1992; 52 (6): 590-596

  Abstract

  Independent of the route of nitroglycerin administration, substantial amounts of 1,2-glyceryl dinitrate (1,2-GDN) and 1,3-glyceryl dinitrate (1,3-GDN) metabolites accumulate in humans. Thus far their pharmacologic activity in comparison to nitroglycerin in humans is unknown. To compare the venodilatory potency of nitroglycerin and of 1,2-GDN and 1,3-GDN in vivo, cumulative dose-response curves were established in nine healthy volunteers by use of the dorsal hand vein compliance technique. Separated by a washout period, two of the three venodilators were infused in randomized order after preconstriction with phenylephrine. Values for maximum vasodilation were similar for all compounds: nitroglycerin, 109%; 1,2-GDN, 100%; and 1,3-GDN, 106%. The respective values for the dose rate exerting 50% of maximum vasodilation were 5.1, 43, and 60 ng/min, indicating that the dinitrates were about 10 times less potent than nitroglycerin (p < 0.001) but not significantly different from each other. The findings support the hypothesis that activity of nitroglycerin metabolites is related to the number of nitrate groups in the molecule and are in agreement with lower dinitrate potencies found in animal experiments.

  View details for Web of Science ID A1992KD48100003

  View details for PubMedID 1458768

• PHARMACOLOGICAL TOLERANCE TO ALPHA-1-ADRENERGIC RECEPTOR ANTAGONISM MEDIATED BY TERAZOSIN IN HUMANS JOURNAL OF CLINICAL INVESTIGATION VINCENT, J., Dachman, W., Blaschke, T. F., Hoffman, B. B. 1992; 90 (5): 1763-1768

  Abstract

  Chronic administration of alpha 1-receptor antagonists is associated with loss of clinical efficacy, especially in congestive heart failure, although the mechanism is uncertain. To evaluate changes in venous alpha 1-adrenoceptor responsiveness during chronic alpha 1-adrenoceptor blockade, dose-response curves to phenylephrine and angiotensin II were constructed in 10 healthy subjects before, during, and after administration of terazosin 1 mg orally for 28 d. Terazosin initially shifted the dose-response curve of phenylephrine to the right, with a significant increase in ED50 for phenylephrine from a control value of 102 to 759 ng/min on day 1 of terazosin (P < 0.001). However, by day 28, the dose-response curve had shifted back towards baseline with an ED50 of 112 ng/min. After discontinuing terazosin, the ED50 for phenylephrine remained near the baseline value, indicating no evidence of supersensitivity to phenylephrine. There was no change in responsiveness to angiotensin II during the course of treatment with terazosin. Plasma terazosin concentrations were stable throughout the period of drug administration. The mean Kd of terazosin was estimated as 11 +/- 15 nM in the first few days of treatment. This study demonstrates that pharmacological tolerance to the alpha 1-adrenoceptor blocking action of terazosin occurs in man and may be responsible for loss in efficacy with chronic therapy.

  View details for Web of Science ID A1992JZ47500017

  View details for PubMedID 1358918

• BRADYKININ-INDUCED VENODILATION IS NOT IMPAIRED WITH AGING IN HUMANS JOURNALS OF GERONTOLOGY Dachman, W. D., Ford, G. A., Hoffman, B. B., Blaschke, T. F. 1992; 47 (5): M166-M170

  Abstract

  The aim of this study was to determine whether there is an age-related decline in vascular responsiveness to bradykinin, whose vasodilatory action is mediated chiefly through endothelium-derived relaxing factor (EDRF). Dose-response curves for bradykinin were constructed using the dorsal hand vein compliance technique in veins preconstricted with phenylephrine in 27 volunteers (16 male, 11 female) aged 18 to 81 years. At the end of the bradykinin study, 12 subjects had a single infusion of a high dose of isoproterenol. There was no correlation between age and the EMAX or the log ED50 for bradykinin, although the same subjects showed a correlation between age and EMAX for isoproterenol, as previously found. There was no significant difference in either the EMAX or the log ED50 between male and female subjects. The results suggest that bradykinin-induced vasodilation is independent of age or gender.

  View details for Web of Science ID A1992JM62400016

  View details for PubMedID 1512432

• ANALYSIS OF FREE INTRACELLULAR NUCLEOTIDES USING HIGH-PERFORMANCE CAPILLARY ELECTROPHORESIS ANALYTICAL CHEMISTRY Ng, M., Blaschke, T. F., Arias, A. A., Zare, R. N. 1992; 64 (15): 1682-1684

  Abstract

  High-performance capillary electrophoresis (HPCE) with UV absorbance detection (254 nm) has been applied for analyzing intracellular free ribonucleotides. The nucleotide profiles obtained from peripheral blood lymphocytes differ from those obtained from Molt4 human leukemic cells. With a 140 mM borate buffer, pH 9.4, a nearly complete profile can be obtained in 25 min. HPCE has comparable resolution to that of high-performance liquid chromatography (HPLC) but is faster in terms of time per sample run (25 min vs 45 min) and requires much less sample (nanoliter range for HPCE vs microliter range for HPLC).

  View details for Web of Science ID A1992JF82700011

  View details for PubMedID 1443617

• PRACTICAL COMPUTER-ASSISTED DOSING FOR AMINOGLYCOSIDE ANTIBIOTICS ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Lenert, L. A., Klostermann, H., Coleman, R. W., Lurie, J., Blaschke, T. F. 1992; 36 (6): 1230-1235

  Abstract

  In principle, computer-assisted individualization of antibiotic dosing offers the prospect of better patient outcomes through improved dosing precision. In practice, however, the expertise in pharmacokinetics required to operate these programs has precluded their use by most physicians and pharmacists. We developed a computer program for individualization of dosing of aminoglycoside antibiotics under conditions in which access to experts in pharmacokinetics is impractical. The program is accurate, yet it requires less effort for data collection than previous drug dosing programs did. The program generates advice on a broad spectrum of topics, including dose adjustment, interpretation of measured drug concentrations in blood, and recommendations for monitoring drug concentrations. We tested its performance by prospectively comparing it with a clinical pharmacokinetic consultation service in a series of 78 consecutive patients. There were no differences in accuracy or bias in the prediction of drug concentrations. The rate of agreement between the program's dosing recommendations and those of the consultation service was 67 percent. This rate of agreement is typical of interexpert variation. In a stratified set of 24 of the 41 instances with significant disagreement regarding the recommended dose, experts ranked the program's recommendations as highly as those of the consultation service (95% confidence interval for difference in rank, -0.30 less than chi less than 0.47). The results suggest that expert systems can be coupled with pharmacokinetic dosing programs to deliver high-quality clinical recommendations for administration of antimicrobial agents.

  View details for Web of Science ID A1992HY42900012

  View details for PubMedID 1416822

• INHIBITION OF DEBRISOQUIN CLEARANCE IN PERFUSED RAT LIVERS AND INHIBITION OF DEXTROMETHORPHAN METABOLISM IN HUMAN LIVER-MICROSOMES BY 4-HYDROXYDEBRISOQUIN OR OTHER METABOLITES OF DEBRISOQUIN DRUG METABOLISM AND DISPOSITION Jaruratanasirikul, S., Cooper, A. D., Blaschke, T. F. 1992; 20 (3): 379-382

  Abstract

  Debrisoquin undergoes oxidative metabolism to 4-hydroxydebrisoquin, catalyzed by cytochrome CYP2D1 in rats and CYP2D6 in humans. Cytochrome CYP2D6 also plays a major role in dextromethorphan O-demethylation. In preliminary studies in perfused Lewis rat livers, we observed a difference in repeat clearance experiments using debrisoquin, but not dextromethorphan. To determine whether this change in clearance with time was due to the accumulation of 4-hydroxydebrisoquin, we sequentially used a recirculating and nonrecirculating perfusion system in the same liver perfusion experiment. We also studied the kinetics of dextromethorphan O-demethylation in microsomes prepared from human and rat livers in the presence and absence of 4-hydroxydebrisoquin. Results from the perfused rat liver experiments showed a drop in clearance from 3.27 +/- 0.57 ml/min (clearance 1) to 1.61 +/- 0.27 ml/min (clearance 2) (p less than 0.05 vs. clearance 1) during recirculation, but clearance returned to 3.21 +/- 0.46 ml/min (clearance 3, no significance vs. clearance 1) after a 30-min period of liver perfusion using a nonrecirculating system. There was significant accumulation of 4-hydroxydebrisoquin in the liver perfusate during recirculation, and concentrations fell when the nonrecirculating system was used. In microsomal studies, 4-hydroxydebrisoquin competitively inhibited dextromethorphan metabolism in human microsomes was 600 microM. These data suggest that: (a) 4-hydroxydebrisoquin and/or other metabolites of debrisoquin have an inhibitory effect on CYP2D1 and CYP2D6; (b) the active site of human CYP2D6 has different substrate specificity than the rat isozyme (CYP2D1) and/or that the pathways of metabolism of dextromethorphan are different in the Lewis rat and not primarily dependent on the activity of CYP2D1.

  View details for Web of Science ID A1992HV76000007

  View details for PubMedID 1355711

• ATENOLOL COMPARED WITH NIFEDIPINE - EFFECT ON COGNITIVE FUNCTION AND MOOD IN ELDERLY HYPERTENSIVE PATIENTS ANNALS OF INTERNAL MEDICINE Skinner, M. H., FUTTERMAN, A., Morrissette, D., Thompson, L. W., Hoffman, B. B., Blaschke, T. F. 1992; 116 (8): 615-623

  Abstract

  To compare the effects of atenolol and nifedipine on mood and cognitive function in elderly hypertensive patients.Randomized, double-blind, crossover trial.Thirty-one elderly volunteers (7 women and 4 men) 60 to 81 years of age with mild to moderate hypertension were recruited from the general community and a Veterans Affairs hospital hypertension clinic. Six volunteers withdrew at early phases of the study for reasons unrelated to adverse drug effects.Participants had 2 weeks of placebo, to 6 weeks of titration with atenolol or nifedipine, and weeks of treatment followed by similar periods with the other drug.Psychometric tests designed to assess mood and cognitive function.In the group first treated with nifedipine, the summed recall score on the Buschke selective reminding test (a test of verbal learning and memory) decreased by 9.3 words (95% CI, 2.8 to 15.6 words), or 0%, during nifedipine treatment compared with placebo (P = 0.031). The group first treated with atenolol showed no improvement in summed recall scores when results seen during atenolol therapy and placebo administration were compared (P = 0.10); however, this group had an improvement of 16.1 words (CI, 5.6 to 26.5 words), or of 16%, when the atenolol score was compared with the nifedipine score (P = 0.026). In the group first treated with nifedipine, 6 of 11 patients 55%) showed a decrease of 5 words or more during nifedipine therapy compared with placebo, whereas only 1 of the 14 patients (7%) in the group first treated with atenolol showed a similar decrease (P less than 0.01). On the digit symbol test (a psychomotor test), patients treated first with atenolol tended to improve, whereas patients treated first with nifedipine tended to decline. The difference between nifedipine and atenolol, in terms of the change from the score seen during placebo, was 4.3 codings (CI, 0.7 to 7.9 codings) or 10% (P = 0.043). No statistically significant differences were seen between nifedipine and atenolol therapy regarding the other measures of psychomotor ability, sustained attention, motor performance, verbal fluency, or abstract reasoning, and no effects of either drug on mood or psychopathologic symptoms were noted.Although atenolol and nifedipine are generally free of gross effects on cognition or mood, nifedipine may subtly impair learning and memory in some elderly hypertensive patients.

  View details for Web of Science ID A1992HN84400002

  View details for PubMedID 1546860

• DESENSITIZATION OF BETA-ADRENOCEPTOR-MEDIATED AND PROSTAGLANDIN-E1 RECEPTOR-MEDIATED HUMAN VASCULAR SMOOTH-MUSCLE RELAXATION JOURNAL OF CARDIOVASCULAR PHARMACOLOGY VINCENT, J., Blaschke, T. F., Hoffman, B. B. 1992; 19 (3): 447-452

  Abstract

  Regulation of beta-adrenoceptors in animal tissues and human cell cultures has been extensively described; on the other hand, relatively little is known about regulation of beta-adrenoceptors in human tissues in vivo. Both beta-adrenoceptors and the prostaglandin E1 (PGE1) receptors stimulate vasodilation. We wondered if prolonged infusion of isoproterenol or PGE1 would cause desensitization of smooth muscle relaxation and used the dorsal hand-vein compliance technique to investigate this question. After constructing a dose-response curve to either the beta-agonist isoproterenol or to PGE1 in a phenylephrine preconstricted vein, isoproterenol (271 ng/min), PGE1 (956 pg/min), or saline was infused for 4 h in separate experiments. There was no change in the ED50 or Emax for either isoproterenol or PGE1 after saline infusion. After a 4-h infusion of isoproterenol, the maximal vasodilator response to isoproterenol was significantly (p less than 0.01) attenuated from 61 +/- 33% to 19 +/- 10%, while the ED50 significantly increased (p less than 0.01) from a geometric mean of 37 to 197 ng/min. After infusion of isoproterenol, the mean maximum PGE1-induced venorelaxation of 129 +/- 29% was modestly but significantly (p less than 0.05) blunted to 96 +/- 35%, while the ED50 of PGE1 increased significantly (p less than 0.01) from a geometric mean of 81 to 398 pg/min. A 4-h infusion of PGE1 significantly (p less than 0.01) attenuated the maximum response to PGE1 from 73 +/- 35 to 28 +/- 16%. The maximal vasodilatory response to isoproterenol was also significantly blunted (p less than 0.05) from 62 +/- 35 to 42 +/- 41%, with no change in ED50.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1992HE96000023

  View details for PubMedID 1378128

• RESPONSIVENESS OF SUPERFICIAL HAND VEINS TO ALPHA-ADRENOCEPTOR AGONISTS IN INSULIN-DEPENDENT DIABETIC-PATIENTS CLINICAL SCIENCE Eichler, H. G., Blaschke, T. F., Kraemer, F. B., Ford, G. A., BLOCHLDAUM, B., Hoffman, B. B. 1992; 82 (2): 163-168

  Abstract

  1. Diabetic autonomic neuropathy causes loss of sympathetic cardiovascular control and is associated with increased vascular sensitivity to catecholamines. Supersensitivity to catecholamines could be due to either a postsynaptic increase in vascular sensitivity or to decreased catecholamine uptake into peripheral sympathetic nerve endings. 2. To differentiate between these possible mechanisms we have measured the responsiveness in vivo to noradrenaline and phenylephrine with local infusions into peripheral veins of diabetic patients with and without symptomatic autonomic neuropathy and of healthy control subjects. The dorsal hand vein compliance technique was used. 3. Symptomatic diabetic patients required significantly lower doses of noradrenaline for half-maximal venoconstriction (ED50) (geometric mean 2.14 ng/min) than control subjects (geometric mean 6.61 ng/min, P = 0.032), but there was no difference in the results from the phenylephrine dose-response curves between the groups. There were no differences in venous responsiveness to noradrenaline or phenylephrine between the asymptomatic diabetic group and the control group. However, in the asymptomatic diabetic group, postural blood pressure change (an index of loss of sympathetic control) was correlated with the ED50 for noradrenaline (r = 0.74, P = 0.014), but not with the ED50 for phenylephrine. In the control group the ED50 values for noradrenaline and phenylephrine were correlated with each other (r = 0.81, P = 0.0005). 4. Both vasopressor drugs act on vascular alpha-adrenoceptors, but only noradrenaline is taken up into peripheral sympathetic nerve endings. Our results suggest that, in diabetic patients, vascular supersensitivity to catecholamines is primarily determined by decreased neuronal catecholamine uptake. A postsynaptic increase in vascular alpha-adrenoceptor stimulation does not appear to be prominent in diabetic autonomic neuropathy.

  View details for Web of Science ID A1992HD88500007

  View details for PubMedID 1347259

• BRADYKININ-INDUCED VENODILATION IS NOT IMPAIRED WITH AGING IN HUMANS Dachman, W. D., Ford, G. A., Hoffman, B. B., Blaschke, T. F. NATURE PUBLISHING GROUP. 1992: 175–75

  View details for Web of Science ID A1992HE70300217

• ADVANCED COMPUTER-PROGRAMS FOR DRUG DOSING THAT COMBINE PHARMACOKINETIC AND SYMBOLIC MODELING OF PATIENTS COMPUTERS AND BIOMEDICAL RESEARCH Lenert, L. A., Lurie, J., Sheiner, L. B., Coleman, R., Klostermann, H., Blaschke, T. F. 1992; 25 (1): 29-42

  Abstract

  In this paper, we describe our design for advanced drug dosing programs that "reason" using a combination of Bayesian pharmacokinetic modeling and symbolic modeling of patient status and drug response. Our design is similar to the design of the Digitalis Therapy Advisor program, but extends this previous work by incorporating a Bayesian pharmacokinetic model, performing a "meta-level" analysis of drug concentrations to identify sampling errors and changes in pharmacokinetics, and including the results of this analysis in reasoning for dosing and therapeutic monitoring recommendations. The design has been implemented in a program for aminoglycoside antibiotics called Aminoglycoside Therapy Manager. The program is user-friendly and runs on low-cost general-purpose hardware. The initial validation study showed that the program was as accurate in predicting future drug concentrations as an expert using commercial Bayesian forecasting software and that its dosing recommendations were similar to those of an expert.

  View details for Web of Science ID A1992HC03200003

  View details for PubMedID 1547625

• POTENTIAL OF POPULATION PHARMACOKINETICS TO REDUCE THE FREQUENCY OF BLOOD-SAMPLING REQUIRED FOR ESTIMATING KINETIC-PARAMETERS IN NEONATES DEVELOPMENTAL PHARMACOLOGY AND THERAPEUTICS COLLART, L., Blaschke, T. F., Boucher, F., Prober, C. G. 1992; 18 (1-2): 71-80

  Abstract

  Data obtained from neonates receiving zidovudine as part of a phase I study were used to estimate the population pharmacokinetic parameters of this drug and to determine the minimum number of data points necessary to provide accurate estimates of the kinetic parameters and their variability. Analysis was performed with 541 concentrations of zidovudine, obtained from 32 infants and with a variety of reduced data sets using NONMEM (nonlinear mixed effect model). The reduced data sets were derived by randomly reducing the number of sampling time points per dosing interval and/or by randomly reducing the number of available subjects. We determined that accurate estimates of pharmacokinetic parameters and their variability were obtained with the inclusion of all 32 patients using only two concentration-time points per dose interval, provided that one of the points was obtained during the first 2 h after administration of the drug. The parameters themselves were adequately estimated with only 24 subjects and two concentration-time points per dose interval. We suggest that NONMEM should be used in addition to the traditional pharmacokinetic analysis to obtain more precise information directly in the population of interest with a minimum of blood sampling from each patient. This is especially critical in infants whose blood volumes are limited.

  View details for Web of Science ID A1992KE42500010

  View details for PubMedID 1483365

• ACCELERATED IMPROVEMENT OF ALCOHOLIC LIVER-DISEASE WITH ENTERAL NUTRITION GASTROENTEROLOGY Kearns, P. J., Young, H., Garcia, G., Blaschke, T., OHANLON, G., Rinki, M., Sucher, K., Gregory, P. 1992; 102 (1): 200-205

  Abstract

  This prospective study compared the effects of tube-fed nutrition with those of a regular diet in alcoholic liver disease. The high prevalence of malnutrition in patients with alcoholic liver disease requires clarification of the benefits of aggressive nutritional support. Patients were randomly assigned a regular diet without or with tube-fed supplementation, delivering 1.5 g/kg protein and 167 kJ/kg daily. Comparisons of encephalopathy, antipyrine clearance, metabolic rate, and biochemical parameters were performed weekly for 4 weeks. Sixteen patients receiving enteral supplementation had antipyrine half-life (50% vs. 3% reduction), serum bilirubin (25% vs. 0% reduction), and median encephalopathy scores that improved more rapidly than those of controls. Initially, 15 controls did not consume adequate calories to meet measured resting energy expenditure. Aggressive nutritional intervention accelerated improvement in alcoholic liver disease. Adverse effects did not offset the demonstrated benefits of a 2-cal/mL, casein-based tube-fed supplement. These findings support the use of standard, casein-based solutions in the treatment of alcoholic liver disease and as the control condition for future studies.

  View details for Web of Science ID A1992GX35500027

  View details for PubMedID 1727754

• VASCULAR REACTIVITY TO PHENYLEPHRINE AND ANGIOTENSIN-II - COMPARISON OF DIRECT VENOUS AND SYSTEMIC VASCULAR-RESPONSES CLINICAL PHARMACOLOGY & THERAPEUTICS VINCENT, J., Blaschke, T. F., Hoffman, B. B. 1992; 51 (1): 68-75

  Abstract

  The objective of this study was to determine the relationship between peripheral venous responsiveness (use of the dorsal hand vein compliance technique) and systemic vascular responsiveness (measurement of blood pressure changes) to phenylephrine and angiotensin II in humans. There was a significant correlation (r = 0.70, p less than 0.02) between the dose causing a 20 mm increase in mean arterial pressure and the dose producing half-maximal response in the hand vein (log ED50) for phenylephrine but not for angiotensin II. There was no correlation between the systemic responses to angiotensin II and phenylephrine, but there was a significant correlation (r = 0.70, p less than 0.02) between the log ED50 measurements for phenylephrine and angiotensin II in the hand vein experiments. These findings suggest that systemic and hand vein responsiveness to phenylephrine are similar. Consequently, in evaluating alpha-adrenergic receptor mediated responses, the dorsal hand vein compliance approach offers a satisfactory alternative to the use of systemic hemodynamic changes.

  View details for Web of Science ID A1992HA81700009

  View details for PubMedID 1732078

• DESENSITIZATION OF NITRATE-INDUCED VENODILATION - REVERSAL WITH ORAL N-ACETYLCYSTEINE IN HUMANS JOURNAL OF CARDIOVASCULAR PHARMACOLOGY VINCENT, J., Kongpatanakul, S., Blaschke, T. F., Hoffman, B. B. 1992; 20 (6): 907-912

  Abstract

  The objective of this study was to determine whether the dorsal hand vein could be used as a model to study tolerance to oral nitrates, and whether oral N-acetylcysteine (NAC) could reverse tolerance if present. Dose-response curves to nitroglycerin were constructed for 11 normotensive volunteers before and during treatment with a sustained-release formulation of isosorbide dinitrate, 80 mg, three times daily for 7 days and followed by concurrent treatment with NAC at a mean dose of 150 mg/kg/day, in divided doses, for 2 days. In separate studies, dose-response curves were constructed for seven normotensive volunteers before and after treatment with oral NAC at the same dose for 2 days. Nitroglycerin's Emax was significantly attenuated from 115 +/- 36 to 77 +/- 22% after treatment with isosorbide dinitrate alone (p < 0.009). Concurrent treatment with NAC reversed this decrease, as nitroglycerin's Emax of 108 +/- 26% during coadministration of isosorbide dinitrate and NAC was not different from its Emax in the control period. There was also no difference in the dose of phenylephrine required to cause 80% of maximal venoconstriction throughout the study. These studies demonstrate that smooth muscle tolerance to nitrates can be demonstrated in medium-sized veins in humans. In addition, high-dose oral NAC can reverse existing tolerance to oral nitrates in human veins. These results indicate that the dorsal hand vein compliance technique is a good model for the clinical investigation of tolerance to nitrates in humans.

  View details for Web of Science ID A1992KC72200010

  View details for PubMedID 1282593

• AGE-RELATED-CHANGES IN ADENOSINE AND BETA-ADRENOCEPTOR RESPONSIVENESS OF VASCULAR SMOOTH-MUSCLE IN MAN BRITISH JOURNAL OF CLINICAL PHARMACOLOGY Ford, G. A., Hoffman, B. B., Vestal, R. E., Blaschke, T. F. 1992; 33 (1): 83-87

  Abstract

  1. Ageing is associated with a decline in beta-adrenergic responsiveness in several tissues. Reduced beta-adrenoceptor mediated smooth muscle relaxation in aged man has been demonstrated using the dorsal hand vein technique. Isoprenaline and adenosine activate adenylate cyclase through separate membrane bound receptors to induce vasodilatation. 2. To determine the specificity of reduced beta-adrenergic responsiveness in smooth muscle of aged man, and possible sites of the defect responsible, venodilatory responses to isoprenaline, a beta-adrenoceptor agonist and adenosine were determined in nine young (age 26 +/- 3 years: mean +/- s.d.) and eight elderly (age 70 +/- 5 years), healthy male volunteers. Veins were partially constricted with the alpha 1-adrenoceptor agonist phenylephrine and increasing doses of adenosine (5 to 1220 micrograms min-1) or isoprenaline (271 ng min-1) were infused. 3. Maximal dilatation induced by isoprenaline was 83 +/- 26% in the young and 51 +/- 34% in the elderly, P = 0.02. Maximal dilatation induced at the highest dose of adenosine (1220 micrograms min-1) was similar in young and elderly: 79 +/- 25% vs 88 +/- 28%, P = 0.26. 4. Adenosine venodilatation was measured before and after infusions of theophylline (6.8 to 135 micrograms min-1) for 30 min in six subjects. Adenosine responsiveness was unchanged following theophylline: 48 +/- 16% to 49 +/- 40%, P = 0.44. 5. The results suggest that the age-associated reduced responsiveness of the beta-adrenergic system in human vascular smooth muscle is not shared by venodilatation mediated by adenosine.

  View details for Web of Science ID A1992GZ12700013

  View details for PubMedID 1311596

• BETA-ADRENERGICALLY MEDIATED CARDIAC CHRONOTROPIC AND VASCULAR SMOOTH-MUSCLE RESPONSES DURING PROPRANOLOL THERAPY AND WITHDRAWAL IN YOUNG AND ELDERLY PERSONS JOURNALS OF GERONTOLOGY Ford, G. A., Hoffman, B. B., Blaschke, T. F. 1992; 47 (1): M22-M26

  Abstract

  Aging is associated with diminished beta-adrenergic responsiveness in a variety of tissues. Desensitization of tissues secondary to the age-associated increase in sympathetic nervous system activity has been proposed as a potential explanation for diminished beta-adrenergic responsiveness. If this hypothesis is correct, then beta-blockade in older people might be expected to reverse the blunted beta-adrenergic responses of tissues having diminished responsiveness. Cardiac chronotropic responses to bolus isoproterenol (ISO) doses and ISO-induced venous smooth muscle dilatation in superficial hand veins were examined in 8 young (26.2 +/- 2.6 yrs) and 9 elderly (68.0 +/- 2.2 yrs) healthy subjects before, during, and 3 and 7 days following 2 weeks of treatment with propranolol. Baseline cardiac chronotropic responsiveness, CD25, was 1.55 +/- 0.77 mcg in the young and 5.97 +/- 2.77 mcg in the elderly subjects (p less than .01), increasing to 84 +/- 56 mcg and 194 +/- 172 mcg during treatment with propranolol. At 3 and 7 days following withdrawal of propranolol, CD25s were respectively 1.24 +/- 0.79 (p = .14) and 1.10 +/- 0.42 (p = .04) in the young and 5.63 +/- 2.34 (p = .31) and 4.85 +/- 2.37 (p = .05) in the elderly subjects. In contrast, there was no decrease in the ED50 or increase in Emax for ISO-induced venodilation of hand veins following propranolol withdrawal. These results demonstrate that both young and elderly subjects have similar increases in cardiac chronotropic responsiveness following discontinuation of beta-blockade and do not support the concept that desensitization is responsible for the diminished beta-adrenergic responsiveness seen with aging.

  View details for Web of Science ID A1992GY68000014

  View details for PubMedID 1730849

• PHENOBARBITAL DOES NOT INCREASE EARLY LABELING OF BILIRUBIN FROM 4-[C-14]-DELTA-AMINOLEVULINIC ACID IN MAN AND RAT HEPATOLOGY Okuda, H., TAVOLONI, N., Blaschke, T. F., Kiang, C. L., JONES, M. J., WAGGONER, J. G., Sardana, M. K., Sassa, S., Shrager, R. I., Berk, P. D. 1991; 14 (6): 1153-1160

  Abstract

  delta-Aminolevulinic acid-4-[14C] and [3H]-bilirubin were administered intravenously to five patients with Gilbert's syndrome and four healthy control subjects on two occasions: before and on days 10 through 14 of a course of phenobarbital (2.5 mg/kg/day). The resulting curves of [3H]-bilirubin and [14C]-bilirubin in plasma were analyzed by computer to determine a number of parameters of physiological interest. As expected, phenobarbital produced a highly significant fall in the plasma concentration of unconjugated bilirubin as a result of a significant increase in hepatic bilirubin clearance in all subjects; plasma bilirubin turnover was unaltered. Surprisingly, the drug produced no change in the incorporation of [14C]-delta-aminolevulinic acid into [14C]-early labeled bilirubin. To explain this unexpected finding, the effects of phenobarbital (75 mg/kg/day for 6 days) on incorporation of [14C]-delta-aminolevulinic acid and 2-[14C]-glycine into [14C]-early labeled bilirubin and on the activity of the enzyme delta-aminolevulinic acid synthase were studied in nonfasted, adult, male Sprague-Dawley rats. At the dose and duration of treatment used, phenobarbital administration increased total hepatic delta-aminolevulinic acid synthase activity and produced a significant increase of 70% in the incorporation of [14C]-glycine into early labeled bilirubin. By contrast, no increase in the incorporation of [14C]-delta-aminolevulinic acid into early labeled bilirubin was observed. These data suggest that delta-aminolevulinic acid is an inappropriate precursor for studies of the rate of heme biosynthesis, presumably because it bypasses delta-aminolevulinic acid synthase, the physiological rate-limiting enzyme in the heme biosynthetic pathway.

  View details for Web of Science ID A1991GT55900032

  View details for PubMedID 1959865

• RESPONSIVENESS OF PERIPHERAL VEINS TO VASODILATORS AND THE EFFECT OF NIFEDIPINE ON ALPHA-ADRENERGIC RESPONSIVENESS IN HYPERTENSION CLINICAL PHARMACOLOGY & THERAPEUTICS Ford, G. A., KATZIR, D., Blaschke, T. F., Hoffman, B. B. 1991; 50 (2): 192-198

  Abstract

  Vasodilators have varying hemodynamic properties that may be important in determining their efficacy for different disorders. We used the dorsal hand vein technique to measure the effects of several vasodilators infused locally and to measure the action of systemically administered nifedipine. The venodilatory effects of hydralazine, verapamil, diazoxide, and nitroglycerin were determined in peripheral veins of healthy subjects. The potency (ED50, the dose producing half-maximal response) was as follows: nitroglycerin (0.0007 micrograms/min) greater than verapamil (6.5 micrograms/min) greater than diazoxide (75 micrograms/min) greater than hydralazine (660 micrograms/min). The effect of oral nifedipine on alpha-adrenergic responsiveness of hand veins was determined. Nifedipine given in therapeutic doses for the treatment of hypertension was associated with a threefold increase in the ED50 for phenylephrine (92 to 277 ng/min; p less than 0.05) and norepinephrine (2.9 to 11.5 ng/min; p less than 0.05). Therapeutic doses of nifedipine are associated with measurable shifts in the dose-response curves to these two alpha-adrenergic agonists in the hand vein. The hand vein technique can be used not only to compare the potency of locally infused drugs but also to measure venous effects of vasoactive drugs at therapeutic concentrations achieved after systemic administration.

  View details for Web of Science ID A1991GC70500011

  View details for PubMedID 1651200

• SEMIQUANTITATIVE SIMULATION FOR REASONING ABOUT PHYSIOLOGICAL MODELS OF DRUG KINETICS AND EFFECTS 58TH ANNUAL MEETING OF THE SOC-SUISSE-DE-MEDECINE-INTERNE AND THE SOC-SUISSE-DINFORMATIQUE-MEDICALE LEEMANN, T. D., Blaschke, T. F. SCHWABE & CO AG VERLAG. 1990: 1849–52

  Abstract

  Inter- and intra-individual pharmacokinetic or pharmacodynamic variability is a major cause of adverse drug reactions or ineffective therapy. We are developing a computer-based tool for predicting the consequences of different physiological and pathological states and for reasoning about the possible causes of observed variability that may be useful both in a clinical decision support environment for drug monitoring and as a research aid in the investigation of the influence of physiological factors on drug response. It is based on a physiological approach to pharmacokinetic modeling in which actual anatomical or physiological entities, such as organs, tissues or blood flows, are represented. These models serve as the basis for semi-quantitative simulation, a method linking classical quantitative simulation (by numerical integration of differential equations) with artificial intelligence-based qualitative simulation techniques. This approach retains the mathematical power of the Systems Dynamics method for solving complex, time-varying systems containing feed-back loops, which are intractable for current qualitative knowledge representation techniques, and extends it with the causal reasoning and explanation power of symbolic inference techniques used in expert systems. It also allows problem solving in situations, so common in medicine, where initial values of variables and parameters cannot be estimated precisely. Simulation outputs are intended to be qualitatively, but not necessarily quantitatively, correct. The semi-quantitative simulation method was originally developed in MacLisp on a DEC 2060 and applied to modeling cardio-vascular physiology. We are porting the code to Common Lisp on a Macintosh and adapting the approach to pharmacology, concentrating on drug metabolism issues, with lidocaine pharmacokinetics as a test case.

  View details for Web of Science ID A1990EM26300004

  View details for PubMedID 2263925

• RANITIDINE ALTERS ANTIPYRINE METABOLISM IN CONTROL AND PHENOBARBITAL-TREATED MICE METHODS AND FINDINGS IN EXPERIMENTAL AND CLINICAL PHARMACOLOGY ESPIRITUQUIZA, F. A., Skinner, M. H., Blaschke, T. F. 1990; 12 (9): 631-635

  Abstract

  The effect of ranitidine on both induced (phenobarbital) and uninduced cytochrome P450 enzymes was investigated in mice using the [14C]-labeled antipyrine breath test. Ranitidine administration resulted in a decrease in the fraction of the administered dose of antipyrine exhaled as radiolabeled CO2 (CERAUC0-infinity) indicating inhibition in the demethylase pathway (Kdm), and resulted in induction of enzymes in the non-demethylase pathways (Kndm) as well. No change in antipyrine total elimination rate constant (Kel) was seen after ranitidine administration alone. Concurrent administration of ranitidine and phenobarbital resulted in an increase in the (Kel) but the change was less than that seen after phenobarbital alone. A reduction in CERAUC0-infinity was seen after the combination treatment while phenobarbital alone resulted in an increase in this parameter. Ranitidine, therefore, alters the pattern of antipyrine metabolism by inhibition of demethylase enzymes and induction of non-demethylase enzymes, the former activity being more pronounced in induced forms. Because of the simultaneous occurrence of both effects, no change in antipyrine half-life was noted with uninduced P450 isozymes.

  View details for Web of Science ID A1990EW47100009

  View details for PubMedID 2084458

• ACETAMINOPHEN METABOLISM IN RECOVERING ALCOHOLICS METHODS AND FINDINGS IN EXPERIMENTAL AND CLINICAL PHARMACOLOGY Skinner, M. H., Matano, R., HAZLE, W., Blaschke, T. F. 1990; 12 (7): 513-515

  Abstract

  The mercapturic acid conjugate of acetaminophen has been proposed as an index of the toxic intermediate of acetaminophen metabolism which is responsible for the increased incidence of liver injury in alcoholics taking the drug. Previous studies which compared alcoholics with normal patients failed to show any significant difference in mercapturic acid production. We undertook a longitudinal study in recovering alcoholics to test the hypothesis that abstinence should lead to a decrease in acetaminophen-mercapturic acid excretion. The patients were given a 1500 mg dose of acetaminophen soon after they stopped drinking then again approximately 2 weeks later. Urine was collected for 24 h and assayed for mercapturic acid conjugate. There was no significant difference in mercapturic acid excretion when the two measurements were compared. If the toxic intermediate hypothesis is correct, either the effect of alcohol is prolonged, or additional factor other than alcohol exposure may influence mercapturic acid excretion.

  View details for Web of Science ID A1990EP64000010

  View details for PubMedID 2087153

• GENTAMICIN PHARMACOKINETICS IN NEONATES UNDERGOING EXTRACORPOREAL MEMBRANE-OXYGENATION PEDIATRIC INFECTIOUS DISEASE JOURNAL Cohen, P., COLLART, L., Prober, C. G., Fischer, A. F., Blaschke, T. F. 1990; 9 (8): 562-566

  Abstract

  We evaluated the effects of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics of gentamicin in 18 infants who underwent ECMO therapy for severe respiratory failure and received gentamicin for possible sepsis. Twelve of these infants continued to receive gentamicin after ECMO had been discontinued. The volume of distribution (Vd) of gentamicin in the newborns receiving ECMO was 0.58 +/- 0.04 liter/kg, compared with a Vd of 0.45 +/- 0.02 liter/kg after ECMO had been discontinued (P = 0.02). The clearance of gentamicin in the patients undergoing ECMO was 42 +/- 3 ml/kg/hour compared with 57 +/- 4 ml/kg/hour in those patients off ECMO (P = 0.003). The elimination half-life in patients receiving ECMO was 10.0 +/- 0.7 hours compared with 5.7 +/- 0.4 hours after ECMO had been discontinued (P less than 0.0001). Neonates undergoing ECMO demonstrate a higher volume of distribution of gentamicin, a lower clearance, and consequently a longer half life for this drug. We conclude that gentamicin and probably other aminoglycosides should be given at dose rates about 25% lower than usual and at longer dosing intervals in patients undergoing ECMO therapy.

  View details for Web of Science ID A1990DT50800007

  View details for PubMedID 2122409

• DECREASED RESPONSIVENESS OF SUPERFICIAL HAND VEINS TO PHENYLEPHRINE IN BLACK NORMOTENSIVE MALES JOURNAL OF CARDIOVASCULAR PHARMACOLOGY Eichler, H. G., Blaschke, T. F., Hoffman, B. B. 1990; 16 (2): 177-181

  Abstract

  Essential hypertension is more prevalent among blacks than whites although the explanation is unknown. It is possible that an altered vascular adrenoceptor responsiveness in blacks may play a role in the etiology of this racial difference. To test this hypothesis, we have compared the diameter changes in superficial veins in response to phenylephrine, an alpha-adrenergic agonist, and to isoproterenol, a beta-adrenergic agonist, in black and white young normotensive males using the dorsal hand vein compliance technique. The maximal venoconstriction after phenylephrine (Emax) was 92 +/- 9% (mean +/- SD) in the whites but only 74 +/- 12% in the blacks (p = 0.00046). The ED50 of phenylephrine was 342 ng/min (geometric mean) in whites and 245 ng/min in blacks (p = 0.50). The Emax and ED50 for isoproterenol-mediated venodilation was not significantly different between the racial groups. These results indicate a decreased maximal responsiveness to alpha-adrenergic stimulation in normotensive blacks. How these changes relate to cardiovascular alterations in hypertensive blacks requires further study.

  View details for Web of Science ID A1990DP61900001

  View details for PubMedID 1697371

• RESEARCH AND THE AMERICAN-SOCIETY-FOR-CLINICAL-PHARMACOLOGY-AND-THERAPEUTICS CLINICAL PHARMACOLOGY & THERAPEUTICS Blaschke, T. F. 1990; 47 (2): 270-272

  View details for Web of Science ID A1990CP98700341

  View details for PubMedID 2302912

• ACETAMINOPHEN METABOLISM IN RECOVERING ALCOHOLICS Skinner, M. H., Matano, R., HAZLE, W., Blaschke, T. F. NATURE PUBLISHING GROUP. 1990: 160–60

  View details for Web of Science ID A1990CP98700138

• EFFECT OF TEMAZEPAM ON BLOOD-PRESSURE REGULATION IN HEALTHY ELDERLY SUBJECTS BRITISH JOURNAL OF CLINICAL PHARMACOLOGY Ford, G. A., Hoffman, B. B., Blaschke, T. F. 1990; 29 (1): 61-67

  Abstract

  1. Blood pressure regulation was studied in 12 healthy elderly subjects after double-blind randomised administration of placebo, 15 mg and 30 mg temazepam at 10.00 h and 22.00 h. 2. Supine and standing heart rate and blood pressure were measured after daytime administration and supine measurements were obtained during sleep. 3. Temazepam caused a fall in systolic blood pressure and an increase in heart rate after morning administration. These changes were greater in the standing position and were dose-dependent; for standing blood pressure and heart rate 1 h after administration there was a 7 mm Hg fall and 6 beats min-1 increase after 15 mg temazepam and a 10 mm Hg fall and 8 beats min-1 increase after 30 mg temazepam. Temazepam magnified the fall in systolic blood pressure and increase in heart rate that occurred with standing. Temazepam enhanced the fall in systolic blood pressure that occurred during sleep (mean +/- s.d.; placebo: -23 +/- 10 mm Hg, 15 mg temazepam: -31 +/- 13 mm Hg, 30 mg temazepam: -36 +/- 14 mm Hg). 4. These changes in blood pressure regulation caused by temazepam may have clinical importance in some elderly individuals.

  View details for Web of Science ID A1990CG78400009

  View details for PubMedID 1967533

• DOSE-DEPENDENT INHIBITION OF CYCLOSPORINE METABOLISM IN MICE BY FLUCONAZOLE CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY LADELFA, I., Xia, Y. F., Blaschke, T. F. 1990; 68 (1): 89-93

  Abstract

  Fluconazole, a potent bis-triazole antimycotic drug, has been demonstrated to inhibit antipyrine metabolism, a cytochrome P-450 dependent process, in vivo in mice. Cyclosporine is metabolized by the cytochrome P-450 enzyme system in both mice and man. We investigated whether fluconazole had any effects on the metabolism of cyclosporine in vivo in mice. The effects of three different doses of fluconazole (1, 5, and 20 mg/kg) on the metabolism of cyclosporine in CD-1 mice were studied in single-dose experiments. Fluconazole produced significant dose-dependent decreases in the elimination rate constant and increases in the terminal half-life of cyclosporine. The 1 mg/kg dose caused a 26% prolongation of the terminal half-life and the 5 and 20 mg/kg dose prolonged the half-life by 72 and 187%, respectively. Fluconazole doses in the 1-5 mg/kg range are effective in mouse models of fungal infections. These results provide further in vivo evidence that fluconazole is a potent inhibitor of the cytochrome P-450 dependent enzyme system in mice. Future experimental studies in animals and humans are needed to evaluate possible metabolic drug-drug interactions involving fluconazole.

  View details for Web of Science ID A1990CQ77300013

  View details for PubMedID 2328446

• NIFEDIPINE PHARMACOKINETICS DURING PRETERM LABOR TOCOLYSIS AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Ferguson, J. E., Schutz, T., PERSHE, R., Stevenson, D. K., Blaschke, T. 1989; 161 (6): 1485-1490

  Abstract

  Nifedipine, a calcium entry blocker, has known relaxing effects on the myometrium. Thirteen women in preterm labor received nifedipine for tocolysis. Blood samples obtained serially during treatment and at the time of delivery were assayed for maternal and neonatal nifedipine concentrations. The peak concentration of nifedipine during sublingual therapy ranged from 23.4 to 197.9 ng/ml and reflected substantial interpatient variability. The mean (+/- SD) measurable trough value in patients who received 20 mg of nifedipine orally every 6 hours was 7.2 +/- 5.5 ng/ml. The maternal mean half-life of nifedipine was 81 minutes (range 49 to 137 minutes). At delivery, neonatal nifedipine levels were nondetectable in 6 of the 11 neonates available for study; in 5, values ranged from 29.5 to 1.8 ng/ml. From these results we conclude that both sublingual and oral nifedipine treatment results in variable but usually measurable maternal plasma concentrations and that placental transfer of nifedipine occurs.

  View details for Web of Science ID A1989CG73300010

  View details for PubMedID 2603904

• CLINICAL-PHARMACOLOGY COMES OF AGE CLINICAL PHARMACOLOGY & THERAPEUTICS Blaschke, T. F. 1989; 46 (5): 485-488

  View details for Web of Science ID A1989CA57400001

  View details for PubMedID 2582704

• RESPONSIVENESS OF PERIPHERAL VEINS TO TRANSDERMAL AND SUBLINGUAL NITROGLYCERIN IN HEALTHY MALE-VOLUNTEERS JOURNAL OF CARDIOVASCULAR PHARMACOLOGY HIREMATH, A. N., Hoffman, B. B., Blaschke, T. F. 1989; 14 (4): 534-541

  Abstract

  Nitroglycerin (NTG) is a potent vascular smooth muscle relaxant. With the widespread use of transdermal NTG patches for the prophylaxis of angina, two important issues have arisen: (a) the relative efficacy of transdermal NTG patches compared to other formulations of NTG, and (b) the possibility of development of tolerance to transdermal NTG. We have investigated these two issues by studying the effect of systemically administered NTG (transdermal patches, ointment, and sublingual tablets) on alpha-adrenergic receptor agonist-mediated constriction of human dorsal hand veins. Nitroglycerin patches and ointment (15-60 mg/24 h) applied for 1-4 h did not modify the sensitivity (ED50) to the alpha-adrenergic agonist, phenylephrine. However, sublingual NTG (0.15-0.60 mg) administration caused significant relaxation of partially constricted veins. Following exposure for 24 h to a NTG patch (15 mg/24 h), NTG dose-response curves were not altered suggesting there was no development of tolerance to transdermal NTG. We conclude from our observations that tolerance to transdermal NTG does not appear in veins, possibly due to the low plasma NTG concentrations produced by this preparation. Our results also indicate that high doses of transdermal NTG do not modify phenylephrine-mediated constriction of peripheral veins in humans.

  View details for Web of Science ID A1989AQ65100004

  View details for PubMedID 2478766

• IMPROVING DRUG DOSING IN HOSPITALIZED-PATIENTS - AUTOMATED MODELING OF PHARMACOKINETICS FOR INDIVIDUALIZATION OF DRUG-DOSAGE REGIMENS COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE Lenert, L., Sheiner, L., Blaschke, T. 1989; 30 (2-3): 169-176

  Abstract

  Many clinical useful drugs have a narrow range of blood concentrations which are both safe and efficacious. Inter-individual and intra-individual variations in drug disposition are important factors causing blood concentrations of drug to fall outside of the therapeutic range. Modeling of the pharmacokinetics of the individual offers an effective approach to the problem of variation in drug disposition. Previous approaches for the modeling of individual pharmacokinetics have required either extensive computations or access to computer software and hardware in the clinical environment, and special expertise to interpret the results. This paper describes a prototype computer program, PK Monitor, which can, when connected with an appropriate interface, automatically monitor drug dosing and recommend changes that may be required to obtain blood concentrations in the therapeutic range. The software can also detect the occurrence of change in drug disposition which will lead to concentrations outside of the therapeutic range, identify potentially erroneous blood concentration measurements, and assess the need for further blood concentration measurements. This program will be an integral part of the MENTOR therapeutic monitoring system of programs. PK Monitor awaits a complete evaluation with the rest of the MENTOR system, but preliminary simulations suggest reasonable sensitivity and specificity in monitoring for unexpected data and change.

  View details for Web of Science ID A1989CA90600010

  View details for PubMedID 2582750

• PHARMACOKINETICS OF RIFABUTIN ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Skinner, M. H., Hsieh, M., TORSETH, J., PAULOIN, D., Bhatia, G., Harkonen, S., Merigan, T. C., Blaschke, T. F. 1989; 33 (8): 1237-1241

  Abstract

  We investigated the pharmacokinetics of rifabutin in 15 male patients as part of a phase I trial of the treatment of early symptomatic human immunodeficiency virus infection. Six or more patients were studied at each of four different oral dosage levels: 300, 600, 900, and 1,200 mg/day. Twelve studies were also conducted with tracer doses of intravenous radiolabeled [14C]rifabutin. Blood and urine samples were collected for at least 72 h after the first (day 1) and last (day 28) doses of rifabutin and analyzed by high-pressure liquid chromatography. The plasma concentration data were best described by a two-compartment open model with a terminal half-life of 36 h. Rifabutin was rapidly absorbed, reaching a peak concentration about 2 to 3 h after an oral dose. Peak and trough concentrations for the 1,200-mg dose were 907 and 194 ng/ml, respectively. Total body clearance was 10 to 18 liters/h. Oral bioavailability was 12 to 20%. The drug was moderately bound to plasma proteins with a free fraction of 29 +/- 2% (mean +/- standard deviation). About 10% of an administered intravenous dose of rifabutin is excreted into the urine unchanged. Renal clearance was 1.5 +/- 0.2 liters/h. The volume of distribution was large (8 to 9 liters/kg), suggesting extensive distribution into the tissues. The area under the curve for the last dose was smaller than that of the first dose, suggesting possible induction of drug-metabolizing enzymes.

  View details for Web of Science ID A1989AJ32000020

  View details for PubMedID 2552902

• EFFECTS OF KETOCONAZOLE ON THE POLYMORPHIC 4-HYDROXYLATIONS OF S-MEPHENYTOIN AND DEBRISOQUINE BRITISH JOURNAL OF CLINICAL PHARMACOLOGY ATIBA, J. O., Blaschke, T. F., Wilkinson, G. R. 1989; 28 (2): 161-165

  Abstract

  Studies were undertaken in 12 normal, male subjects to determine whether a metabolic interaction occurs between ketoconazole and mephenytoin. A single dose (400 mg) of ketoconazole produced a reduction in the 0-8 h urinary R/S ratio of mephenytoin following oral administration (100 mg) of racemic drug and after 28 daily doses the median value was further reduced to 42.9% of its baseline value. Within 7 days following discontinuation of ketoconazole the enantiomeric ratio had returned to its pre-study value. These findings are consistent with ketoconazole being a potent in vivo inhibitor of mephenytoin's 4-hydroxylation and confirm the ability of such an interaction to be predicted by in vitro studies with human liver microsomes. By contrast, ketoconazole had a much smaller effect on the 0-8 h urinary metabolic ratio of debrisoquine, indicating that ketoconazole has a selective inhibitory effect on different forms of cytochrome P-450.

  View details for Web of Science ID A1989AK20900006

  View details for PubMedID 2775621

• EVALUATION OF THE ANTIVIRAL EFFECT OF RIFABUTIN IN AIDS-RELATED COMPLEX JOURNAL OF INFECTIOUS DISEASES TORSETH, J., Bhatia, G., Harkonen, S., Child, C., SKINNER, M., Robinson, W. S., Blaschke, T. F., Merigan, T. C. 1989; 159 (6): 1115-1118

  View details for Web of Science ID A1989U854200018

  View details for PubMedID 2542419

• RESPONSIVENESS OF SUPERFICIAL HAND VEINS TO ADRENERGIC STIMULI IN PATIENTS WITH CYSTIC-FIBROSIS CLINICAL SCIENCE Eichler, H. G., Eichler, I., LEWISTON, N., Blaschke, T. F., Hoffman, B. B. 1989; 76 (3): 283-287

  Abstract

  1. The basic biochemical defect of cystic fibrosis (CF) remains undetermined, but impaired function of the beta-adrenoceptor-mediated adenosine 3':5'-cyclic monophosphate (cyclic AMP)-dependent regulatory pathway in secretory cells is likely to be involved in the pathophysiology of the disease. 2. We have compared responsiveness to beta-adrenergic stimulation in vivo by infusing isoprenaline locally into peripheral veins of CF patients and control subjects; the dorsal hand vein technique was used to measure the vascular response to isoprenaline. 3. CF patients required significantly higher doses of isoprenaline for half-maximal dilatation of the preconstricted veins (ED50) than controls (geometric mean: 44.5 ng/min in CF patients compared with 14.8 ng/min in controls; P less than 0.05). Maximal venodilatation was 74 +/- 30% of baseline in CF patients compared with 94 +/- 50% in controls (NS between groups). 4. The clinical score of CF patients was uncorrelated with the ED50 of isoprenaline. Thus the decreased beta-adrenergic responsiveness does not seem to be related to the severity of the disease. 5. Our results indicate a defect in the cyclic-AMP-dependent pathway in vascular smooth muscle cells of CF patients. Whether this is associated with the CF gene defect itself requires further study.

  View details for Web of Science ID A1989T589700010

  View details for PubMedID 2924520

• IL-2 DOES NOT ALTER ZIDOVUDINE KINETICS Skinner, M. H., PAULOIN, D., Schwartz, D., Merigan, T. C., Blaschke, T. F. MOSBY-YEAR BOOK INC. 1989: 128–28

  View details for Web of Science ID A1989T270600028

• FLUCONAZOLE IS A POTENT INHIBITOR OF ANTIPYRINE METABOLISM INVIVO IN MICE DRUG METABOLISM AND DISPOSITION LADELFA, I., Zhu, Q. M., MO, Z. G., Blaschke, T. F. 1989; 17 (1): 49-53

  Abstract

  Fluconazole, a bis-triazole antifungal, is distinguished from imidazole antifungals (e.g. ketoconazole) by its potency and pharmacokinetic characteristics. Imidazole-containing compounds are well documented to inhibit the hepatic cytochrome P-450-dependent enzyme system; whether this effect occurs with a bis-triazole agent is unknown. The [14C]antipyrine breath test was employed to investigate the effects of fluconazole on this enzyme system in CD-1 male mice. Control, ketoconazole (100 mg/kg), and fluconazole (1 and 10 mg/kg) were studied in single- and multiple-dose experiments. Fluconazole had potent inhibitory effects on the total (mean = -73% +/- 2%), demethylase (mean = -90% +/- 2%), and nondemethylase (mean = -60% +/- 4%) elimination rate constants (all p less than 0.001). The fraction of the administered radioactivity excreted as 14CO2 was decreased by 50-80% in the fluconazole groups (p less than 0.001). These effects were seen after single- and multiple-dose studies; however, return to baseline occurred more quickly in the multiple-dose group. These effects were significantly more pronounced than those observed with equipotent doses of ketoconazole. These results provide evidence that fluconazole is a potent, partially selective, and reversible inhibitor of the cytochrome P-450-dependent enzyme system in mice. Future studies will be required to assess this property and possible interactions with drugs metabolized by this enzyme system in humans.

  View details for Web of Science ID A1989T089200009

  View details for PubMedID 2566469

• THEOPHYLLINE TOXICITY SUBSEQUENT TO RANITIDINE ADMINISTRATION - A POSSIBLE DRUG-DRUG INTERACTION AMERICAN JOURNAL OF MEDICINE Skinner, M. H., Lenert, L., Blaschke, T. F. 1989; 86 (1): 129-132

  View details for Web of Science ID A1989R651200028

  View details for PubMedID 2910084

• RESPONSIVENESS OF SUPERFICIAL HAND VEINS TO PHENYLEPHRINE IN ESSENTIAL-HYPERTENSION - ALPHA ADRENERGIC-BLOCKADE DURING PRAZOSIN THERAPY JOURNAL OF CLINICAL INVESTIGATION Eichler, H. G., Ford, G. A., Blaschke, T. F., Swislocki, A., Hoffman, B. B. 1989; 83 (1): 108-112

  Abstract

  Patients with essential hypertension show an increase in vascular resistance. It is unclear whether this is caused by structural changes in the arterial wall or by hyperresponsiveness of vascular smooth muscle to endogenous alpha adrenergic agonists. Using the dorsal hand vein compliance technique we compared the changes in diameter of superficial veins in response to phenylephrine, an alpha 1 adrenergic receptor agonist, and to nitroglycerin, a venorelaxant, in patients with essential hypertension and in normotensive subjects. The dose of phenylephrine that produced 50% of maximal venoconstriction (ED50) in the hypertensive subjects was 257 ng/min (geometric mean; log mean +/- SD was 2.41 +/- 0.54). In the control subjects the ED50 was 269 ng/min (geometric mean; log mean was 2.43 +/- 0.43). Maximal response (Emax) for phenylephrine was 84 +/- 13% in the hypertensive subjects and 90 +/- 6% in the control subjects. Differences in the group means of the ED50 (P = 0.92) or the Emax (P = 0.27) were not significant. There were no significant differences in the ED50 (P = 0.54) or the Emax (P = 0.08) for nitroglycerin between the two groups. These results show no evidence for a generalized change in alpha adrenergic responsiveness in hypertension and support the concept that increased blood pressure responses to alpha adrenergic stimulation in hypertensives are due to structural and geometric changes in the arterial wall rather than to an increased responsiveness of postsynaptic alpha adrenergic receptors. The phenylephrine studies were repeated in seven hypertensive patients during treatment with prazosin, an alpha 1 adrenergic antagonist. The mean dose ratio of the shift in phenylephrine ED50 (ED50 during prazosin therapy/ED50 before prazosin therapy) was 6.1. This indicates that small doses of prazosin (1-2 mg) cause significant in vivo shifts in the dose-response relationship of alpha adrenergic agonists. The dorsal hand vein compliance technique is useful in detecting systemic effects of alpha adrenergic antagonists.

  View details for Web of Science ID A1989R755100016

  View details for PubMedID 2562959

• COMPARISON OF AGE-RELATED-CHANGES IN PROSTAGLANDIN-E1 AND BETA-ADRENERGIC RESPONSIVENESS OF VASCULAR SMOOTH-MUSCLE IN ADULT MALES JOURNALS OF GERONTOLOGY HIREMATH, A. N., PERSHE, R. A., Hoffman, B. B., Blaschke, T. F. 1989; 44 (1): M13-M17

  Abstract

  Aging in humans is associated with a general decline in beta-adrenergic receptor responsiveness. Whether this is a consequence of a defect at the receptor level or along the adenylate cyclase pathway is not known. Using a technique to measure compliance of dorsal hand veins, we investigated the venodilatory response to isoproterenol and prostaglandin E1 (PGE1), which interact with distinct membrane-bound receptors but activate the same adenylate cyclase system. Studies were conducted in 7 young (Y, less than 30 years) and 7 elderly (E, greater than 60 years) healthy male volunteers. Dilatation induced by isoproterenol (mean +/- SD) was 43 +/- 8% in E vs 97 +/- 17% in Y, p = .003. However, PGE, produced complete relaxation in both Y and E subjects (122 +/- 17% vs 97 +/- 19% respectively, p = .270). The sensitivity to PGE1 was not significantly different between the Y and E. Our results demonstrate that PGE1 is a potent venodilator in humans and that the age-related decline in vascular response is specific to beta-adrenoceptor agonists and does not reflect a generalized loss in responsiveness to adenylate cyclase coupled receptors.

  View details for Web of Science ID A1989R841500004

  View details for PubMedID 2536054

• VENOUS RESPONSIVENESS TO ATRIAL NATRIURETIC FACTOR IN MAN BRITISH JOURNAL OF CLINICAL PHARMACOLOGY Ford, G. A., Eichler, H. G., Hoffman, B. B., Blaschke, T. F. 1988; 26 (6): 797-799

  Abstract

  The venorelaxant effect of atrial natriuretic factor in man was studied using the dorsal hand vein technique. Infusion of met-ANF to preconstricted veins at doses up to 240 ng min-1 in 11 healthy male subjects caused only minimal venorelaxation. Atrial natriuretic factor is unlikely to have a significant venorelaxant effect at physiological doses in man.

  View details for Web of Science ID A1988R422100018

  View details for PubMedID 2977285

• EFFECT OF ETOMIDATE ON HEPATIC DRUG-METABOLISM IN HUMANS ANESTHESIOLOGY ATIBA, J. O., Horai, Y., White, P. F., TREVOR, A. J., Blaschke, T. F., Sung, M. L. 1988; 68 (6): 920-924

  Abstract

  The authors studied the effect of etomidate on drug metabolism in vivo in humans and in vitro using human liver microsomes. When these liver microsomes were incubated with different concentrations of etomidate, dose-dependent inhibition of ketamine N-demethylation, a cytochrome P-450-dependent enzymatic process, was produced. Cytochrome P-450 binding spectra displayed type II binding with a UV light absorption maximum (lambda max) at a wavelength of 424 nm in the presence of etomidate. In vivo studies were conducted using ketamine and antipyrine as substrates. Evaluation of antipyrine's pharmacokinetic variables after an intravenous infusion of etomidate (0.34 +/- 0.17 mg/kg) revealed an 18% increase in its elimination half-life (P = 0.04). In addition, there were 16% and 11% decreases in the area under the curve (P = 0.05) and in the clearance rate (P = 0.07) for antipyrine, respectively. In patients administered a bolus dose of ketamine during brief outpatient operations, etomidate produced no significant changes in ketamine's pharmacokinetics compared to thiopental. The authors conclude that the etomidate-induced inhibition of hepatic drug metabolism can prolong the elimination of drugs with low hepatic clearance rates (e.g., antipyrine). However, etomidate would not be expected to alter the rate of elimination of high clearance anesthetics and analgesic drugs (e.g., ketamine, fentanyl).

  View details for Web of Science ID A1988N741400014

  View details for PubMedID 3377236

• STEREOSELECTIVE BINDING OF DISOPYRAMIDE TO PLASMA-PROTEINS PHARMACEUTICAL RESEARCH Valdivieso, L., Giacomini, K. M., Nelson, W. L., PERSHE, R., Blaschke, T. F. 1988; 5 (5): 316-318

  View details for Web of Science ID A1988N597000012

  View details for PubMedID 3244643

• ABSENCE OF AGE-RELATED-CHANGES IN VENOUS RESPONSIVENESS TO NITROGLYCERIN INVIVO IN HUMANS CLINICAL PHARMACOLOGY & THERAPEUTICS Eichler, H. G., Hiremath, A., KATZIR, D., Blaschke, T. F., Hoffman, B. B. 1987; 42 (5): 521-524

  Abstract

  We have previously demonstrated a progressive loss in the ability of the beta-receptor agonist isoproterenol to relax veins with increasing age. In this study the influence of age on the responsiveness of medium-sized veins to local infusions of nitroglycerin was studied in two groups of 15 healthy male volunteers using the dorsal hand vein compliance technique. A dorsal hand vein was preconstricted with submaximally effective doses of phenylephrine and a dose-response curve with nitroglycerin was established. The nitroglycerin dose that caused a 50% venodilation ranged from 0.7 to 22.4 ng/min (geometric mean 3.6 ng/min) in the younger group (aged 19 to 29 years; mean +/- SD 23 +/- 3 years) and from 0.2 to 17.9 ng/min (geometric mean 3.6 ng/min) in the older subjects (aged 50 to 74 years; mean +/- SD 63 +/- 7 years) (P = 0.49 between geometric means). The mean (+/- SD) maximal venodilation, based on the pretreatment baseline, was 103% +/- 65% in the younger and 125% +/- 64% in the older subjects (P = 0.18). These results indicate that there is no age-related change in venous responsiveness to nitroglycerin.

  View details for Web of Science ID A1987K962200008

  View details for PubMedID 3119271

• PLASMA ANTIPYRINE HALF-LIFE CAN BE DETERMINED FROM URINE DATA BRITISH JOURNAL OF CLINICAL PHARMACOLOGY ATIBA, J. O., Taylor, G., PERSHE, R. A., Blaschke, T. F. 1987; 23 (6): 715-719

  Abstract

  Antipyrine half-life has been determined from measurements of antipyrine concentrations in spontaneously voided urine specimens in eleven subjects, studied on a total of forty-seven different occasions while receiving no drugs, interferon or ketoconazole. Plasma and saliva half-lives show good intrasubject correlation. Plasma and urine half-lives show good intrasubject correlation provided total urine output is at least 1.1 l day-1. The range of intrasubject correlation coefficients for plasma and urinary half-lives was 0.76 to 0.98, with a median value of 0.85. Saliva and urine half-lives show good intrasubject correlation, with the range of intrasubject correlation coefficients from 0.74 to 0.98, and with a median value of 0.75. There is a small but consistent bias towards shorter urinary half-life estimates; this averaged 0.75 h for the plasma-urine studies and 0.192 h for the saliva-urine studies. There were parallel changes in antipyrine half-life estimated from plasma and urine for one of our subjects who received multiple doses of recombinant beta-interferon and had a 150% increase in antipyrine half-life over the study period.

  View details for Web of Science ID A1987H680200009

  View details for PubMedID 2440468

  View details for PubMedCentralID PMC1386166

• ETOMIDATE INHIBITS ANTIPYRINE METABOLISM IN MICE AMERICAN JOURNAL OF THE MEDICAL SCIENCES ATIBA, J. O., Blaschke, T. F. 1987; 293 (6): 361-365

  View details for Web of Science ID A1987H726300003

• PHARMACODYNAMICS OF CYCLOSPORINE-KETOCONAZOLE INTERACTION IN MICE - COMBINED THERAPY POTENTIATES CYCLOSPORINE IMMUNOSUPPRESSION AND TOXICITY TRANSPLANTATION Anderson, J. E., Morris, R. E., Blaschke, T. F. 1987; 43 (4): 529-533

  Abstract

  We have previously studied the pharmacokinetics of the cyclosporine-ketoconazole interaction and shown that ketoconazole inhibits the metabolism of cyclosporine in mice. In the present study we investigated the pharmacodynamics of the interaction and found that ketoconazole increased the immunosuppressive activity and toxicity of cyclosporine in vivo. Mice were treated orally with cyclosporine (25-200 mg/kg/day), ketoconazole (100 mg/kg/day), drug vehicle, or drug combination for 14 days. Immunosuppression was studied by assaying radiometrically the delayed hypersensitivity response in mice that were sensitized and challenged to keyhole limpet hemocyanin. The dose-response curve for cyclosporine was shifted to the left when cyclosporine and ketoconazole were coadministered compared with treatment with cyclosporine alone. The dose that produced 50% of the maximal immunosuppression (ED50) for cyclosporine alone was 89 mg/kg/day, whereas the ED50 for cyclosporine, when combined with ketoconazole, was 33 mg/kg/day. Ketoconazole alone was not immunosuppressive. Toxicity was measured by the length of survival during a ten-day period of treatment. Animals receiving both drugs had a significantly lower survival: the ten-day survival of animals treated with 200 mg/kg/day of cyclosporine was 100% in the absence of ketoconazole treatment and 62.5% with 100 mg/kg/day of ketoconazole. The results of our study have two important implications. First, the effect of ketoconazole on cyclosporine immunosuppression is quantitatively similar to its effect on cyclosporine kinetics. Because of this two- to three-fold increase in both unchanged cyclosporine blood levels and immunosuppression, our results suggest that unchanged cyclosporine--not its metabolites--is the primary pharmacological agent of cyclosporine in vivo immunosuppression. Second, to avoid cyclosporine-induced nephrotoxicity, it has been recommended that the dosage of cyclosporine be decreased when this drug combination is used clinically. The results of this study suggest that a decrease in cyclosporine dosage will not lower the level of immunosuppression in these patients.

  View details for Web of Science ID A1987G987600015

  View details for PubMedID 3576671

• KETOCONAZOLE POTENTIATES CYCLOSPORINE IMMUNOSUPPRESSION AND TOXICITY IN MICE TRANSPLANTATION PROCEEDINGS Anderson, J. E., Morris, R. E., Blaschke, T. F. 1987; 19 (1): 1267-1268

  View details for Web of Science ID A1987G101400132

  View details for PubMedID 3274315

• KETOCONAZOLE POTENTIATES CYCLOSPORINE IMMUNOSUPPRESSION AND TOXICITY IN MICE Anderson, J. E., Morris, R. E., Blaschke, T. F. SLACK INC. 1987: A115–A115

  View details for Web of Science ID A1987F528500654

• DECLINE IN BETA-ADRENERGIC RECEPTOR-MEDIATED VASCULAR RELAXATION WITH AGING IN MAN JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS PAN, H. Y., Hoffman, B. B., PERSHE, R. A., Blaschke, T. F. 1986; 239 (3): 802-807

  Abstract

  Beta adrenergic relaxation of vascular smooth muscle, mediated by cyclic AMP, is blunted with age in a variety of experimental animals. The applicability of these observations to man is uncertain. The dorsal hand vein technique provides an excellent method to examine the direct effects of aging on vascular responsiveness. Thirty-nine healthy male volunteers over the age range of 19 to 79 were studied. No differences in vascular responsiveness to phenylephrine, an alpha adrenergic agonist, were found for either the ED50 (dose producing 50% vasoconstriction) or Emax (maximum vasoconstriction attained). In marked contrast, vascular relaxation induced by isoproterenol, a beta adrenergic agonist, was significantly different in both the ED50 (dose producing 50% of maximum relaxation from a preconstricted state) and Emax (maximum relaxation attained). ED50 +/- S.E.M. for the youngest and oldest deciles were 8.9 +/- 2.3 and 60 +/- 17.0 ng/min, respectively (P less than .05); Emax +/- S.E.M. were 96.7 +/- 3.3 and 37.7 +/- 8.7%, respectively (P less than .001). Nitroglycerin, a smooth muscle relaxant whose effects are not mediated through the cyclic AMP system, was also used to examine the specificity of this blunted response to isoproterenol. Almost complete relaxation was achieved with the infusion of nitroglycerin in the older group. These results suggest that aging is associated with a specific decrease in beta adrenoreceptor-mediated vascular relaxation.

  View details for Web of Science ID A1986F424700028

  View details for PubMedID 3025419

• INVIVO INTERACTION OF THE ENANTIOMERS OF DISOPYRAMIDE IN HUMAN-SUBJECTS JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS Giacomini, K. M., Nelson, W. L., PERSHE, R. A., Valdivieso, L., TURNERTAMIYASU, K., Blaschke, T. F. 1986; 14 (4): 335-356

  Abstract

  Disopyramide, an antiarrhythmic agent, is marketed as a racemic mixture of two enantiomers. The racemic drug has unusual pharmacokinetic properties because of its concentration-dependent binding to plasma proteins in the therapeutic plasma concentration range. This study examined, in healthy subjects, the individual pharmacokinetic properties of both total and unbound d- and 1-disopyramide in plasma after intravenous administration of each enantiomer separately (1.5 mg/kg). Also investigated is the pharmacokinetics of total d- and 1-disopyramide in plasma after intravenous administration of a pseudoracemate. Both d- and 1-disopyramide are found to exhibit concentration-dependent binding to plasma proteins, with d-disopyramide being more avidly bound at lower concentrations. The stereoselective, concentration-dependent binding to plasma proteins resulted in distinct pharmacokinetic properties when the enantiomers were given together as the pseudoracemate. d-Disopyramide had a lower plasma clearance and renal clearance, a longer half-life, and a smaller apparent volume of distribution than 1-disopyramide. However, when the enantiomers were administered separately, there were no differences in the clearance, renal clearance, and volume of distribution between enantiomers calculated from either total or unbound drug concentrations. The results reveal an important pharmacokinetic interaction between the enantiomers of disopyramide when given as a racemic mixture, which may be dose-dependent and is not apparent upon administration of the enantiomers separately.

  View details for Web of Science ID A1986E472500001

  View details for PubMedID 3772736

• KETOCONAZOLE INHIBITS CYCLOSPORINE METABOLISM INVIVO IN MICE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Anderson, J. E., Blaschke, T. F. 1986; 236 (3): 671-674

  Abstract

  Several case reports have suggested that ketoconazole, an antifungal drug, inhibits the metabolism of cyclosporine, an immunosuppressant drug used in patients undergoing organ transplantation. We have used a mouse model to study this possible pharmacokinetic interaction. Eight mice received 95 mg/kg of ketoconazole p.o. for 3 days; eight mice, receiving vehicle only, served as controls. A therapeutic 2.6 mg/kg dose plus a radiolabeled tracer dose of cyclosporine were administered as a bolus i.v. injection. Blood samples were drawn sequentially over 7 hr. Unchanged cyclosporine and metabolites were extracted and concentrated from whole blood with ether. After separation from metabolites using high-performance liquid chromatography, the concentration of unchanged cyclosporine was determined from its radioactivity. A comparison of the pharmacokinetic parameters of unchanged drug between control and treated animals showed that pretreatment with ketoconazole inhibited the metabolism of cyclosporine. In the presence of ketoconazole, cyclosporine clearance decreased from 15.4 to 7.6 ml/hr; terminal half-life increased from 4.1 to 11.2 hr; and steady-state volume of distribution did not change significantly. If a similar phenomenon occurs in humans, these findings could have important clinical implications. Although the therapeutic range for cyclosporine has not been clearly established, cyclosporine toxicity may be related to elevated concentrations. Therefore, patients who receive the combination of cyclosporine and ketoconazole should have blood levels of cyclosporine and signs of toxicity monitored closely.

  View details for Web of Science ID A1986A484500018

  View details for PubMedID 3950868

• KETOCONAZOLE POTENTIATES CYCLOSPORINE IMMUNO-SUPPRESSION AND TOXICITY IN MICE Anderson, J. E., Morris, R. E., Blaschke, T. F. BLACKWELL MUNKSGAARD. 1986: 209–209

  View details for Web of Science ID A1986D896000619

• DISCREPANCIES BETWEEN PHARMACOKINETIC STUDIES OF AMITRIPTYLINE CLINICAL PHARMACOKINETICS Schulz, P., Dick, P., Blaschke, T. F., Hollister, L. 1985; 10 (3): 257-268

  Abstract

  In this article, studies on the disposition of amitriptyline after administration of a single dose, as well as following long term administration are reviewed. While long term studies showed bias towards a higher mean apparent oral clearance, studies in normal subjects nevertheless indicated a higher apparent oral clearance than that calculated from steady-state concentrations in depressed patients. Methodological issues could account for some of the discrepancies in mean values of the pharmacokinetic parameters of amitriptyline. Broad individual variability in the elimination rate of amitriptyline has been confirmed but could not be attributed to the clinical characteristics of the subjects.

  View details for Web of Science ID A1985AKQ0400005

  View details for PubMedID 3893842

• INTERFERON REDUCES HEPATIC DRUG-METABOLISM INVIVO IN MICE DRUG METABOLISM AND DISPOSITION Taylor, G., MARAFINO, B. J., Moore, J. A., GURLEY, V., Blaschke, T. F. 1985; 13 (4): 459-463

  Abstract

  The effects of two highly purified human leukocyte interferons (IFN-A and IFN-AD) on drug-metabolizing capacity in mice have been investigated. IFN-AD was found to produce significant changes in antipyrine half-life, assessed by analysis of 14CO2 exhalation rates following 14C-antipyrine administration. By contrast, IFN-A, which has considerably less antiviral potency than IFN-AD, was found to have no effect on antipyrine half-life. The administration regimen was found to markedly alter the effects seen with IFN-AD. When IFN-AD was given as single daily doses (5 X 10(7) units/kg/day X 3 days), the half-life of antipyrine increased by a mean of 40% (from 21.0 to 28.9 min). However, when a smaller daily dose (3 X 10(7) units/kg/day) was given as a continuous infusion, the antipyrine half-life increased by more than 3-fold (from 20.8 to 68.5 min) after 3 days of administration. Continued infusion for a further 3 days produced no additional change in antipyrine half-life. These results demonstrate that human leukocyte interferons can significantly inhibit hepatic metabolic activity in vivo.

  View details for Web of Science ID A1985AMN2600012

  View details for PubMedID 2863111

• ELECTROPHYSIOLOGY OF THE ENANTIOMERS OF DISOPYRAMIDE IN DOGS JOURNAL OF CARDIOVASCULAR PHARMACOLOGY Giacomini, J. C., Giacomini, K. M., Nelson, W. L., HARRISON, D. C., Blaschke, T. F. 1985; 7 (5): 884-890

  Abstract

  The antiarrhythmic agent disopyramide comprises two enantiomers. In the present study, we examined the effects of the individual enantiomers on in vivo electrophysiology in anesthetized, closed-chest dogs. Six dogs received d-disopyramide, seven received l-disopyramide, and three dogs served as controls. Electrophysiologic measurements were performed at a series of geometrically increasing steady-state plasma concentrations of d- or l-disopyramide. Concentration-response curves were constructed for each electrophysiologic parameter, and the slopes of the regression lines of response versus plasma concentration were compared between enantiomers. Electrophysiologic parameters in the control dogs did not significantly change with time. However, stereoselective electrophysiologic effects were observed, with l-disopyramide being more potent than d-dispopyramide in prolonging sinus cycle length, Wenckebach cycle length, and atrioventricular nodal refractoriness (p less than 0.05). These findings are consistent with the established increased anticholinergic activity of the d-enantiomer which appeared to offset its local anesthetic or sodium channel inhibiting properties. Interrelationships between the autonomic nervous system and the cardiac electrophysiologic effects of disopyramide may be important in its antiarrhythmic effects.

  View details for Web of Science ID A1985ARF5000011

  View details for PubMedID 2413296

• EFFECT OF CONCENTRATION-DEPENDENT BINDING TO PLASMA-PROTEINS ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF DISOPYRAMIDE CLINICAL PHARMACOKINETICS Giacomini, K. M., Blaschke, T. F. 1984; 9: 42-48

  Abstract

  Disopyramide exhibits concentration-dependent binding to plasma proteins at therapeutic plasma concentrations. This paper reviews the effect of this type of binding on both the pharmacokinetic and pharmacodynamic properties of the drug. For a drug with capacity-limited, binding-sensitive elimination like disopyramide, concentration-dependent binding to plasma proteins produces a non-linear relationship between dosing rate and total plasma concentrations of the drug. However, when dosing rate is related to unbound concentrations of drug, the relationship is linear. Renal clearance of total disopyramide has been found to depend on the unbound fraction whereas renal clearance of unbound drug may be dependent upon time after drug administration as well as route of drug administration. However, due to some potential methodological problems, these data need verification. The concentration-dependent binding of disopyramide to plasma proteins, with its resultant effects on clearance and distribution, produces a concave curvature in the log unbound concentration versus time curves and a log-linear decline in total plasma concentration versus time after intravenous administration of the drug. Several pharmacological studies suggest that the unbound drug is active in terms of producing both desirable and undesirable effects. Hence, monitoring unbound concentrations of disopyramide seems more rational for clinical purposes. The few studies that have been carried out examining the optical isomers of disopyramide have suggested that both the pharmacokinetic and pharmacodynamic properties of the drug are stereoselective. Recent data reveal stereoselective binding to plasma proteins in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1984SK72300006

  View details for PubMedID 6705426

• HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHIC ANALYSIS OF HYPOXANTHINE ARABINOSIDE IN PLASMA JOURNAL OF CHROMATOGRAPHY Smith, G. A., Giacomini, K. M., Smith, C. T., Gregory, P. B., Robinson, W. S., Merigan, T. C., Blaschke, T. F. 1984; 307 (2): 410-415

  View details for Web of Science ID A1984SU47300019

  View details for PubMedID 6203924

• AMITRIPTYLINE DISPOSITION IN YOUNG AND ELDERLY NORMAL MEN CLINICAL PHARMACOLOGY & THERAPEUTICS Schulz, P., TURNERTAMIYASU, K., Smith, G., Giacomini, K. M., Blaschke, T. F. 1983; 33 (3): 360-366

  Abstract

  The disposition of a single parenteral or single oral dose of amitriptyline was followed in seven young (mean age 22 yr, range 21 to 23) and five elderly (mean age 71 yr, range 62 to 81) healthy men. The mean systemic clearance did not change with age (10.8 +/- 2.1 ml/min/kg in elderly and 12.5 +/- 2.3 ml/min/kg in young subjects). Mean t 1/2 was longer in the older (21.7 +/- 2.9 hr) than in the younger group (16.2 +/- 6.1 hr) as a result of an increase in the volume of distribution (17.1 +/- 2.4 and 14.1 +/- 2.0 l/kg). The bioavailability and the fraction of the drug bound to plasma proteins did not change with age. Single doses of amitriptyline were not well tolerated clinically by either elderly or young subjects, which confirms the need for a gradual buildup in the therapeutic regimen and for close clinical surveillance of elderly depressed patients treated with amitriptyline.

  View details for Web of Science ID A1983QG80300015

  View details for PubMedID 6825390

• EFFECT OF LOW-DOSES OF HEPARIN ON THE PLASMA-BINDING OF PHENYTOIN AND PRAZOSIN IN NORMAL MAN EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY Schulz, P., Giacomini, K. M., Luttrell, S., TURNERTAMIYASU, K., Blaschke, T. F. 1983; 25 (2): 211-214

  Abstract

  The effect of low doses of heparin on the binding of phenytoin and prazosin to plasma proteins was evaluated in four normal subjects. Heparin activates the hydrolysis of triglycerides in plasma. The ensuing increase in non-esterified fatty acids (NEFA) was more marked in vitro than in vivo and increased the free fraction (FF) of phenytoin and prazosin in plasma. The higher FF caused a change in the plasma to whole blood ratio (P/B ratio) of both drugs. The changes in FF and P/B ratio after heparin were small, but could be of significance in pharmacokinetic studies.

  View details for Web of Science ID A1983RK96000011

  View details for PubMedID 6628503

• EFFECT OF HEPARIN ON THE RED BLOOD CELL-TO-PLASMA CONCENTRATION RATIO OF DIPHENYLHYDANTOIN AND PRAZOSIN THERAPEUTIC DRUG MONITORING Schulz, P., ABANG, A., Giacomini, J. C., Blaschke, T. F., Giacomini, K. M. 1983; 5 (4): 497-499

  View details for Web of Science ID A1983RT93800019

  View details for PubMedID 6659020

• THE CARDIAC EFFECTS OF DISOPYRAMIDE ISOMERS Pollick, C., GIACOMINI, K., TURNERTAMIYASU, K., HUFNAGL, V., Blaschke, T. F., Popp, R. L. EXCERPTA MEDICA INC. 1982: 1003–

  View details for Web of Science ID A1982NF98000440

• ACETATE METABOLISM IN NORMAL HUMAN-SUBJECTS AMERICAN JOURNAL OF KIDNEY DISEASES Richards, R. H., Vreman, H. J., Zager, P., Feldman, C., Blaschke, T., Weiner, M. W. 1982; 2 (1): 47-57

  View details for Web of Science ID A1982PB51800007

  View details for PubMedID 6808830

• THE EFFECT OF SATURABLE BINDING TO PLASMA-PROTEINS ON THE PHARMACOKINETIC PROPERTIES OF DISOPYRAMIDE JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS Giacomini, K. M., SWEZEY, S. E., TURNERTAMIYASU, K., Blaschke, T. F. 1982; 10 (1): 1-14

  Abstract

  Disopyramide exhibits saturable binding to plasma proteins in the therapeutic plasma concentration range. Because of this property, controversy exists in the literature regarding the pharmacokinetic properties of the drug. The purposes of this study were to reassess the pharmacokinetic properties of disopyramide in humans, taking into consideration both total and unbound concentrations and to use disopyramide as a model compound to study the effect of drug binding on the renal clearance of both total and unbound drug. A single intravenous dose of disopyramide (1.5 mg/kg) was administered to eight normal volunteers. Blood and urine samples were collected for 36 h. Total concentrations of disopyramide in plasma and urine were determined by high pressure liquid chromatography. Binding of disopyramide to plasma proteins was determined by equilibrium dialysis. In all subjects the binding of disopyramide to plasma proteins was saturable, but there were considerable differences in binding between subjects. The volume of distribution, total body clearance, and renal clearances of both total and unbound drug were calculated. Because only the total body clearance and renal clearance of unbound compound are not dependent upon unbound fraction (alpha), these are the only parameters which can be reported without qualification as to the concentration. The mean +/-DS total body clearance of unbound drug in the eight subjects was 5.40 +/- 2.80 ml/min/kg. About 50% of this was due to renal elimination. A statistically significant negative correlation of the renal clearance of total disopyramide with time was observed in seven of eight subjects, whereas a significant correlation between the renal clearance of unbound disopyramide and time was observed in only one subject. This suggests that the renal clearance of unbound disopyramide is independent of alpha, while the renal clearance of total disopyramide is dependent upon alpha.

  View details for Web of Science ID A1982NL23900001

  View details for PubMedID 7069575

• THE CARDIAC EFFECTS OF D-DISOPYRAMIDE AND L-DISOPYRAMIDE IN NORMAL SUBJECTS - A NON-INVASIVE STUDY CIRCULATION Pollick, C., Giacomini, K. M., Blaschke, T. F., Nelson, W. L., TURNERTAMIYASU, K., BRISKIN, V., Popp, R. L. 1982; 66 (2): 447-453

  Abstract

  Commercially available disopyramide is a racemic mixture of equal parts of dextrorotatory (d-) and levorotatory (l-) optical isomers. We studied the cardiac effects of i.v. administration of each isomer and the racemic mixture (dl-) in six normal males by digitized echocardiography, systolic time intervals and ECG. Both isomers and the racemic mixture produced equally marked dose-dependent negative inotropic effects (28.1 +/- 11.8% mean maximal reduction in fractional shortening of left ventricular dimension) and diastolic effects (28.6 +/- 24.1% mean maximal reduction in peak left ventricular filling rate). However, only the d-isomer prolonged QTc duration (by 13.6 +/- 5.2% at maximum, p less than 0.001 vs l-isomer). We conclude that disopyramide, in the doses used, produces marked adverse effects on left ventricle systolic and diastolic function in normal subjects independent of optical rotation. The production of these effects by the l-isomer without affecting QTc duration suggests different subcellular mechanisms for the myocardial depressant effects and some of the electrophysiologic effects of disopyramide.

  View details for Web of Science ID A1982NY67700029

  View details for PubMedID 7094252

• HIGH-PRESSURE LIQUID-CHROMATOGRAPHIC DETERMINATION OF AMITRIPTYLINE AND ITS MAJOR METABOLITES IN HUMAN WHOLE-BLOOD JOURNAL OF PHARMACEUTICAL SCIENCES Smith, G. A., Schulz, P., Giacomini, K. M., Blaschke, T. F. 1982; 71 (5): 581-583

  Abstract

  A sensitive, specific, high-pressure liquid chromatographic method using an internal standard was developed for the determination of amitriptyline and its major metabolites in whole blood. Analysis was carried out on a microparticulate silica column with a mobile phase consisting of acetonitrile-methanol-aqueous ammonium hydroxide (93:7:0.4). Linear calibration curves ranging to 250 ng/ml were obtained for all compounds using UV absorbance detection at 220 nm. The lower limit of detection was 2 ng/ml for amitriptyline and 10-hydroxyamitriptyline, and 6 and 16 ng/ml for nortriptyline and its 10-hydroxylated metabolite, respectively. Human whole blood samples collected after single intravenous and single oral doses can be analyzed using this procedure.

  View details for Web of Science ID A1982NQ08700023

  View details for PubMedID 7097507

• EFFECT OF NALOXONE, A SPECIFIC OPIOID INHIBITOR, ON BLOOD-PRESSURE FALL DURING SLEEP CIRCULATION Rubin, P., Blaschke, T. F., Guilleminault, C. 1981; 63 (1): 117-121

  Abstract

  The study was designed to investigate the possible role of endogenous opioids in the fall in blood pressure (BP) seen during initial sleep. Seven normal men, ages 20-30 years, were studied for three consecutive nights. Each night, electroencephalogram, chin electromyogram, electrooculogram, heart rate (all continuously), and blood pressure (every 15 minutes) were recorded. Night 1 was used for orientation. On nights 2 and 3, subjects received, in randomized order, an infusion of naloxone 0.2 mg/kg over 1 minute or volume-matched saline. Blood pressure data from the first 4 hours of non-rapid eye movement sleep were combined. On the placebo night, systolic BP fell from 114.6 +/- 6 mm Hg to 103.7 +/- 8 mm Hg (+/- SD) (p < 0.05, Wilcoxon rank-sum test). On the naloxone night, systolic BP did not change. Neither diastolic BP nor heart rate were influenced by naloxone. these data suggest that endogenous opioids could be involved in the fall in systolic BP seen during initial sleep.

  View details for Web of Science ID A1981KV09600015

  View details for PubMedID 7438385

• VITAMIN-K1, VITAMIN-K1 EPOXIDE AND WARFARIN INTERRELATIONSHIPS IN THE DOG BIOCHEMICAL PHARMACOLOGY Carlisle, D. M., Blaschke, T. F. 1981; 30 (21): 2931-2936

  View details for Web of Science ID A1981MQ81400008

  View details for PubMedID 7317089

• FUROSEMIDE DISPOSITION IN CIRRHOTIC-PATIENTS GASTROENTEROLOGY Sawhney, V. K., Gregory, P. B., SWEZEY, S. E., Blaschke, T. F. 1981; 81 (6): 1012-1016

  Abstract

  Furosemide disposition in 7 cirrhotic subjects and 4 age-matched healthy controls was studied to determine the contribution of differences in pharmacokinetics to the decreased responsiveness observed in cirrhotics. Subjects were given 80 mg of furosemide orally and intravenously on separate occasions, and plasma and urine samples were collected and analyzed for furosemide by high performance liquid chromatography. The half-life of furosemide was 74% greater in the cirrhotic subjects, the result of a smaller increase in volume of distribution (30%) and a decrease in total plasma clearance (15%). The change in plasma clearance was due entirely to a change in nonrenal clearance, since renal clearance was very similar in both groups. The fraction of furosemide not bound to plasma proteins increased by 48%. Furosemide bioavailability was the same in cirrhotic subjects and controls. Consistent with other reports, there was considerable intersubject variability in all of the measured and computed parameters. The results show that differences in disposition play little, if any, role in the decreased renal responsiveness to furosemide.

  View details for Web of Science ID A1981MP88900006

  View details for PubMedID 7286579

• SYNTHESIS AND ANTICHOLINERGIC PROPERTIES OF THE ENANTIOMERS OF 4-(ISOPROPYLAMINO)-2-(2-PYRIDYL)-2-PHENYLBUTYRAMIDE, THE MONO-N-DEALKYLATED METABOLITE OF DISOPYRAMIDE JOURNAL OF MEDICINAL CHEMISTRY Nelson, W. L., SNEED, C. K., Giacomini, K. M., Giacomini, J. C., Stauss, J., Blaschke, T. F., Cox, B. M. 1981; 24 (5): 614-617

  Abstract

  The 2R and 2S enantiomers of 4-isopropyl-2-(2-pyridyl)-2-phenylbutyramide [(2R)-2 and (2S)-2] were prepared from the respective 2R and 2S enantiomers of disopyramide [(2R)-1 and (2S)-1] by oxidation with peracid, Cope elimination, and subsequent zinc/HCl reduction of the resulting hydroxylamines (2R)-3 and (2S)-3. The enantiomers were tested as antagonists to the contraction of guinea pig ileum longitudinal muscle produced in response to electrically stimulated release of acetylcholine. The enantiomers showed IC50 values of 5.0 X 10(-6) and 14 X 10(-6) M for (2S)-2 and (2R)-2 respectively, about a 3-fold difference between enantiomers. Data are presented showing direct antagonism of acetylcholine in the guinea pig ileum assay. In a comparison of the anticholinergic effects of 2 and 1, the metabolite (2) was slightly less potent than disopyramide (1).

  View details for Web of Science ID A1981LM55600024

  View details for PubMedID 7241519

• Acetate metabolism and acid-base homeostasis during hemodialysis: influence of dialyzer efficiency and rate of acetate metabolism. Kidney international. Supplement Vreman, H. J., ASSOMULL, V. M., Kaiser, B. A., Blaschke, T. F., Weiner, M. W. 1980; 10: S62-74

  View details for PubMedID 6934339

• COMPARATIVE ANTICHOLINERGIC POTENCIES OF R-DISOPYRAMIDE AND S-DISOPYRAMIDE IN LONGITUDINAL MUSCLE STRIPS FROM GUINEA-PIG ILEUM LIFE SCIENCES Giacomini, K. M., Cox, B. M., Blaschke, T. F. 1980; 27 (13): 1191-1197

  View details for Web of Science ID A1980KJ24000011

  View details for PubMedID 7421405

• ACETATE METABOLISM AND ACID-BASE HOMEOSTASIS DURING HEMODIALYSIS - INFLUENCE OF DIALYZER EFFICIENCY AND RATE OF ACETATE METABOLISM KIDNEY INTERNATIONAL Vreman, H. J., ASSOMULL, V. M., Kaiser, B. A., Blaschke, T. F., Weiner, M. W. 1980; 18: S62-S74

  View details for Web of Science ID A1980KP08500013

• SALIVA AND PLASMA-LEVELS AND PLASMA-PROTEIN BINDING OF CLOFIBRINIC ACID IN UREMIC PATIENTS CLINICAL PHARMACOLOGY & THERAPEUTICS Bjornsson, T. D., MEFFIN, P. J., PETERS, F. A., Blaschke, T. F. 1980; 27 (2): 230-235

  Abstract

  Clofibrinic acid in saliva and plasma and its plasma protein binding were determined in 18 patients with renal impairment after a single 2-gm dose of clofibrate. A weak but significant correlation (r2 = 0.378; p less than 0.02) between free plasma and saliva levels of clofibrinic acid was found. The free fraction of clofibrinic acid in plasma is higher (p less than 0.02) in long-term hemodialysis patients (0.0915 +/- 0.0141) than in nondialysis patients (0.0715 +/- 0.0143). During dialysis, 2 hemodialysis patients had a free fraction more than twice as high (mean, 0.2083) as that in the other hemodialysis patients who were studied on interdialysis days. These observations suggest that saliva pH determinations are essential for optimal interpretation of saliva to plasma level ratios of weakly acidic drugs and that, during hemodialysis, patients may temporarily be exposed to increased risks of drug toxicity due to rises in free concentrations of drugs.

  View details for Web of Science ID A1980JF71700014

  View details for PubMedID 7353345

• STUDIES ON THE CLINICAL-PHARMACOLOGY OF PRAZOSIN .2. THE INFLUENCE OF INDOMETHACIN AND OF PROPRANOLOL ON THE ACTION AND DISPOSITION OF PRAZOSIN BRITISH JOURNAL OF CLINICAL PHARMACOLOGY Rubin, P., Jackson, G., Blaschke, T. 1980; 10 (1): 33-39

  Abstract

  1 The possibility of pharmacodynamic and pharmacokinetic interactions of prazosin with indomethacin and with propranolol have been studied in healthy subjects. 2 In four out of nine individuals indomethacin considerably attenuated prazosin-induced hypotension, but noradrenaline concentrations were unchanged from the day when blood pressure fell greatly. The effect of prazosin in the other five subjects was not influenced by indomethacin. 3 Indomethacin prevented the rise in plasma renin activity seen following administration of prazosin alone. 4 Propranolol did not prevent the syncope associated with the first dose of prazosin. 5 Propranolol affected neither the absorption nor elimination of prazosin. 6 It is concluded that in certain subjects indomethacin can largely prevent the hypotensive effect of parazosin, possible by increasing adrenergic receptor sensitivity. The theoretical possibility that propranolol could influence prazosin disposition or syncope was not substantiated.

  View details for Web of Science ID A1980KA84800004

  View details for PubMedID 7397054

• PRAZOSIN PROTEIN-BINDING IN HEALTH AND DISEASE BRITISH JOURNAL OF CLINICAL PHARMACOLOGY Rubin, P., Blaschke, T. 1980; 9 (2): 177-182

  View details for Web of Science ID A1980JF54600009

  View details for PubMedID 7356906

• STUDIES ON THE CLINICAL-PHARMACOLOGY OF PRAZOSIN .1. CARDIOVASCULAR, CATECHOLAMINE AND ENDOCRINE CHANGES FOLLOWING A SINGLE DOSE BRITISH JOURNAL OF CLINICAL PHARMACOLOGY Rubin, P. C., Blaschke, T. F. 1980; 10 (1): 23-32

  View details for Web of Science ID A1980KA84800003

  View details for PubMedID 6994759

• EFFECT OF NALOXONE ON BLOOD-PRESSURE FALL DURING INITIAL SLEEP IN MAN Rubin, P., Blaschke, T., Guilleminault, C. PORTLAND PRESS LTD. 1980: P28–P28

  View details for Web of Science ID A1980JD41500112

• EFFECT OF NALOXONE ON BLOOD-PRESSURE FALL DURING INITIAL SLEEP IN MAN Rubin, P., Blaschke, T., Guilleminault, C. SLACK INC. 1980: A243–A243

  View details for Web of Science ID A1980JN16000549

• STEREOSPECIFIC ELIMINATION OF DISOPYRAMIDE IN THE DOG Giacomini, K. M., Giacomini, J. C., SWEZEY, S. E., HARRISON, D. C., Blaschke, T. F. SLACK INC. 1980: A69–A69

  View details for Web of Science ID A1980JB49200407

• ABSENCE OF EFFECT OF HEPARIN ON THE BINDING OF PRAZOSIN AND PHENYTOIN TO PLASMA-PROTEINS BIOCHEMICAL PHARMACOLOGY Giacomini, K. M., Giacomini, J. C., Blaschke, T. F. 1980; 29 (24): 3337-3340

  View details for Web of Science ID A1980KX34600021

  View details for PubMedID 7213407

• HEPARIN DECREASES PLASMA-PROTEIN BINDING OF DRUGS GIACOMINI, K., Giacomini, J., Blaschke, T. NATURE PUBLISHING GROUP. 1980: 256–56

  View details for Web of Science ID A1980JF71700062

• ADMINISTRATION OF HEPARIN CAUSES INVITRO RELEASE OF NON-ESTERIFIED FATTY-ACIDS IN HUMAN-PLASMA LIFE SCIENCES Giacomini, K. M., SWEZEY, S. E., Giacomini, J. C., Blaschke, T. F. 1980; 27 (9): 771-780

  View details for Web of Science ID A1980KF14500009

  View details for PubMedID 7412503

• THE STEREOSELECTIVE DISPOSITION OF DISOPYRAMIDE IN THE DOG JOURNAL OF CARDIOVASCULAR PHARMACOLOGY Giacomini, K. M., Giacomini, J. C., SWEZEY, S. E., HARRISON, D. C., Nelson, W. L., Burke, T. R., Blaschke, T. F. 1980; 2 (6): 825-832

  Abstract

  The disposition of d-, 1-, and d,1-disopyramide was studied in 5 conscious dogs after intravenous administration (15 mg/kg) of each compound using a balanced crossover design. The clearance of d-disopyramide (15.4 +/- 5.10 ml/min/kg) was significantly greater than that of the l-isomer (9.45 +/- 2.52 ml/min/kg) (p < 0.001). The clearance of the d,1-mixture was intermediate between that obtained for the d- and l-isomers. The steady-state volume of distribution of the three compounds was similar (approximately 1.4 liters/kg). The elimination half-life reflected differences in clearance, being 76.4 +/- 7.30 min for d-disopyramide, 112 +/- 23.4 min for 1-disopyramide, and 97.2 +/- 15.1 min for d,1-disopyramide. The effect of general anesthesia with urethane and chloralose on the disposition of the compounds was also examined. General anesthesia decreased the clearance and increased the half-life of all three compounds. No consistent differences in the volume of distribution were observed with anesthesia as compared to control. Thus, there is stereoselective elimination of the optical isomers of disopyramide in the dog, and general anesthesia decreases the clearance of d-, 1-, and d,1-disopyramide.

  View details for Web of Science ID A1980KM24300011

  View details for PubMedID 6160331

• CLOFIBRATE DISPLACES WARFARIN FROM PLASMA-PROTEINS IN MAN - EXAMPLE OF A PURE DISPLACEMENT INTERACTION JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Bjornsson, T. D., MEFFIN, P. J., Swezey, S., Blaschke, T. F. 1979; 210 (3): 316-321

  Abstract

  Clofibrate is known to potentiate the anticoagulant effect of warfarin during chronic administration. We examined the disposition of racemic warfarin in four healthy volunteers before and during clofibrate coadministration using an intravenous-continuous oral sequence of warfarin administration. An interaction between warfarin and clofibrate, evidenced by longer prothrombin and prothrombin-proconvertin times, was seen in all four subjects. Clofibrate caused a displacement of warfarin from plasma protein binding sites, with a 13% increase in the free drug fraction in plasma. As predicted from theoretical considerations, this displacement resulted in a small (18%) increase in the steady-state volume of distribution, and an increase in total plasma clearance, which, for warfarin, is independent on the free fraction of drug in plasma. The net effect of these changes is that the free concentration of warfarin was not changed during clofibrate coadministration, although total plasma concentrations were lower. This study documents the occurrence in man of a displacement pharmacokinetic interaction between clofibrate and warfarin. However, this pharmacokinetic interaction does not account for the clinical interaction between the two drugs, since free warfarin concentrations are unchanged.

  View details for Web of Science ID A1979HN29300002

  View details for PubMedID 480183

• PLASMA-CATECHOLAMINES IN MAN ARE NOT INFLUENCED BY THE INHIBITION OF PROSTAGLANDIN SYNTHESIS PROSTAGLANDINS Rubin, P., Blaschke, T. 1979; 17 (4): 581-585

  Abstract

  Indomethacin has been reported to potentiate the release of noradrenaline from sympathetic nerve endings in vitro and to increase urinary noradrenaline excretion in rats. We have studied the influence of indomethacin on plasma catecholamine levels in 10 normal men, using measurement of plasma renin activity (PRA) as an index of the pharmacodynamic effect of indomethacin. Both in the supine and standing positions indomethacin failed to alter the plasma concentrations of noradrenaline, adrenaline or dopamine, while PRA was markedly suppressed. It is concluded that in the intact human indomethacin does not influence catecholamine concentrations.

  View details for Web of Science ID A1979GV64100009

  View details for PubMedID 461821

• PRAZOSIN 1ST-PASS METABOLISM AND HEPATIC EXTRACTION IN THE DOG JOURNAL OF CARDIOVASCULAR PHARMACOLOGY Rubin, P., Yee, Y. G., Anderson, M., Blaschke, T. 1979; 1 (6): 641-647

  Abstract

  The short half-life, low plasma concentrations, and extensive biotransformation of prazosin suggest that it might be subject to extensive first-pass metabolism. Bioavailability, disposition, and hepatic extraction were studied in the dog. In conscious dogs whole blood prazosin concentrations were measured after oral and intravenous administration of the drug. Anesthetized dogs were used to measure prazosin concentrations in arterial and hepatic venous blood samples drawn simultaneously. The bioavailability of prazosin was 0.38 +/- 0.11. In anesthetized dogs the hepatic extraction of prazosin was 0.47 +/- 0.08 for a predicted availability of 0.53 +/- 0.08. Pharmacokinetic parameters were similar in conscious and anesthetized animals. Following intravenous administration to conscious dogs, prazosin concentrations in whole blood declined with a fast half-life of 3.9 +/- 1.74 min and a slow half-life of 153 +/- 24 min, the volume of distribution at steady state being 48.6 +/- 15.3 liters in dogs (mean weight, 22.6 kg). We conclude that prazosin availability following oral administration is low and that first-pass hepatic metabolism is largely responsible for this. A one-compartment model adequately describes prazosin pharmacokinetics in the dog.

  View details for Web of Science ID A1979HZ88300005

  View details for PubMedID 94630

• INFLUENCE OF CONGESTIVE HEART-FAILURE ON PRAZOSIN KINETICS CLINICAL PHARMACOLOGY & THERAPEUTICS Jaillon, P., Rubin, P., Yee, Y. G., Ball, R., Kates, R., Harrison, D., Blaschke, T. 1979; 25 (6): 790-794

  Abstract

  The kinetics of oral prazosin was studied in 10 healthy normal subjects (NS) and in 9 patients with congestive heart failure (CHF). NS received a single 5-mg dose, and blood concentrations of prazosin (CB) were measured, using a specific HPLC assay, during an 8-hr period. CHF patients received a 2-mg dose after which CB was measured for 10 hr. These patients then received 2 to 5 mg prazosin every 8 hr for 48 hr. After the last dose of prazosin, CB was measured for 24 hr. After the initial dose, time to peak CB did not differ significantly between that of the NS (123 +/- 19 SEM min) and of patients with CHF (132 +/- 31.3 min). AUC/mg prazosin was greater (p less than 0.001) in patients with CHF (3,385 +/- 380 Ng x min/ml) than in NS (1,603 +/- 208 ng x min/ml). Elimination of prazosin from blood was slower in CHF patients (t1/2 = 374 +/- 33.4 min) than in NS (t1/2 = 144.5 +/- 4.3 min) (p less than 0.001). These data suggest that in patients with CHF the elimination of prazosin is substantially slower than in NS and therefore higher steady-state prazosin concentrations can be expected in CHF patients than in NS.

  View details for Web of Science ID A1979GZ19600005

  View details for PubMedID 445945

• PHARMACOKINETICS OF ORAL PRAZOSIN IN NORMAL SUBJECTS AND IN PATIENTS WITH CONGESTIVE HEART-FAILURE Jaillon, P., Rubin, P., Yee, Y. G., Kates, R., Blaschke, T., Harrison, D. MOSBY-YEAR BOOK INC. 1979: 231–31

  View details for Web of Science ID A1979GJ78500082

• PRAZOSIN STIMULATES RENIN RELEASE AND INDOMETHACIN REVERSES THIS EFFECT Rubin, P., Blaschke, T. SLACK INC. 1979: A74–A74

  View details for Web of Science ID A1979GC72700433

• EFFECTS OF CLOFIBRATE AND WARFARIN ALONE AND IN COMBINATION ON THE DISPOSITION OF VITAMIN-K1 JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Bjornsson, T. D., MEFFIN, P. J., SWEZEY, S. E., Blaschke, T. F. 1979; 210 (3): 322-326

  Abstract

  Clofibrate may interact with warfarin by potentiating its effects on vitamin K disposition. To examine this possibility, specifically labeled [3H]vitamin K was given intravenously to four healthy volunteers under conditions of no drug administration, administration of warfarin or clofibrate alone, or co-administration of both drugs. Clofibrate alone did not affect the disposition of tritiated vitamin K. Warfarin alone produced an accumulation in plasma of substantial amounts of vitamin K epoxide, a metabolite of vitamin K which is reconverted to vitamin K by a specific reductase. Although reconversion is apparently blocked to a large extent by warfarin, the plasma disappearance of tritiated vitamin K in the presence of warfarin is almost superimpossible to that observed in the absence of drugs. Clofibrate coadministration did not result in greater accumulation of vitamin K epoxide in plasma. These results indicate that clofibrate does not enhance the inhibition of the reductase enzyme. Analysis of the tritiated vitamin K plasma disappearance data indicates that the pool size of vitamin K in the body is small, and is turned over almost 10 times daily. The vitamin K epoxide data suggest that, in the absence of drugs, a relatively small proportion of the epoxide is reconverted to the vitamin.

  View details for Web of Science ID A1979HN29300003

  View details for PubMedID 480184

• NALOXONE LOWERS PLASMA-PROLACTIN IN MAN LANCET Rubin, P., Swezey, S., Blaschke, T. 1979; 1 (8129): 1293-1293

  View details for Web of Science ID A1979GZ98900025

  View details for PubMedID 87748

• HEPATIC 1ST-PASS METABOLISM IN LIVER-DISEASE CLINICAL PHARMACOKINETICS Blaschke, T. F., Rubin, P. C. 1979; 4 (6): 423-432

  View details for Web of Science ID A1979HW47100002

  View details for PubMedID 391462

• ATENOLOL DETERMINATION BY HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY AND FLUORESCENCE DETECTION JOURNAL OF CHROMATOGRAPHY Yee, Y. G., Rubin, P., Blaschke, T. F. 1979; 171 (APR): 357-362

  Abstract

  A high-performance liquid chromatographic procedure using a fluorescence detector for the analysis of atenolol in plasma and whole blood is described. It employs a simple and rapid method of preparation. Atenolol and metoprolol as the internal standard are chromatographed as ion pairs with heptanesulfonic acid. The method is sensitive and reproducible with accurate detection at concentrations as low as 2 ng/ml in whole blood and plasma, and a coefficient of variation of 4.7% over the range 2 ng/ml to 1000 ng/ml.

  View details for Web of Science ID A1979GS38300036

  View details for PubMedID 546856

• ENHANCED BIOAVAILABILITY AND DECREASED CLEARANCE OF ANALGESICS IN PATIENTS WITH CIRRHOSIS GASTROENTEROLOGY NEAL, E. A., MEFFIN, P. J., Gregory, P. B., Blaschke, T. F. 1979; 77 (1): 96-102

  Abstract

  The effect of moderate cirrhosis on the bioavailability and systemic clearance of three model analgesic compounds (pethidine, pentazocine, and salicylamide) with substantial first-pass metabolism was examined in 8 cirrhotic subjects and 4 agematched healthy controls. There was a 46% decrease in the clearance of pentazocine and a 278% increase in bioavailability. The corresponding figures for pethidine were 36% and 81%. The area under the plasma curve after oral salicylamide was increased by 551% in cirrhotic subjects compared with controls. This study demonstrated that drugs with the highest hepatic clearance will have the largest relative increases in bioavailability in cirrhotic patients due to portosystemic shunting. The decrease in clearance and increase in bioavailability will have multiplicative, rather than simply additive, effects on total area under the curve and, if related, pharmacologic response.

  View details for Web of Science ID A1979GZ61000016

  View details for PubMedID 447033

• PRAZOSIN MECHANISM IN MAN - CARDIAC AND NEURO-ENDOCRINE CHANGES FOLLOWING A SINGLE DOSE Rubin, P., Blaschke, T. SLACK INC. 1979: A237–A237

  View details for Web of Science ID A1979GR63100558

• QUANTITATION OF RADIO-LABELED VITAMIN-K1 AND VITAMIN-K1 EPOXIDE IN PLASMA BY HIGH-PRESSURE LIQUID-CHROMATOGRAPHY THROMBOSIS AND HAEMOSTASIS Bjornsson, T. D., SWEZEY, S. E., MEFFIN, P. J., Blaschke, T. F. 1978; 39 (2): 466-473

  Abstract

  A convenient, accurate and reproducible high pressure liquid chromatographic method for the quantitation of radio-labelled vitamin K1 and vitamin K1 epoxide in plasma is described. The method involves the determination of total ether extractable radioactivity, and a chromatographic separation to determin the relative quantities of radio-labelled vitamin K1 and vitamin K1 epoxide. The method is useful over a wide range of ratios of the two compounds, and has a coeffcient of variation of approximately 5%.

  View details for Web of Science ID A1978FE73500021

  View details for PubMedID 580994

• DISPOSITION OF ACETONE FOLLOWING ACUTE ACETONE INTOXICATION WESTERN JOURNAL OF MEDICINE Ramu, A., Rosenbaum, J., Blaschke, T. F. 1978; 129 (5): 429-432

  View details for Web of Science ID A1978FZ62200021

  View details for PubMedID 726426

  View details for PubMedCentralID PMC1238409

• PROBENECID INHIBITION OF METHOTREXATE CEREBROSPINAL FLUID PHARMACOKINETICS IN DOGS CANCER TREATMENT REPORTS Ramu, A., FUSNER, J. E., Blaschke, T., Glaubiger, D. L. 1978; 62 (10): 1465-1470

  Abstract

  Cerebrospinal fluid (CSF) and plasma concentrations of methotrexate (MTX) were followed in dogs for 72 hours after intracisternal injection of MTX with and without probenecid pretreatment. CSF levels declined as a biexponential function of time. Probenecid pretreatment of the animals prolonged the second phase half-disappearance time of MTX from 5.20 +/- 0.89 to 7.086 +/- 0.23 hours (mean +/- SD). The peak mean plasma concentration of MTX was lower in the presence of probenecid. Also, the rate of decline of plasma MTX concentrations was slower after treatment with probenecid, with mean half-disappearance times of 7.60 +/- 0.77 and 11.32 +/- 1.08 hours. These CSF and plasma data support the proposal that probenecid inhibits the transfer of MTX from CSF to blood.

  View details for Web of Science ID A1978FZ91700008

  View details for PubMedID 581360

• PROBENECID INHIBITION OF METHOTREXATE EXCRETION FROM CEREBROSPINAL-FLUID IN DOGS JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS Ramu, A., GLAUBIGER, D., RAMU, N. P., Eldridge, N., Blaschke, T. F. 1978; 6 (5): 389-397

  View details for Web of Science ID A1978FX06700003

  View details for PubMedID 731407

• INDOCYANINE GREEN KINETICS IN HEPATIC DISEASE Williams, R. L., Blaschke, T. F., MEFFIN, P. J., Tozer, T. N., Rowland, M. SLACK INC. 1977: A278–A278

  View details for Web of Science ID A1977DB15800468

• PROTEIN-BINDING AND KINETICS OF DRUGS IN LIVER-DISEASES CLINICAL PHARMACOKINETICS Blaschke, T. F. 1977; 2 (1): 32-44

  Abstract

  Although the liver is the major site for drug biotransformation, the effect of hepatic dysfunction on drug disposition has not been consistent or predictable. Most early studies of drug kinetics in liver disease measured only half-life. Only in the past few years has it been realised that liver diseases can affect drug absorption, hepatic metabolism, tissue distribution, and protein binding, which complicate interpretation of any change, or lack of change in drug half-life. Furthermore, it is now apparent that the efficiency with which a drug is metabolised by the liver, the extent of binding to blood constituents, and the aetiology and stage of the hepatic disorder are each important in determining whether significant alterations in drug disposition will occur. A pharmacokinetic perfusion model which takes into account many of the above factors has been proposed, and appears to be useful for predicting changes in the disposition of rapidly metabolised compounds. Nevertheless, the state of knowledge about those factors which limit the rate of metabolism of individual drugs or classes of drugs in inadequate, and no general model or guidelines which are useful clinically have been developed. Patients with hepatic disorders may show increases or decreases in sensitivity independent of alterations in drug disposition. The clinician caring for such patients must be cautious about the use of any drugs, and rely heavily on careful patient observation to determine efficacy or toxicity.

  View details for Web of Science ID A1977CW81800003

  View details for PubMedID 322909

• HIGH-PRESSURE LIQUID-CHROMATOGRAPHIC ANALYSIS OF DRUGS IN BIOLOGICAL-FLUIDS .4. DETERMINATION OF CLOFIBRINIC ACID JOURNAL OF CHROMATOGRAPHY Bjornsson, T. D., Blaschke, T. F., MEFFIN, P. J. 1977; 137 (1): 145-152

  Abstract

  A rapid, sensitive and specific high-pressure liquid chromatographic method is described for the quantitative analysis of clofibrinic acid in plasma, saliva and urine. In contrast to previously reported gas-liquid chromatographic methods, which require derivatization of clofibrinic acid before chromatography, the present method involves a simple two-step extraction procedure and chromatographic determination of the underivatized clofibrinic acid. Concentrations between 1.0 and 25.0 microgram per sample can be measured with a coefficient of variation from 1 to 6%.

  View details for Web of Science ID A1977DN19400015

  View details for PubMedID 893579

• INFLUENCE OF ACUTE VIRAL-HEPATITIS ON DISPOSITION AND PLASMA BINDING OF TOLBUTAMIDE CLINICAL PHARMACOLOGY & THERAPEUTICS Williams, R. L., Blaschke, T. F., MEFFIN, P. J., Melmon, K. L., Rowland, M. 1977; 21 (3): 301-309

  Abstract

  To study the influence of acute hepatic disease on the disposition of tolbutamide, we measured tolbutamide plasma protein binding and pharmacokinetic parameters after intravenous administration of the drug to 5 subjects during and after apparent recovery from acute viral hepatitis. Although during the acute phase of illness protein binding of the drug decreased in all, volume of distribution of tolbutamide (0.15 +/- 0.03 L/kg) did not change. Clearance based on total concentration of tolbutamide in plasma increased in all subjects during the acute phase of study (26 +/- 5.4 ml/hr/kg) in comparison to the recovery phase (18 +/- 2.8 ml/hr/kg, p less than 0.02). Protein binding decreased after unconjugated bilirubin was added to plasma from the recovery phase, but not to the extent observed during the acute phase of illness at comparable levels of bilirubin. Clearance based on unbound drug concentration, calculated by dividing the observed plasma clearance by the fraction of unbound drug in plasma, did not differ significantly between the 2 study phases (300 +/- 47 and 260 +/- 39 ml/hr/kg). These observations suggest that the increase in clearance based on total drug concentration in plasma during hepatitis can be attributed solely to decreased plasma binding. This decrease in binding may be attributed in part, but not entirely, to increased combination of bilirubin during illness. The concentration of unbound drug in plasma at steady-state is determined by the rate of drug administration and the clearance based on unbound drug. If this clearance does not change during hepatic disease, no dosage alterations for tolbutamide and other comparable drugs are necessary to maintain a constant concentration of unbound drug.

  View details for Web of Science ID A1977CZ47200009

  View details for PubMedID 837649

• RESPONSE OPTIMIZATION OF DRUG-DOSAGE - ANTIARRHYTHMIC STUDIES WITH TOCAINIDE CLINICAL PHARMACOLOGY & THERAPEUTICS MEFFIN, P. J., WINKLE, R. A., Blaschke, T. F., FitzGerald, J., HARRISON, D. C., HARAPAT, S. R., Bell, P. A. 1977; 22 (1): 42-57

  Abstract

  The benefits of using antiarrhythmic response to optimize dosage regimens of antiarrhythmic drugs in individual patients have been examined. Graded antiarrhythmic response and simultaneously measured plasma drug concentrations have been obtained in 15 patients receiving multiple oral doses of a new antiarrhythmic, tocainide. Plasma drug concentration-antiarrhythmic response data from each of 11 subjects responding to the drug have been fitted by a generalized concentration effect function which is valid over the entire range of response. With the use of experimentally determined pharmacokinetic parameters to define the dose-plasma concentration relationship and plasma drug concentration-response parameters estimated for individual patients, simulations were carried out to show the effect of various dosage regimens on antiarrhythmic response in individual patients. Such simulations provide a means of assessing antiarrhythmic effect in the range of clinical interest (80% to 100% of maximum effect), where the antiarrhythmic effect is a nonlinear function of dose, plasma drug concentration, or their logarithms. The simulations also demonstrate that for identical daily doses and dosing intervals patients show marked variability in antiarrhythmic response.

  View details for Web of Science ID A1977DN84100006

  View details for PubMedID 872495

• INTERACTION OF CLOFIBRATE WITH WARFARIN .1. EFFECT OF CLOFIBRATE ON DISPOSITION OF OPTICAL ENANTIOMORPHS OF WARFARIN JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS Bjornsson, T. D., MEFFIN, P. J., Blaschke, T. F. 1977; 5 (5): 495-505

  View details for Web of Science ID A1977EA27700005

  View details for PubMedID 925883

• ANTIPYRINE AND INDOCYANINE GREEN AS INDICATORS OF DRUG DISPOSITION DURING ACUTE VIRAL-HEPATITIS Williams, R. L., Blaschke, T. F., MEFFIN, P. J., Melmon, K. L., Rowland, M. SLACK INC. 1976: A259–A259

  View details for Web of Science ID A1976BU02800565

• NEW APPROACH TO QUANTITATION OF VARIOUS SOURCES OF BILIRUBIN IN MAN JOURNAL OF LABORATORY AND CLINICAL MEDICINE Berk, P. D., Blaschke, T. F., Scharschmidt, B. F., WAGGONER, J. G., Berlin, N. I. 1976; 87 (5): 767-780

  Abstract

  Studies of the "early labeling" of fecal bile pigment have been widely interpreted as indicating that 10 to 20 per cent of total bile pigment production in normal man is derived from the processes which give rise to the "early labeled" pigment peak (ELP). However, this conclusion is based on a very small number of studies with inherent experimental and analytic limitations. In the present study, a new experimental approach was employed. Plasma bilirubin turnover (BRT), total red blood cell volume (TRCV), and red cell survival were measured in 26 normal volunteers and 35 patients with various hepatic and/or hematologic disorders. The quantity of bilirubin derived from red blood cell degradation (BRRBC) was calculated from TRCV and the mean red cell life-span, and the difference between BRT and BRRBC, designated "excess bilirubin synthesis (EBS)," was considered to represent the quantity of bilirubin derived from the processes responsible for ELP. In normal volunteer subjects, EBS averaged 1.0 mg. per kilogram per day, and accounted for 25 per cent of daily bilirubin turnover. Hence, results derived by this approach exceeded the range estimated from analysis of "early labeled peak" data. Further analysis of the data in terms of a simple model of bilirubin sources was compatible with the hypothesis that EBS consists of an essentially constant component, averaging 0.8 mg. per kilogram per day, presumably derived principally from the liver, and a second component which varies with the erthropoietic rate. Hence, in normal man the liver may contribute the major fraction of EBS.

  View details for Web of Science ID A1976BQ36800005

  View details for PubMedID 1270887

• INFLUENCE OF VIRAL-HEPATITIS ON DISPOSITION OF 2 COMPOUNDS WITH HIGH HEPATIC CLEARANCE - LIDOCAINE AND INDOCYANINE GREEN CLINICAL PHARMACOLOGY & THERAPEUTICS Williams, R. L., Blaschke, T. F., MEFFIN, P. J., Melmon, K. L., Rowland, M. 1976; 20 (3): 290-299

  Abstract

  The disposition of lidocaine and indocyanine green was studied in 6 individuals during and after recovery from an episode of acute viral hepatitis. Both compounds are highly cleared from the blood by the liver so that clearance of both should be sensitive to changes in hepatic blood flow. During the acute phase of illness, clearance of indocyanine green decreased without apparent change in volume of distribution, whereas clearance of lidocaine, decreased in 4, did not change in 1, and increased in 1 during the acute phase of hepatitis. Volume changes for lidocaine were also variable. We observed no significant correlation between any parameters of lidocaine disposition and any of several tests of liver function or any parameters of indocyanine green disposition. The absence of correlation between pharmacokinetic parameters of the disposition of lidocaine and indocyanine green indicates that the influence of hepatic disease on the hepatic processes that lead to the elimination of each compound is not predictable. No useful clinical correlates are now available by means of which to predict lidocaine disposition in patients with altered hepatic function.

  View details for Web of Science ID A1976CE40100006

  View details for PubMedID 954351

• INFLUENCE OF ACUTE VIRAL-HEPATITIS ON DISPOSITION AND PHARMACOLOGIC EFFECT OF WARFARIN CLINICAL PHARMACOLOGY & THERAPEUTICS Williams, R. L., Schary, W. L., Blaschke, T. F., MEFFIN, P. J., Melmon, K. L., Rowland, M. 1976; 20 (1): 90-97

  Abstract

  Five patients received a small oral dose of warfarin during and after recovery from acute viral hepatitis. Mean (+/- SD) clearance, volume of distribution, and half-life of the drug were 6.1 +/- 0.9 ml/hr/kg, 0.09 +/- 0.04 L/kg, and 23 +/- 5 hr, respectively, during the acute period. After apparent recovery, observed values were 6.1 +/- 0.7 ml/hr/kg, 0.21 +/- 0.02 L/kg, and 25 +/- 3 hr. These differences were not significant. Pattern of renal elimination of warfarin metabolites and drug protein binding did not change between the two phases. During the acute period of illness, prothrombin time increased in 2 of the 5 subjects, but remained within normal limits in all participants during the recovery period. This study shows that warfarin disposition may not change as a consequence of mild or moderate hepatic impairment.

  View details for Web of Science ID A1976BX60600012

  View details for PubMedID 1277729

• INFLUENCE OF ACUTE VIRAL-HEPATITIS ON PHENYTOIN KINETICS AND PROTEIN-BINDING CLINICAL PHARMACOLOGY & THERAPEUTICS Blaschke, T. F., MEFFIN, P. J., Melmon, K. L., Rowland, M. 1975; 17 (6): 685-691

  Abstract

  Patients with liver disease are thought to have abnormal responses to drugs metabolized by the liver, although supportive evidence is sparse. The influence of acute viral hepatitis on the pharmacokinetics and protein binding of phenytoin (DPH) was examined in 5 patients. A longitudinal study design was used so that each patient acted as his own control. DPH clearance was unaffected by acute viral hepatitits over theconcentration range studie, but the percentage of unboudn DPH increased by an average of nearly one-third during acute viral hepatitis. A small decline in serum albumin concentration and elevated serum bilirubin levels may be responsible for the alterations in protein bindig. These results indicate that acute inflammatory liver disease has complex and perhaps paradoxical effects on durg disposition. Clinical and laboratory observations including plasma durg concentrations, still provide the best means for adjusting dosage regimens in patients with fluctuating hepatic function.

  View details for Web of Science ID A1975AF21900007

  View details for PubMedID 1139859

• DIFFERENCES BETWEEN PLASMA INDOCYANINE GREEN DISAPPEARANCE RATES OF NORMAL MEN AND WOMEN PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE Martin, J. F., Mikulecky, M., Blaschke, T. F., WAGGONER, J. G., Vergalla, J., Berk, P. D. 1975; 150 (3): 612-617

  View details for Web of Science ID A1975BB90900015

  View details for PubMedID 1208580

• UNCONJUGATED HYPERBILIRUBINEMIA - PHYSIOLOGIC EVALUATION AND EXPERIMENTAL APPROACHES TO THERAPY ANNALS OF INTERNAL MEDICINE Berk, P. D., Martin, J. F., Blaschke, T. F., Scharschmidt, B. F., Plotz, P. H. 1975; 82 (4): 552-570

  Abstract

  The plasma concentration of unconjugated bilirubin is determined by the rate at which newly synthesized bilirubin enters the plasma (bilirubin turnover) and the rate of irreversible bilirubin removal by the liver (hepatic bilirubin clearance). Measurement of each of these variables by kinetic studies with radiolabeled bilirubin permits a precise classification of cases of unconjugated hyperbilirubinemia into those due to increased bilirubin turnover (for example, hemolysis), those due to decreased bilirubin clearance (for example, Gilbert's syndrome), and those in which both mechanisms operate. The ability to quantitate hepatic bilirubin clearance makes it possible to detect gilbert's syndrome even in the presence of concomitant hemolysis. Of the hereditary disorders of bilirubin metabolism, Gilbert's syndrome is common but innocuous, whereas Crigler-Najjar syndrome is rare but devastating. An unusual case of Crigler-Najjar syndrome is described in which bilirubin encephalopathy developed at age 10. Various modalities used in an attempt to reduce her plasma bilirubin concentration by either increasing bilirubin clearance or reducing bilirubin turnover are described.

  View details for Web of Science ID A1975W058000023

  View details for PubMedID 1119773

• LIDOCAINE BLOOD CONCENTRATIONS DURING FIBEROPTIC BRONCHOSCOPY AMERICAN REVIEW OF RESPIRATORY DISEASE Patterson, J. R., Blaschke, T. F., Hunt, K. K., MEFFIN, P. J. 1975; 112 (1): 53-57

  Abstract

  Blood lidocaine concentrations were measured in 21 patients during routine fiberoptic bronchoscopy. In one patient, concentrations were in the toxic range. Measureable, but generally safe, concentrations were observed in the remaining patients. Cardiac and central nervous system toxicity may result from lidocaine adsorption, particularly in the seriously ill patient, although none was observed during the course of these studies.

  View details for Web of Science ID A1975AJ85800009

  View details for PubMedID 1147383

• INFLUENCE OF ACUTE VIRAL-HEPATITIS ON LIDOCAINE DISPOSITION IN MAN Williams, R. L., Blaschke, T. F., MEFFIN, P. J., Melmon, K. L., Rowland, M. SLACK INC. 1975: A226–A226

  View details for Web of Science ID A1975W188500349

• [Clinical significance of pharmacologic effects of roentgen contrast media]. Der Internist Blaschke, T. F., Melmon, K. L. 1974; 15 (8): 439-443

  View details for PubMedID 4140165

• CLINICAL SIGNIFICANCE OF PHARMACOLOGICAL EFFECTS OF CONTRAST-MEDIA INTERNIST Blaschke, T. F., Melmon, K. L. 1974; 15 (8): 439-443

  View details for Web of Science ID A1974U054800009

• COMPARISON OF PLASMA BILIRUBIN TURNOVER AND CARBON-MONOXIDE PRODUCTION IN MAN JOURNAL OF LABORATORY AND CLINICAL MEDICINE Berk, P. D., RODKEY, F. L., Blaschke, T. F., COLLISON, H. A., WAGGONER, J. G. 1974; 83 (1): 29-37

  View details for Web of Science ID A1974R804500003

  View details for PubMedID 4808654

• DRUGS AND LIVER .1. EFFECTS OF GLUTETHIMIDE AND PHENOBARBITAL ON HEPATIC BILIRUBIN CLEARANCE, PLASMA BILIRUBIN TURNOVER AND CARBON-MONOXIDE PRODUCTION IN MAN BIOCHEMICAL PHARMACOLOGY Blaschke, T. F., Berk, P. D., RODKEY, F. L., Scharschmidt, B. F., COLLISON, H. A. 1974; 23 (20): 2795-2806

  View details for Web of Science ID A1974U455500002

• CRIGLER-NAJJAR SYNDROME - UNUSUAL COURSE WITH DEVELOPMENT OF NEUROLOGIC DAMAGE AT AGE 18 PEDIATRIC RESEARCH Blaschke, T. F., Berk, P. D., Scharschmidt, B. F., GUYTHER, J. R., VERGALLA, J. M., WAGGONER, J. G. 1974; 8 (5): 573-590

  View details for Web of Science ID A1974T028800006

  View details for PubMedID 4825526

• Clinical importance of the pharmacologic effects of radiopaque dyes. Rational drug therapy Blaschke, T. F., Melmon, K. L. 1973; 7 (10): 1-5

  View details for PubMedID 4742335

• EFFECT OF INDUCED FEVER ON SULFOBROMOPHTHALEIN KINETICS IN MAN ANNALS OF INTERNAL MEDICINE Blaschke, T. F., Elin, R. J., Berk, P. D., Song, C. S., WOLFF, S. M. 1973; 78 (2): 221-226

  View details for Web of Science ID A1973O755700006

  View details for PubMedID 4683751