Bio

Academic Appointments


Administrative Appointments


  • Assistant Dean for Medical Student Advising, Stanford University School of Medicine (2006 - Present)
  • Associate Dean for Medical Student Advising, Stanford University School of Medicine (2002 - 2006)

Honors & Awards


  • Oscar B. Hunter Award, American Society for Clinical Pharmacology and Therapeutics (ASCPT) (2007)
  • Henry W. Elliott Distinguished Service Award, American Society for Clinical Pharmacology and Therapeutics (ASCPT) (2006)
  • Honorary Fellowship, American College of Clinical Pharmacology (2004)
  • Rawls-Palmer Progress in Medicine Lecture and Award, American Society for Clinical Pharmacology and Therapeutics (2002)
  • Henry J. Kaiser Award for Outstanding Contributions to Medical Education, Stanford University School of Medicine (1999)

Professional Education


  • B.S., University of Denver, Honors Program, Mathematics (1964)
  • M.D., Columbia University, P&S, Medicine (1968)

Community and International Work


  • Senior Program Officer

    Topic

    Global Health Translational Sciences

    Partnering Organization(s)

    Bill and Melinda Gates Foundation

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • AMPATH Program, Eldoret, Kenya

    Topic

    Treatment of HIV/AIDS

    Partnering Organization(s)

    Indiana University School of Medicine

    Populations Served

    Sub-Saharan Africa

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

Research & Scholarship

Current Research and Scholarly Interests


My ongoing Stanford research activities involve studies on the clinical pharmacology of drugs used in HIV-infected patients.
A focus of my laboratory’s efforts in investigating drugs used in HIV-infected patients is to optimize the individual benefit/risk of pharmacotherapy of HIV or opportunistic infections by discovering and quantifying the pharmacokinetics and pharmacodynamics (PK/PD) of drugs used in such therapy; i.e., the distribution of individual-specific dose-concentration-effect relationships in the population. My laboratory has a special interest in understanding the relationships between antiviral drug exposure and virologic and toxicological responses. In the past this has lead to studies examining drug-taking behavior in these patients, since exposure is a function of both individual variability in pharmacokinetics and individual patterns of drug-taking behavior.
At the present time, my interests in HIV are in the access and quality of antiretroviral drugs for patients from less developed countries. The use of substandard drugs carries a high risk of promoting drug resistant variants of HIV, which could have widespread consequences over the long term. Another interest is drug-drug interactions between antiretroviral drugs and drugs used to treat opportunistic infections, in particular drugs used to treat tuberculosis.

Teaching

2013-14 Courses


Graduate and Fellowship Programs


Publications

Journal Articles


  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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 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

  • 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

  • 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 AIDS Kastrissios, H., Suarez, J. R., Hammer, S., KATZENSTEIN, D., Blaschke, T. F. 1998; 12 (17): 2305-2311

    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 AIDS Kastrissios, H., Suarez, J. R., KATZENSTEIN, D., GIRARD, P., Sheiner, L. B., Blaschke, T. F. 1998; 12 (17): 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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 Web of Science ID A1995QL72800017

    View details for PubMedID 7882286

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

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

Conference Proceedings


  • The clinical pharmacokinetics of rifabutin 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

  • SEMIQUANTITATIVE SIMULATION FOR REASONING ABOUT PHYSIOLOGICAL MODELS OF DRUG KINETICS AND EFFECTS LEEMANN, T. D., Blaschke, T. F. SCHWABE & CO AG VERLAG. 1990: 1849-1852

    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

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