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Biomedical subjects

R L Woosley

Publications and source records attributed to R L Woosley.

At least 73 records · Page 4Linked to original sources
PubMed1994

The essential role of integrative biomedical sciences in protecting and contributing to the health and well-being of our nation.

The biomedical sciences in the United States are currently experiencing the effects of an increased emphasis on in vitro models of biological and disease processes. Advances in cellular and subcellular biology have been a driving force in the funding of new research, the training of new scientists, and new drug discovery and development. The importance of new findings at the cellular and subcellular levels is not disputed. However, the corresponding decline in funding and training opportunities for biologically relevant investigations at the level of the intact animal (including humans; hereafter designated as integrative biology) is a serious threat to continued biomedical advances. The lack of resources for integrative biology has far-reaching negative consequences in 1) the development and utilization of whole animal models of disease and dysfunction; 2) assessing the relevancy of in vitro studies to physiological mechanisms; 3) the evaluation of the scientific merit of whole animal investigations and their relevancy to the nation's scientific imperatives; 4) the instruction of young scientists in the technology and especially in the methods of integrative biology, including how to develop appropriate experimental hypotheses; 5) the instruction of graduate, medical, dental, pharmacy, and nursing students in drug and disease processes in the intact human; and 6) the ability of the pharmaceutical manufacturers, the FDA, the EPA and academia to hire scientists who can develop drugs and evaluate the effects of exogenous agents on the intact animal. These negative consequences can be alleviated in a variety of ways. These include 1) increasing the availability of funding for research in integrative biology, 2) increasing the opportunities for training in integrative biology, and 3) instituting grant reviews of integrative biomedical research by peers in integrative biomedical sciences. These measures can revitalize integrative biomedical research, help ensure the continued advancement of biomedical understanding, and consequently contribute to the alleviation of human suffering.

Animals↗
PubMed1993

QT interval: a measure of drug action.

Historically, QT prolongation, occurring with or without drug therapy, has been considered primarily as a clinical marker for risk of arrhythmia. However, as understanding of cardiac repolarization improves and ability to measure accurately small changes in QT interval increases, the QT interval will be used as a marker for drug action as well. In addition, QT prolongation may prove to be a valuable tool for detecting and quantifying risk of arrhythmia due to drugs. This has been emphasized recently by the experience with terfenadine. Use of the QT interval as a marker for toxicity and efficacy will require sensitive and specific methods that are currently being developed and validated. The current methodologies for detecting small changes in the QT interval and the significance of those changes are discussed.

Anti-Arrhythmia Agents↗
PubMed1993

Immediate- versus controlled-release disopyramide: importance of saturable binding.

OBJECTIVE: To examine the effects of saturable plasma binding on the pharmacokinetics of immediate-release (IR) and controlled-release (CR) disopyramide. BACKGROUND: Saturable binding causes a lack of correspondence between the pharmacokinetics of total and unbound plasma disopyramide. Levels of total drug may therefore be insensitive to important differences between formulations. METHODS: Patients receiving long-term disopyramide underwent serial blood sampling during withdrawal of equivalent doses of IR and CR disopyramide, and during accumulation of IR disopyramide. Plasma disopyramide was measured by enzyme-multiplied immunoassay technique, protein binding by ultrafiltration, and alpha 1-acid glycoprotein by radial immunodiffusion. Pharmacologic effect was assessed by use of high-speed ECGs. Values for plasma area under the concentration-time curve and elimination half-life were determined from the log-plasma concentration data; rate of plasma drug accumulation was determined by nonlinear modeling. RESULTS: Saturable plasma binding was evident in all patients. Comparison of total to unbound drug showed that peak-to-trough ratios during steady state were smaller (1.45 versus 2.39; p < 0.001), elimination half-life was longer (12.1 versus 4.5 hours; p < 0.001), and the time to achieve 50% of steady-state levels during drug accumulation was shorter (8.1 versus 4.3 hours; p < 0.05). Comparison of IR and CR disopyramide showed that unbound drug levels for CR disopyramide revealed lower peak plasma concentrations (0.75 versus 0.96 micrograms/ml) and peak-to-trough ratios (1.83 versus 2.31; p < 0.001). Trough plasma concentrations were similar. Fluctuations in ECG intervals during usual dosing were observed only with IR disopyramide. CONCLUSIONS: Because of saturable plasma binding, total plasma concentrations underestimate fluctuations in unbound disopyramide during usual dosing and are insensitive to significant differences between IR and CR formulations. CR disopyramide provides less interdose variation in free drug levels and more constant pharmacologic effects.

Aged↗
PubMed1993

d-sotalol reduces heart rate in vivo through a beta-adrenergic receptor-independent mechanism.

d-Sotalol was developed as an antiarrhythmic agent with a relative lack of antagonist activity at beta-adrenergic receptors. Exercise heart rate reduction has been observed after administration to humans. The purpose of this study was to determine directly whether this effect of d-sotalol was attributable to beta-blockade. Plasma samples from normal volunteers who randomly received either atenolol, d-sotalol, or placebo were used in an in vitro radioreceptor assay to determine occupancy of beta 1-adrenergic receptors by antagonist present in the plasma. Occupancy was compared with the observed pharmacologic effects. A reduction in exercise heart rate of 7.7% +/- 3.8% for d-sotalol and 15.9% +/- 3.0% for atenolol occurred with beta 1-adrenergic receptor occupancy of 0% and 33.9% +/- 21.4%, respectively. Absence of antagonist effect in the radioreceptor assay eliminates the potential role of beta 1-blockade in d-sotalol-induced heart rate reduction. This effect is most likely a result of prolongation of the sinus node action potential duration.

Adult↗
PubMed1993

N-acetylation phenotype and genotype and risk of bladder cancer in benzidine-exposed workers.

Several studies in subjects occupationally exposed to arylamine carcinogens have shown increased risks for bladder cancer associated with the slow acetylator phenotype. To follow up these reports, a case-control study of N-acetylation and bladder cancer risk was carried out among subjects occupationally exposed to benzidine, in benzidine dye production and use facilities in China. Thirty-eight bladder cancer cases and 43 controls from these factories were included for study of acetylation phenotype, by dapsone administration, and for polymorphisms in the NAT2 gene, by a polymerase chain reaction (PCR)-based test. In contrast to previous studies, no increase in bladder cancer risk was found for the slow N-acetylation phenotype (OR = 0.3; 95% CI = 0.1-1.3) or for slow N-acetylation-associated double mutations in NAT2 (OR = 0.5; 95% CI = 0.1-1.8). Examination of specific mutations and adjustment for age, weight, city and tobacco use did not alter the results. When examined by level of benzidine exposure in the cases, the bladder cancer risks associated with low (OR = 0.3, 95% CI = 0.0-2.2), medium (OR = 0.7, 95% CI = 0.1-4.5) and high (OR = 0.6, 95% CI = 0.1-3.5) exposure showed no interaction between genotype and benzidine exposure, within the range of exposures experienced by subjects in this study. This study, which is the first to incorporate phenotypic and genotypic analyses, provides evidence that the NAT2-related slow N-acetylation polymorphism is not associated with an increased risk of bladder cancer in workers exposed to benzidine, and may have a protective effect.

Acetylation↗
PubMed1993

Correlation between N-acetyltransferase activity and NAT2 genotype in Chinese males.

Eighty-four healthy Chinese male control subjects derived from an occupation-based case-control study of bladder cancer were evaluated for hepatic N-acetyltransferase activity by dapsone and for NAT2 genotype using allele-specific amplification of peripheral leukocyte DNA by the polymerase chain reaction. Fifty-nine percent of the overall variation in acetylation activity was explained by genotype (p < 0.0001). The remaining variation in acetylation was not associated with dapsone N-hydroxylation activity, age, current smoking status, or weight in the study population, or within any genotype subgroup. Although acetylation activity in the homozygous mutant group did not overlap with the other genotype categories, there was moderate overlap in acetylation between the heterozygous mutant and wildtype groups, and substantial variation in acetylation within them. Considering all subjects with the identical NAT2 genotype as phenotypically similar and all subjects with differing NAT2 genotypes as phenotypically distinct may result in misclassification of metabolic risk factors in epidemiological investigations. As such, it would seem prudent, where possible, to collect both acetylation phenotype and NAT2 genotype data, since the advantages and limitations of these two sources of information complement, and serve to assess the accuracy of each other.

Aged↗
PubMed1992

The Cardiac Arrhythmia Suppression Trial: first CAST ... then CAST-II.

The Cardiac Arrhythmia Suppression Trial (CAST) was a study designed to test the hypothesis that suppression of ventricular premature complexes after a myocardial infarction would improve survival. Preliminary results showed that suppression of ventricular premature complexes with encainide and flecainide worsened survival, and the CAST continued as the CAST-II with moricizine compared with its placebo. The protocol for the CAST-II was changed to attempt to enroll patients more likely to experience serious arrhythmias. The enrollment time was narrowed to 4 to 90 days after myocardial infarction; the qualifying ejection fraction was lowered to less than or equal to 0.40; a higher dose of moricizine could be used; early titration itself was double-blind with a placebo, and the definition of disqualifying ventricular tachycardia was changed to allow patients with more serious arrhythmias to be entered into the trial. The Cardiac Arrhythmia Suppression Trial-II was subsequently terminated prematurely because 1) patients treated with moricizine had an excessive cardiac mortality rate during the 1st 2 weeks of exposure to the drug, and 2) there appeared to be little chance of showing a long-term survival benefit from treatment with moricizine. This report outlines the rationale behind the Cardiac Arrhythmia Suppression Trial and the reasons for selection of the drugs used in the CAST and CAST-II.

Anti-Arrhythmia Agents↗
PubMed1992

Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin.

Terfenadine is a nonsedating H1-antagonist that when overdosed, used with hepatic compromise, or when given with ketoconazole results in accumulation of parent terfenadine, prolongation of the QT interval, and torsades de pointes in susceptible patients. Nine subjects were given the recommended dose of terfenadine (60 mg every 12 hours) for 7 days before initiation of oral erythromycin (500 mg every 8 hours). All subjects increased metabolite concentrations after the addition of erythromycin for 1 week. The maximum concentration of metabolite increased by a mean of 107% and the mean metabolite area under the concentration-time curve increased by 170%. Three subjects accumulated unmetabolized terfenadine after administration of erythromycin for 1 week. Electrocardiographic data revealed changes in QT intervals and ST-U complexes in a subset of subjects who accumulated terfenadine. We conclude that erythromycin alters the metabolism of terfenadine, leading to accumulation of terfenadine in certain individuals that is associated with altered cardiac repolarization.

Administration, Oral↗
PubMed1992

Clinical implications of variable antiarrhythmic drug metabolism.

Due to their narrow therapeutic indices, antiarrhythmic drugs have a great potential for adverse outcome. This is amplified by extreme inter-individual variability in their disposition and their pharmacological actions. Genetically determined inter-individual differences in metabolism account for a great deal of this variability. However, because of active metabolites, chirally-specific actions and chirally-specific metabolism, it is not possible to generalize about the outcome of phenotypic differences in the metabolism of a given drug. Careful study of these factors can enable physicians to understand the spectrum of potential responses to a drug. Newly developed molecular biology techniques now make it possible to determine the genotype for the CYP2D6 gene that controls metabolism of many antiarrhythmic drugs. This information, combined with a full understanding of the drugs' clinical pharmacology now makes it possible to predict the clinical outcome for drugs such as encainide, flecainide, mexiletine, propafenone and combinations of these drugs with quinidine.

Anti-Arrhythmia Agents↗
PubMed1991

Prospective pharmacokinetically based development of effective infusion regimens for ACC-9358, a new antiarrhythmic drug.

In this study we evaluated the clinical pharmacology of intravenous ACC-9358, a new antiarrhythmic drug derived from a Chinese herbal remedy. In a first-study phase, 0.125 to 1.0 mg/kg during 10 minutes was administered to six patients with chronic nonsustained ventricular arrhythmias. These data were then used to design 3-hour infusions to maintain stable plasma concentrations: these infusions suppressed arrhythmias by 90% or greater for 2 1/2 hours or more at plasma concentrations of 114 to 1010 ng/ml (mean, 400 +/- 421 ng/ml [SD]), and with QRS interval increases of 2.5% to 8.8% (5.1% +/- 2.9%). Mean clearance was 478 +/- 151 ml/min, and elimination half-life was 19.1 +/- 6.1 hours. ACC-9358 did not produce adverse effects in this study. ACC-9358 shows antiarrhythmic activity in humans at concentrations that prolong QRS only slightly and do not alter rate-corrected QT; further studies in other patient populations, at dosages and plasma concentrations defined here, are required to establish a clinical role for ACC-9358. The pharmacokinetically based dose-ranging approach allowed the safe initial evaluation of ACC-9358 in patients.

Aged↗
PubMed1991

Salivary analysis for determination of dextromethorphan metabolic phenotype.

Debrisoquin oxidative phenotype is a determinant of pharmacologic response for many drugs. Poor and extensive metabolizers can be identified by the dextromethorphan metabolic ratio (dextromethorphan/dextrorphan). We developed and tested a method to determine debrisoquin phenotype on the basis of the metabolic ratio in saliva. Each of 62 normal volunteers was given a 50 mg capsule of dextromethorphan hydrobromide and collected urine (0 to 8 hours) and saliva (at 3 hours). Dextromethorphan and dextrorphan in saliva and urine were assayed by HPLC. The distributions of paired urinary and 3-hour salivary metabolic ratios of samples from 61 subjects were compared. The urinary and salivary metabolic ratios were distributed trimodally and bimodally, respectively. The Spearman rank correlation coefficient for logarithm of urinary metabolic ratio vs that of salivary metabolic ratio was 0.704. All the poor metabolizers identified by urinary metabolic ratio were also identified by the metabolic ratio in saliva at 3 hours (100% concordance). This study demonstrates that salivary analysis for determination of dextromethorphan metabolic phenotype is feasible.

Administration, Oral↗
PubMed1990

The role of genetically determined polymorphic drug metabolism in the beta-blockade produced by propafenone.

Propranolol and the sodium-channel-blocking antiarrhythmic agent propafenone share structural features. Although propafenone's beta-blocking actions are readily demonstrable in vitro, clinically significant beta-blockade occurs inconsistently in vivo. In this study, we tested the hypothesis that genetically determined variations in the biotransformation of propafenone to its 5-hydroxy metabolite account for variations in the drug's beta-blocking action. We assessed beta-blockade by measuring the reduction in tachycardia produced by boluses of isoproterenol and treadmill exercise in 14 normal subjects during treatment with placebo and with 150, 225, and 300 mg of propafenone every eight hours for five days each. Nine subjects (with the extensive-metabolizer phenotype) metabolized most of the propafenone to 5-hydroxy propafenone, and five (with the poor-metabolizer phenotype) did not produce this metabolite. At the lower dosages, beta-blockade was present in both groups but was significantly greater in the subjects with poor metabolism, in whom deficient 5-hydroxylation was associated with higher plasma propafenone levels. At the highest dose, a similar degree of beta-blockade was observed in the two groups. Propafenone also had a higher affinity for beta 2 receptors in vitro than either of its major metabolites. We conclude that the degree of beta-blockade during propafenone therapy reflects genetically determined variations in the metabolism of the parent drug, which is necessary for beta-blockade, and that this action of propafenone is considerably enhanced in patients with deficient 5-hydroxylation of propafenone.

Adrenergic beta-Antagonists↗