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Biomedical subjects

R L Woosley

Publications and source records attributed to R L Woosley.

At least 55 records · Page 3Linked to original sources
PubMed1996

Determination of dextromethorphan metabolic phenotype by salivary analysis with a reference to genotype in Chinese patients receiving renal hemodialysis.

BACKGROUND: The polymorphic metabolism of debrisoquin and sparteine by cytochrome P450IID6 (CYP2D6) is genetically determined. Determination of the CYP2D6 metabolic phenotype with conventional urine analytic methods is not feasible in anuric patients with renal failure. The possibility of using salivary analysis, with dextromethorphan as a probe drug, to determine the CYP2D6 metabolic phenotype in patients with renal failure was evaluated. METHODS AND RESULTS: One hundred four Chinese patients with renal failure were recruited. All 104 patients were receiving hemodialysis. Saliva was collected before and at 3 hours after each patient took a capsule of dextromethorphan hydrobromide (30 mg). Four patients were excluded because of insufficient samples of saliva. The distribution of logarithms of the metabolic ratios (log[MR]) in the 100 patients appeared to be normal. Administration of quinidine sulfate (200 mg twice daily) to nine of the patients significantly and markedly increased the dextromethorphan metabolic ratios. The metabolic ratios of nine patients pretreated with quinidine were higher than any of the 100 patients with renal failure who did not receive quinidine pretreatment. A metabolic ratio of 33 separated these two groups. Genomic deoxyribonucleic acid was extracted from whole blood in a subset of patients. Polymerase chain reaction (PCR)-based methods were used to detect the CYP2D6 and B mutant genes. Mutant B alleles (which are common in white poor metabolizers) of CYP2D6 genes were not detected in any of the 47 subjects tested. A PCR-based test of cytosine (C188) to thymine (T188) polymorphism at 188 base pairs in exon 1 of CYP2D6 genes was performed in 61 patients. Subjects who were homozygous for C188 had significantly (p = 0.0067) lower log[MR] values than those who were homozygous for T188. CONCLUSIONS: Determination of dextromethorphan metabolic ratios in saliva is feasible in patients with renal failure requiring hemodialysis. All subjects in this study appeared to be "extensive metabolizer" phenotype for CYP2D6, and no poor metabolizer was identified. From the results with quinidine pretreatment, a metabolic ratio of 33 is suggested to be a tentative antimode for identification of poor metabolizers in patients with renal failure.

Adult↗
PubMed1996

Survey of clinical pharmacology training in the United States and Canada.

A survey of 139 medical schools in the United States and Canada was conducted in 1993-1994 to determine where active training programs in clinical pharmacology were located. A secondary survey of clinical pharmacology program directors followed in 1994-1995. Thirty-nine active programs were identified where 113 fellows (84 physicians and 29 nonphysicians) were enrolled. Sixty-eight percent of current physician fellows were trained in internal medicine before they entered their clinical pharmacology program. Forty-four percent of trainees were reported to be U.S. citizens. Fewer than 20 fellows complete training each year. The reported content of training programs was 12% didactic, 72% research, 12% clinical service, and 9% supervised teaching. Funding sources for trainees varied considerably. Nearly 50% of trainees were supported all or in part by funds from the National Institutes of Health (NIH), and approximately 40% relied on international sources of support. No correlation between salary and funding source or fellow degree was found. Nearly two-thirds of recent program graduates obtained employment in an academic setting, whereas 15% entered the pharmaceutical industry. These data indicate that subspecialty training in clinical pharmacology is available at 39 medical schools in the United States and Canada. Current fellowship training is primarily research based and nearly equally supported by NIH and international sources.

Canada↗
PubMed1996

Amiodarone-induced lymphocyte toxicity and mitochondrial function.

Amiodarone is one of the most effective antiarrhythmic drugs available. However, its use is often limited by potentially life-threatening toxicities, including hepatotoxicity and pulmonary toxicity. We have used human lymphocytes as a system in which to study amiodarone-induced cytotoxicity. Using a tetrazolium dye reduction assay, we observed amiodarone-induced cytotoxicity with a lethal dose (LD)50 of 10.0 +/- 31.1 microM (mean +/- SD, n = 5) with a cellular concentration of 2.2 +/- 0.2 million/ml and of 55.5 and 39.2 microM with cellular concentrations of 8.9 and 7.2 million/ml, respectively, after only 2.75 h of drug exposure. Damage to mitochondria, but not other organelles, was observed with electron microscopy at an amiodarone concentration of 7.3 microM. Alterations in ATP synthesis and lactate dehydrogenase (LDH) release from cells had concentration-response curves similar to those for cytotoxicity. However, we did not observe extracellular accumulation of adenine nucleotides. These results suggest that amiodarone may have a direct toxic effect on mitochondria, beginning at < 10 microM, with membrane-damaging effects at higher drug concentrations.

Adenosine↗
PubMed1996

Cardiac actions of antihistamines.

Two of the nonsedating antihistaminic drugs, terfenadine and astemizole, have recently been recognized in rare cases to induce the syndrome of torsades de pointes, i.e. QT interval prolongation and life-threatening ventricular tachycardia. Each was found to prolong cardiac repolarization when its metabolic elimination was impaired, such as by liver disease or drugs that inhibit the 3A family of cytochrome P450. In vitro studies indicate that this action is due to blockade of one or more of the cardiac potassium channels that determine the duration of the action potential. Prescription guidelines are now available to reduce the risk of developing arrhythmias with these two drugs. Two agents recently marketed in the United States, Ioratidine and cetirizine, appear to lack the ability to prolong repolarization and induce torsades de pointes. Evaluation of the potential cardiac actions of investigational antihistamines is essential and may be of value for some of the older conventional agents.

Animals↗
PubMed1995

Multicenter trial of sotalol compared with procainamide in the suppression of inducible ventricular tachycardia: a double-blind, randomized parallel evaluation. Sotalol Multicenter Study Group.

Sotalol is the prototype class III agent that combines beta-blocking properties with the propensity to prolong the effective refractory period by lengthening the action potential duration. Its precise effect on the prevention of ventricular tachycardia-ventricular fibrillation (VTVF) compared to class I agents has not been evaluated in a blinded study. In a double-blind parallel-design multicenter study, the electrophysiologic and antiarrhythmic effects of intravenous and oral sotalol (n = 55) and procainamide (n = 55) were therefore compared in patients with VTVF inducible by programmed electric stimulation. Sotalol produced a greater effect on lengthening the ventricular effective refractory period (VERP). It prevented the inducibility of VTVF in 30% versus 20% for procainamide, but this was not significantly different. In an alternate therapy group (n = 41) of similar patients previously refractory to or intolerant of procainamide, intravenous sotalol prevented inducibility in 32%. The pooled overall sotalol efficacy rate was 31%. There was a significant relation between the increase in the VERP and the prevention of inducibility of VTVF (n = 56; p < 0.02). VERP of > or = 300 msec was critical for the prevention of VTVF inducibility. Thirteen sotalol and 6 procainamide responders from the randomized group and 30 from the nonrandomized groups completed 1 year of oral sotalol therapy follow-up. Life-table analysis of these patient in each group showed a trend in favor of sotalol; however, statistical analysis was not possible because of the small numbers of patients. Both sotalol and procainamide were well tolerated. In the randomized group there was one case of sudden death during treatment with sotalol and two cases of nonfatal torsades de pointes in the procainamide group and two in the sotalol group; in the nonrandomized alternate therapy group, there were 6 cases of nonfatal torsades de pointes. The data support the emerging role of sotalol in the control of symptomatic ventricular tachycardia and fibrillation.

Administration, Oral↗
PubMed1995

S-mephenytoin hydroxylation phenotypes in a Jordanian population.

We tested the ability of 194 unrelated, healthy Jordanian volunteers to metabolize S-mephenytoin. Mephenytoin (100 mg) was coadministered with debrisoquin (10 mg) orally and urine was collected for 8 hours. Mephenytoin metabolism was tested according to three measures: the amount of 4-hydroxymephenytoin, the S/R enantiomeric ratio, and the presence of a polar, acid-labile metabolite in urine collected for 8 hours after the dose. The S/R ratio and the presence of the acid-labile metabolite were determined in the urine of 16 patients who had low amounts of 4-hydroxymephenytoin (log hydroxylation index > or = 1). On examination of these three parameters of oxidation status, nine subjects were found to be poor metabolizers of mephenytoin by all three parameters. Thus 4.6% (95% confidence interval of 1.6% to 7.6%) of Jordanian subjects studied were poor metabolizers of mephenytoin. According to the Hardy-Weinberg Law, the frequency of the recessive autosomal gene controlling the poor metabolizer status of mephenytoin was predicted to be 0.215% (95% confidence interval of 0.146% to 0.283%). These results are on the same order of magnitude as those determined in European white populations and constitute the first report in Arab populations.

Adolescent↗
PubMed1995

Chlorpheniramine plasma concentration and histamine H1-receptor occupancy.

The plasma concentration-response relationship of the antihistamine chlorpheniramine is poorly characterized. This study examined concurrently the concentrations of chlorpheniramine and presence of H1-receptor antagonist in plasma after administration of 8 mg chlorpheniramine in normal volunteers. Six extensive metabolizers and five poor metabolizers, as judged by CYP2D6 phenotype (dextromethorphan metabolic ratio), were enrolled in the study. More than 80% occupancy of H1-receptors by antagonist in plasma was observed for 12 hours after the dose in extensive metabolizers and greater than 60% from 12 to 30 hours in poor metabolizers, when plasma concentrations had fallen below those that should result in 50% occupancy of receptors. The results suggest that (+/-)-chlorpheniramine plasma concentrations do not predict H1-receptor antagonist in plasma. In addition, a role is suggested for CYP2D6 in formation of a potent active metabolite of chlorpheniramine.

Adult↗
PubMed1995

The hydroxylation of omeprazole correlates with S-mephenytoin metabolism: a population study.

We compared omeprazole and mephenytoin as probes for the CYP2C19 metabolic polymorphism. Single oral doses of omeprazole (20 mg) or mephenytoin (100 mg) were administered at least 1 week apart to 167 healthy volunteers. Mephenytoin metabolism was measured using the amount of 4'-hydroxymephenytoin and the S/R ratio of mephenytoin in an 8-hour urine collection. Omeprazole hydroxylation was measured using the ratio of omeprazole to 5'-hydroxyomeprazole in serum 2 hours after dosing. All three methods separated poor- or extensive-metabolizer phenotypes with complete concordance. Omeprazole hydroxylation correlated with the S/R ratio of mephenytoin in extensive metabolizers (r2 = 0.681; p < 0.001). Genotyping tests showed that six poor metabolizers of omeprazole were homozygous for a single base pair mutation in exon 5 of CYP2C19. These results support the hypothesis that omeprazole 5'-hydroxylation cosegregates with the CYP2C19 metabolic polymorphism.

Adult↗
PubMed1995

Acute treatment of recent-onset atrial fibrillation and flutter with a tailored dosing regimen of intravenous amiodarone. A randomized, digoxin-controlled study.

A 24 h intravenous dosing regimen of amiodarone was designed to reach a peak plasma concentration at 1 h and to maintain the concentration above a certain level during the infusion period. A randomized, open-label, digoxin-controlled study was undertaken to observe the efficacy and safety of the dosing regimen of amiodarone in treating recent-onset, persistent, atrial fibrillation and flutter with ventricular rates above 130 beats.min-1. Fifty patients with a mean age of 70 +/- 7 (SD) years were enrolled and randomly assigned to receive either amiodarone intravenously (n = 26) or digoxin (n = 24). Amiodarone HCl was infused over 24 h according to the following regimen: 5 mg.min-1, 3 mg.min-1, 1 mg.min-1 and 0.5 mg.min-1 for 1, 3, 6 and 14 h, respectively, for a 70-kg subject. Digoxin (0.013 mg.kg-1) was infused in three divided doses, each dose 2 h apart and infused over 30 min. The mean heart rates in the amiodarone group decreased significantly from 157 +/- 20 beats.min-1 to 122 +/- 25 beats.min-1 after 1 h (P < 0.05 vs baseline), and then decreased further to stabilize at 96 +/- 25 beats.min-1 after 6 h (P < 0.05). The digoxin group had fewer dramatic alterations in heart rates, compared to the amiodarone group, in the first 8 h (P < 0.05, respectively). Maximum reduction was reached only after 8 h. The amiodarone infusion was prematurely aborted in two patients due to severe bradycardia and death after conversion in one patient and aggravation of heart failure in the other.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

Terfenadine increases the QT interval in isolated guinea pig heart.

Torsades de pointes ventricular tachycardia (VT) has been reported in patients taking the nonsedating antihistamine, terfenadine. We performed electrophysiologic studies of 14 isolated guinea pig hearts using the Langendorff technique to assess whether terfenadine exerted actions that could be responsible for inducing the arrhythmia. Twelve hearts were perfused with an oxygenated Tyrode's solution containing a 2-microM preparation of either racemic, R-, or S-terfenadine. QT interval (QT), monophasic action potential duration (APD), and ventricular effective refractory periods (ERP) were measured at a fixed range of cycle lengths (CL). At 400-ms CL, both isomers and racemate prolonged QT and APD by 8% and ERP was increased by 14%. Infusion of vehicle, dimethyl sulfoxide (DMSO), alone in two hearts caused a slight decrease in QT and APD, suggesting that the direct effect of terfenadine on QT may have been underestimated. One-way analysis of variance (ANOVA) showed no statistical difference in effect on QT, APD, or ERP for the three forms of terfenadine (p < 0.05). These results support the conclusion that terfenadine induces torsades de pointes because of direct actions in delaying cardiac repolarization. The lack of stereospecificity in this action indicates that chirally pure formulations are not likely to have greater safety than the racemate.

Action Potentials↗
PubMed1994

Sotalol.

Sotalol is a novel antiarrhythmic agent combining beta-adrenergic-antagonist actions with the ability to increase cardiac repolarization and refractoriness. The drug's electrophysiologic and clinical profile is different from that of conventional beta-receptor antagonists. As compared with other antiarrhythmic agents, sotalol prevents recurrences of arrhythmia in a higher proportion of patients, particularly among those presenting with ventricular tachycardia and aborted sudden cardiac death. The net hemodynamic effect of sotalol is the result of a balance between the depressant effects due to beta-receptor blockade and an action that tends to increase contractility. Although initially marketed in the United States for treatment of life-threatening ventricular arrhythmias, sotalol also has demonstrated efficacy in many patients with supraventricular arrhythmias. As with all drugs that prolong the QT interval, the syndrome of torsade de pointes is a serious potential adverse effect.

Action Potentials↗
PubMed1994

New insights into the definition and meaning of proarrhythmia during initiation of antiarrhythmic drug therapy from the Cardiac Arrhythmia Suppression Trial and its pilot study. The CAST and CAPS Investigators.

OBJECTIVES: This study was undertaken to determine the characteristics of worsening ventricular arrhythmia during antiarrhythmic drug titration. BACKGROUND: Proarrhythmia is an evolving concept in cardiology. Its definition, incidence and clinical significance in various patient settings require refinement. METHODS: The impact of early proarrhythmia was analyzed in 3,840 patients in the Cardiac Arrhythmia Suppression Trial (CAST). RESULTS: Drug therapy did not affect the incidence of new, sustained but nonfatal ventricular tachycardia (placebo 0.5%, active drug 0.4%). Nevertheless, there was a threefold increase in arrhythmic death (placebo 0.5% vs. active drug 1.6%). The incidence of increased ventricular premature depolarizations was equivalent (3% to 5%) for the three study drugs and indistinguishable from that seen with placebo. Patients with increased ventricular premature depolarizations on the first drug tested had fewer at baseline (65 +/- 94 vs. 137 +/- 260 per hour; mean +/- SD) (p < 0.01). When increased ventricular premature depolarizations occurred with the first drug, they were much more likely also to be present with the second drug (for example, 42% vs. 5%, p < 0.001). Increased ventricular premature depolarizations during initiation of therapy independently predicted increased risk of subsequent arrhythmic death (independent relative risk 2.34, p = 0.0053) in the absence of continued antiarrhythmic drug therapy. CONCLUSIONS: The overall incidence of early worsening of arrhythmia in the present study was low. In the absence of placebo control, the incidence of proarrhythmia will be overestimated. Increased ventricular premature depolarizations had characteristics that suggest they often represent spontaneous variability rather than proarrhythmia. The main finding is that markedly increased ventricular premature depolarizations during drug titration predict long-term increased risk of arrhythmic death in this patient population despite absence of long-term antiarrhythmic drug therapy.

Aged↗
PubMed1994

The electrocardiographic effects of cetirizine in normal subjects.

OBJECTIVE: To establish whether the antihistamine cetirizine has the potential to prolong the QTc interval in normal volunteers at up to six times the usual recommended dose. METHODS: Twenty-five healthy volunteers were studied in a prospective, double-blind crossover design conducted on inpatients in a Clinical Research Center. The primary end point of the study was QTc prolongation on the surface electrocardiogram (ECG). Plasma concentrations of cetirizine were also measured for pharmacokinetic analysis. The end point for the pharmacokinetic analysis was the dose/area under the concentration-time curve (apparent clearance of an oral dose). The subjects received the following three treatments in random sequence: placebo, 20 mg/day cetirizine, and 60 mg/day cetirizine for 7 consecutive days. A series of baseline ECGs was recorded over 2 days before each treatment, while the subject receiving placebo. ECG effects of the treatments were then compared with the baseline ECGs. RESULTS: Analysis of variance showed no difference between the treatment groups (placebo, 20 mg cetirizine, and 60 mg cetirizine every day) in effect on QTc compared with baseline. A paired Student t test showed no difference in dose/area under the concentration-time curve between the 20 mg/day and 60 mg/day dosing groups at steady state. CONCLUSION: In healthy volunteers, cetirizine does not prolong the QTc interval at doses of up to six times the usual recommended dose.

Adult↗
PubMed1994

Pharmacogenetic characteristics of the eosinophilia-myalgia syndrome.

This study tested the hypothesis that patterns of xenobiotic metabolism in patients with eosinophilia-myalgia syndrome (EMS) differed from healthy control subjects. We determined the genotypes of 27 EMS patients with EMS and 114 control subjects for the cytochrome P450 CYP2D6 polymorphism. The metabolic phenotypes of patients with EMS for S-mephenytoin hydroxylation (n = 17) and dapsone acetylation (n = 19) were determined and compared with 29 healthy control subjects. The incidence of the CYP2D6 poor metabolizer genotype (mutant/mutant) was 0.185 in patients with EMS and 0.061 in control subjects (Mantel-Haenszel, chi 2 = 7.213, p = 0.007). The mephenytoin S/R ratios were 0.39 +/- 0.23 in patients with EMS versus 0.18 +/- 0.13 in control subjects (p < or = 0.005). There was no difference in dapsone acetylation between the two groups. A pattern of xenobiotic metabolism may play a role in the pathogenesis of EMS, but the precise role that it plays remains unclear.

Alleles↗