A computerized scoring system to improve assessment of heparin-induced thrombocytopenia risk.

Essentials Current risk scores for heparin-induced thrombocytopenia (HIT) are not computer-friendly. We compared a new computerized risk score with the 4Ts score in a large healthcare system. The computerized risk score agrees with the 4Ts score 85% of the time. The new score could potentially improve HIT diagnosis via incorporation into decision support. SUMMARY: Background (HIT) is an immune-mediated adverse drug event associated with life-threatening thrombotic complications. The 4Ts score is widely used to estimate the risk for HIT and guide diagnostic testing, but it is not easily amenable to computerized clinical decision support (CDS) implementation. Objectives Our main objective was to develop an HIT computerized risk (HIT-CR) scoring system that provides platelet count surveillance for timing and degree of thrombocytopenia to identify those for whom diagnostic testing should be considered. Our secondary objective was to evaluate clinical management and subsequent outcomes in those identified as being at risk for HIT. Methods We retrospectively analyzed data from a stratified sample of 150 inpatients treated with heparin to compare the performance of the HIT-CR scoring system with that of a clinically calculated 4Ts score. We took a 4Ts score of ≥ 4 as the gold standard to determine whether HIT diagnostic testing should be performed. Results The best cutoff point of the HIT-CR score was a score of 3, which yielded 85% raw agreement with the 4Ts score and a kappa of 0.69 (95% confidence interval 0.57-0.81). Ninety per cent of patients with 4Ts score of ≥ 4 failed to undergo conventionally recommended diagnostic testing; 38% of these experienced persistent, unexplained thrombocytopenia, and 4% suffered life-threatening thrombotic complications suggestive of undiagnosed HIT. Conclusion The HIT-CR scoring system is practical for computerized CDS, agrees well with the 4Ts score, and should be prospectively evaluated for its ability to identify patients who should be tested for HIT.

Drug development and the FDA's Critical Path Initiative.

Advances in biomedical research over recent decades have substantially raised expectations that the pharmaceutical industry will generate increasing numbers of safe and effective therapies. However, there are warning signs of serious limitations in the industry's ability to effectively translate biomedical research into marketed new therapies. Clinical pharmacologists should be aware of these signals and their potential impact. Here, we discuss a strategy, where clinical pharmacology can play an important role to improve the process of drug development.

Tolerance to the humoral and hemodynamic effects of caffeine in man.

Acute caffeine in subjects who do not normally ingest methylxanthines leads to increases in blood pressure, heart rate, plasma epinephrine, plasma norepinephrine, plasma renin activity, and urinary catecholamines. Using a double-blind design, the effects of chronic caffeine administration on these same variables were assessed. Near complete tolerance, in terms of both humoral and hemodynamic variables, developed over the first 1-4 d of caffeine. No long-term effects of caffeine on blood pressure, heart rate, plasma renin activity, plasma catecholamines, or urinary catecholamines could be demonstrated. Discontinuation of caffeine ingestion after 7 d of administration did not result in a detectable withdrawal phenomenon relating to any of the variables assessed.

Suppression of ventricular arrhythmias in man by d-propranolol independent of beta-adrenergic receptor blockade.

To investigate the mechanisms of ventricular arrhythmia suppression by propranolol, we determined the antiarrhythmic efficacy of d-propranolol in 10 patients with frequent ventricular ectopic depolarizations (VEDs) and nonsustained ventricular tachycardia. After an initial placebo phase, 40 mg d-propranolol was administered orally every 6 h with dosage increased every 2 d until arrhythmia suppression (greater than or equal to 80% VED reduction), intolerable side effects, or a maximal dosage (1,280 mg/d) was reached. Response was verified by documenting return of arrhythmia during a final placebo phase. Arrhythmia suppression occurred in six patients while two more had partial responses. Effective dosages were 320-1,280 mg/d (mean 920 +/- 360, SD) of d-propranolol with corresponding plasma concentrations of 60-2,280 ng/ml (mean 858 +/- 681). For the entire group, the QTc interval shortened by 4 +/- 4% (P = 0.03). Arrhythmia suppression was accompanied by a reduction in peak heart rate during exercise of 0-29%. To determine whether arrhythmia suppression could be attributed to beta-blockade, racemic propranolol was then administered in dosages producing the same or greater depression of exercise heart rate. In 3/8 patients, arrhythmias were not suppressed by racemic propranolol indicating that d-propranolol was effective via a non-beta-mediated action. By contrast, in 5/8 patients racemic propranolol also suppressed VEDs. We conclude that propranolol suppresses ventricular arrhythmias by both beta- and non-beta-adrenergic receptor-mediated effects.

Encainide and its metabolites. Comparative effects in man on ventricular arrhythmia and electrocardiographic intervals.

To assess the relative contributions of encainide and its putatively active metabolites, O-demethyl encainide (ODE) and 3 methoxy-O-demethyl encainide (3MODE), to the drug's pharmacologic effects, we compared intravenous infusions and sustained oral therapy in two phenotypically distinct groups of patients, extensive and poor metabolizers of encainide. Unlike poor metabolizers, extensive metabolizers had appreciable quantities of both metabolites detectable in plasma and had fourfold shorter elimination half-lives for encainide. By quantitating electrocardiogram intervals, arrhythmia frequency, and plasma concentrations, we found that, in poor metabolizers, arrhythmia suppression and ventricular complex (QRS) prolongation were correlated positively with encainide concentrations (r greater than or equal to 0.570, P less than 0.014). In these two subjects, antiarrhythmic concentrations of encainide (greater than 265 ng/ml) were at least fivefold higher than those sustained in the six extensive metabolizers during steady state oral therapy. In extensive metabolizers, encainide concentrations were uncorrelated with effects. Arrhythmia suppression and QRS prolongation in extensive metabolizers correlated best with ODE (r greater than or equal to 0.816, P less than 0.001); QTc change correlated positively with both 3MODE and ODE. Arrhythmia suppression paralleled QRS prolongation; the relationship between them appeared similar in both phenotypic groups. In most patients, extensive metabolizers, encainide effects during oral therapy are mediated by metabolites, probably ODE.

Medical decision support systems and therapeutics: The role of autopilots.

For decades, medical practice has increasingly relied on prescription medicines to treat, cure, or prevent illness but their net benefit is reduced by prescribing errors that result in adverse drug reactions (ADRs) and tens of thousands of deaths each year. Optimal prescribing requires effective management of massive amounts of data. Clinical decision support systems (CDSS) can help manage information and support optimal therapeutic decisions before errors are made by operating as the prescribers' "autopilot."

Gadolinium decreases stretch-induced vulnerability to atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is frequently associated with atrial dilatation caused by pressure or volume overload. Stretch-activated channels (SACs) have been found in myocardial cells and may promote AF in dilated atria. To prove this hypothesis, we investigated the effect of the SAC blocker gadolinium (Gd(3+)) on AF propensity in the isolated rabbit heart during atrial stretch. METHODS AND RESULTS: In 16 isolated Langendorff-perfused rabbit hearts, the interatrial septum was perforated to equalize biatrial pressures. Caval and pulmonary veins were occluded. Intra-atrial pressure (IAP) was increased in steps of 2 to 3 cm H(2)O by increasing the pulmonary outflow fluid column. Vulnerability to AF was evaluated by 15-second burst pacing at each IAP level. At baseline, IAP needed to be raised to 8.8+/-0.2 cm H(2)O (mean+/-SEM) to induce AF. A dose-dependent decrease in AF vulnerability was observed after Gd(3+) 12.5, 25, and 50 micromol/L was added. AF threshold increased to 19.0+/-0.5 cm H(2)O with Gd(3+) 50 micromol/L (P<0.001 versus baseline). Spontaneous runs of AF occurred in 5 hearts on a rise of IAP to 13.8+/-3.3 cm H(2)O at baseline but never during Gd(3+). Atrial effective refractory period shortened progressively from 78+/-3 ms at 0.5 cm H(2)O to 52+/-3 ms at 20 cm H(2)O (P<0.05). Gd(3+) 50 micromol/L had no significant effect on effective refractory period. CONCLUSIONS: Acute atrial stretch significantly enhances the vulnerability to AF. Gd(3+) reduces the stretch-induced vulnerability to AF in a dose-dependent manner. Block of SAC might represent a novel antiarrhythmic approach to AF under conditions of elevated atrial pressure or volume.

Clinical features and basic mechanisms of quinidine-induced arrhythmias.

Quinidine therapy is one of the most common causes of the acquired long QT syndrome and the morphologically distinctive tachyarrhythmia torsade de pointes. Clinical data from our institution and others have revealed a number of characteristic features: quinidine plasma concentrations are generally low, marked QRS prolongation is absent, hypokalemia is frequent and abrupt heart rate slowing just before the initiation of a paroxysm is almost invariable. The lack of correlation between plasma quinidine concentrations and this adverse drug effect raises the possibility either that external factors (for example, hypokalemia) modulate the response to quinidine in vivo or that one or more unmeasured active metabolites play a role. Therefore, the effect of alterations in extracellular potassium and stimulation rate on the electrophysiologic effects of quinidine were examined in canine Purkinje fibers. It was found that a form of triggered automaticity, early afterdepolarizations, is reliably produced in the presence of quinidine when extracellular potassium is lowered and the stimulation rate is slowed. More recently, the effects of a number of quinidine metabolites, as well as the commonly found impurity dihydroquinidine, were characterized in canine Purkinje fibers in a similar fashion. Although quinidine was the most potent of the substances tested, both dihydroquinidine and 3-hydroxyquinidine prolonged action potential and produced early afterdepolarizations as did quinidine at long cycle lengths. Quinidine-induced torsade de pointes is a potentially lethal adverse drug effect, occurring in 1 to 3% of patients. Hypokalemia and slow heart rates are commonly observed in a clinical setting and, in the tissue bath, quinidine and several of its metabolites induce abnormal automatic behavior when extracellular potassium is lowered and stimulation rate is slowed.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

Intravenous amiodarone for recurrent sustained hypotensive ventricular tachyarrhythmias. Intravenous Amiodarone Multicenter Trial Group.

OBJECTIVES: We sought to determine the response rate and safety of intravenous amiodarone in patients with ventricular tachyarrhythmias refractory to standard therapies. BACKGROUND: Numerous small retrospective reports suggest a response of refractory ventricular tachyarrhythmias to intravenous amiodarone, yet no controlled prospective trials exist. METHODS: Two hundred seventy-three patients with recurrent hypotensive ventricular tachyarrhythmias refractory to lidocaine, procainamide and bretylium were randomized to receive one of three doses of intravenous amiodarone: 525, 1,050 or 2,100 mg/24 h (mean [+/- SE] dose 743.7 +/- 418.7, 1,175.2 +/- 483.7, 1,921.2 +/- 688.8 mg, respectively) by continuous infusion over 24 h. RESULTS: Of the 273 patients, 110 (40.3% response rate) survived 24 h without another hypotensive ventricular tachyarrhythmic event while being treated with intravenous amiodarone as a single agent (primary end point). A significant difference in the time to first recurrence of ventricular tachyarrhythmia (post hoc analysis) over the first 12 h was observed when the combined 1,050- and 2,100-mg dose groups were compared with the 525-mg dose group (p = 0.046). The number of supplemental (150 mg) infusions of intravenous amiodarone (given for breakthrough destabilizing tachyarrhythmias) during hours 0 to 6 (prespecified secondary end point) was significantly greater in the 525-mg dose group than in the 2,100-mg dose group (1.09 +/- 1.57 vs. 0.51 +/- 0.97, p = 0.0043). However, there was no clear dose-response relation observed in this trial with respect to success rates (primary end point), time to first recurrence of tachyarrhythmia (post hoc analysis) or mortality (secondary end point) over 24 h. CONCLUSIONS: Intravenous amiodarone is a relatively safe therapy for ventricular tachyarrhythmias refractory to other medications.

Electrophysiologic actions of high plasma concentrations of propranolol in human subjects.

The authors have previously shown that 40% of patients whose ventricular arrhythmias respond to propranolol require plasma concentrations in excess of those producing substantial beta-receptor blockade (greater than 150 ng/ml). However, the electrophysiologic actions of propranolol have only been examined in human beings after small intravenous doses achieving concentrations of less than 100 ng/ml. In this study, the electrophysiologic effects of a wider concentration range of propranolol was examined in nine patients. Using a series of loading and maintenance infusions, measurements were made at baseline, at low mean plasma propranolol concentrations (104 +/- 17 ng/ml) and at high concentrations (472 +/- 68 ng/ml). Significant (p less than 0.05) increases in AH interval and sinus cycle length were seen at low concentrations of propranolol, with no further prolongation at the high concentrations; these effects are typical of those produced by beta-blockade. However, progressive shortening of the endocardial monophasic action potential duration and QTc interval were seen over the entire concentration range tested (p less than 0.05). At high concentrations, there was significant (p less than 0.05) further shortening of both the QTc and monophasic action potential duration beyond that seen at low propranolol concentrations, along with a progressive increase in the ratio of the ventricular effective refractory period to monophasic action potential duration. No significant changes were seen in HV interval, QRS duration or ventricular effective refractory period. In summary, the concentration-response relations for atrioventricular conductivity and sinus node automaticity were flat above concentrations of 150 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

Pharmacokinetics and nondialyzability of mexiletine in renal failure.

Mexiletine is an investigational antiarrhythmic drug eliminated primarily by hepatic metabolism. To evaluate its pharmacokinetics in patients with renal failure, we gave 14 subjects (creatinine clearance from 0 to 68.9 ml/min, including five subjects who required maintenance dialysis) a single, 200 mg dose of mexiletine. Serial blood samples were drawn and analyzed for mexiletine concentration by gas chromatography. The elimination t1/2 was 18.9 +/- 7.4 hours and oral clearance was 378 +/- 109 ml/min (means +/- SD). There was no correlation between these parameters and creatinine clearance. In subjects receiving dialysis, the study was also repeated during dialysis 1 week later. There was no significant difference between the AUCs either while receiving dialysis or when calculated on a day when the subject was not receiving dialysis. Thus dosing adjustments for mexiletine should not be necessary in patients with creatinine clearance values as low as 10 ml/min or in patients receiving dialysis. Furthermore, supplemental doses of mexiletine are not likely to be needed after dialysis. Evaluation of the kinetics at steady state are necessary to extrapolate further our observations after a single oral dose.

Greater quinidine-induced QTc interval prolongation in women.

BACKGROUND: Prolongation of the electrocardiographic QT interval by drugs is associated with the occurrence of a potentially lethal form of polymorphic ventricular tachycardia termed torsades de pointes. Women are at greater risk than men for development of this adverse event when taking drugs that prolong the QT interval. To determine whether this may be the result of gender-specific differences in the effect of quinidine on cardiac repolarization, we compared the degree of quinidine-induced QT interval lengthening in healthy young men and women. METHODS: Twelve women and 12 men received a single intravenous dose of quinidine (4 mg/kg) or placebo in a single-blind, randomized crossover trial. Total plasma and protein-free concentrations of quinidine and 3-hydroxyquinidine were measured in serum. QT intervals were determined and corrected for differences in heart rate with use of the method of Bazett (QTc = QT/RR1/2). RESULTS: As expected, the mean QTc interval at baseline was longer for women than for men (mean +/- SD; 407 +/- 7 versus 395 +/- 9 ms, P < .05). The slope of the relationship between change in the QTc interval (delta QTc) from baseline to the serum concentration of quinidine was 44% greater for women than for men (mean +/- SE; 42.2 +/- 3.4 versus 29.3 +/- 2.6 ms/microg per mL, P < .001). These results were not influenced by analysis of 3-hydroxyquinidine, free concentrations of quinidine and 3-hydroxyquinidine, or the JT interval. CONCLUSIONS: Quinidine causes greater QT prolongation in women than in men at equivalent serum concentrations. This difference may contribute to the greater incidence of drug-induced torsades de pointes observed in women taking quinidine and has implications for other cardiac and noncardiac drugs that prolong the QTc interval. Adjustment of dosages based on body size alone are unlikely to substantially reduce the increased risk of torsades de pointes in women.

Plasma concentrations of quinidine, its major metabolites, and dihydroquinidine in patients with torsades de pointes.

We examined the hypothesis that excess accumulation of major quinidine metabolites or the commercial impurity dihydroquinidine contributes to the development of polymorphic ventricular tachycardia (torsades de pointes, [TdP]) in patients taking quinidine. Total and free plasma concentrations of these compounds were measured by reverse-phase HPLC with fluorescence detection and equilibrium dialysis in 19 patients with TdP and 38 control patients tolerating quinidine therapy without toxicity. No significant differences were found between the two groups of patients. Ratios of metabolite or dihydroquinidine to quinidine varied up to tenfold among patients but were similarly distributed in the TdP and control groups. Only the metabolite 3-hydroxyquinidine was present at free plasma concentrations that exceeded free concentrations of quinidine. We conclude that although quinidine metabolism is highly variable, there does not appear to be any correlation between the plasma concentrations of quinidine, its metabolites or dihydroquinidine, and the subsequent development of TdP.

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.

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.