Bedside physician led US-guided supra-clavicular lymph node biopsy and ROSE (rapid on-site evaluation): SVC obstruction swift management in lung cancer.

Superior vena cava obstruction (SVCO) is an oncological emergency and can often be linked to an underlying lung malignancy. Due to the potential life-threatening risks associated with SVCO, it necessitates urgent diagnosis and management. In this report, we discuss 3 case studies where the use of ultrasound-guided supraclavicular lymph node biopsy was used to obtain a biopsy from patients with SVCO, followed by rapid on-site evaluation (ROSE). The benefits of this technique ensure a more rapid histological diagnosis, while also involving a less invasive procedure for the patient. The histological diagnosis is essential in improving patient outcomes when treating those with SVCO as the recommended treatments vary depending on the underlying type of lung malignancy. Having this information can help the clinician swiftly employ the optimal treatment pathway for the patient.

High-consequence infectious diseases: the conception and development of a multi-disciplinary, interprofessional simulation training programme.

BACKGROUND: High-consequence infectious diseases (HCIDs) represent a group of acute infectious diseases with the potential to impact healthcare systems and public health profoundly. Effective management requires a system-based strategy focused on early detection, initiation of infection prevention and control measures, and appropriate use of personal protective equipment (PPE). Inadequate training in the safe use of HCID PPE, and lack of familiarity with key processes such as HCID waste and spills management, exacerbates the risk posed to healthcare workers (HCWs). Enhanced training opportunities are required to ensure that staff are equipped with the necessary knowledge and capabilities to protect themselves from pathogen exposure and infection. AIM: To create a bespoke interprofessional HCID simulation training programme. METHODS: A detailed learning needs analysis was undertaken, which identified multiple areas amenable to educational intervention. A full-day HCID simulation programme was developed, providing HCWs the opportunity to practice and gain proficiency in various domains. FINDINGS: Six interprofessional participants took part in the HCID simulation programme pilot. All six (100%) participants felt that the stated learning objectives had been achieved, and five and one participants found the programme to be extremely useful (83%) or very useful (17%), respectively. Following refinement based on pilot feedback, a further six courses have been run for 38 participants, of whom 97% found the programme to be extremely useful or very useful. CONCLUSION: The development of a training intervention in the low-frequency, high-risk field of HCIDs had a positive impact. Given the disproportionate impact on HCWs at times of HCID outbreaks, more investment is needed to keep the workforce upskilled.

Cord formation in BACTEC(TM) medium aids rapid identification of Mycobacterium tuberculosis complex.

Mycobacterium tuberculosis complex (MTC) organisms form serpentine cords in fluid culture medium. Reporting of a presumptive identification of MTC based on cording allows rapid identification of patients with tuberculosis. A total of 612 positive mycobacterial cultures from 316 patients over 3 years (2008-2010) were evaluated for the presence of cord formation. Cording was identified in 426 (69.6%) specimens, while the reference laboratory confirmed M. tuberculosis in 424 specimens (69.3%). Sensitivity of the test in our laboratory was 99.1% (95%CI 97.4-99.7) and specificity was 96.8% (95%CI 92.8-98.7). Presumptive identification of M. tuberculosis by the presence of cording formation is both sensitive and specific.

Identifying abnormalities in symbiotic development between Trifolium spp. and Rhizobium leguminosarum bv. trifolii leading to sub-optimal and ineffective nodule phenotypes.

BACKGROUND AND AIMS: Legumes overcome nitrogen limitations by entering into a mutualistic symbiosis with N(2)-fixing bacteria (rhizobia). Fully compatible associations (effective) between Trifolium spp. and Rhizobium leguminosarum bv. trifolii result from successful recognition of symbiotic partners in the rhizosphere, root hair infection and the formation of nodules where N(2)-fixing bacteroids reside. Poorly compatible associations can result in root nodule formation with minimal (sub-optimal) or no (ineffective) N(2)-fixation. Despite the abundance and persistence of strains in agricultural soils which are poorly compatible with the commercially grown clover species, little is known of how and why they fail symbiotically. The aims of this research were to determine the morphological aberrations occurring in sub-optimal and ineffective clover nodules and to determine whether reduced bacteroid numbers or reduced N(2)-fixing activity is the main cause for the Sub-optimal phenotype. METHODS: Symbiotic effectiveness of four Trifolium hosts with each of four R. leguminosarum bv. trifolii strains was assessed by analysis of plant yields and nitrogen content; nodule yields, abundance, morphology and internal structure; and bacteroid cytology, quantity and activity. KEY RESULTS: Effective nodules (Nodule Function 83-100 %) contained four developmental zones and N(2)-fixing bacteroids. In contrast, Sub-optimal nodules of the same age (Nodule Function 24-57 %) carried prematurely senescing bacteroids and a small bacteroid pool resulting in reduced shoot N. Ineffective-differentiated nodules carried bacteroids aborted at stage 2 or 3 in differentiation. In contrast, bacteroids were not observed in Ineffective-vegetative nodules despite the presence of bacteria within infection threads. CONCLUSIONS: Three major responses to N(2)-fixation incompatibility between Trifolium spp. and R. l. trifolii strains were found: failed bacterial endocytosis from infection threads into plant cortical cells, bacteroid differentiation aborted prematurely, and a reduced pool of functional bacteroids which underwent premature senescence. We discuss possible underlying genetic causes of these developmental abnormalities and consider impacts on N(2)-fixation of clovers.

Usefulness of cardiac resynchronisation therapy in patients with right bundle branch block: is viability an important piece of the puzzle?

BACKGROUND: Benefits of cardiac resynchronisation therapy (CRT) in patients with heart failure (HF) and left bundle branch block (LBBB) have been well established. The presence of asynchronism and viability predicts response to CRT with good accuracy. Viability in the region of the pacing lead as predictor of response to CRT in patients with HF, intraventricular asynchrony and right bundle branch block (RBBB) has never been evaluated. METHODS: We studied 4 consecutive patients with RBBB (QRS>120 ms) advanced ischemic HF, low ejection fraction (≤35%) and intraventricular asynchrony ≥50 ms scheduled for CRT. Dobutamine stress echocardiography (DSE) was performed within the week before CRT. Viability was defined as increased wall thickening during DSE. Viability in the region of left ventricular (LV) pacing lead was defined as the presence of viability in 2 contiguous segments. Response was defined by LV reverse remodeling (i.e. ≥15% reduction in LV end-systolic volume) 3-6 months after CRT. RESULTS: Three patients demonstrated LV reverse remodeling at follow-up. Responders showed LV end-systolic volume decrease of -31 ± 16% from baseline to follow-up whereas no change was observed in the non responder patient. Similar LV asynchronism was found in all patients. All responders had viability in ≥2 segments in the region of LV pacing. CONCLUSION: This preliminary report suggests that similar reverse remodeling can be observed in RBBB patients as patients with LBBB after CRT. Intraventricular asynchrony and RBBB, viability in the region of pacing lead may help to predict response to CRT in patients with HF.

Combination of phenotype assessments and CYP2C9-VKORC1 polymorphisms in the determination of warfarin dose requirements in heavily medicated patients.

The relative contribution of phenotypic measures and CYP2C9-vitamin K epoxide reductase complex subunit 1 (VKORC1) polymorphisms to warfarin dose requirements at day 14 was determined in 132 hospitalized, heavily medicated patients. Phenotypic measures were (1) the urinary losartan metabolic ratio before the first dose of warfarin, (2) the S:R-warfarin ratio at day 1, and (3) a dose-adjusted international normalized ratio (INR) at day 4. CYP2C9 and VKORC1 genotypes were determined by gene chip analysis. In multivariate analyses, the dose-adjusted INR at day 4 explained 31% of variability observed in warfarin doses at day 14, whereas genotypic measures (CYP2C9-VKORC1) contributed 6.5%. When S:R-warfarin ratio was used, genotypes contributed more significantly (23.5%). Finally, urinary losartan metabolic ratio was of low predictive value. The best models obtained explained 51% of intersubject variability in warfarin dose requirements. Thus, combination of a phenotypic measure to CYP2C9-VKORC1 genotypes represents a useful strategy to predict warfarin doses in patients receiving multiple drugs (11+/-4 drugs/day).

Isolation and characterization of rhizosphere bacteria with potential for biological control of weeds in vineyards.

AIMS: Deleterious rhizosphere inhabiting bacteria (DRB) have potential to suppress plant growth. This project focuses on the isolation of DRB with potential for development as commercial products for weed control. METHODS AND RESULTS: Bacteria were isolated from the rhizosphere, rhizoplane, and endorhizosphere of seedlings and mature plants of wild radish (Raphanus raphanistrum), annual ryegrass (Lolium rigidum) and capeweed (Arctotheca calendula) growing in vineyards in the Swan Valley, Western Australia. A majority (81.5%) of the 442 strains was obtained from either rhizospheres or rhizoplanes. Rapid screening techniques were developed to evaluate in the laboratory and glasshouse the effects of bacteria on plants. Strains were screened in the glasshouse for deleterious effects on annual ryegrass, wild radish, grapevine rootlings (Vitis vinifera) and the legume cover crop subterranean clover (Trifolium subterraneum). Three strains were identified using the Biolog system and 16S rRNA gene sequencing as two strains of Pseudomonas fluorescens (WSM3455 and WSM3456) and one strain of Alcaligenes xylosoxidans (WSM3457). One of the P. fluorescens (WSM3455) strain produced hydrogen cyanide, an inhibitor of plant roots and a broad-spectrum antimicrobial compound. CONCLUSIONS: Three strains specifically inhibited wild radish but had no significant deleterious effects on either grapevine rootlings or subterranean clover. SIGNIFICANCE AND IMPACT OF THE STUDY: This study suggested manipulation of the weed seedling rhizosphere using identified DRB as a potential biocontrol agent for wild radish.

Study of the drug-drug interaction between simvastatin and cisapride in man.

OBJECTIVE: The objective of our study was to evaluate in humans the drug-drug interaction occurring during the concomitant administration of cisapride and simvastatin, two well-known substrates of CYP3A4. METHODS: Eleven healthy men aged between 20 years and 35 years gave their written informed consent to participate in the study. Each participant received repeated doses of cisapride and/or simvastatin. At first, subjects received cisapride alone, 10 mg every 8 h, for 3 days. Then, the drug was given at the same regimen during concomitant administration of simvastatin, 20 mg every 12 h for 4 days, starting on the night of day 3. Finally, cisapride was stopped and subjects received simvastatin (20 mg every 12 h) for four additional days. RESULTS: Simvastatin administration caused a 14 +/- 20% increase in the AUC0-8 of cisapride. In contrast, plasma concentrations of simvastatin were unaltered by the coadministration of cisapride, whereas plasma concentrations of simvastatin acid, its active metabolite, were decreased by 33 +/- 24%. CONCLUSION: The concomitant administration of the prokinetic agent cisapride and the 3-hydroxy-3-methylgluaryl CoA reductase inhibitor simvastatin resulted in altered pharmacokinetics of both drugs. Increased plasma concentrations of cisapride suggest that some patients may be at risk of toxicity while receiving both drugs, whereas the decrease in simvastatin acid plasma concentrations suggests that cholesterol lowering effects of simvastatin treatment may be blunted.

Electrocardiographic findings in athletes: the prevalence of left ventricular hypertrophy and conduction defects.

OBJECTIVES: To determine whether there are electrocardiographic differences or distinctive abnormalities between athletes and sedentary subjects, and to verify the relationship between vagal activity measured by heart rate variability (SD of all normal-to-normal intervals [SDNN]) and possible electrocardiographic abnormalities. SUBJECTS AND METHODS: Resting electrocardiograms and heart rate variability measurements were performed separately during a single visit on 100 athletes and 50 nonathlete control subjects aged 18 to 55 years. The athletes were from the following various sports disciplines: long-distance running, mountain biking, cross-country skiing, biathlon, speed skating, swimming and triathlon. RESULTS AND CONCLUSIONS: There were significantly longer RR intervals, PR intervals and QT intervals in athletes than in control subjects (all P<0.05). The QRS complex and QTc did not show significant differences (both P>0.05). The prevalence of left ventricular hypertrophy (LVH) and incomplete right bundle branch block (IRBBB) was 10% and 7%, respectively, in athletes, but these conditions were absent in control subjects; among athletes, 2% presented with both conditions. LVH and IRBBB were more common among long-distance runners (six of 14 and four of 14, respectively) and could be attributed to normal, long term adaptation to intense, repeated exercise. LVH was related to age (P=0.04), whereas IRBBB was influenced by the number of years of training in the respective sports discipline (P=0.03). The mean SDNN value was significantly more elevated in athletes (P=0.0001), reflecting a higher parasympathetic tone than in sedentary control subjects. However, there was no relationship between vagal activity and LVH or IRBBB (both P>0.05).

Randomized trial of a noninvasive strategy to reduce hospital stay for patients with low-risk myocardial infarction.

OBJECTIVES: This study evaluated the feasibility, pertinence and psychosocial repercussions of a noninvasive reduced hospital stay strategy (three days) for low-risk patients with acute myocardial infarction using simple clinical criteria and predischarge 24-h ambulatory ST-segment ischemic monitoring. BACKGROUND: Previous studies evaluating shorter stays for uncomplicated myocardial infarction have been limited by retrospective or nonrandomized design and overdependence on invasive cardiac procedures. METHODS: One-hundred twenty consecutive patients admitted with an acute myocardial infarction fulfilling low-risk criteria were randomized 2:1 to a short hospital stay (80 patients) or standard stay (40 patients). Short-stay patients with no ischemia on ST-segment monitoring were discharged on day 3, returning for exercise testing a week later. All analyses were on an intention-to-treat basis. RESULTS: Forty-one percent of all screened patients with acute myocardial infarction would have been medically eligible for the short-stay strategy. Seventeen patients (21%) were not discharged early because of ischemia on ST-monitoring or angina. Median initial hospital stay was halved from 6.9 days in the standard stay to 3.5 days in the short-stay group. At six months, median total days hospitalized were 7.5 in the standard stay and 3.6 in the short-stay group (p < 0.0001). Adverse events and readmissions were low and not significantly different, and there were 25% fewer invasive cardiac procedures in the short-stay group. Psychosocial outcomes, risk factor changes and exercise test results were similar in the two groups. CONCLUSIONS: This reduced hospital stay strategy for low-risk patients with acute myocardial infarction is feasible and worthwhile, resulting in a substantial and sustained reduction in days hospitalized. It is without unfavorable psychosocial consequences, appears safe and does not increase the number of invasive cardiac procedures.

Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans.

CYP2D6 is the major enzyme involved in the metabolism of venlafaxine. Subjects with a low CYP2D6 activity have increased plasma concentrations of venlafaxine that may predispose them to cardiovascular side effects. In vitro and in vivo studies showed that diphenhydramine, a nonprescription antihistamine, can inhibit CYP2D6 activity. Therefore, the authors investigated in this study a potential drug interaction between diphenhydramine and venlafaxine. Fifteen male volunteers, nine with the extensive metabolizer (EM) and six with the poor metabolizer (PM) phenotype of CYP2D6, received venlafaxine hydrochloride 18.75 mg orally every 12 hours for 48 hours on two occasions (1 week apart): once alone and once during the concomitant administration of diphenhydramine hydrochloride (50 mg every 12 hours). Blood and urine samples were collected for 12 hours under steady-state conditions. In EMs, diphenhydramine decreased venlafaxine oral clearance from 104+/-60 L/hr to 43+/-23 L/hr (mean +/- SD; p < 0.05) without any effect on renal clearance (4+/-1 L/hr during venlafaxine alone and 4+/-2 L/hr during venlafaxine plus diphenhydramine). In PMs, coadministration of diphenhydramine did not cause significant changes in oral clearance and partial metabolic clearances of venlafaxine to its various metabolites. Diphenhydramine disposition was only slightly affected by genetically determined low CYP2D6 activity or concomitant administration of venlafaxine. In conclusion, diphenhydramine, at therapeutic doses, inhibits CYP2D6-mediated metabolism of venlafaxine in humans. Clinically significant interactions could be encountered during the concomitant administration of diphenhydramine and other antidepressant or antipsychotic drugs that are substrates of CYP2D6.

Phylogenetic relationships of three bacterial strains isolated from the pasture legume Biserrula pelecinus L.

Three bacterial strains (WSM 1283, WSM 1284, WSM 1497) isolated from root nodules of the pasture legume Biserrula pelecinus L. growing in Morocco, Italy and Greece, respectively, were studied in order to determine their phylogenetic relationship to the other members of the family Rhizobiaceae. A polyphasic approach, which included analyses of morphological and physiological characteristics, plasmid profiles, symbiotic performance and 16S rRNA gene sequencing, indicated that these strains belong to the genus Mesorhizobium.

Pharmacokinetic and pharmacodynamic interaction between mexiletine and propafenone in human beings.

BACKGROUND AND OBJECTIVE: Mexiletine and propafenone are often used concomitantly and are metabolized by the same cytochrome P450 isozymes, namely CYP2D6, CYP1A2, and probably CYP3A4. Our objective was to study the potential pharmacokinetic and electrophysiological interactions between mexiletine and propafenone. METHODS: Fifteen healthy volunteers, 8 extensive metabolizers and 7 poor metabolizers of CYP2D6, received oral doses of mexiletine 100 mg two times daily from day 1 to day 8 and oral doses of propafenone 150 mg two times daily from day 5 to day 12. Interdose studies were performed at steady-state on mexiletine alone (day 4), mexiletine plus propafenone (day 8), and propafenone alone (day 12). RESULTS: In subjects in the extensive metabolizer group, coadministration of propafenone decreased oral clearances of R-(-)-mexiletine (from 41+/-11 L/h to 28+/-7 L/h) and S-(+)-mexiletine (from 43+/-15 L/h to 29+/-11 L/h) to an extent such that these values were no longer different between the extensive and the poor metabolizer groups. Propafenone coadministration also decreased partial metabolic clearances of mexiletine to hydroxymethylmexiletine, p-hydroxymexiletine, and m-hydroxymexiletine in extensive metabolizers by 71%, 67%, and 73%, respectively. In contrast, propafenone did not alter the kinetics of mexiletine enantiomers in subjects in the poor metabolizer group except for a slight decrease in the formation of hydroxymethylmexiletine. Pharmacokinetic parameters of propafenone were not changed during concomitant administration of mexiletine in subjects of either phenotype. Finally, electrocardiographic parameters (QRS duration, QTc, RR, and PR intervals) were not modified during the combined administration of the drugs. CONCLUSION: Propafenone is a potent CYP2D6 inhibitor that may cause an increase in plasma concentrations of coadministered CYP2D6 substrates.

Sildenafil (Viagra) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current.

BACKGROUND-Several cases of unexpected death have been reported with sildenafil in patients predisposed to ischemic cardiac events. Although acute episodes of ischemia could account for some of these deaths, we hypothesized that sildenafil may have unsuspected electrophysiological effects predisposing some patients to proarrhythmia. METHODS AND RESULTS-Studies were undertaken in 10 isolated guinea pig hearts that demonstrated prolongation of cardiac repolarization in a reverse use-dependent manner by sildenafil 30 mcmol/L. Action potential duration increased 15% from baseline 117+/-3 to 134+/-2 ms with sildenafil during pacing at 250 ms cycle length, whereas a 6% increase from 99+/-2 to 105+/-2 ms was seen with pacing at 150 ms cycle length. Experiments in human ether-a-go-go-related gene (HERG)-transfected HEK293 cells (n=30) demonstrated concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current: activating current was 50% decreased at 100 mcmol/L. This effect was confirmed using HERG-transfected Chinese hamster ovary (CHO) cells, which exhibit no endogenous I(K)-like current. CONCLUSIONS-Sildenafil possesses direct cardiac electrophysiological effects similar to class III antiarrhythmic drugs. These effects are observed at concentrations that may be found in conditions of impaired drug elimination such as renal or hepatic insufficiency, during coadministration of another CYP3A substrate/inhibitor, or after drug overdose and offer a new potential explanation for sudden death during sildenafil treatment.

Ischemia-induced action potential shortening is blunted by d-sotalol in a pig model of reversible myocardial ischemia.

The purpose of this study was to investigate, in an anesthetized pig model of low-flow myocardial ischemia, the electrophysiologic effects of the class III drug d-sotalol during myocardial ischemia. Serial monophasic action potential (MAPD90) recordings and refractory period determinations from the anterior and posterior left ventricular wall were taken in 25 pigs during baseline, after low-flow posterior wall ischemia, after d-sotalol infusion under nonischemic conditions, and after repeated posterior wall ischemia while continuing the drug. Measurements were done at 60 and 150 beats/min after radiofrequency ablation of atrioventricular conduction. At baseline, MAPD90 and refractory periods were comparable in the anterior and posterior wall (323 +/- 15 vs. 318 +/- 10 ms, and 267 +/- 10 vs. 262 +/- 11 ms at 60 beats/min, respectively). In the absence of d-sotalol, low-flow regional ischemia was associated with a significant shortening of MAPD90 in the posterior versus the anterior wall (267 +/- 20 vs. 317 +/- 20 ms at 60 beats/min; p = 0.006). Similarly, ischemia-induced shortening of the refractory periods in the posterior wall was apparent (230 +/- 16 ms in the posterior wall vs. 274 +/- 14 ms in the anterior wall at 60 beats/min). In contrast, ischemia was no longer associated with shortening of MAPD90 (360 +/- 17 ms posterior wall and 360 +/- 20 ms anterior wall at 60 beats/min) and refractory periods (304 +/- 19 ms posterior wall vs. 316 +/- 15 ms anterior wall at 60 beats/min) during combined posterior wall ischemia and d-sotalol infusion. Similar findings were obtained during pacing at 150 beats/min. d-Sotalol attenuates ischemia-induced action potential shortening. This property should decrease dispersion of cardiac repolarization and be antiarrhythmic. On the other hand, longer APD under ischemic conditions may favor calcium overload, which may trigger new arrhythmias.

Comparison of propafenone versus procainamide for the acute treatment of atrial fibrillation after cardiac surgery.

A prospective, randomized, double-blind study to compare the efficacy in terminating postoperative atrial fibrillation of the class Ic drug propafenone versus class Ia drug procainamide was conducted. Intravenous propafenone was superior to procainamide in achieving rapid cardioversion and a better rate control with a lower incidence of symptomatic hypotension.

Block of potassium currents in guinea pig ventricular myocytes and lengthening of cardiac repolarization in man by the histamine H1 receptor antagonist diphenhydramine.

Treatment with second generation histamine H1 receptor antagonists has been associated with lengthening of the Q-T interval and proarrhythmia. Similarly, lengthening of the Q-T interval has been reported in patients after overdosing with diphenhydramine (DPH), a first generation agent. Therefore, our study was designed 1) to assess effects of DPH on cardiac repolarization and 2) to characterize effects of the drug on major voltage-dependent cardiac K+ currents. First, we noticed that oral administration of DPH at usual dosages to healthy volunteers or to patients (prior to angioplasty) was associated with prolongation of the Q-Tc interval. Although this effect was modest in most individuals, Q-Tc was increased more than 20 ms in 7 of 20 patients. Second, we noticed that exposure of isolated guinea pig hearts to DPH 10(-5) M caused a lengthening of monophasic action potential duration. This effect was potentiated by the combined perfusion of other K+ channel blockers such as indapamide. Finally, experiments performed with the patch-clamp technique demonstrated unequivocal block of the rapid component of the delayed rectifier (IKr) by DPH; however, IC50 determined for block of IKr (3 x 10(-5) M) is approximately 40-fold greater than plasma concentrations of the drug measured at usual dosages (7 x 10(-7) M). Consequently, in agreement with the long-term clinical use of the drug, prolongation of cardiac repolarization should be minimal in most patients at usual dosages but may be observed with overdosing. Nevertheless, caution remains since excessive lengthening of cardiac repolarization may occur after administration of DPH with other drugs due to 1) concomitant block of other ionic currents or 2) pharmacokinetic interactions leading to toxic concentrations of DPH.

Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans.

According to in-vitro studies with microsomes from human livers and from yeast expression systems with high CYP2D6 activity, the major oxidation pathway of venlafaxine is catalysed by CYP2D6. In this study, we investigated the role of the CYP2D6 polymorphism and the effects of low-dose quinidine, a selective inhibitor of, CYP2D6, on the disposition of venlafaxine. Fourteen healthy men, eight with the extensive metabolizer and six with the poor metabolizer phenotype were administered venlafaxine hydrochloride 18.75 mg orally every 12 h for 48 h on two occasions (1 week apart); once alone and once during the concomitant administration of quinidine sulfate 100 mg every 12 h. Blood and urine samples were collected under steady-state conditions over one dosing interval (12 h). When venlafaxine was administered alone, the oral clearance of venlafaxine was more than fourfold less in poor metabolizers compared to extensive metabolizers (P < 0.05). This was mainly due to a decreased capability of poor metabolizers to form O-desmethylated metabolites at the position 4 of the aromatic moiety. In extensive metabolizers, quinidine decreased venlafaxine oral clearance from 100 +/- 62 l/h to 17 +/- 5 l/h (mean +/- SD; P < 0.05) without any effects on renal clearance (4 +/- 1 l/h during venlafaxine alone and 4 +/- 1 l/h during venlafaxine plus quinidine). In these individuals, the sequential metabolism of venlafaxine to O-desmethylvenlafaxine and to N,O-didesmethylvenlafaxine was inhibited by quinidine coadministration so that metabolic clearances to O-desmethylated metabolites decreased from 43 +/- 32 l/h to 2 +/- 1 l/h (P < 0.05). In poor metabolizers, coadministration of quinidine did not cause significant changes in oral clearance and partial metabolic clearances of venlafaxine to its various metabolites. Decreased CYP2D6 activity could also be associated with cardiovascular toxicity as observed in four patients during treatment with the drug. Thus, genetically determined or pharmacologically altered CYP2D6 activity represents a major determinant of venlafaxine disposition in humans.