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.

Adenosine A1-receptor occupancy predicts A1-receptor antagonist effects of N-0861.

OBJECTIVE: To evaluate the relationship between dose of N-0861 ([+/-]N6-endo-norbornan-2-yl-9-methyladenine), N-0861 plasma concentrations, and antagonism of adenosine-induced slowing of atrioventricular nodal conduction and to evaluate A1-receptor occupancy by antagonist present in plasma of subjects after administration of N-0861 to determine A1-selectivity of these effects. METHODS: The study was conducted in patients undergoing a clinically indicated electrophysiology study to evaluate atrioventricular nodal conduction. Nineteen subjects were enrolled in the study and received adenosine (60 to 140 microg/kg) before or during a bolus dose and maintenance infusion of specific doses of N-0861. Adenosine-induced slowing of atrioventricular nodal conduction was determined by measuring A-H intervals on the intracardiac electrocardiograms. Plasma concentrations of N-0861 were determined with an HPLC method. A1-Receptor occupancy by antagonist present in plasma from identical time points was determined with use of a radioreceptor assay. RESULTS: A linear relationship was shown between plasma concentration and dose of N-0861. A-H interval lengthening by 60 microg/kg adenosine was reduced by administration of N-0861. A linear relationship was observed between A1 occupancy and N-0861 concentration and between occupancy and antagonism of adenosine-induced A-H prolongation. CONCLUSION: The results suggest that the effect of N-0861 on antagonism of adenosine-induced prolongation of A-H interval, at the doses used in this study, were the result of effects at the A1 receptor.

Cardiology for the primary care provider: heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is classified as two distinct entities: HIT I and HIT II. HIT I is mild thrombocytopenia that occurs in approximately 25% of patients within the first 5 days of starting therapy and is clinically benign. HIT II is a syndrome of severe thrombocytopenia and thrombosis that occurs 6 days to 14 days into therapy in about 2% of patients and is associated with considerable morbidity and mortality. The severe form of HIT appears to be due to antibodies directed against a complex of heparin and platelet factor 4 (PF4) that leads to platelet activation, endothelial injury, and thrombosis. Treatment is problematic, but heparin administration must be immediately discontinued. In uncontrolled trials, agents such as warfarin, hirudin, and danaparoid have shown some efficacy. Early recognition by monitoring daily platelet counts during therapy may decrease the incidence of thrombosis.

Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolongation of repolarization on the electrocardiogram.

OBJECTIVES: To establish whether the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine are affected by concomitant administration of grapefruit juice and to determine whether any effect of grapefruit juice is dependent on the timing of administration in relation to the dose of terfenadine. METHODS: Twelve healthy volunteers were studied in a prospective randomized trial. The primary end points were QT prolongation on the surface electrocardiogram and the pharmacokinetic parameters: area under the concentration-time curve (AUC), maximum concentration, and time to maximum concentration of terfenadine and its acid metabolite terfenadine carboxylate. All subjects received 60 mg terfenadine twice a day with 240 ml water for 7 days. They were then randomized to drink 240 ml of double-strength grapefruit juice simultaneously with terfenadine (simultaneous group) for an additional 7 days or to drink the same dose of grapefruit juice 2 hours after terfenadine for 7 days (delayed group). Twelve timed electrocardiograms and plasma terfenadine and metabolite levels were measured on days 7 and 14. RESULTS: None of the 12 subjects had quantifiable levels of terfenadine when the drug was administered with water. All six subjects who took terfenadine and drank grapefruit juice simultaneously had quantifiable terfenadine levels. Only two of six who drank grapefruit juice 2 hours after terfenadine had quantifiable levels. The AUC of the acid metabolite increased 55% (p < 0.05) in the simultaneous group and 22% (p = NS) in the delayed group. The mean QT interval increased from 420 to 434 msec (p < 0.05) in the simultaneous group and decreased from 408 to 407 msec (p = NS) in the delayed group. CONCLUSIONS: Administration of grapefruit juice concomitantly with terfenadine may lead to an increase in systemic terfenadine bioavailability and result in increases in QT interval. The clinical significance of an increase in QT interval of this magnitude is unclear.

Survey in central Kentucky for prevalence of Anoplocephala perfoliata in horses at necropsy in 1992.

A total of 118 horses was examined at necropsy in central Kentucky for the tapeworm Anoplocephala perfoliata. The examination period was between 28 August and 21 December 1992. Prevalence was 64% for Thoroughbreds (n = 81 examined) and 54% for non-Thoroughbreds (n = 37 examined). The number of tapeworms per infected horse varied from one to 853. Data on infections are categorized by breed, sex (n = 38 males, 8 geldings, and 72 females), age (1-31 years), and month of necropsy of the horses.

Predictors of coronary angiography in patients with idiopathic dilated cardiomyopathy: the Washington, DC Dilated Cardiomyopathy Study.

Although a number of clinical and demographic factors have been associated with the performance of angiography in cardiac patients, clinical studies of idiopathic dilated cardiomyopathy (DCM) have often excluded patients who have not undergone coronary angiography to rule out coronary artery disease (CAD). To examine the impact of this diagnostic criterion on population-based studies of idiopathic DCM, we examined characteristics of probable cases of DCM who did or did not have a recorded history of angiography. The cases (n = 129) were ascertained from five medical centers in the Washington, DC metropolitan area over the period 1 July 1990 through 29 February 1992. All of these cases had evidence of ventricular dilation and hypokinesis, with a left ventricular ejection fraction of less than 40%. Cases with a history of known CAD, congenital heart disease, valvular heart disease, or secondary cardiomyopathy were excluded. Sixty-two (48%) of the cases had a recorded history of angiography. Age, educational level, diabetes, alcohol use, insurance status, and type of hospital were significantly associated with angiography in bivariate analysis (p < 0.05). Diabetes and hypertension were inversely associated with history of angiography among black cases, and positively associated with angiography among whites. In logistic regression analysis, age was the strongest independent predictor of angiography (p < 0.025). The associations with educational attainment and alcohol use were of borderline significance (p < 0.10). Thus, in epidemiologic studies of idiopathic DCM, particularly in biracial populations, the exclusion of cases who have not undergone angiography may bias risk estimates and result in the underestimation of incidence and prevalence.