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R L Woosley

Publications and source records attributed to R L Woosley.

At least 37 records · Page 2Linked to original sources
PubMed1999

Comparison of tegaserod (HTF 919) and its main human metabolite with cisapride and erythromycin on cardiac repolarization in the isolated rabbit heart.

Tegaserod (HTF 919) is a new drug being developed for gastrointestinal motility disorders. Because other gastrointestinal prokinetic agents, such as cisapride and erythromycin, cause slowing of cardiac repolarization and have been implicated in the development of the potentially fatal ventricular arrhythmia, torsades de pointes, a study was initiated to determine whether tegaserod and its main human metabolite adversely influence cardiac repolarization. By using isolated Langendorff-perfused rabbit hearts, we show that QT intervals remain unchanged at concentrations of tegaserod from 0.5 to 10 microM. It was not until the tegaserod concentration was increased to 50 microM (roughly 500-5,000 times more concentrated than those typically found in human plasma after administration of recommended clinical dosages), that a small, but significant increase in the QT interval (12+/-4%; p < 0.05; n = 4) was observed. No significant changes in QT occurred in the presence of the tegaserod metabolite at any of the concentrations tested (0.5-50 microM). In contrast, cisapride caused QT lengthening at concentrations as low as 0.1 microM, with significant QT increases occurring when 5-50 microM cisapride was used (22+/-4% to >70%, respectively; p < 0.01; n = 4). Erythromycin also caused significant lengthening of QT intervals (11+/-2%; p < 0.001; n = 4), although 100 microM concentrations of this drug were required to achieve this effect. These results demonstrate that both cisapride and erythromycin can slow cardiac repolarization at therapeutic doses and that tegaserod's lack of QT prolongation at therapeutic doses suggests that it has the potential to be a safer alternative to cisapride as a gastrointestinal prokinetic agent.

Animals↗
PubMed1999

Female gender is a risk factor for torsades de pointes in an in vitro animal model.

Recent clinical observations indicate that female gender is associated with a higher risk of developing torsades de pointes (TdP) cardiac arrhythmia. In this study, we used the Langendorff technique in isolated perfused rabbit hearts and the whole-cell patch-clamp technique in ventricular myocytes to examine the gender difference in TdP incidence and gain insight into the underlying mechanisms. Isolated rabbit hearts were perfused by using the Langendorff technique. TdP was induced by abrupt changes of cycle length (deltaCL) in the presence of Tyrode's solution containing 1 mM 4-aminopyridine (4AP) and 50% reduced Mg2+ and K+ (low K/Mg). The effects of 1 mM 4AP on cardiac potassium currents were characterized by using the patch-clamp technique. Results demonstrated that (a) no significant gender difference was observed in the absolute QT interval before or after 4AP perfusion in the presence of low K/Mg; (b) 4AP caused marked QT prolongation in the ECG; (c) a significantly higher TdP incidence (nine of 12) was found in female hearts compared with male hearts (three of 12; p < 0.05); (d) 1 mM 4AP primarily inhibited Ito, although a slight inhibition of IKr also occurred in low-K/Mg Tyrode's solution. (e) No inhibition of IK1 was observed. (f) No gender difference was found in the potassium current block produced by 4AP. Female gender is associated with a higher incidence of TdP in an experimental isolated heart model and mechanisms subsequent to QT prolongation may contribute to such a gender difference.

4-Aminopyridine↗
PubMed1998

Cardiac actions of erythromycin: influence of female sex.

CONTEXT: Erythromycin is a widely used antibiotic that infrequently causes QT-prolongation and torsades de pointes cardiac arrhythmias. For antiarrhythmic drugs, women are at a higher risk for these cardiac arrhythmias, but few other classes of drugs have been studied. OBJECTIVES: To determine whether female sex is a risk factor for cardiac arrhythmias associated with erythromycin, and if this can be correlated with in vitro measurements of the QT-response to erythromycin in male and female rabbit hearts. DESIGN: Food and Drug Administration (FDA) MEDWATCH database analysis and in vitro experiment. MAIN OUTCOME MEASURES: Cardiac arrhythmia reports associated with erythromycin from 1970 until 1996 classified by patient sex and age, and effect of female sex on erythromycin-induced QT-prolongation in isolated perfused rabbit hearts. RESULTS: We observed a sex difference in cardiac arrhythmias associated with administration of erythromycin. A total of 346 cases were found in the FDA database: 201 females (58%), 110 males (32%), and 35 unspecified (10%). Forty-nine were life-threatening ventricular arrhythmias and deaths directly related to intravenous erythromycin lactobionate: 33 women (67%) and 16 men (33%) (P=.03). During the same period, no sex imbalance was present in the prescription pattern for intravenous erythromycin lacobionate (men 47%, women 49%, unspecified 4%). Perfusion with erythromycin caused significantly greater QT-prolongation in female rabbit hearts (mean [SD], 11.8% [2.3%]) than in male hearts (6.9% [2.1%]; P = .03). CONCLUSIONS: As has been shown in reports of antiarrhythmic drugs, we found a female predominance in the FDA reports of erythromycin-associated cardiac arrhythmias. Based on in vitro experiments, a sex difference in cardiac repolarization response to erythromycin is a potential contributing factor.

Animals↗
PubMed1998

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.

Adenine↗
PubMed1998

Female gender as a risk factor for drug-induced cardiac arrhythmias: evaluation of clinical and experimental evidence.

One of the most pronounced gender-based differences in response to drugs is women's far greater risk of developing the life-threatening ventricular arrhythmia called torsades de pointes (TdP). A review of the literature and databases of the Food and Drug Administration reveals that a much higher percentage of women than men develop TdP arrhythmias after taking a variety of drugs, such as antihistamines (terfenadine, astemizole), antibiotics (erythromycin), antimalarials (halofantrine), antiarrhythmics (quinidine, d-sotalol), and miscellaneous other drugs. All of these drugs have in common the ability to block potassium currents, thereby prolonging cardiac repolarization and the QT interval on the ECG. The available experimental data support the hypothesis that gender differences in specific cardiac ion current densities are responsible, at least in part, for the greater susceptibility of females for developing TdP arrhythmias. In isolated perfused rabbit hearts (Langendorff technique), female rabbit hearts display greater baseline and drug-induced (quinidine and d-sotalol) changes in QT intervals than male hearts, and at least two different repolarizing potassium current densities (IKr and IKl) are found to be significantly lower in ventricular cardiomyocytes from female rabbits compared with those from males. Thus, it appears that as in humans, clear gender differences exist in the electrophysiologic characteristics governing cardiac repolarization in rabbits. This model and perhaps others should be examined as predictors of functional and pharmacologic differences between men and women. Understanding the potential mechanisms responsible for the greater risk of drug-induced arrhythmias in women could lead to screening methods for identification of individuals at risk for drug-induced arrhythmias or to the development of drugs with reduced risk of inducing arrhythmia.

Animals↗
PubMed1998

Prolongation of QT interval in isolated feline hearts by antipsychotic drugs.

Some antipsychotic drugs have been found to prolong the QT interval on electrocardiographic (ECG) recordings, a phenomenon which, when severe, may facilitate the occurrence of complex ventricular arrhythmias such as torsade de pointes. However, the effects of these drugs on the cardiac repolarization process have not been evaluated extensively. This study was designed to examine the potency of five antipsychotic drugs in lengthening the QT interval of the perfused feline heart: haloperidol, risperidone, sertindole, clozapine, and olanzapine. The hearts were infused with increasing concentrations of drugs (0.1-20 micromol/L) for 40-minute intervals at each concentration. ECG recordings were made, with signals amplified and data recorded on a strip chart recorder. Four representative beats from each set of three signal recordings were chosen for QT interval measurement. Our data indicated that all tested drugs prolonged the QT interval in a concentration-dependent manner (p < 0.01). Haloperidol and risperidone were significantly more potent than sertindole, clozapine, and olanzapine (p < 0.001). At a concentration of 0.5 micromol/L over a 40-minute infusion interval, haloperidol lengthened the interval by 26.2+/-0.7%, risperidone by 19.4+/-2.2%, and sertindole by 8.9+/-3.5% (p < 0.05 compared with baseline); clozapine and olanzapine were less potent. Although species differences may limit extrapolation of our findings to humans, the cardiac potassium channels of felines clearly resemble those of humans. This model may serve as the basis for further studies of drug-induced prolongation of the QT interval and precipitation of ventricular arrhythmias.

Analysis of Variance↗
PubMed1998

"Conventional" antihistamines slow cardiac repolarization in isolated perfused (Langendorff) feline hearts.

We examined the effects of "conventional" antihistamines on cardiac repolarization by using the isolated perfused feline heart model. Representative drugs from the major classes of antihistamines were tested. Each of the antihistamines evaluated in this study elicited a dose-dependent slowing of cardiac repolarization, as indicated by the QT prolongations observed from electrocardiogram (ECG) tracings recorded during these experiments. The concentrations of drugs tested ranged from 1 to 30 microM. Of the drugs analyzed, clemastine and hydroxyzine appeared to be the most potent (relative EC50 values, 5.2 and 6.6 microM, respectively), causing the QT to lengthen by as much as 40-50% at a concentration of 10 microM. Brompheniramine, chlorpheniramine, and diphenhydramine displayed intermediate potencies with respect to QT prolongation (relative EC50 values, 11-13 microM), whereas cyproheptadine, chlorcyclizine, and promethazine were the least potent of the antihistamines tested (relative EC50 values, 16-20 microM). It is concluded that the antihistamines evaluated in this study act directly on the heart to slow cardiac repolarization. These findings could have important clinical relevance for patients taking excessive dosages of conventional antihistamines and those at risk of developing cardiac arrhythmias.

Animals↗
PubMed1998

Gender difference in the cycle length-dependent QT and potassium currents in rabbits.

Women are known to have a longer electrocardiographic Q-T than men, which may contribute to their being at greater risk of developing drug-induced polymorphic ventricular arrhythmias. However, little is known about the underlying mechanisms. In the present study, we evaluated potential gender differences in Q-T interval in isolated perfused rabbit hearts using the Langendorff technique and evaluated the density of outward potassium currents in single ventricular myocytes using the whole-cell patch-clamp technique. We found that female hearts demonstrated a greater Q-T lengthening (delta Q-T%) upon an increase in cycle length (CL), resulting in a significantly longer Q-T (301 +/- 4.8 ms, CL = 2.3 s) at a long CL in female hearts compared with male hearts (267 +/- 4.0 ms, P < .01). Ventricular myocytes isolated from female hearts showed a smaller IK(tail) and peak IKI outward current density. A 50% reduction in extracellular K+ and Mg++ shifted the I-V relationship of IKI and Ito and reduced their amplitude. However, neither the I-V relationship of IKr nor the gender difference in the Q-T-CL relationship was significantly altered. We conclude that 1) female rabbit ventricular myocytes have significantly lower IKr and IKl outward current densities than do male cells, which may contribute to the gender difference in Q-T, and 2) a lower base-line IKr density may contribute to the steeper Q-T-CL relationship in female hearts.

Animals↗
PubMed1998

The antiestrogen tamoxifen blocks the delayed rectifier potassium current, IKr, in rabbit ventricular myocytes.

Tamoxifen is an antiestrogen drug commonly used to treat breast cancer and has been shown to cause prolongation of the electrocardiographic QT interval in humans. Because QT prolongation could influence cardiac arrhythmias, we sought to determine the electrophysiologic mechanism(s) underlying the tamoxifen action. The whole-cell patch-clamp technique was used to study the effect of tamoxifen on the delayed rectifier (IKr), the inward rectifier (IK1), the transient outward current (Ito), and the inward L-type calcium current (ICa) in rabbit ventricular myocytes. By switching to the current-clamp mode, the effect of tamoxifen on action potential duration (APD) was also studied. Tamoxifen blocked IKr in a time-, concentration- and voltage-dependent fashion. IKr tail currents were completely blocked by 10 micromol/l tamoxifen with no recovery after 15 min of washout. At +50 mV, tamoxifen 1 and 3.3 micromol/l blocked IKr by 39.5 +/- 1.7% (P <.01) and 84.8 +/- 1.3% (P <.01) respectively, while no significant block of IK1 or Ito was observed. Significant block of ICa by tamoxifen was also observed at concentrations greater than 1 micromol/l, with almost complete inhibition at 10 micromol/l. Tamoxifen showed no significant effect on APD at concentrations up to 3.3 micromol/l. We conclude that tamoxifen potently blocks both IKr and ICa at clinically relevant concentrations. The observed QT prolongation by tamoxifen in humans may be a result of its predominant effect on IKr. Inhibition of IKr, in conjunction with other QT-prolonging factors in patients could increase their risk of developing torsades de pointes-type cardiac arrhythmias.

Animals↗
PubMed1997

Is dispersion of ventricular repolarization rate dependent?

QT dispersion has been adopted as a new index for the noninvasive assessment of the inhomogeneity of repolarization and has been evaluated in several clinical studies as an index of arrhythmia propensity. In most of these studies, indices of dispersion of repolarization were rate corrected by the Bazett formula calculating QT dispersion as QT cmax-QT cmin or JT dispersion as JT cmax-JT cmin, implying that dispersion of repolarization also changes with heart rate. This study aimed to determine in the electrically paced isolated heart whether dispersion of ventricular repolarization is rate dependent. Multiple (5-7) monophasic action potentials (MAPs) were recorded simultaneously from the epicardium and endocardium of both ventricles in 18 isolated Langendorff-perfused rabbit hearts. Hearts were paced from a right ventricular site at basic cycle lengths (CL) between 1,200 and 300 ms in 100-ms decrements. Action potential duration was measured at 90% repolarization (APD90), and recovery time (RT) was defined as the sum of APD90 and activation time in each of the simultaneous MAP recordings. The dispersion of APD90 and RT, respectively, were calculated as the maximal difference among all recordings. APD90 and RT shortened continuously throughout the range of paced steady-state CLs from 1,200 to 300 ms. APD90 was 197.6 +/- 6.1 ms at a CL of 1,200 ms and decreased to 148.5 +/- 2.5 ms at a CL of 300 ms (P < 0.0001). RT was 228.2 +/- 6.2 ms at a CL of 1,000 ms and decreased to 175.9 +/- 2.9 at a CL of 300 ms (P < 0.0001). In contrast, dispersion of APD90 and RT did not change significantly. Dispersion of APD90 was 24.8 +/- 2.3 ms at a CL of 1,200 ms, 26.1 +/- 1.9 msec at a CL of 1,000 ms, and 21.6 +/- 2.1 at a CL of 300 ms (NS). Dispersion of RT was 29.7 +/- 3.4 ms at a CL of 1,200 ms, 29.0 +/- 3.0 ms at a CL of 1,000 ms, and 32.7 +/- 3.2 ms at a CL of 300 ms (NS). In contrast to the duration of the QT interval, dispersion of ventricular repolarization does not change significantly with pacing induced changes in CL. Assuming that the rate-dependent behavior of action potential duration is similar between the rabbit and human heart, a rate correction of parameters of dispersion of repolarization is probably unnecessary.

Action Potentials↗
PubMed1997

Electrophysiologic features of torsades de pointes: insights from a new isolated rabbit heart model.

INTRODUCTION: The exact electrophysiologic mechanism of torsades de pointes (TdP) is under intense investigation. No isolated animal heart model of this particular arrhythmia exists. METHODS AND RESULTS: In isolated rabbit hearts, TdP was induced by means of bradycardia in the presence of a high concentration of d-sotalol (10(-4) M) and shortly after lowering the concentration of potassium and magnesium in the perfusate. Multiple simultaneous epicardial and endocardial monophasic action potentials (MAPs) and volume-conducted 12-lead ECGs were recorded. d-Sotalol prolonged repolarization and increased dispersion of ventricular repolarization compared to baseline recordings. With the onset of low potassium and magnesium concentrations, repolarization was further prolonged and dispersion of repolarization was further increased followed by the occurrence of early afterdepolarizations (EADs) in the majority of MAP recordings, i.e., at both endocardial and epicardial locations of both ventricles. Upon increase of EAD amplitude, triggered arrhythmias with TdP of up to 42 beats ensued in 10 of 11 hearts studied. MAP duration at 90% repolarization (APD90), dispersion of APD90, and the incidence of EADs as well as dispersion of the QT interval and T wave area were significantly higher in beats triggering bigemini, couplets, or runs of TdP. CONCLUSION: TdP observed in this new isolated heart model was associated with markedly increased dispersion of ventricular repolarization and the occurrence of EADs in multiple locations of the heart. TdP is initiated when the amplitude of an EAD reaches threshold for initiation of the first beat of an episode.

Action Potentials↗
PubMed1997

Differential effects of D-sotalol, quinidine, and amiodarone on dispersion of ventricular repolarization in the isolated rabbit heart.

INTRODUCTION: Increased dispersion of ventricular repolarization has been suggested as a cause of proarrhythmic effects of Class IA or III antiarrhythmic drugs, such as d-sotalol, quinidine, and amiodarone. METHODS AND RESULTS: The influence of d-sotalol, quinidine, and amiodarone on the dispersion of monophasic action potential (MAP) durations was studied in 55 isolated Langendorff-perfused rabbit hearts at different pacing cycle lengths (CLs). MAP duration measured at 90% repolarization (APD90) was determined from 6 to 8 endocardial and epicardial MAP recordings with dispersion of ventricular repolarization defined as the range of APD90. The protocol was repeated 60 minutes after initiation of a perfusate containing increasing concentrations of d-sotalol (n = 12, 10[-6] M, 10[-5] M, and 5 x 10[-5] M) and quinidine (n = 8, 10[-6] M and 10[-5] M). Seventeen rabbits were fed with an aqueous solution of amiodarone (50 mg/kg per day over 4 weeks). The data of these experiments (n = 17) were compared with a series of 18 untreated control rabbits. Dispersion of ventricular repolarization was unchanged with the low concentration of d-sotalol (10[-6] M) but was increased-particularly at long CLs-with higher d-sotalol concentrations. With both concentrations of quinidine, dispersion of ventricular repolarization was increased in a rate-independent manner. Amiodarone did not affect dispersion of ventricular repolarization. CONCLUSIONS: Rate-dependent and concentration-dependent increases in dispersion of ventricular repolarization by d-sotalol and quinidine in this isolated rabbit heart model may help explain their proarrhythmic effects while the absence of an increase in dispersion of ventricular repolarization with amiodarone correlates with its clinically observed lower incidence of proarrhythmia.

Action Potentials↗
PubMed1996

Sex hormones prolong the QT interval and downregulate potassium channel expression in the rabbit heart.

BACKGROUND: Sex hormones are known to exert direct and indirect effects on cardiovascular function, but their effects on cardiac repolarization have not been elucidated. The repolarization phase of the cardiac action potential or QT interval of the ECG is regulated largely by potassium channels such as the delayed rectifier currents HK2 and IsK. METHODS AND RESULTS: The effects of ovariectomy (OVX) and estradiol (E2) or dihydrotestosterone (DHT) treatment were evaluated on HK2, HERG, and IsK mRNA levels, QT duration, and quinidine-induced changes in QT interval in isolated rabbit hearts. HK2 and 0.7-kilobase IsK mRNA were downregulated in cardiac ventricular tissue from OVX rabbits treated with either E2 or DHT. The QT interval was prolonged in E2- and DHT-treated animals (OVX + vehicle, 223 +/- 6 ms; OVX + DHT, 236 +/- 10 ms; and OVX + DHT, 245 +/- 6 ms; P < .05). CONCLUSIONS: The association between hormone-induced changes in baseline QT interval and the mRNA level for these channels suggests that sex hormones may play a critical role in regulating cardiac repolarization. However, the changes in baseline QT and potassium channel mRNA after hormone treatment were not concordant with the changes in QT interval after the infusion of quinidine, after which E2-treated animals responded similarly to controls (18.4 +/- 4.6% and 19.3 +/- 4.6% increase in QT interval, respectively) and DHT-treated animals exhibited less QT prolongation (11.4 +/- 3.8% increase; P < .03).

Animals↗
PubMed1996

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.

Amiodarone↗
PubMed1996

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.

Adult↗