Transdermal Testosterone Attenuates Drug-Induced Lengthening of Both Early and Late Ventricular Repolarization in Older Men.

We have previously reported that transdermal testosterone attenuates drug-induced QT interval lengthening in older men. However, it is unknown whether this is due to modulation of early ventricular repolarization, late repolarization, or both. In a secondary analysis of a prospective, randomized, double-blind, placebo-controlled three-way crossover study, we determined if transdermal testosterone and oral progesterone attenuate drug-induced lengthening of early and late ventricular repolarization, represented by the electrocardiographic measurements J-Tpeak c and Tpeak -Tend , respectively, as well as Tpeak -Tend /QT, a measure of transmural dispersion of repolarization. Male volunteers ≥ 65 years of age (n = 14) were randomized to receive transdermal testosterone 100 mg, oral progesterone 400 mg, or matching transdermal/oral placebo daily for 7 days. On the morning following the seventh day, subjects received intravenous ibutilide 0.003 mg/kg, after which electrocardiograms were performed serially. One subject was excluded due to difficulty in T-wave interpretation. Pre-ibutilide J-Tpeak c was lower during the testosterone phase than during progesterone and placebo (216 ± 23 vs. 227 ± 28 vs. 227 ± 21 ms, P = 0.002). Maximum post-ibutilide J-Tpeak c was also lower during the testosterone phase (233 ± 22 vs. 246 ± 29 vs. 248 ± 23 ms, P < 0.0001). Pre-ibutilide Tpeak -Tend was not significantly different during the three phases, but maximum post-ibutilide Tpeak -Tend was lower during the testosterone phase (80 ± 12 vs. 89 ± 18 vs. 86 ± 15 ms, P = 0.002). Maximum Tpeak -Tend /QT was also lower during the testosterone phase (0.199 ± 0.023 vs. 0.216 ± 0.035 vs. 0.209 ± 0.031, P = 0.005). Progesterone exerted minimal effect on drug-induced lengthening of J-Tpeak c, and no effect on Tpeak -Tend or Tpeak -Tend /QT. Transdermal testosterone attenuates drug-induced lengthening of both early and late ventricular repolarization in older men.

Progesterone pretreatment reduces the incidence of drug-induced torsades de pointes in atrioventricular node-ablated isolated perfused rabbit hearts.

INTRODUCTION: Higher progesterone concentrations are protective against drug-induced prolongation of ventricular repolarization. We tested the hypothesis that pretreatment with progesterone reduces the incidence of drug-induced torsades de pointes (TdP). METHODS AND RESULTS: Female New Zealand white rabbits (2.5-3.2 kg) underwent ovariectomy and were randomized to undergo implantation with subcutaneous 21-day sustained release pellets containing progesterone 50 mg (n = 22) or placebo (n = 23). After 20 days, hearts were excised, mounted, and perfused with modified Krebs-Henseleit solution. The atrioventricular (AV) node was destroyed manually. Following a 15-minute equilibration period, hearts were perfused with dofetilide 100 nM for 30 minutes, during which the electrocardiogram was recorded continuously. Incidences of spontaneous TdP, other ventricular arrhythmias and mean QTc intervals were compared. Median serum progesterone concentrations were higher in progesterone vs placebo-treated rabbits (3.8 [range, 2.8-5.1] vs 0.7 [0.4-1.7] ng/mL, P < 0.0001). Median serum estradiol concentrations were similar (58 [22-72] vs 53 [34-62] pg/mL), P = 0.79). The incidence of TdP was lower in hearts from progesterone-treated rabbits (27% vs 61%, P = 0.049). The incidences of bigeminy (36% vs 74%, P = 0.03) and trigeminy (18% vs 57%, P = 0.01) were also lower in hearts from progesterone-treated rabbits. There was no significant difference between groups in incidence of couplets (59% vs 74%, P = 0.54) or monomorphic ventricular tachycardia (14% vs 30%, P = 0.28). Maximum QT c interval and short-term beat-to-beat QT interval variability during dofetilide perfusion were significantly shorter in hearts from progesterone-treated rabbits. CONCLUSIONS: Pretreatment with progesterone reduces the incidence of drug-induced TdP, bigeminy, and trigeminy in isolated perfused AV node-ablated rabbit hearts.

Amiodarone for prevention of atrial fibrillation following esophagectomy.

OBJECTIVES: Atrial fibrillation (AF) is a common complication after esophagectomy and is associated with symptoms, hemodynamic instability, prolonged hospital stay, and an increased incidence of mortality. Our objective was to determine the efficacy and safety of intravenous amiodarone for prophylaxis of postesophagectomy AF. METHODS: In this retrospective cohort study, 309 patients who underwent esophagectomy formed the initial cohort. Following propensity score-matching, 110 patients who received prophylactic amiodarone 43.75 mg/hour via continuous intravenous infusion over 96 hours (total dose, 4200 mg) were matched to a control group of patients who did not undergo amiodarone prophylaxis (n = 110). The propensity score was obtained using a multivariate logistic regression model with amiodarone as the variable and the following covariates: age, sex, surgical approach, history of neoadjuvant chemotherapy and/or radiation, chronic obstructive pulmonary disease, heart failure, cardiovascular disease, alcohol use (>7 drinks/week), preadmission ß-blockers discontinued during hospitalization, preoperative use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, preoperative use of corticosteroids, postoperative use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, postoperative use of corticosteroids, postoperative use of statins, and preoperative Charlson comorbidity index. RESULTS: The incidence of AF requiring treatment due to rapid ventricular rate and symptoms was lower in the amiodarone group (17 out of 110 [15.5%] vs 32 out of 110 [29.1%]; odds ratio, 0.45; 95% confidence interval, 0.23-0.86; P = .015). There were no significant differences between the groups in median postoperative length of hospital stay, incidence of pulmonary complications, or mortality. The incidences of hypotension requiring treatment (42.7% vs 21.8%; P = .001), bradycardia (8.2% vs 0.0%; P = .002), and corrected QT interval prolongation (10.9% vs 0.0%; P ≤ .0001) were significantly higher in the amiodarone group. CONCLUSIONS: Prophylactic intravenous amiodarone is associated with a reduction in the incidence of AF following esophagectomy, but is not associated with shorter postoperative length of hospital stay. Intravenous amiodarone for prophylaxis of postesophagectomy AF is associated with hypotension, bradycardia, and corrected QT interval prolongation.

Efavirenz Inhibits the Human Ether-A-Go-Go Related Current (hERG) and Induces QT Interval Prolongation in CYP2B6*6*6 Allele Carriers.

BACKGROUND: Efavirenz (EFV) has been associated with torsade de pointes despite marginal QT interval lengthening. Since EFV is metabolized by the cytochrome P450 (CYP) 2B6 enzyme, we hypothesized that EFV would lengthen the rate-corrected QT (QTcF) interval in carriers of the CYP2B6*6 decreased functional allele. OBJECTIVE: The primary objective of this study was to evaluate EFV-associated QT interval changes with regard to CYP2B6 genotype and to explore mechanisms of QT interval lengthening. METHODS: EFV was administered to healthy volunteers (n = 57) as a single 600 mg dose followed by multiple doses to steady-state. Subjects were genotyped for known CYP2B6 alleles and ECGs and EFV plasma concentrations were obtained serially. Whole-cell, voltage-clamp experiments were performed on cells stably expressing hERG and exposed to EFV in the presence and absence of CYP2B6 expression. RESULTS: EFV demonstrated a gene-dose effect and exceeded the FDA criteria for QTcF interval prolongation in CYP2B6*6/*6 carriers. The largest mean time-matched differences ∆∆QTcF were observed at 6 hours (14 milliseconds; 95% CI [1; 27]), 12 hours (18 milliseconds; 95% CI [-4; 40]), and 18 hours (6 milliseconds; 95% CI [-1; 14]) in the CYP2B6*6/*6 genotype. EFV concentrations exceeding 0.4 µg/mL significantly inhibited outward hERG tail currents (P < 0.05). CONCLUSIONS: This study demonstrates that homozygous carriers of CYP2B6*6 allele may be at increased risk for EFV-induced QTcF interval prolongation via inhibition of hERG.

Distressed family caregivers of lung cancer patients: an examination of psychosocial and practical challenges.

PURPOSE: Lung cancer and its treatment impose many demands on family caregivers, which may increase their risk for distress. However, little research has documented aspects of the caregiving experience that are especially challenging for distressed caregivers of lung cancer patients. This study aimed to explore caregivers' key challenges in coping with their family member's lung cancer. METHODS: Single, semi-structured qualitative interviews were conducted with 21 distressed family caregivers of lung cancer patients. RESULTS: Caregivers described three key challenges in coping with their family member's lung cancer. The most common challenge, identified by 38 % of caregivers, was a profound sense of uncertainty regarding the future as they attempted to understand the patient's prognosis and potential for functional decline. Another key challenge, identified by 33 % of caregivers, involved time-consuming efforts to manage the patient's emotional reactions to the illness. Other caregivers (14 %) characterized practical tasks, such as coordinating the patient's medical care, as their greatest challenge. CONCLUSIONS: Results suggest that clinical efforts are needed to assist distressed caregivers in providing practical and emotional support to the patient and attending to their own emotional needs.