Browsing by Subject "Sulfonamides"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Progesterone pretreatment reduces the incidence of drug-induced torsades de pointes in atrioventricular node-ablated isolated perfused rabbit hearts
    (Wiley, 2019-04-21) Tisdale, James E.; Jaynes, Heather A.; Overholser, Brian R.; Sowinski, Kevin M.; Kovacs, Richard J.; Medicine, School of Medicine
    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 versus 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) versus 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 QTc 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.
  • Thumbnail Image
    Item
    Race and sex differences in response to endothelin receptor antagonists for pulmonary arterial hypertension
    (Elsevier, 2012-01) Gabler, Nicole B.; French, Benjamin; Strom, Brian L.; Liu, Ziyue; Palevsky, Harold I.; Taichman, Darren B.; Kawut, Steven M.; Halpern, Scott D.; Biostatistics, School of Public Health
    Background Recently studied therapies for pulmonary arterial hypertension (PAH) have improved outcomes among populations of patients, but little is known about which patients are most likely to respond to specific treatments. Differences in endothelin-1 biology between sexes and between whites and blacks may lead to differences in patients' responses to treatment with endothelin receptor antagonists (ERAs). Methods We conducted pooled analyses of deidentified, patient-level data from six randomized placebo-controlled trials of ERAs submitted to the US Food and Drug Administration to elucidate heterogeneity in treatment response. We estimated the interaction between treatment assignment (ERA vs placebo) and sex and between treatment and white or black race in terms of the change in 6-min walk distance from baseline to 12 weeks. Results Trials included 1,130 participants with a mean age of 49 years; 21% were men, 74% were white, and 6% were black. The placebo-adjusted response to ERAs was 29.7 m (95% CI, 3.7-55.7 m) greater in women than in men (P = .03). The placebo-adjusted response was 42.2 m for whites and −1.4 m for blacks, a difference of 43.6 m (95% CI, −3.5-90.7 m) (P = .07). Similar results were found in sensitivity analyses and in secondary analyses using the outcome of absolute distance walked. Conclusions Women with PAH obtain greater responses to ERAs than do men, and whites may experience a greater treatment benefit than do blacks. This heterogeneity in treatment-response may reflect pathophysiologic differences between sexes and races or distinct disease phenotypes.
  • Thumbnail Image
    Item
    Transdermal Testosterone Attenuates Drug-Induced Lengthening of Both Early and Late Ventricular Repolarization in Older Men
    (Wiley, 2021) Tomaselli Muensterman, Elena; Jaynes, Heather A.; Sowinski, Kevin M.; Overholser, Brian R.; Shen, Changyu; Kovacs, Richard J.; Tisdale, James E.; Medicine, School of Medicine
    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.