sildenafil-citrate and Cardiotoxicity

Cardiovascular adverse effects in drug development are a major source of compound attrition. Characterization of blood pressure (BP), heart rate (HR), stroke volume (SV), and QT-interval prolongation are therefore necessary in early discovery. It is, however, common practice to analyze these effects independently of each other. High-resolution time courses are collected via telemetric techniques, but only low-resolution data are analyzed and reported. This ignores codependencies among responses (HR, BP, SV, and QT-interval) and separation of system (turnover properties) and drug-specific properties (potencies, efficacies). An analysis of drug exposure-time and high-resolution response-time data of HR and mean arterial blood pressure was performed after acute oral dosing of ivabradine, sildenafil, dofetilide, and pimobendan in Han-Wistar rats. All data were modeled jointly, including different compounds and exposure and response time courses, using a nonlinear mixed-effects approach. Estimated fractional turnover rates [h

Topics: Animals; Biomarkers, Pharmacological; Blood Pressure; Cardiotoxicity; Cardiovascular Agents; Heart Rate; Ivabradine; Male; Phenethylamines; Pyridazines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfonamides

Sildenafil is a phosphodiesterase type-5 inhibitor. We evaluated the effects of sildenafil on the sinoatrial rate, developed tension of the papillary muscle and coronary blood flow by using the canine isolated, blood-perfused sinoatrial node and papillary muscle preparations. The former preparation had a regular automaticity rate of 106 ± 1 beats/min (n = 4), whereas the latter showed a developed tension of 22 ± 4 mN (n = 4) and a coronary blood flow of 3.9 ± 0.1 mL/min (n = 4). Intracoronary injection of 10, 30 and 100 µg of sildenafil, which would provide about 20 to 200 times higher plasma drug concentrations than its therapeutic level, increased the automaticity rate by 4, 12 and 22%, the developed tension by 19, 55 and 118% and the coronary blood flow by 42, 95 and 142%, respectively. These results indicate that supratherapeutic concentration of sildenafil possesses direct positive chronotropic and inotropic effects together with a coronary vasodilator action, confirming that caution has to be paid on the use of sildenafil for patients with ischemic heart diseases, obstructive hypertrophic cardiomyopathy and/or ventricular arrhythmias. The information on sildenafil reported in this study may help establish a guidance on cardiac safety assessment of newer phosphodiesterase type-5 inhibitors.

Topics: Animals; Cardiotonic Agents; Cardiotoxicity; Coronary Circulation; Coronary Vessels; Dogs; Dose-Response Relationship, Drug; Female; Heart Rate; Isolated Heart Preparation; Male; Muscle Contraction; Papillary Muscles; Phosphodiesterase 5 Inhibitors; Risk Assessment; Sildenafil Citrate; Sinoatrial Node; Vasodilation; Vasodilator Agents