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Introduction: Erectile dysfunction (ED) is a highly prevalent condition affecting nearly one in five men worldwide. The advent of phosphodiesterase type 5 inhibitors (PDE5i) has revolutionised the ED treatment landscape and provided effective, minimally invasive therapies to restore male sexual function., Materials and Methods: A pubmed search was performed of all English language articles from 1996 to present reviewing PDE5i, including pharmacokinetics, efficacy profiles and comparisons, where available., Results: Currently available PDE5i in the United States include sildenafil, vardenafil, tadalafil and avanafil, each of which has unique side effect, pharmacokinetic and outcome profiles. Sildenafil is associated with increased rate of visual changes, vardenafil with QT prolongation and tadalafil with lower back pain. Avanafil and vardenafil orodispersible tablet rapidly achieve peak plasma concentration, which results in faster onset of action, whereas tadalafil exhibits the longest half-life. First time response to PDE5i is approximately 60-70%, with no significant differences in efficacy noted among therapies. The literature does not clearly demonstrate a preference for one drug. High-treatment success rates (89%) were reported when patients were prescribed all available PDE5i. Daily dosing with tadalafil is associated with improved erectile function (EF) over time. Finally, novel modes of patient-provider interaction, including internet-based education, communication and prescribing, may also improve long-term adherence., Conclusions: PDE5i represent first line therapy for ED with excellent overall efficacy and satisfactory side effect profiles. Enhanced communciation, coupled with increased knowledge of drug characteristics, comparative treatment regimens and optimal prescribing patterns, offer compelling tools to improve long-term treatment success., (© 2013 John Wiley & Sons Ltd.)

Clopidogrel, a new platelet ADP receptor antagonist used for the prevention of vascular ischemic events, is converted to an active metabolite via the cytochrome P450 system. Patients with cirrhosis may not metabolize drugs normally and may, in addition, have a number of defects in the coagulation system. To assess the effect of cirrhosis on the pharmacokinetics and pharmacodynamics of clopidogrel, the authors performed an open-label, parallel-group study of 12 patients with Child-Pugh Class A or B cirrhosis and 12 matched controls. All 24 subjects received clopidogrel 75 mg PO QD for 10 days. Pharmacokinetics of clopidogrel and the major metabolite SR 26334 were analyzed on Days 1 and 10; pharmacodynamics were assessed by the inhibition of ADP-induced platelet aggregation and by bleeding time prolongation factor. Pharmacokinetic analysis of clopidogrel was limited due to low plasma concentrations arising from rapid hydrolysis to SR 26334. The Cmax at SS for clopidogrel was higher in cirrhotics than in normals. However, exposures to the metabolite SR 26334, as measured by AUC(tau), were comparable. At Day 10, there was not a statistically significant difference in mean inhibition of platelet aggregation (49.2% +/- 38.6% in cirrhotics vs. 66.7% +/- 7.5% in normals) or in bleeding time prolongation factor (1.64 +/- 0.49 in cirrhotics vs. 1.54 +/- 0.87 in normals) between groups. No significant adverse events, including bleeding events, were reported. In conclusion, there were no significant differences in the pharmacokinetics and pharmacodynamics of clopidogrel in this group of subjects with cirrhosis and matched normals. Therefore, no dosage adjustment of clopidogrel is required in patients with Child-Pugh Class A or B cirrhosis.

The natriuretic and diuretic effects of a 100-mg dose of torsemide administered as a continuous infusion of torsemide and as a single bolus were compared in a group of patients with stable mild-to-moderate congestive heart failure (CHF). Patients received in random order 100 mg of torsemide as an intravenous bolus and as a 75-mg infusion over 24 hours started simultaneously with a 25-mg loading bolus. Administration of torsemide to patients with CHF as a continuous infusion was an effective dosing regimen, resulting in 24-hour diuresis and natriuresis that was numerically but not statistically greater than that observed with bolus administration. The response with continuous infusion occurred with less torsemide in the urine, resulting in a significantly greater efficiency of torsemide with this regimen. The effectiveness of torsemide as a continuous infusion does not mean that this mode of administration should be used in all patients. The response to 100 mg of torsemide in patients with mild-to-moderate CHF is the same whether administered as an intravenous bolus, a continuous intravenous infusion, or by mouth. This is consistent with the high bioavailability demonstrated in previous studies. The mode of therapy used should be dictated by each individual patient's needs. This study shows that continuous infusion is a viable option for administration of torsemide, and dosing guidelines for use of such a strategy are presented.

The bioavailability, pharmacokinetics, and pharmacodynamics of torsemide (10 mg orally and intravenously) and furosemide (40 mg orally and 20 mg intravenously) were determined in a randomized crossover clinical trial in 16 patients with compensated congestive heart failure. Torsemide (time to reach maximum concentration [tmax], 1.1 +/- 0.9 hour) was more rapidly absorbed than furosemide (tmax, 2.4 +/- 2.5 hours), the absorption of which was delayed compared with that in healthy volunteers. Bioavailability of torsemide was also greater and less variable than that of furosemide. All four treatments yielded comparable changes from baseline in 24-hour electrolyte excretion. Based on the relationships between sodium excretion rate and fractional sodium and urinary drug excretion rate, response to both diuretic agents at the level of the nephron was decreased compared with previous studies with healthy subjects. Assessment of the clinical relevance, if any, of the difference in the variability of absorption warrants further study.

The pharmacodynamics of torsemide (a new loop diuretic of the pyridine sulfonylurea class) was studied in 16 subjects who had compensated congestive heart failure and had been receiving stable diuretic therapy. Oral doses of 50, 100, and 200 mg were studied by use of a randomized crossover design. The results of this study show that the pharmacokinetics of torsemide is linear up to at least a dose of 200 mg in patients with congestive heart failure. Approximately 20% of each of the three doses was excreted unchanged, consistent with previous findings in healthy volunteers. A hyperbolic relationship between diuretic effect and drug excretion rate was defined. The maximum urinary sodium excretion rate attained was about 0.6 mEq/min, which is about 20% of that in healthy subjects, indicating diuretic resistance in these patients. Although there was no saturation of the urinary excretory pathway with doses as high as 200 mg, the upper plateau of the dose-response curve was reached with doses of 50 mg, indicating that this dose represents a ceiling dose in patients with New York Heart Association class II and III congestive heart failure.