Aims To investigate the effect of the antiretroviral protease inhibitors saquinavir (soft gelatin capsule) and ritonavir on the pharmacokinetic properties and tolerability of sildena®l and to investigate the effect of sildena®l on the steady-state pharmacokinetics of saquinavir and ritonavir. Methods Two independent, 8 day, open, randomized, placebo-controlled, parallelgroup studies (containing a double-blind crossover phase) were conducted at P®zer Clinical research units (Canterbury, UK. and Brussels, Belgium). Twenty-eight healthy male volunteers entered each study. In each study, volunteers were randomized (n=14 per group) to receive sildena®l on day 1 followed by a 7-day treatment period (days 2±8) with saquinavir or placebo (Study I) or ritonavir or placebo (Study II). Sildena®l or placebo (Study I and Study II) was administered alternately on day 7 or day 8, depending on initial randomization. The effect of saquinavir and ritonavir on the pharmacokinetics of sildena®l and its primary circulating metabolite (UK-103, 320) and the effect of single-dose sildena®l on the steady-state pharmacokinetics of saquinavir (1200 mg three times daily) and ritonavir (500 mg twice daily) were determined. The safety and tolerability of sildena®l coadministered with saquinavir or ritonavir were also assessed. Results Both protease inhibitors signi®cantly increased C max , AUC, t max and t K values for both sildena®l and UK-103, 320. Ritonavir showed a signi®cantly greater effect than saquinavir with increases in sildena®l AUC and C max of 11-fold (95% CI: 9.0, 12.0) and 3.9-fold (95% CI: 3.2, 4.9), respectively. This compared with increases of 3.1-fold (95% CI: 2.5, 4.0) and 2.4-fold (95% CI: 1.8, 3.3) for coadministration with saquinavir. In contrast, the steady-state pharmacokinetics of saquinavir and ritonavir were unaffected by sildena®l. The increases in systemic exposure to sildena®l and UK-103, 320 were not associated with an increased incidence of adverse events or clinically signi®cant changes in blood pressure, heart rate or ECG parameters. Conclusions These results indicate that both saquinavir and ritonavir modify the pharmacokinetics of sildena®l presumably through inhibition of CYP3A4. The more pronounced effect of ritonavir may be attributed to its additional potent inhibition of CYP2C9. No change in safety or tolerability was observed when sildena®l was coadministered with either protease inhibitor. However, given the extent of the interactions, a lower sildena®l starting dose (25 mg) should be considered for patients receiving saquinavir and it is recommended not to exceed a maximum single dose of 25 mg in a 48 h period for patients receiving ritonavir.

Coadministration of sildenafil with ISMN or GTN produced significantly greater reductions in BP than ISMN or GTN alone. Based on these data, sildenafil should not be administered to patients taking nitrates.

Aims To determine the onset and duration of action of sildena®l in patients with erectile dysfunction (ED). Methods Two randomised, double-blind, placebo-controlled, two-way crossover studies were conducted in men with ED of no known organic cause. Study I: The time to onset of erections after sildena®l (50 mg) or placebo dosing following visual sexual stimulation (VSS) was assessed in 17 patients. Patients not achieving >60% penile rigidity by 70 min postdose as measured by a RigiScan 1 monitoring device were assigned an onset time of 70 min. Study II: The duration of grade 3 (hard enough for penetration) and grade 4 (fully hard) erections, determined by self-assessment during 60 min of VSS starting 2 and 4 h after sildena®l (100 mg) or placebo dosing, was measured in 16 patients. Results Study I: The median time (range) to onset of erections was 27 min (in a range of 12±70) after receiving sildena®l 50 mg. In the sildena®l group, 71% of patients experienced onset of erections within 30 min of dosing, and 82% responded within 45 min. Of the patients who achieved >60% penile rigidity after sildena®l, 86% had done so by 30 min after dosing. Study II: When VSS began 2 h postdose, the median duration of grade 3 or 4 erections was 19.5 min (0±55) for sildena®l vs 0 min (0±23) for placebo. When VSS began 4 h postdose, the median duration was 5 min (0±45) for sildena®l compared with 0 min for placebo (0±27). Conclusions Sildena®l is an effective oral treatment for ED that produces a penetrative erection as early as 12 min and for most patients, within 30 min after dosing, and a duration of action lasting at least 4 h.

Introduction Viagra® (sildenafil citrate) has a rapid onset of action for the treatment of erectile dysfunction (ED). However, its duration of action has not been thoroughly investigated. Practical knowledge of the time window available for sexual intercourse would be valuable for couples planning sexual activity. Aim We investigated the duration of action of sildenafil in men with ED. Methods This was a double-blind, randomized, placebo-controlled, four-way crossover study of 16 men, mean age of 55 years (range, 36–68 years) with ED of no known organic cause. Participants received oral sildenafil (100 mg) or placebo 1, 8, or 12 hours before visual sexual stimulation (VSS). Measurements included the duration of erections of ≥ 60% rigidity, assessed by penile plethysmography (RigiScan®), and the proportion of sildenafil responders, defined as patients with erections of ≥ 60% rigidity for ≥ 4 minutes and ≥ 50% improvement over erections achieved in their placebo arm. Self-assessed duration of grade 3 (hard enough for penetration) or grade 4 (fully hard) erections was also recorded. Results At 1, 8, and 12 hours after dosing with sildenafil, the mean duration of erections with ≥ 60% rigidity was 26, 11, and 8 minutes, respectively, compared with only 3 minutes after placebo dosing (P < 0.05). However, the mean duration of self-assessed erections was 33, 23, and 16 minutes, respectively, compared with 7 minutes after placebo dosing (P < 0.05), and was greater than that assessed by RigiScan. Of the 69% sildenafil responders at 1 hour, 82% responded at 8 hours and 45% responded at 12 hours after sildenafil administration. Conclusion Sildenafil improved objective and self-assessed erectile function in men with ED, and the duration of action of sildenafil was longer than that previously reported. These data suggest that sildenafil may be effective in a significant proportion of men with ED up to 12 hours after being taken.

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