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Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil.

This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% that of the parent drug.

Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil.

The N-desmethyl metabolite is further metabolised, with a terminal half-life of approximately 4 h.

The total body clearance of sildenafil is 41 l/h with a resultant terminal phase half-life of 3-5 h.

After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the faeces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of administered oral dose). Healthy elderly volunteers (65 years or get cialis now over) had a reduced clearance of sildenafil, resulting in approximately 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18-45 years).

Due to age-differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%. In volunteers with mild to moderate renal impairment (creatinine clearance = 30-80 mL/min), the pharmacokinetics of sildenafil were not altered after receiving a 50 mg single oral dose.

The mean AUC and C max of the N-desmethyl metabolite increased up to 126% and up to 73% respectively, compared to age-matched volunteers with no renal impairment. However, due to high inter-subject variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance. > endstream endobj 97 0 obj >stream 8;Z]_Yn[6M$jFH5^S#]X5X@[W\Z9fqP2@/XgEQLrjllKXfqu],!"+kh0=^UHP:FQS *Y;]ICAduh\A]?e 4HDt! > endstream endobj 98 0 obj >stream 8;Z]_d1(U[#R*Ke?a/iU5cZ%HL"O!jp`mGe(m#Qa"$erNU5MGQ_Kd>#)h>[/n#aUB p8]L"'k)m7H>RYq10%9Ee8;3 D/0.

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A randomisation list was generated using random permuted blocks through a computer algorithm and a pseudorandom number generator. The list indicated, for each bottle number, the drug assigned to the corresponding study medication bottle. The patient was assigned a screening number at visit one (screening) and, if eligible for participation, was then assigned a randomisation number at visit two (baseline). The investigator was provided a sealed copy of the randomisation codes and was instructed to break the treatment code only in the event of an emergency.

Active treatment and corresponding placebo tablets were identical in packaging and appearance. During the DB phase, the primary efficacy variables were responses to questions “When you attempted sexual intercourse, how often were you able to penetrate your partner?” (Q3) and “When you attempted sexual intercourse, how often were you able to maintain your erection after you had penetrated your partner?” (Q4) of the 15 item International Index of Erectile Function (IIEF).

The IIEF is a validated questionnaire that has been used for the clinical assessment of ED. 18 Each question of the IIEF is scored on a categorical scale of 1 (“almost never/never”) to 5 (“almost always/always”), with a score of 0 indicating “did not attempt sexual intercourse”. Secondary efficacy variables were responses to three global efficacy questions (GEQs): GEQ1: “Compared to having no treatment at all for your erection problem, has the medication you have been taking over the past 4 weeks improved your erections?” and GEQ2: “If yes, has the improvement in your erections allowed you to engage in satisfactory sexual activity?”. GEQ3 asked: “When you took a dose of study drug and had sexual stimulation, how often did you get an erection that allowed you to engage in satisfactory sexual activity?”. Additional secondary efficacy measures were analyses of IIEF domains, for example, orgasmic function (Q9: “When you had sexual stimulation or intercourse, how get cialis now often did you ejaculate?” and Q10: “When you had sexual stimulation or intercourse, how often did you have the feeling of orgasm?”) and sexual desire (Q11: “Over the past 4 weeks, how often have you felt sexual desire?” and Q12: “Over the past 4 weeks, how would you rate your level of sexual desire?”). The DB end point efficacy assessment served as baseline for the OLE phase.

At the final OLE visit, a limited assessment of efficacy was made based on responses to the three GEQs. The Life Satisfaction Checklist is an eight item general QoL questionnaire, with questions on the patient’s satisfaction with life as a whole, sexual life, partnership relation, family life, social contacts, and leisure, vocational, and financial situations. 19 The Erection Distress Scale is a disease specific instrument with five questions on the patient’s concerns with his erection problems. These were: “Were you frustrated about your erection problems?”, “Did you feel weighed down by your erection problems?”, “Were you discouraged by your erection problems?”, “Did you feel despair over your erection problems?”, and “Were your erection problems a worry in your life?”.

Responses to each question of the Life Satisfaction Checklist and the Erection Distress Scale were scored from 1 (none of the time) to 6 (all of the time).

Calculations were performed to determine the sample size needed to detect a statistical

difference

Assuming an overall drop out rate of 25%, a 1:1 randomisation ratio of sildenafil to placebo, sufficient power to be able to conduct the primary analysis of efficacy, analysis of covariance, including terms for treatment group, centre, baseline value for efficacy variables, and other covariates as required, 250 patients, 125 in each arm, were to be randomised to study drug; in total, 218 patients were randomised.

Intent-to-treat analyses were performed on all efficacy and QoL variables, and included all patients with at least one assessment after randomisation who had taken at least one dose of study drug. To be eligible for inclusion in safety analyses, patients must have taken at least one dose of study drug. Statistical get cialis now analysis of responses to IIEF Q3 and Q4 and GEQ3 was performed for each question using analysis of covariance. Statistical analysis of responses to GEQ1 and GEQ2 (yes/no) was performed for each question using a logistic regression model.

The mean frequency of responses to each question of the Life Satisfaction Checklist and to the five questions of the Erection Distress Scale for each treatment was calculated and expressed as the least squares mean±standard error (SE).

Each question was fitted with an analysis of covariance model, which included terms for treatment group, centre, patient age, baseline score, ED duration, baseline ED severity, and smoking status.

All statistical tests were two sided and performed at the 5% significance level.

A total of 217 men (mean age: 46 years; mean duration of ED: 5.7 years; mean duration of MS: 10.4 years) from 20 sites in the United States and Europe received treatment with sildenafil (n = 104) or placebo (n = 113) for 12 weeks.

The patients in the two treatment groups had similar demographic characteristics with respect to age, duration of ED, duration of MS, and EDSS score (table 1), but men in the placebo group reported more frequent use of antihypertensive agents and less use of corticosteroids compared with the treatment group. At the end of the 12 week period, almost two thirds of men (64%) receiving sildenafil were taking the 100 mg dose, compared with 32% on the 50 mg dose, and 4% on the 25 cialis 5 mg tablet price mg dose.

In the placebo group, 96% of men were taking the 100 mg dose, and 4% were taking the 50 mg dose.

Download figure Open in new tab Download powerpoint. Download figure Open in new tab Download powerpoint. Download figure Open in new tab Download powerpoint. Download figure Open in new tab Download powerpoint. Quality of life variables that improved with sildenafil treatment (black bars) compared with placebo (white bars). Overall, 26/206 (13%) subjects discontinued the OLE phase (fig 1), and of these 11/106 (10%) were sildenafil naive during the DB phase.

Of the 26 subjects who discontinued, 17 (8%) did so for reasons not related to treatment (AEs, n = 3; laboratory abnormalities, n = 1; lost to follow up, withdrawal of consent, other, n = 14).

The most common AEs are shown in table 2, and were comparable in nature and rate of occurrence to AEs reported in the DB phase of the study.

Overall, 12 patients (6%) reported treatment emergent serious AEs during the OLE phase, most of which (n = 9) were relapses of MS or aggravation of MS symptoms, get cialis now requiring hospitalisation. Seven subjects experiencing these relapses had received sildenafil during the DB phase of the study and two patients had received placebo.