The History and Development of Sildenafil Citrate

This study shows that sildenafil is safe and effective for the treatment of ED in renal allograft recipients.

Viagra et environnement

Based on the investigator’s judgment of efficacy and tolerability, the dose could be increased to 100 mg or decreased to 25 mg of sildenafil or placebo. The initial dose of the drug was taken 1 hour before sexual intercourse, avoiding heavy meals or excessive alcohol intake. All patients completed the International Index of Erectile Function (IIEF) and a diary card to record response to the drug and the occurrence of side effects. Efficacy was assessed by using the self-administered IIEF, a 15-question validated measure of ED,17,18 and a global efficacy question (Did the treatment improve your erection? The IIEF system is used for clinical assessment of ED and treatment outcome in clinical studies.

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It evaluates several aspects of sexual performance, rating each answer from 0 to 5, with 0 meaning no sexual activity/no attempt at sexual intercourse, 1 meaning the worst response (almost never/never), and 5 meaning the best response (almost always/always). Total score ranges from 5 to 75. Treatment efficacy was assessed through the answer to questions 3 (penetration ability) and 4 (maintenance frequency). Efficacy also was evaluated through the score for the 5 separate response domains of male sexual function of the IIEF: erectile function (questions 1 to 5 and 15; total score, 1 to 30), intercourse satisfaction (questions 6 to 8; total score, 0 to 15), orgasmic function (questions 9 and 10; total score, 0 to 10), sexual desire (questions 11 and 12; total score, 2 to 10), and overall satisfaction (questions 13 and 14; total score, 2 to 10). The final score of each domain is the sum of scores for individual questions in that domain.

Autres utilisations

Patients with a score of 26 or higher on the erectile function domain were considered to have no ED and were excluded from analysis. In a selected group of 5 patients with normal graft function, cyclosporine level was estimated at 0-, 0.5-, 1-, 2-, 3-, 4-, and 6-hour intervals with and without sildenafil, and the AUC of cyclosporine level was estimated to see the effect of sildenafil on cyclosporine level. AUC was estimated by using a linear trapezoid rule. The study was conducted at Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India, a tertiary-care academic institute. Informed consent was obtained from all patients included in the study. This is the first randomized, placebo-controlled, crossover study to show the efficacy of sildenafil in renal transplant recipients.

Drug Class	Interaction Effect	Clinical Significance
Nitrates	Potentiates hypotension	Absolute contraindication
Alpha-blockers	Increased hypotensive effect	Use with caution
CYP3A4 inhibitors	Increased sildenafil levels	Dose adjustment needed
Protease inhibitors	Elevates sildenafil exposure	Increased side effects

sildenafil has an efficacy similar to that in other nontransplantation patients with ED.9-11 sildenafil significantly improved erectile function score, although it did not improve desire level and sexual frequency as expected (Table 1) and also reported in other studies.9,19 These results are similar to previous results in patients with diabetes,19 hemodialysis patients,8-11 and renal transplant recipients12-16 with ED.

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Treatment efficacy assessed through questions 3 (penetration ability) and 4 (maintenance frequency) was significantly better in these renal transplant recipients (P < 0.001), similar to other patients with ED in another study.19 In this study, all IIEF domain scores improved significantly after sildenafil, except for the sexual desire domain, whereas IIEF domain score did not improve after placebo (Table 2). Similar results were reported in patients with ED with diabetes19 and hemodialysis patients.9 Studies focusing on the use of sildenafil in renal transplant recipients showed a satisfactory response in 60% to 81% of transplant patients with ED.12-16,20 However, in our study, the response rate was 81.3%, on the higher side of the range. Recently, Zhang et al13 also showed a response in 81.5% of patients, similar to our study.

Ways to Maximize the Effectiveness of Sildenafil

Both sildenafil and placebo of identical aspect were provided by Zydus Cadila (Ahmedabad, India) free of charge. The authors received no other support from the drug and placebo provider to avoid any conflict of interest. Mean ± SD was calculated for each IIEF question or domain. Results of the placebo and sildenafil groups were compared by using t-test and Mann-Whitney U test for parametric and nonparametric data, respectively. Comparison of basal and final results in each group was performed by using paired t-test and Wilcoxon test for parametric and nonparametric data, respectively.

Storage Class

Thirty-two eligible renal transplant recipients were included in this study. Mean duration of the transplant was 4.7 ± 3 years, duration of ED was 17 ± 22 months, and duration of dialysis therapy was 3.5 ± 2 months. All patients had undergone living-related transplantations. No patient in our study had a vascular anastomosis to both the internal iliac artery and hypogastric artery. Of these patients, 14 patients had chronic glomerulonephritis, 8 patients had chronic interstitial nephritis, 7 patients had diabetic nephropathy, and 3 patients had other basic diseases.

Interactions that increase your risk for side effects

No patient had autonomic neuropathy at time of enrollment into this study. At baseline, mean hemoglobin level was 12.3 ± 1.5 g/dL (123 ± 15 g/L), mean blood urea nitrogen level was 18.3 ± 7.6 mg/dL (6.53 ± 2.71 mmol/L), and creatinine level was 1.48 ± 0.3 mg/dL (131 ± 27 μmol/L). In total, 32 tablets of sildenafil or placebo were offered to patients during the study period. At end of the study, mean numbers of tablets of sildenafil and placebo taken by patients were 24.3 ± 3.3 and 23.8 ± 2.6, respectively (P = 0.49). Table 1 lists scores for each of the 15 IIEF questions. This higher response rate may be caused by a shorter duration of dialysis therapy (mean, 3 months; range, 1 to 5.5 months) before transplantation in our patients.

• Sildenafil can cause sudden vision loss (rare side effect).
• Men with a history of retina problems should use caution.
• It may cause a drop in blood pressure, leading to dizziness.
• Patients should report any persistent erection lasting over 4 hours.
• It is crucial to have proper medical evaluation before use.
• Not suitable for individuals with severe liver or kidney conditions.
• The medication is also investigated for breast cancer treatment.
• Proper hydration can help minimize some side effects.

Prieto Castro et al12 showed a satisfactory response in 60% of transplant recipients, with a mean time on dialysis therapy of 23 months in patients with a satisfactory response, compared with 43 months in patients for whom the drug was not effective.

What other information should I know?

After treatment with sildenafil, patients administered sildenafil had highly significantly better scores in 13 of 15 questions. The only questions for which differences were not significant were questions 11 (desire frequency; P = 0.39) and 12 (desire level; P = 0.61). Treatment efficacy assessed through questions 3 (penetration ability; P < 0.001) and 4 (maintenance frequency; P < 0.001) was significantly better after sildenafil therapy. Data show no significant differences between baseline and post–placebo treatment scores, sildenafil 100 mg tab except for question 13 (relationship satisfaction), which was significantly better after placebo treatment. The 5 IIEF domains are listed in Table 2.

Dysfonction érectile

No significant differences between placebo and baseline scores were detected in any domain. Patients treated with sildenafil had better scores in 4 domains in comparison to the baseline score, but no difference was observed in the sexual desire domain (P = 0.32). On analyzing the outcome of efficacy of sildenafil on the global efficacy question (whether treatment showed an improvement), 26 of 32 patients (81.3%) showed improvement in the sildenafil group, whereas only 6 patients (18.7%) showed improvement with placebo (P ≤ 0.01). On analyzing AUC and maximum concentration (Cmax) of cyclosporine in 5 selected patients, mean AUC and Cmax were not different with and without sildenafil. Mean AUC of cyclosporine was 7,454 ± 1,483 ng/h/mL with sildenafil compared with 7,460 ± 1,480 ng/h/mL without sildenafil. We do not have a maintenance hemodialysis program, and only patients with a renal transplantation prospect are accepted for hemodialysis therapy.

Parameter	Frequency	Purpose	Notes
Blood Pressure	Before and after dosage	Check for hypotension	Especially in high-risk groups
Visual Function	Periodic	Monitor for retinal issues	Baseline and follow-up
Liver Function Tests	As needed	Detect hepatotoxicity	For long-term users

The drug is more effective in patients who have less time on dialysis therapy before transplantation because penile vascular disease is less advanced.12 A greater prevalence of ED usually is seen in patients with a longer duration of maintenance hemodialysis.2,3 In a large experience of 22 years of ED in renal transplant recipients, Lasaponara et al16 reported that ED is an important problem in male renal transplant recipients, and cultural resistance to treatment is common.

• Sildenafil citrate can be combined with lifestyle changes.
• Exercise and weight management improve erectile function.
• Quitting smoking enhances medication effectiveness.
• Reducing alcohol intake minimizes side effects.
• Psychological therapy may support ED treatment.
• Counseling can address underlying emotional issues.
• Regular medical check-ups are recommended.
• Patient education improves safe and effective use.

However, sildenafil is an accepted mode of treatment.

Country	Legal Status	Prescription Requirement	Notes
USA	Prescription-only medication	Yes	FDA approved
UK	Prescription-only	Yes	MHRA regulated
India	Over-the-counter and prescription	Both are possible	Varies by state
Australia	Prescription only	Yes	TGA regulated

They also showed that more renal transplant patients are reporting ED (78%) after 1998, after the invention of sildenafil, compared with 45% before 1998.16 Russo et al14 showed improvement in IIEF domain scores in 20 renal transplant recipients with ED with the use of sildenafil.

• Sildenafil citrate is sometimes used off-label for other conditions.
• Off-label uses include altitude sickness and Raynaud’s phenomenon.
• Research continues into additional therapeutic effects.
• The drug’s development was led by Pfizer.
• It is often used in combination with other ED treatments.
• Patients should avoid grapefruit juice, which can affect drug levels.
• Some formulations include chewable or dissolvable tablets.
• Ongoing studies investigate its cardiovascular benefits.

This study was designed more to show the effect of renal transplantation on ED, rather than the effect of sildenafil.14 Chatterjee et al21 also showed a good response to combined testosterone and sildenafil therapy in all patients, but only 8 of 12 patients were renal transplant recipients and 4 patients were on hemodialysis therapy in this pilot study with a different design.

4. Bottom Line

Mean Cmax also was similar: 1,605 ng/mL with sildenafil compared with 1,604 ng/mL without sildenafil. As listed in Table 3, there were no significant differences between biochemical parameters pre– and post–sildenafil treatment. Serum creatinine and blood urea nitrogen levels were not significantly different in the pre–and post–sildenafil treatment period. Five patients developed headache, 2 patients developed rhinorrhea and flushing, and 1 patient each developed generalized body ache and typical bluish visual hallucination with sildenafil, whereas only 2 patients developed headache with placebo. No patient discontinued the drug, except for the 1 patient with visual hallucination. Therefore, the response rate to combined sildenafil and testosterone therapy cannot be compared with the response rate of sildenafil alone in our renal transplant recipients. Sildenafil and cyclosporine are metabolized through cytochrome P-450 isoform 3A4, and there is concern of a drug interaction between the 2 drugs. However, AUC and Cmax were not changed after use of sildenafil, and this may have been caused by highly selective action on phosphodiesterase type 5 and the short half-life (60 to 90 minutes) of sildenafil.