Combining programmed intracavernous PGE1 injections and sildenafil on demand to salvage sildenafil nonresponders.

Gutierrez P, Hernandez P, Mas M.

1Department of Physiology and CESEX, Faculty of Medicine, Campus CC Salud, University of La Laguna, Tenerife, Spain.

In a prospective, placebo-controlled, one group crossover design study, we tested whether adding programmed intracavernous PGE1 injections (IC-PGE1) can improve the effectiveness of sildenafil in erectile dysfunction (ED) patients unresponsive to monotherapy with this drug. In all, 40 ED patients who had experienced unsatisfactory erections with both the 50 and 100 mg sildenafil doses were treated with four bi-weekly 20 mug IC-PGE1 injections given in the clinic and provided with either placebo or 50 mg sildenafil capsules for the next 4 weeks. Thereafter, they were crossed over to the other oral treatment for an additional 4-week period. The IIEF-Erectile Function domain score (IIEF-EFS), the main outcome measure, was found considerably higher (P<0.001) with the combined IC-PGE1-50 mg sildenafil treatment than with IC-PGE1-placebo or sildenafil alone (50 or 100 mg) in a subset of 26 subjects (65%). They thus shifted from the 'severe' or 'moderate' to the 'mild' grading of ED classification.International Journal of Impotence Research advance online publication, 10 February 2005; doi:10.1038/sj.ijir.3901290.

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Sildenafil selectively inhibits acute pulmonary embolism-induced pulmonary hypertension.

Dias-Junior CA, Vieira TF, Moreno H Jr, Evora PR, Tanus-Santos JE.

Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil.

Selective pulmonary vasodilators attenuate acute pulmonary embolism (APE)-induced pulmonary hypertension. We examined the effects of intravenous sildenafil on the hemodynamic and respiratory changes caused by APE in anesthetized dogs. Sham operated animals (n=3) received only saline infusions. APE was induced by intravenous injections of microspheres in amounts adjusted to increase mean pulmonary artery pressures (MPAP) by 20mmHg. Hemodynamic evaluation was performed and arterial blood samples were drawn for blood gas analysis at baseline, 15 and 30min after APE was induced, and then 15, 30, and 45min after the sildenafil infusion (1mgkg(-1) infused intravenously in 15min followed by 0.3mgkg(-1)h(-1) for 30min) started in the Sildenafil group (n=7), or saline infusion started in the control group (n=8). APE induced sustained pulmonary hypertension and 325% increase in pulmonary vascular resistance index (PVRI) without significant changes in the other hemodynamic parameters. While the animals in the control group showed no further changes in MPAP and PVRI, a significant decrease in MPAP and PVRI (-25 and -45%, respectively; P<0.05 both) was observed with sildenafil. No significant changes in the other hemodymamic parameters were observed in both groups. APE decreased PaO(2), whereas sildenafil attenuated the decrease in PaO(2) (P<0.05). We conclude that intravenous sildenafil can selectively attenuate the increases in MPAP and PVRI after APE.

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Sildenafil citrate and vacuum constriction device combination enhances sexual satisfaction in erectile dysfunction after radical prostatectomy.

Raina R, Agarwal A, Allamaneni SS, Lakin MM, Zippe CD.

Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.

OBJECTIVES: To assess the effectiveness of combining sildenafil citrate with a vacuum constriction device (VCD) in men (after radical prostatectomy) unsatisfied with the results of the VCD alone. METHODS: A total of 31 patients unsatisfied with the early use of VCD alone after radical prostatectomy (mean follow-up of 4.5 months) were instructed to take 100 mg of sildenafil 1 to 2 hours before VCD use for sexual intercourse. Patients used combination therapy for a minimum of five attempts before assessment with the abridged International Index of Erectile Function (IIEF) questionnaire and a visual analogue scale to gauge rigidity. The effect of combination therapy on the total IIEF-5 score and penile rigidity score were assessed. RESULTS: Of the 31 patients, 7 (22%) had no improvement with the addition of sildenafil with VCD and discontinued the drug, and 24 (77%) reported improved penile rigidity and sexual satisfaction. The IIEF-5 score revealed statistically significant improvement in each domain, and patients reported that sildenafil enhanced their erections 100% of the time. The penile rigidity scores on a scale of 0 to 100 with the VCD alone averaged 55% (range 23% to 85%) for the men and 59% (range 26% to 90%) for their partners. With the addition of sildenafil, it increased to 76% for the men and 82% for their partners. Of the 24 men, 7 (30%) reported a return of natural erections at 18 months using combination therapy, with 5 of 7 reporting erections sufficient for vaginal penetration. CONCLUSIONS: In this study, the addition of sildenafil with VCD improved sexual satisfaction and penile rigidity in patients unsatisfied with VCD alone after radical prostatectomy.

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Fatal variceal rupture after sildenafil use: Report of a case.

Finley DS, Lugo B, Ridgway J, Teng W, Imagawa DK.

Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, University of California, Irvine, Orange, California, USA.

Sildenafil may increase the risk of variceal bleeding in portal hyptertension by increasing splanchnic blood flow. We report herein the second case of variceal rupture after sildenafil use.

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Comparison of clinical trials with sildenafil, vardenafil and tadalafil in erectile dysfunction.

Doggrell SA.

Doggrell Biomedical Communications, 47 Caronia Crescent, Lynfield, Auckland, New Zealand. s_doggrell yahoo.com.

Erectile dysfunction (ED) affects up to 50% of men, between 40 and 70years of age. In the first major trial of sildenafil in ED, at 24weeks, improved erections were reported by 77 and 84% of men taking sildenafil 50 and 100mg, respectively. Subsequently, sildenafil has been reported to be effective in men with ED associated with diabetes and prostate cancer, and in psychogenic ED. Sildenafil is safe in men with coronary artery disease, provided it is not used with the nitrates (a contraindication). The most commonly reported adverse effects with sildenafil are headache, flushing and dyspepsia. Vardena-fil is more potent and more selective than sildenafil at inhibiting phosphodiesterase-5. Vardenafil is similarly effective to sildenafil in the treatment of ED. The only advantage that vardenafil has over sildenafil is that it does not inhibit phosphodiesterase-6 to alter colour perception, a rare side effect which sometimes occurs with sildenafil. Tadalafil has a longer duration of action than sildenafil and vardenafil. Tadalafil is similarly effective as sildena-fil in the treatment of ED. In comparison studies, tadalafil is preferred to sildenafil (50/100mg) by men with ED, possibly because of its longer duration of action. Of the phosphodiesterase inhibitors, tadalafil may displace sild-enafil as the drug of choice among men with ED.

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Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction.

Wareing M, Myers JE, O'hara M, Baker PN.

Maternal & Fetal Health Research Centre, The University of Manchester, St. Mary's Hospital, Manchester, U.K.

Background: Fetal growth restriction (FGR) affects up to 8% of all pregnancies and has massive short-term (increased fetal morbidity and mortality) and long-term (increased incidence of cardiovascular disease in adulthood) health implications. Doppler waveform analysis of pregnancies complicated by FGR suggests compromised uteroplacental circulation and placental hypoperfusion. Our aim was to determine whether myometrial small artery function was aberrant in FGR, and to assess if sildenafil citrate could improve vasodilatation in FGR pregnancies. Methods: Small arteries dissected from myometrial biopsies obtained at Caesarean section from normal pregnant (n = 27) or women whose pregnancies were complicated by FGR (n = 12) were mounted on wire myographs. Vessels were constricted (with arginine vasopressin or U46619) and relaxed (with bradykinin) pre- and post-incubation with a phosphodiesterase-5 inhibitor, sildenafil citrate. Results: We demonstrated increased myometrial small artery vasoconstriction and decreased endothelium-dependent vasodilatation in vessels from women whose pregnancies were complicated by FGR. Sildenafil citrate significantly reduced vasoconstriction and significantly improved relaxation of FGR small arteries. Conclusions: We conclude that sildenafil citrate improves endothelial function of myometrial vessels from women whose pregnancies are complicated by intrauterine growth restriction. Sildenafil citrate may offer a potential therapeutic strategy to improve uteroplacental blood flow in FGR pregnancies.

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Efficacy and optimal dose of sildenafil in primary pulmonary hypertension.

Chockalingam A, Gnanavelu G, Venkatesan S, Elangovan S, Jagannathan V, Subramaniam T, Alagesan R, Dorairajan S.

Department of Cardiology, Madras Medical College and Research Institute, Chennai 600 003, India.

Purpose: We aimed to assess the effects of sildenafil and evaluate optimal dosing in primary pulmonary hypertension (PPH). Sildenafil selectively inhibits phosphodiesterase 5 (PDE5), which is abundant in pulmonary and penile tissue. This results in increasing nitric oxide (NO) at tissue level leading to pulmonary vasodilatation. Subjects and methods: Our study was a prospective study of sildenafil in 15 consecutive patients with severe symptomatic PPH of NYHA class III-IV. All patients were stabilized for a minimum period of 5 days with antifailure medications. Sildenafil was started at 50 mg twice daily for 4 weeks and increased to 100 mg bid for 4 more weeks in a step-up protocol. Primary end-points were change in Borg dyspnea index, NYHA class and 6-min walk distance, estimated at baseline 1, 2, 4 and 8 weeks. Results: NYHA class (baseline 3.8+/-0.4 vs. 4 weeks 2.4+/-0.5, p=0.002), Borg dyspnea index (8.1+/-1.7 vs. 4.4+/-1.9, p=0.0007), 6-min walk distance (234+/-44 vs. 377+/-128 m, p=0.001) and Pulmonary artery pressure (125+/-15 vs. 113+/-18 mm Hg p=0.05) are significantly improved with sildenafil 50 mg bid at 4 weeks. Increasing the dose to 100 mg bid did not produce further benefit. Echocardiography parameters of right heart dimensions and functions did not change markedly in the study period. Conclusion: Sildenafil is well tolerated with no adverse effects in severe pulmonary hypertension. It reduces symptoms, improves effort tolerance and controls refractory heart failure significantly by 2 weeks in 70% of patients at 50 mg twice daily. Three patients (20%) failed to respond with sildenafil.

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Early haemodynamic benefit of sildenafil in patients with coexisting chronic thromboembolic pulmonary hypertension and left ventricular dysfunction.

Sheth A, Park JE, Ong YE, Ho TB, Madden BP.

Department of Cardiothoracic surgery, St Georges Hospital, London SW17 0QT, UK.

Sildenafil, a phosphodiesterase type-5 inhibitor, offers potential to treat pulmonary hypertension associated with a variety of conditions. We assessed the early impact of sildenafil on a cohort of patients referred to our unit who had severe pulmonary hypertension secondary to chronic thromboembolic disease which was not amenable to pulmonary thromboendarterectomy and who also had coexisting left ventricular dysfunction. Six patients were studied. Diagnosis of pulmonary embolic disease was made by ventilation perfusion scanning and/or CT pulmonary angiography. All patients were anticoagulated with oral coumarin derivatives and none were considered suitable for pulmonary thromboendarterectomy. Pulmonary hypertension was diagnosed by right heart catheterisation and each patient had Medical Research Council (MRC) dyspnoea score and New York Heart Association (NYHA) class noted and 2D echocardiography prior to commencement of sildenafil 50 mg three times a day. After 6 weeks of sildenafil therapy, right heart catheterisation and 2D echocardiography were repeated, and MRC dyspnoea score, NYHA class and exercise capacity were recorded. All patients demonstrated an improvement in mean pulmonary artery pressure, mean pulmonary capillary wedge pressure, MRC dyspnoea score, NYHA class and gas transfer. No adverse effects of sildenafil were noted. Our data suggests that sildenafil is an effective and well-tolerated therapy for patients with severe pulmonary hypertension associated with pulmonary thromboembolic disease and impaired left ventricular function, producing beneficial effects as early as 6 weeks.

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