A prospective study comparing paroxetine alone versus paroxetine plus sildenafil in patients with premature ejaculation.

Salonia A, Maga T, Colombo R, Scattoni V, Briganti A, Cestari A, Guazzoni G, Rigatti P, Montorsi F.

Department of Urology, University of Vita-Salute, School of Medicine, Scientific Institute H. San Raffaele, Milan, Italy.

PURPOSE: We compared the efficacy of paroxetine alone and combined with sildenafil in patients complaining of premature ejaculation. MATERIALS AND METHODS: Enrolled in this study were 80 consecutive potent men 19 to 47 years old (mean age 34) with premature ejaculation but without any obvious organic cause. Pretreatment evaluation included a history, self-administration of the International Index of Erectile Function (IIEF) questionnaire, physical examination and the Meares-Stamey test to exclude genital tract infection. The initial 40 patients received 10 mg. paroxetine daily for 21 days and then 20 mg. as needed, that is 3 to 4 hours before planned sexual activity, for 6 months (group 1). The other group of 40 men received 10 mg. paroxetine daily for 21 days and then 20 mg. as needed plus 50 mg. sildenafil as needed, that is 1 hour before planned sexual activity, for 6 months (group 2). Patients were followed 3 and 6 months after beginning therapy and were evaluated using several general assessment questions, IIEF and ejaculatory latency time. RESULTS: Mean ejaculatory latency time +/- SE in group 1 was 0.33 +/- 0.04, 3.7 +/- 0.10 (p <0.01) and 4.2 +/- 0.03 (p <0.01) minutes at baseline, 3 and 6-month followup, while in group 2 it was 0.35 +/- 0.03, 4.5 +/- 0.07 (p <0.01) and 5.3 +/- 0.02 (p <0.001) minutes, respectively. When improvement in ejaculatory latency time was compared in the 2 groups, group 2 results proved to be significantly greater (p <0.05). Baseline, and 3 and 6-month mean intercourse satisfaction domain values of the IIEF were 9, 11 and 11 (p = 0.09, not significant), and 9, 11 and 14 (p <0.05) in groups 1 and 2, respectively. Group 2 patients reported significantly greater intercourse satisfaction than those in group 1 (p <0.05). At baseline, 3 and 6 months there was a mean of 0.9 +/- 0.1, 1.7 +/- 0.3 (not significant) and 2.5 +/- 0.3 (p <0.01) coitus episodes weekly in group 1, and 1 +/- 0.2, 2.3 +/- 0.3 (p <0.01) and 3.2 +/- 0.1 (p <0.001) in group 2, respectively. Group 2 patients reported a significantly higher number of coitus episodes weekly (p <0.05). Side effects in the 40 group 1 cases included anejaculation in 1 (2.5%), gastrointestinal upset and/or nausea in 5 (12.5%), headache in 4 (10%) and decreased libido in 2 (5%). Side effects in the 40 group 2 cases included anejaculation in 1 (2.5%), headache in 8 (20%), gastrointestinal upset and/or nausea in 6 (15%) and flushing in 6 (15%). Group 2 patients reported significantly more headaches (p <0.01) and flushing episodes (p <0.001) than those in group 1. After 6 months of treatment 33 men (82.5%) in group 1 and 36 (90%) in group 2 were willing to continue therapy (not significant). CONCLUSIONS: Paroxetine combined with sildenafil appears to provide significantly better results in terms of ejaculatory latency time and intercourse satisfaction versus paroxetine alone in potent patients with premature ejaculation. However, combined treatment is associated with a mild increase in drug related side effects.

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[Sildenafil for treatment of severe pulmonary hypertension and commencing right-heart failure]

[Article in German]

Ghofrani HA, Olschewski H, Seeger W, Grimminger F.

Medizinische Klinik II, Zentrum fur Innere Medizin der Justus-Liebig-Universitat Giessen, Germany.

Pulmonary hypertension (PHT) is mainly explained by four underlying pathophysiological phenomena: 1. Vasoconstriction, 2. reduction of pulmonary vascular bed, 3. reduction in vessel elasticity, and 4. obliteration of the vessel lumen by thrombotic material and subsequent cellular alterations of the vessel wall (vascular remodeling). Chronic right heart load is thus a consequence of increased pulmonary pressure and vascular resistance. Main targets of advanced therapeutic strategies are therefore first: resolution of chronically increased vascular tone by smooth muscle cell relaxation (vasodilators), second: reversal of vascular remodeling and third: prevention from pulmonary embolization and/or in-situ thrombosis (chronic anticoagulation). Long term administration of high dose calcium channel blockers (though operative only in a minority of 10 - 15 % of all patients), prostanoids (eg. prostacyclin, iloprost), and the recently approved unselective oral endothelin antagonist bosentan are regarded as established medical therapies for treatment of chronic PHT. However, applicability of these substances can be limited by potentially serious adverse events and/or necessity for elaborate parenteral application. Recent data are indicative for a strong pulmonary vasodilative potency of the selective phosphodiesterase-5 (PDE5) inhibitor sildenafil. Smaller clinical studies and numerous case reports underline the good tolerability of this orally applied substance in various form of PHT. Based on these encouraging results, the simple availability, and the low costs (in comparison to "established therapies") of the drug, sildenafil is currently widely used in an "off-label" indication for treatment of PHT. Controlled randomized studies have to confirm the current findings, before general recommendations regarding the use of sildenafil for treatment of PHT can be made.

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Sildenafil influences lower urinary tract symptoms.

Sairam K, Kulinskaya E, McNicholas TA, Boustead GB, Hanbury DC.

Lister Hospital Stevenage, and Health Research Support Unit (HRDSU), Hatfiel, Herts, UK.

OBJECTIVE: To assess the possible relationship between erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) in men, and whether treatment of their ED with sildenafil influences their LUTS. PATIENTS AND METHODS: In all, 112 men with ED attending the andrology outpatient clinic were offered oral sildenafil and reviewed 1 and 3 months after treatment. They completed the International Index of Erectile Function and the International Prostate Symptom Score (IPSS) questionnaires at baseline and each review. Scores were designated to indicate the visit number and differences between the visits calculated. RESULTS: A third of the men had an initial IPSS of > 7; there was no relationship between baseline urinary and sexual function scores. After treatment with sildenafil, the urinary scores at 3 months correlated strongly with the sexual function scores. There was a significant inverse relationship between the baseline IPSS and sexual function scores after treatment. The overall trend in the IPSS was towards improvement after treatment with sildenafil. CONCLUSIONS: In men with ED there is no relationship between sexual function scores and urinary symptom scores before treating ED. Treatment with sildenafil appears to improve urinary symptom scores. A lower IPSS at baseline appears to predict a better response to ED therapy with sildenafil.

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Chronic oral sildenafil therapy in severe pulmonary artery hypertension.

Kothari SS, Duggal B.

Cardiothoracic Centre, All India Institute of Medical Sciences, New Delhi. kotharis del2.vsnl.net.in

BACKGROUND: Sildenafil, a selective phosphor-diesterase-5 inhibitor, may be of clincal benefit in patients with pulmonary artery hypertension. METHODS AND RESULTS: Fourteen patients, aged 5-30 years, with severe pulmonary artery hypertension (9 with primary pulmonary hypertension, 5 with operated congenital heart disease) received oral sildenafil in addition to conventional therapy. Twelve patients were in New York Heart Association functional class III or IV. The drug was started in low dose and empirically increased. Finally a median dose of 87.5 mg/day was used in children weighing less than 30 kg, and 150 mg/day in those with weight more than 30 kg. The patients were followed up by assessing their functional status, six-minute walk test, Doppler echocardiography and hemodynamic study (in selected cases). On mean follow-up of 7.3+/-2.4 months (range 3-14 months), New York Heart Association functional class improved from 3.31+/-0.75 to 2.00+/-0.71 (p<0.002). There was a remarkable improvement on the six-minute walk test from a baseline of 264.1+/-193.7 m to 408.2+/-156.97 m at 3 months (p<0.001) and 453.2+/-159.81 (p<0.0001) at 6 months. The right ventricular systolic pressure estimated echocardiographically declined from 112.40+/-45.21 mmHg to 101.86+/-47.86 mmHg (p<0.002). The mean pulmonary artery pressure decreased from 62 mmHg to 47 mmHg in 4 patients of primary pulmonary hypertension recatheterized after a mean of 7 months of sildenafil treatment. Clinical improvement was seen even when no decrease in pulmonary artery pressure was demonstrated in one patient with secondary pulmonary artery hypertension. However, 2 patients died during follow-up despite clinical improvement. CONCLUSIONS: Oral sildenafil was well tolerated and led to an improved clinical condition and exercise performance. Whether the drug improves mortality remains to be established. Larger trials a rewarranted.

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A study of clinical efficacy of sildenafil in patients with primary pulmonary hypertension.

Sastry BK, Narasimhan C, Reddy NK, Anand B, Prakash GS, Raju PR, Kumar DN.

Department of Cardiology, CARE Hospitals and CARE Foundation, Hyderabad. bkssastry hotmail.com

BACKGROUND: Primary pulmonary hypertension is a disorder with limited treatment options and poor outcome. Sildenafil, a pulmonary vasodilator, is likely to be beneficial in primary pulmonary hypertension. We studied the clinical efficacy of sildenafil in patients with primary pulmonary hypertension. METHODS AND RESULTS: A registry of patients with primary pulmonary hypertension has been maintained in our hospital since January 1999. Of a total of 60 patients. 29 (M:16, F:13) consented to try sildenafiL. New York Heart Association functional class, six-minute walk test and Doppler echocardiographic evaluation of pulmonary artery pressure was done before and after treatment with sildenafil. Sildenafil was initiated at a dose of 25 mg thrice a day and increased up to 100 mg thrice a day as tolerated. There was a significant improvement in the functional class. The six-minute walked distance increased from 297.07+/-130.69 m at baseline to 427.68+/-85.35 m after 3 months of sildenafil therapy (p<0.0003). The mean of the pulmonary artery systolic pressure before starting sildenaffil was 109.26+/-24.15 mmHg (mean+/-SD) and it decreased to 95.15+/-24.64 mmHg (p<0.008). While 19 of the 31 historical controls in whom sildenafil was not given died during follow-up (11-44 months), only 1 of the 29 patients given sildenafil died (in an accident) during follow-up (5-20 months). CONCLUSIONS: Sildenafil, a pulmonary vasodilator, has a beneficial effect in patients with primary pulmonary hypertension in improving the functional class, six-minute walked distance and in decreasing the pulmonary artery pressures.

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Synthesis of sildenafil analogues from anacardic acid and their phosphodiesterase-5 inhibition.

Paramashivappa R, Phani Kumar P, Subba Rao PV, Srinivasa Rao A.

Vittal Mallya Scientific Research Foundation, PO Box 406, K R Road, Bangalore-560 004, India.

Anacardic acid (6-pentadecylsalicylic acid), a major component of cashew nut shell liquid, consists of a heterogeneous mixture of monoenes, dienes, and trienes. The enes mixture of anacardic acid was hydrogenated to a saturated compound. Using saturated anacardic acid as a starting material, analogues of sildenafil [a potent phosphodiesterase-5 (PDE(5)) inhibitor and an orally active drug for the treatment of erectile dysfunction] were synthesized, to observe the effect of the pentadecyl side chain on PDE(5) inhibition. The synthesized compounds were characterized by spectral studies and tested for PDE(5) inhibition, and the results were compared with those obtained with sildenafil.

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A novel compound JPM8: in vivo penile activity promotion in rats, effect on the relaxation and cGMP/cAMP accumulation in isolated rabbit corpora cavernosa.

El-Thaher TS, Khatib S, Saleem M, Shnoudeh A, Badwan AA.

The Jordanian Pharmaceutical Manufacturing Ltd, Naor Jordan.

JPM8 is a novel sildenafil-like PDE5 inhibitor. Its efficacy was tested in vivo by the oral administration of drugs to a rat model and recording penile activity changes. Effect on the relaxation of the rabbit cavernosa was tested in vitro using an organ bath were drugs are added to the tissue media and relaxation was recorded using a transducer connected to a chart recorder. The accumulation of cGMP and cAMP was measured by incubation of cavernosa strips and then extracting the produced cGMP and cAMP in the incubation mixture, then quantitating it using ELISA. JPM8 showed increased and promoted sexual and penile activity in rats in a similar but slightly higher trend than the positive control sildenafil. JPM8 was more efficient in relaxing the rabbit corpora cavernosa than sildenafil. The cGMP and cAMP accumulation showed a similar trend for both drugs. We concluded that JPM8 was very effective in promoting sexual activity in rats, relaxing the corpora cavernosa and promoting cGMP accumulation in rabbits.

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Is sildenafil failure in men after radical retropubic prostatectomy (RRP) due to arterial disease? Penile duplex Doppler findings in 174 men after RRP.

McCullough A, Woo K, Telegrafi S, Lepor H.

Department of Urology, New York University School of Medicine, New York 10016, USA. andy.mccullough msnyuhealth.org

Sildenafil is frequently the first-line treatment for post-radical retropubic prostatectomy (RRP) erectile dysfunction (ED) with maximum treatment satisfaction rates of 43%-80%. The etiology of erectile dysfunction after RRP has been attributed to psychogenic, vascular, veno- occlusive or nerve injury causes. The purpose of this study was to gain insight into the penile duplex Doppler arterial parameters in men with ED after RRP who failed sildenafil. The purpose was to assess whether sildenafil failure after RRP is associated with underlying corporal arterial disease. A total of 174 consecutive men presenting with sildenafil refractory ED after nerve-sparing RRP underwent color duplex penile Doppler evaluation with vasoactive injection. Mean age was 59.6 y and mean time from surgery was 11.6 months. Some 81% (141/174) of the men had no pre-operative ED (PED). Significant differences in penile duplex Doppler parameters for arterial disease were seen between men with and without PED. In men without PED, 19% (27/141) manifested arterial insufficiency. However, in men with PED, 50% (16/33) demonstrated arterial disease. Nerve sparing status did not affect the presence of arterial disease. Sildenafil refractory erectile dysfunction after RRP in men without PED is not predominantly associated with penile Doppler parameters consistent with arterial insufficiency.

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