Efficacy of sildenafil as adjuvant therapy to selective serotonin reuptake inhibitor in alleviating premature ejaculation.

Chen J, Mabjeesh NJ, Matzkin H, Greenstein A.

Department of Urology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

OBJECTIVES: To evaluate the efficacy of sildenafil and selective serotonin reuptake inhibitor in alleviating premature ejaculation (PE) in patients in whom other treatments had failed. METHODS: Healthy men evaluated for primary PE graded their ejaculation on a scale of 0 to 8 (0 = almost never, 8 = almost always). The intravaginal ejaculatory latency time (IVELT) was graded on a scale of 0 to 3 (0 = longer than 5 minutes, 3 = shorter than 1 minute). The 138 men who scored their PE as 4 or greater and IVELT as 2 or greater comprised the study group. Psychological and behavioral counseling was provided during the study. PE was graded using the same scales 3 months after the initiation of each treatment. Topical 5% lidocaine ointment comprised the initial treatment: dissatisfied patients (PE grade 4 or greater, IVELT 2 or greater), took one tablet of paroxetine 20 mg for 30 days and then one tablet 7 hours before intercourse. Sildenafil was added to the treatment of patients dissatisfied with paroxetine alone. RESULTS: The mean initial PE grade was 5.67 +/- 0.13 and that for IVELT was 2.9 +/- 0.19 for all participants (mean age 28.7 years). Thirty-eight reported improvement (PE grade 2.0 +/- 0.8, P <0.01; IVELT 0.13 +/- 0.34, P <0.001) after local lidocaine application. Of the 100 treated with paroxetine, 42 reported improvement (PE grade 2.5 +/- 0.1, P <0.01; IVELT 0.28 +/- 0.46, P <0.001), and 56 of the remaining 58 who were treated with a combination of paroxetine and sildenafil reported improvement (PE grade 1.78 +/- 0.23, P <0.001; IVELT 0.16 +/- 0.37, P <0.001). Two patients remained dissatisfied with all treatment modalities. CONCLUSIONS: Sildenafil combined with paroxetine and psychological and behavioral counseling alleviated PE in patients in whom other treatments failed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12559295&dopt=Abstract sildenafil Viagra online



Sildenafil, a phosphodiesterase-5 inhibitor, enhances the antinociceptive effect of morphine.

Jain NK, Patil CS, Singh A, Kulkarni SK.

Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.

Various evidence has demonstrated a role of the nitric oxide (NO)/cGMP signaling pathway in the processing of nociception. The exact role of phosphodiesterase-5 (PDE-5) via the NO/cGMP pathway is not fully understood in pain response. The aim of the present study was to investigate the possible peripheral interaction between a PDE-5 inhibitor (sildenafil) and morphine. Carrageenan-induced hyperalgesia in rats and the acetic-acid-induced writhing test in mice were used as animal models. Local administration of sildenafil (50-200 microg/paw, i.pl.) exhibited a dose-dependent antinociceptive effect against the paw pressure test. Sildenafil also demonstrated an antinociceptive effect (1-10 mg/kg, i.p.) against in the writhing test. Co-administration of sildenafil (100 microg/paw, i.pl. and 2 mg/kg, i.p.) significantly enhanced the antinociceptive effect of morphine (2 microg/ paw, i.pl. and 2 mg/kg, i.p respectively). The antinociception produced by the drugs alone or combined was due to a local action, as its administration in the contralateral paws was ineffective. Pretreatment with N(G)-nitro-L-arginine methyl ester (an NO synthesis inhibitor), methylene blue (gunalyl cyclase inhibitor) or naloxone (opioid receptor antagonist) blocked the effect of a sildenafil-morphine combination in both tests. The results suggest that opioid receptor (NO and cGMP) mechanisms are involved in the combined antinociceptive effect. Further, sildenafil produced antinociception per se and increased the response of morphine, probably through the inhibition of cGMP degradation. Copyright 2003 S. Karger AG, Basel

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[Effect of sildenafil ciltrate on the sexual activities of male rats]

[Article in Chinese]

Huang XB, Xiong CL, Shen JY, Zhou JL, Xiao HZ.

Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei 430030, China.

OBJECTIVE: To obtain related pharmacodynamic data for the clinical experiment by observing the sexual activities of male rats after using sildenafil ciltrate through stomach irrigation. METHODS: Forty male Sprague-Dawlay rats were distributed into 4 groups with different dosages (control with distilled water, low dosage: 0.08%, medium dosage: 0.24% and high dosage: 0.72%). After the male Sprague-Dawlay rats were mated with their female counterparts in pairs, the latent period of chasing, the frequencies of chasing in 60 minutes, the latent period of intercourse and the frequencies of intercourse in 60 minutes were recorded. RESULTS: Compared with the control, the frequencies of chasing were significantly increased and the latent periods of chasing were significantly shortened in both high dosage and medium dosage groups after using sildenafil (P < 0.01); The frequencies of intercourse in 60 minutes were significantly increased and the latent periods of intercourse were significantly shortened in all the groups after the use of sildenafil. CONCLUSIONS: The sexual activities of male rats treated with sildenafil were significantly activated.

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Use of medications for erectile dysfunction in the United States, 1996 through 2001.

Wysowski DK, Swann J.

Office of Drug Safety, Food and Drug Administration, Rockville, Maryland, USA.

PURPOSE: We describe the use during 1996 through 2001 of the primary medications approved in the United States for treatment of erectile dysfunction, namely alprostadil injection and urethral suppository, and sildenafil.MATERIALS AND METHODS Two pharmaceutical research data bases, the National Prescription Audit Plus, and National Disease and Therapeutic Index, were accessed and analyzed. Ancillary data were obtained from 2 health plans. RESULTS: Increases in the number of dispensed prescriptions for alprostadil injection and urethral suppository marketed in 1995 and 1996, respectively, were reversed in 1998 by the marketing of sildenafil. From 1998 through 2001 the estimated number of prescriptions for sildenafil increased 1.87-fold or 87% from 7.5 million to 14 million, while those for alprostadil injection decreased 33% from 239,000 to 159,000 and those for alprostadil suppository decreased 67% from 400,000 to 132,000. Sildenafil was prescribed proportionately more frequently for younger men than alprostadil injection or suppository (p <0.0001). Compared with men for whom sildenafil was prescribed in 1998 those prescribed the drug in 2001 were younger (p <0.0001). Alprostadil injection and suppository were prescribed proportionately more frequently by urologists than sildenafil. Ancillary data from 2 health plans indicated a 173% increase in 1 plan and a 25% decrease in the other due to restrictions in sildenafil prescriptions from 1998 through 2001. CONCLUSIONS: Due to the marketing of sildenafil in 1998 through 2001 the use of 2 approved medications for erectile dysfunction, namely alprostadil injection and alprostadil urethral suppository, decreased, while the use of sildenafil increased. Sildenafil was prescribed proportionately more frequently for younger men than alprostadil injection or suppository. Alprostadil was prescribed proportionately more frequently by urologists than sildenafil, which was most commonly prescribed by family and general practitioners, and internists. The data indicate the wide adoption and use of sildenafil for erectile dysfunction.

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Sildenafil response is influenced by the G protein beta 3 subunit GNB3 C825T polymorphism: a pilot study.

Sperling H, Eisenhardt A, Virchow S, Hauck E, Lenk S, Porst H, Stief C, Wetterauer U, Rubben H, Muller N, Siffert W.

Department of Urology, University Hospital Essen, Germany.

PURPOSE: Sildenafil is the oral phosphodiesterase-5 inhibitor that revolutionized treatment for erectile dysfunction. We investigated a potential association of the G protein beta 3 subunit (GNB3) C825T polymorphism, a determinant of intracellular signal transduction, with the drug response to sildenafil in patients with erectile dysfunction. MATERIALS AND METHODS: In 113 men with erectile dysfunction and 111 healthy male controls genotype status of the GNB3 C825T polymorphism was determined by polymerase chain reaction and restriction analysis. Patients with erectile dysfunction received sildenafil at a dose of 25 to 100 mg. according to the individual erectile response. Drug response was measured by interviewing the patient according to the erection scale of 0 to 5. RESULTS: The GNB3 genotype distribution of patients with erectile dysfunction exactly matched that of healthy controls. Analysis of the response to sildenafil revealed a significant association of C825T allele status with the erectile response to sildenafil. In the group with TT genotype we observed a 90.9% response but only a 50.9% and 48.9% response in patients with the CC and TC genotype, respectively. The odds ratio for a positive erectile response was 10.0 (95% CI 1.2 to 81.1) for patients with the TT versus the TC/CC genotype (p = 0.01). CONCLUSIONS: The response to sildenafil is significantly associated with GNB3 C825T genotype status in patients with erectile dysfunction.

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Long-term use of sildenafil.

Carson CC.

University of North Carolina School of Medicine, Chapel Hill 27599-7000, USA. carson med.unc.edu

The treatment of erectile dysfunction (ED) has been revolutionised by new agents to inhibit the enzyme PDE5. The scientific basis of this treatment of ED includes relaxation of the corpus cavernosum smooth muscle tissue by inhibition of PDE5 that breaks down cGMP, the key pathway for the production of erectile function in humans. Many clinical studies, both pre- and post-marketing, have demonstrated the clinical efficacy and safety of sildenafil (Viagra, Pfizer) - the first approved selective PDE inhibitor for the treatment of ED. Sildenafil is inhibitory of PDE5 at a rate tenfold higher than for the next PDE (PDE6), which produces visual changes through the retinal rods. Its clinical effectiveness has been well documented in the majority of men with ED irrespective of aetiology. The aetiology of ED, also, does not appear to effect the function of sildenafil in relaxing corpus cavernosum smooth muscle tissue. Adverse events are usually associated with the vascular changes from PDE5 inhibition. These include headache and flushing. Each of these adverse events, however, declines with medication use. With the use of sildenafil, it has been clearly, clinically demonstrated that the selective inhibition of PDE5 is an appropriate, effective, safe method for the treatment of ED of all aetiologies and severities.

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Effects of sildenafil on cardiopulmonary responses during stress.

Stanopoulos I, Hatzichristou D, Tryfon S, Tzortzis V, Apostolidis A, Argyropoulou P.

Respiratory Failure Unit and Department of Urology, Aristotle University of Thessaloniki, Greece.

PURPOSE: To investigate possible effects of sildenafil on the cardiopulmonary responses during sexual intercourse we evaluated cardiopulmonary responses during exercise in a group of impotent patients. MATERIALS AND METHODS: The study sample included patients with erectile dysfunction who underwent a cardiopulmonary exercise test before and after the administration of 100 mg. sildenafil citrate. Cardiopulmonary exercise test parameters at rest, at the anaerobic threshold, at peak exercise and at 1-minute recovery were recorded, including systolic and diastolic blood pressure, the heart rate, O2 consumption, CO2 production, ventilation and the respiratory rate. Furthermore, O2 consumption per kg. body weight, the ventilatory equivalent for O2 consumption (ventilation/O2 consumption) and CO2 production (ventilation/CO2 production), the respiratory quotient, metabolic equivalents metabolic equivalents, oxygen pulse (O2 consumption/heart rate) and the change in O2 consumption/change in heart rate were calculated. RESULTS: In 2 of the 43 patients enrolled in the study myocardial ischemia and high blood pressure were detected at rest in 2, respectively, who were excluded from analysis. In the remaining 41 patients with a mean age +/- SD of 52.3 +/- 8.6 years a statistically significant decrease in systolic and diastolic blood pressure was noted after sildenafil use at all stages tested (p <0.002 to 0.001). The heart rate mildly increased after sildenafil use at rest and at peak exercise (p = 0.018). The O2 pulse decreased at the anaerobic threshold (p = 0.003), peak exercise (p = 0.001) and recovery (p = 0.047). In the 11 patients with a mean age of 40.8 +/- 10.12 years who had psychogenic erectile dysfunction the only 2 parameters affected were an increased heart rate and decreased systolic blood pressure at rest, while O2 consumption/heart rate decreased at the anaerobic threshold. In the 18 patients with a mean age of 61.1 +/- 8.9 years who had organic erectile dysfunction and an unremarkable medical history a decrease was noted in systolic and diastolic blood pressure at rest and at peak exercise, and diastolic blood pressure also at recovery, while the heart rate increased at recovery. In the 12 patients with a mean age of 60.16 +/- 9.12 years who had treated cardiovascular disease systolic and diastolic blood pressure decreased at all states and O2 consumption/heart rate at the anaerobic threshold and at peak exercise, while increased values were noted for the respiratory rate at the anaerobic threshold and ventilation/CO2 production at recovery. CONCLUSIONS: Hemodynamic changes after sildenafil administration should be considered minimal in concert with patient health status. Younger patients without signs of systemic atherosclerosis compensate the vasodilatory effect of sildenafil during exercise, while in older patients with vasculogenic erectile dysfunction moderate changes may be noted regardless of cardiovascular disease in the medical history.

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Sildenafil induces delayed preconditioning through inducible nitric oxide synthase-dependent pathway in mouse heart.

Salloum F, Yin C, Xi L, Kukreja RC.

Division of Cardiology, Box 980281, Virginia Commonwealth University, Richmond, VA 23298, USA.

Sildenafil citrate (Viagra) is the most widely used drug for treating erectile dysfunction in men. We recently demonstrated that it induces potent protective effects against ischemia-reperfusion (I-R) injury in rabbit hearts through the opening of mitochondrial ATP-dependent K+ channels. In the present study, we investigated the role of the NO-dependent signaling pathway in delayed cardioprotection by sildenafil. Adult male ICR mice were treated with saline or sildenafil (0.7 mg/kg IP) 24 hours before global I-R in the Langendorff mode. Infarct size was reduced from 27.6+/-3.3% in saline-treated control mice to 6.9+/-1.2% in sildenafil-treated mice (mean+/-SEM, P<0.05) without compromising cardiac function. Reverse transcription-polymerase chain reaction revealed a transient increase in endothelial and inducible NO synthase (eNOS and iNOS, respectively) mRNA in sildenafil-treated mice, peaking at 45 minutes (eNOS) and 2 hours (iNOS) after sildenafil injection. The magnitude of mRNA increase was more pronounced for iNOS than for eNOS. In addition, a significant increase in both iNOS and eNOS protein was detected 24 hours after sildenafil treatment. A selective inhibitor of iNOS, 1400W (10 mg/kg IP given 30 minutes before I-R), abolished sildenafil-induced protection (23.7+/-2.8%, P<0.05 versus sildenafil). These data suggest that the induction of NO synthase isoforms is an essential component of the signaling mechanism for sildenafil-induced delayed preconditioning. However, iNOS appears to be the primary isoform that mediates the robust cardioprotection.

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