Stimulation of serotonin transport by the cyclic GMP phosphodiesterase-5 inhibitor sildenafil.

Zhu CB, Hewlett WA, Francis SH, Corbin JD, Blakely RD.

Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, USA.

The serotonin (5-hydroxtryptamine, 5-HT) transporter (SERT) plays a critical role in the inactivation of synaptic 5-HT and has been implicated in multiple psychiatric and peripheral disorders. SERT regulation studies demonstrate that activation of cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)-linked pathways can increase SERT activity. As cGMP actions are limited by cGMP-specific phosphodiesterase (PDEs), we investigated whether the cGMP-specific PDE5 inhibitor sildenafil (Viagra) can stimulate 5-HT uptake and potentiate cGMP-mediated regulation. In RBL-2H3 cells, SERT activity was stimulated by sildenafil in a concentration- and time-dependent manner. Sildenafil also enhanced the stimulation of SERT triggered by the adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA), effects blocked by the PKG inhibitor N-[2-(methylamino)ethy]-5-isoquinoline-sulfonamide (H8). Sildenafil stimulation of 5-HT uptake arises from an increase in 5-HT transport Vmax and is paralleled by elevated SERT surface antagonist binding, also H8-sensitive. These findings implicate cGMP-targeted PDEs in limiting the regulation of antidepressant-sensitive 5-HT transport.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15507214&dopt=Abstract sildenafil Viagra online



Sublingual sildenafil in the treatment of erectile dysfunction: faster onset of action with less dose.

Deveci S, Peskircioglu L, Aygun C, Tekin MI, Dirim A, Ozkardes H.

Department of Urology, Baskent University School of Medicine, Ankara, Turkey.

BACKGROUND: The aim of the present study was to show the efficacy and safety of sublingual sildenafil and to determine whether lower doses cause the same effect with a faster onset of action in this mode of application. METHODS: Forty consecutive patients with erectile dysfunction for more than three months were included in the study. The mean age was 55 years (range, 25-65). Serum glucose and testosterone levels, lipid profile and erectile function scores were obtained in all patients. Twenty patients received placebos and the other 20 patients received 20 mg sublingual sildenafil in a double blind randomized design. RESULTS: The effect of sildenafil on erection was significantly higher than that of placebo. Sixty-five percent of patients (13/20) who received sublingual sildenafil achieved satisfying erections and coitus, whereas the rate was 15% in the placebo group (3/20). The mean onset of action with sublingual sildenafil was 15.5 min and lasted for an average of 40 min. Minimal headaches, sweating and flushing were noted as the side-effects. CONCLUSIONS: 20 mg sublingual sildenafil is safe and effective in the treatment of erectile dysfunction. Sublingual administration has some advantages as it is not effected by food ingestion and quickly appears in the circulation. These advantages provide a faster onset of action with a lower dose when compared to oral sildenafil. Sublingual use of sildenafil may be more cost-effective and possibly provides a more predictable onset of action.

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Post-marketing surveillance study of the safety and efficacy of sildenafil prescribed in primary care to erectile dysfunction patients.

Sunwoo S, Kim YS, Cho BL, Cheon KS, Seo HG, Rho MK, Cheong YS, Hong MH, Kim SW, Kim DH.

1Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

In order to investigate the safety and efficacy of sildenafil prescribed in primary care, a post-marketing surveillance study was undertaken. A total of 651 men with erectile dysfunction (ED) were enrolled from 31 family physicians in Korea from December 1999 to July 2002. Patients were regularly followed up to ascertain the safety and efficacy of sildenafil. Of the 651 patients enrolled, 572 (87.9%) returned for safety evaluation and efficacy assessment. In all, 458 (80.1%) of 572 patients reported improved erectile function with sildenafil. Hypertension, diabetes and low-dose sildenafil were associated with poor efficacy. A total of 71 adverse events were reported among 56 patients (8.6%), with the most frequent being hot flushes (5.6%), followed by headache (2.6%), palpitation (1.0%), anxiety (0.5%) and elevated ALT (0.5%). Only six patients (1.0%) discontinued sildenafil as a direct result of adverse events. These results suggest that sildenafil prescribed by primary care physicians was well tolerated and improved erectile function in patients with ED.International Journal of Impotence Research (2005) 17, 71-75. doi:10.1038/sj.ijir.3901263 Published online 14 October 2004.

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Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension.

Richalet JP, Gratadour P, Robach P, Pham I, Dechaux M, Joncquiert-Latarjet A, Mollard P, Brugniaux J, Cornolo J.

Laboratoire Reponses cellulaires et fonctionnelles a l'hypoxie, Universite Paris, Bobigny, France. richalet smbh.univ-paris13.fr

Exposure to high altitude induces pulmonary hypertension that may lead to life-threatening conditions. In a randomized, double-blind, placebo-controlled study, the effects of oral sildenafil on altitude-induced pulmonary hypertension and gas exchange in normal subjects were examined. Twelve subjects (sildenafil [SIL] n = 6; placebo [PLA] n = 6) were exposed for 6 days at 4,350 m. Treatment (3 x 40 mg/day) was started 6 to 8 hours after arrival from sea level to high altitude and maintained for 6 days. Systolic pulmonary artery pressure (echocardiography) increased at high altitude before treatment (+29% versus sea level, p < 0.01), then normalized in SIL (-6% versus sea level, NS) and remained elevated in PLA (+21% versus sea level, p < 0.05). Pulmonary acceleration time decreased by 27% in PLA versus 6% in SIL (p < 0.01). Cardiac output and systemic blood pressures increased at high altitude then decreased similarly in both groups. Pa(O(2)) was higher and alveolar-arterial difference in O(2) lower in SIL than in PLA at rest and exercise (p < 0.05). The altitude-induced decrease in maximal O(2) consumption was smaller in SIL than in PLA (p < 0.05). Sildenafil protects against the development of altitude-induced pulmonary hypertension and improves gas exchange, limiting the altitude-induced hypoxemia and decrease in exercise performance.

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[Treatment of post radical prostatectomy erectile dysfunction with sildenafil in a non-selected group of patients]

[Article in Spanish]

Rubio Briones J, Iborra Juan I, Dumont Martinez R, Casanova Ramon-Borja J, Monros Lliso JL, Ricos Torrent JV, Collado Serra A, Solsona Narbon E.

Instituto Valenciano de Oncologia, Valencia.

OBJECTIVE: To evaluate erectile disfunction (ED) after radical prostatectomy in a non selected group of patients and their response to sildenafil. METHODS: We included our patients who were operated on between 1998 and 2001. The patients filled in a modification of IIEF (mIIEF) before the RP operation. We tried sildenafil with doses of 100 mg in 3 different periods: 3-6, 12 and 18-24 months after the RP operation. In the event of a complete response they filled in the mIIEF again. RESULTS: The mean age of the patients was 62.8 years old and the mean observation period was 31.7 months. Only 111 (62%) of the total number of patients operated on wanted treatment and only 90 took sildenafil in the proposed protocol; 27 (30%), 18 (20%) and 45 (50%) patients had a complete response, a partial response or no response to the sildenafil respectively. The mIIEF showed 6.5+/-5.7 points less than the mIIEF pre-treatment. In the univariate analysis, the preservation of bundles, the presence of a previous partial response and the presence of the previous tumescence were significantly related to the complete response; however, only tumescence kept its value in the multivariate study. CONCLUSIONS: Urologists must involve themselves in the early rehabilitation of the erectile function even in those patients where preservation of the NVB was not possible. One must always try to preserve, uni or bilaterally, whenever the patient desires preservation of EF. The response to sildenafil is better after the first year and in patients who have previous tumescence.

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Sildenafil citrate (viagra) induces cardioprotective effects after ischemia/reperfusion injury in infant rabbits.

Bremer YA, Salloum F, Ockaili R, Chou E, Moskowitz WB, Kukreja RC.

Division of Pediatric Cardiology, Department of Pediatrics, Virginia Commonwealth University Health System, Richmond, VA 23298, USA.

Infants undergoing surgery for congenital heart disease are at risk for myocardial ischemia during cardiopulmonary bypass, circulatory arrest, or low-flow states. The purpose of this study was to demonstrate the effects of sildenafil, a selective phosphodiesterase-5 (PDE-5) inhibitor on myocardial functional improvement and infarct size reduction during ischemia/reperfusion injury in infant rabbits. Infant rabbits (aged 8 wk) were treated with sildenafil citrate (0.7 mg/kg i.v.) or normal saline 30 min before sustained ischemia for 30 min and reperfusion for 3 h. Transesophageal echocardiography (TEE) was used to assess left ventricular cardiac output (LVCO) and aortic velocity time integral (VTI). After ischemia/reperfusion, risk area was demarcated by Evan's blue dye and infarct size determined by computer morphometry of triphenyltetrazolium chloride-stained sections. The sildenafil-treated group had preservation and elevation in LVCO (143% of baseline, p < 0.05) and an elevated aortic VTI (145% of baseline, p < 0.05) after 30 min of ischemia compared with the control group LVCO (72% of baseline, p < 0.05) and aortic VTI (73% of baseline, p < 0.05). This is a statistically significant increase in LVCO and aortic VTI in the sildenafil group compared with controls (n = 6/group, p < 0.05). The sildenafil-treated group had significant reduction in infarct size (15.5 +/- 1.2 versus 33 +/- 2.3 in the saline group, % risk area, mean +/- SEM, n = 10-15/group, p < 0.05). For the first time, we have shown that sildenafil citrate promotes myocardial protection in infant rabbits as evidenced by postischemic preservation and elevation in LVCO and aortic VTI and reduction in infarct size.

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PROSPECTIVE, RANDOMIZED, CROSSOVER COMPARISON OF SUBLINGUAL APOMORPHINE (3 mg) WITH ORAL SILDENAFIL (50 mg) FOR MALE ERECTILE DYSFUNCTION.

Pavone C, Curto F, Anello G, Serretta V, Almasio PL, Pavone-Macaluso M.

From the Department of Urology and Institute of Internal Medicine (PLA), University of Palermo, Palermo, Italy.

PURPOSE:: We established the efficacy and safety of sublingual apomorphine compared with oral sildenafil in comparable groups of patients with erectile dysfunction (ED). MATERIALS AND METHODS:: This prospective, randomized, crossover study included 77 heterosexual men with ED of various etiologies and severities. A total of 62 men were randomized but only 34 were evaluable for efficacy and tolerability. The study started with a run-in period of 2 to 4 weeks. The first 4 weeks of treatment were followed by a washout period of 4 weeks, after which patients changed to the alternate treatment for an additional 4-week period. The sequence of the 2 treatments was established by a randomization list in blocks in closed packets. The primary efficacy end point was the percent of attempts resulting in erection firm enough for intercourse. Additional variables were the percent of attempts resulting in intercourse and improvement in ED, as evaluated by the erectile function domain score of the International Index of Erectile Function questionnaire. RESULTS:: Sildenafil was significantly more effective than apomorphine in regard to the percent of attempts resulting in erection firm enough for intercourse (85% vs 44%, p <0.0001) and actually resulting in intercourse (81% vs 43%, p <0.0001) as well as erectile function evaluated by the erectile function domain score of the International Index of Erectile Function (p <0.001). The incidence of adverse events was not significantly different for the 2 drugs. Although the number of patients was small, this study had strong statistical power due to the striking difference in results. CONCLUSIONS:: Sildenafil was significantly more effective than apomorphine for ED. No statistical difference in adverse events was noted.

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The role of sildenafil in the treatment of erectile dysfunction in patients with pelvic fracture urethral disruption.

Shenfeld OZ, Gofrit ON, Gdor Y, Landau I, Katz R, Pode D.

From the Department of Urology, Hebrew University Hadassah Medical Center, Jerusalem, Israel.

PURPOSE:: Erectile dysfunction (ED) is a common sequel of pelvic fracture urethral disruption (PFUD). After repair of the urethral injury ED may be the most devastating long-term effect for the patient. Some patients with ED may regain normal erectile function. We prospectively studied the response to sildenafil and the erectile function of patients with ED due to PFUD. MATERIALS AND METHODS:: The erectile function of patients referred to us with PFUD for urethroplasty were prospectively evaluated before surgery. Patients underwent nocturnal penile tumescence testing and, if results were abnormal, penile duplex ultrasonography with intracavernous injection and arteriography were performed to diagnose the etiology of ED. Patients were questioned about erectile function every 3 months after surgery and if they complained of ED they were offered 100 mg sildenafil. Patients were followed for at least 18 months after surgery. RESULTS:: A total of 29 consecutive patients were evaluated and 22 (76%) of them had ED before surgery. Sufficient followup was available for 15 of the patients. Overall 47% of these patients responded favorably to sildenafil. Of the patients 60% with neurogenic ED and 20% of those with arterial ED responded to this treatment. In 33% of the patients ED resolved within the followup period. All patients with spontaneous resolution of ED previously responded to sildenafil (71% of sildenafil responders). CONCLUSIONS:: In patients with ED due to PFUD, those with neurogenic ED are more likely to respond to sildenafil than those with arterial damage. Favorable response to sildenafil may predict spontaneous resumption of normal erectile function over time.

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