Sildenafil, a phosphodiesterase-5 inhibitor, delays gastric emptying and gastrointestinal transit of liquid in awake rats.

de Rosalmeida MC, Saraiva LD, da Graca JR, Ivo BB, da Nobrega MV, Gondim FA, Rola FH, dos Santos AA.

Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, Brazil.

We studied the effect of sildenafil on gastric emptying (GE) and gastrointestinal (GI) transit in awake rats. After cervical vessel cannulation and 24 hr of fasting, the animals received an intravenous (IV) injection of sildenafil (4 mg/kg) or vehicle. Next they were gavage fed (1.5 ml) with a test meal (phenol red in 5% glucose solution, 0.5 mg/ml) and sacrificed 10, 20, or 30 min later. Experimental and control subsets consisted of 5-10 rats. Gastric and proximal, medial, and distal small intestine dye retentions (GDR and IDR, respectively) were obtained by spectrophotometry. Data were compared by ANOVA and Student-Newman-Keuls test. In sildenafil-treated animals, GDR increased (P < 0.05) by 20.3%, 46.9%, and 55,5% while medial IDR decreased (P < 0.05) by 35.1%, 43.4%, and 41.6%, respectively, at 10, 20, and 30-min intervals. Proximal and distal IDR values did not change in sildenafil-treated animals. Mean arterial pressure (MAP) decreased 25% (P < 0.05) right after sildenafil administration but normalized afterwards while in controls MAP remained unchanged. In conclusion, sildenafil delays GE and GI transit of a liquid meal while transiently decreases MAP in awake rats.

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Success of sildenafil for erectile dysfunction in men treated with brachytherapy or external beam radiation for prostate cancer.

Shemtov OM, Radomski SB, Crook J.

School of Medicine, Queen's University, Kingston, Ontario, Canada.

PURPOSE: We undertook to determine if any significant differences in the efficacy of sildenafil citrate for erectile dysfunction (ED) exists between patients who have received external beam radiation or brachytherapy for prostate cancer. MATERIALS AND METHODS: Thirty-one patients who had received external beam radiation and nineteen patients who had received brachytherapy for prostate cancer and were subsequently treated with sildenafil citrate for post-irradiation ED comprised the patient population. A chart analysis was performed to determine either the presence or absence of concomitant risk factors for ED (coronary artery disease, diabetes, hypertension and smoking history) as well as age at radiation and time lapse between radiation completion and sildenafil citrate administration. Patients were then contacted to ascertain sildenafil citrate efficacy (defined as the continued use of sildenafil citrate), dosage used and medication tolerance. RESULTS: Continued use of sildenafil citrate was reported by 12/19 (63%) of the brachytherapy patients and 7/31 (22%) of the external beam radiation patients, a significant difference (P<0.007). Of those with continued use of sildenafil citrate, the patients who had undergone external beam radiation had a longer mean period of use (33.7 months) than those who had been treated with brachytherapy (14.3 months) (P=0.006). The mean elapsed time between completion of radiation and administration of sildenafil citrate was 7.6 months and 21.6 months for the brachytherapy and external beam radiation patients respectively (P=0.002). A significant difference in mean age existed between the patient groups, with the external beam radiation group being significantly older (69.8 years and 65.1 years respectively, P=0.007) at the time of sildenafil citrate administration. Of the risk factors for ED examined in each patient group, none were found to predict treatment failure with sildenafil citrate. Of the patients who did not experience success with sildenafil citrate, both groups used the medication for comparable periods of time. CONCLUSIONS: Sildenafil citrate improved ED in a significantly greater number of patients who had undergone brachytherapy over those who had received external beam radiation. However, the patients who had received external beam radiation were both older and experienced a longer lapse of time between completion of radiotherapy and administration of sildenafil citrate than the brachytherapy patient group. This may explain the poorer success in the external beam radiation patients. The success of sildenafil in both groups of patients was lower than has previously been reported.

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Clinical responses to sildenafil in Waldenstrom's macroglobulinemia.

Treon SP, Tournilhac O, Branagan AR, Hunter Z, Xu L, Hatjiharissi E, Santos DD.

Bing Program for Waldenstrom's Macroglobulinemia, Dana-Farber Cancer Institute, nLG102, 44 Binney Street, Boston, MA 02115, USA. steven_treon dfci.harvard.edu

Waldenstrom's macroglobulinemia (WM) is an incurable B-cell malignancy. Interestingly, an unusual response activity was observed in 5 patients with WM that appeared related to their use of sildenafil, a phosphodiesterase inhibitor used to treat erectile dysfunction. One patient demonstrated a complete remission, and 4 other patients demonstrated less dramatic, but also unexpected, responses associated with sildenafil. In view of these findings, WM tumor cells were culture-sorted with sildenafil at pharmacologically achievable levels and apoptosis was demonstrated in tumor cells from all 5 patients. These studies suggest that sildenafil may be an active agent in the treatment of WM.

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Aggressive behavior increases after termination of chronic sildenafil treatment in mice.

Hotchkiss AK, Pyter LM, Gatien ML, Wen JC, Milman HA, Nelson RJ.

Department of Psychology, Ohio State University, Columbus, OH 43210, USA.

Recent reports to the U.S. Food and Drug Administration Adverse Event Reporting System implicate sildenafil citrate in adverse emotional and aggressive behaviors. Sildenafil citrate (Viagra) is widely prescribed for erectile dysfunction and acts by inhibiting phosphodiesterase Type-5, resulting in accumulation of cyclic-guanosine monophosphate (cGMP). Cyclic-GMP is synthesized by guanylyl cyclase that is directly activated by the messenger molecule, nitric oxide (NO), formed throughout the CNS by the enzyme nitric oxide synthase (NOS). Elevated concentrations of cGMP have been associated with increased aggressive behavior. In addition, the potential effect of cGMP accumulation on NO-mediated behavioral and neuroendocrine function through possible feedback mechanisms remains unspecified; however, neuronal NOS (nNOS) inhibition by pharmacologic agents or ablation of the gene encoding nNOS increases aggressive behavior in male mice. We tested the hypothesis that sildenafil citrate may increase aggression via its actions on cGMP and potential feedback inhibition of NO concentrations. Male C57BL/6 mice were injected with saline vehicle (0), 2, 5, 8, or 10 mg/kg of sildenafil citrate thrice weekly for 4 weeks. Latency to display aggressive behavior, frequency, and duration of aggressive behavior were recorded during neutral-arena aggression tests. No change in agonistic behavior was observed in mice during treatment with sildenafil citrate. However, sildenafil-treated mice given the highest dose were generally more aggressive 1 week post-cessation of drug treatment as compared to vehicle-treated mice. Additional investigation into potential withdrawal effects or abuse doses seems warranted.

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Does sildenafil combined with testosterone gel improve erectile dysfunction in hypogonadal men in whom testosterone supplement therapy alone failed?

Greenstein A, Mabjeesh NJ, Sofer M, Kaver I, Matzkin H, Chen J.

Department of Urology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel. surge04 post.tau.ac.il

PURPOSE: We evaluated the efficacy of testosterone gel (T-gel) alone and in combination with sildenafil in hypogonadal patients with erectile dysfunction (ED). MATERIALS AND METHODS: A total of 49 hypogonadal men (mean age 60.7 years) with ED participated for a mean of 20.2 months. Blood was tested for total and bioavailable testosterone, and prostate specific antigen. Sexual function was assessed using the International Index of Erectile Function questionnaire and a global assessment question (GAQ). Men received 1% 5 gm T-gel for 6 months, and 100 mg sildenafil was added to those with a "no" response to the GAQ after 3 months on testosterone supplement. RESULTS: A total of 31 patients reported significant improvement in the sexual desire domain (from a mean +/- SD of 4.2 +/- 0.8 to 8.6 +/- 0.4) and erectile function (EF) domain (from 13.6 +/- 1.9 to 27 +/- 0.8) following treatment with testosterone supplement alone. One patient was excluded from study after urinary retention developed and 9 reported irritation at the gel application site. In spite of normalization of total and bioavailable testosterone values, and significant improvement of sexual desire domain scores, the EF of 17 men remained less than 26 or they responded "no" to the GAQ. These men received combined T-gel and sildenafil, after which all graded EF greater than 26 and responded positively to the GAQ. CONCLUSIONS: Combined treatment with sildenafil and T-gel has a beneficial effect on ED in hypogonadal patients in whom treatment with testosterone supplement alone failed.

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Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunts.

Erceg S, Monfort P, Hernandez-Viadel M, Rodrigo R, Montoliu C, Felipo V.

Laboratory of Neurobiology, Fundacion Valenciana de Investigaciones Biomedicas, Valencia, Spain.

Patients with liver disease with overt or minimal hepatic encephalopathy show impaired intellectual capacity. The underlying molecular mechanism remains unknown. Rats with portacaval anastomosis or with hyperammonemia without liver failure also show impaired learning ability and impaired function of the glutamate-nitric oxide-cyclic guanine monophosphate (glutamate-NO-cGMP) pathway in brain. We hypothesized that pharmacological manipulation of the pathway in order to increase cGMP content could restore learning ability. We show by in vivo brain microdialysis that chronic oral administration of sildenafil, an inhibitor of the phosphodiesterase that degrades cGMP, normalizes the function of the glutamate-NO-cGMP pathway and extracellular cGMP in brain in vivo in rats with portacaval anastomosis or with hyperammonemia. Moreover, sildenafil restored the ability of rats with hyperammonemia or with portacaval shunts to learn a conditional discrimination task. In conclusion, impairment of learning ability in rats with chronic liver failure or with hyperammonemia is the result of impairment of the glutamate-NO-cGMP pathway. Moreover, chronic treatment with sildenafil normalizes the function of the pathway and restores learning ability in rats with portacaval shunts or with hyperammonemia. Pharmacological manipulation of the pathway may be useful for the clinical treatment of patients with overt or minimal hepatic encephalopathy.

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Clinical application of prognostic factors for patients with organic causes of erectile dysfunction on 100 mg of sildenafil citrate.

Chia SJ, Ramesh K, Earnest A.

Section of Urology, Department of General Surgery, Tan Tock Seng Hospital, Singapore. Sing_joo_chia ttsh.com.sg

OBJECTIVES: There are still no clinical predictive factors to determine the response rate of erectile dysfunction (ED) patients to sildenefil citrate. The aim of the present study is to evaluate and stratify the risk factors and attempted to determine the prognostic factors in clinical practice to predict the response rate. This is important in improving cost effectiveness and avoiding side-effects. MATERIAL AND METHODS: This is an open label prospective study including patients attending the andrology clinic in Tan Tock Seng Hospital, Singapore, over 2 years. The patients were evaluated and investigated for possible underlying causes and ED severity was assessed by five-items of the International Index of Erectile Function questionnaire (IIEF-5), together with the duration, degree and rigidity of erection. Psychogenic causes were excluded with a minimal follow up of 6 months. All patients were placed on 100 mg of sildenafil citrate and were reassessed at the end of 6 months. Logistic regression with univariate and multivariate was used as the method of statistical analysis. RESULTS: A total of 232 patients were in the cohort. The overall response rate was 43%, with the best response rate in veno-occlusive cases and the worst responses from neurogenic causes. Age, smoking, diabetes mellitus, hypertension, hyperlipidemia, pretreatment IIEF-5 score, interval to achieve erection and duration of erection were significant in univariate analysis, but only age, smoking and IIEF-5 score were significant in multivariate analysis. With a combination of these factors, a table was formed to determine the possible response rate in clinical practice. This will assist physicians in selecting patients with potentially favorable responses and avoid side-effects and an unnecessary wastage of time and cost. CONCLUSION: Possible factors could be determined and used clinically to predict the response rate to sildenafil citrate.

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Phosphodiesterase-5 inhibitor, sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis: Essential role of NO signaling.

Das A, Xi L, Kukreja RC.

Medicine, Virginia Commonwealth University Medical Center, Richmond, Va 23298.

We recently demonstrated a potent preconditioning-like effect of phosphodiesterase-5 (PDE5) inhibitor, sildenafil citrate against myocardial infarction following ischemia-reperfusion injury in rabbit and mouse heart. It is not known whether sildenafil induces protection against necrosis or apoptosis in cardiomyocytes independent of its hypotensive effect. Adult mouse ventricular cardiomyocytes were treated with sildenafil (1 or 10 muM) for 1 hour before 40 min of simulated ischemia (SI). Necrosis was determined by trypan blue exclusion and lactate dehydrogenase (LDH) release following SI alone or plus 1 hour or 18 hours of reoxygenation (RO). Apoptosis was assessed by TUNEL assay and mitochondrial membrane potential measured using a fluorescent probe 5,5',6,6'-tetrachloro-l,l',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide (JC-1). Sildenafil reduced necrosis as indicated by decrease in trypan blue positive myocytes and leakage of LDH compared with non-treated cells after either SI or SI-RO. The number of TUNEL positive myocytes or loss of JC-1 fluorescence following SI and 18 hrs of RO was attenuated in the sildenafil-treated group with concomitant inhibition of caspase 3 activity. An early increase in Bcl-2 to Bax ratio with sildenafil treatment was also observed in myocytes after SI-RO. The increase of Bcl-2 expression by sildenafil was inhibited by NOS inhibitor, L-nitro-amino-methyl-ester. The drug also enhanced mRNA and protein content of iNOS and eNOS in the myocytes. Sildenafil-induced protection against necrosis and apoptosis was absent in the myocytes derived from iNOS knockout mice and was attenuated in eNOS knockout myocytes. The upregulation of Bcl-2 expression by sildenafil was also absent in iNOS deficient myocytes. RT-PCR, Western blots and immunohistochemical assay confirmed the expression of PDE5 in mouse cardiomyocytes. These data provide strong evidence for a direct protective effect of sildenafil against necrosis and apoptosis through NO signaling pathway. The results may have possible therapeutic potential in preventing myocyte cell death following ischemia/reperfusion.

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