Chronic sildenafil improves erectile function and endothelium-dependent cavernosal relaxations in rats: lack of tachyphylaxis.

Behr-Roussel D, Gorny D, Mevel K, Caisey S, Bernabe J, Burgess G, Wayman C, Alexandre L, Giuliano F.

Pelvipharm, Domaine CNRS, 1 Avenue de la terrasse, Batiment 5, 91190 Gif sur Yvette, France.

OBJECTIVES: Sildenafil is a widely-prescribed effective on-demand treatment of erectile dysfunction (ED). Chronic treatment with sildenafil could help patients with ED. METHODS: The effects of an 8-week long treatment with sildenafil (60 mg/kg/d sc) in male Sprague Dawley rats were evaluated on electrically-elicited erectile responses in vivo before and after an acute injection of sildenafil (0.3mg/kg iv). In addition, endothelium-dependent and -independent relaxations of strips of corpus cavernosum in vitro were examined. All experiments were performed 36 hours after the last injection of sildenafil. RESULTS: Endothelium-dependent relaxations of cavernosal strips to acetylcholine were enhanced after chronic treatment with sildenafil while relaxations to A23187 or sodium nitroprusside were unchanged. Frequency-dependent erectile responses elicited by cavernous nerve stimulation were significantly improved. Moreover, the erectile responses to acute sildenafil were greater in chronically-treated rats with sildenafil. CONCLUSIONS: This is the first report providing experimental support for chronic dosing with sildenafil which could be of use for patients that are poor responders to on-demand treatment. Chronic sildenafil may regulate the transduction pathway leading to the activation of eNOS but has no effect on NO bioavailability or on the cGMP pathway, thereby eliminating a possible concern for tachyphylaxis.

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Phosphodiesterase inhibition by sildenafil citrate attenuates the learning impairment induced by blockade of cholinergic muscarinic receptors in rats.

Devan BD, Sierra-Mercado D Jr, Jimenez M, Bowker JL, Duffy KB, Spangler EL, Ingram DK.

Behavioral Neuroscience Section, Laboratory of Experimental Gerontology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD, 21224, USA. DevanBr grc.nia.nih.gov

We examined whether treatment with sildenafil citrate (the active compound of Viagra), a cyclic nucleotide phosphodiesterase type 5 inhibitor (PDE5), would reverse the learning impairment induced by cholinergic muscarinic (mACh) receptor blockade [0.75 mg/kg scopolamine HCl, intraperitoneal (i.p.) injections]. Rats were pretrained in a one-way active avoidance of foot shock in a straight runway and the next day received 15 training trials in a 14-unit T-maze. Performance in this maze paradigm requires accurate responding to avoid mild foot shock and has been shown to be sensitive to aging and to impairment in central cholinergic systems. Intraperitoneal (i.p.) injections of scopolamine or saline and sildenafil or vehicle were given 30 and 15 min before training, respectively. The combined treatment conditions were as follows: saline+vehicle (control), scopolamine (0.75 mg/kg)+vehicle, and scopolamine (0.75 mg/kg)+sildenafil (1.5, 3.0, or 4.5 mg/kg). Behavioral measures of performance included deviations from the correct pathway (errors), run time from start to goal, shock frequency, and duration. Statistical analysis revealed that scopolamine impaired maze performance and that sildenafil (3.0 mg/kg) significantly attenuated this impairment in a dose-dependent manner. These results suggest that sildenafil citrate may serve as a cognitive enhancer for therapeutic treatment of cholinergic dysfunction in age-related cognitive decline and Alzheimer's dementia (AD).

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Sildenafil citrate for erectile dysfunction in men receiving multiple antihypertensive agents: a randomized controlled trial.

Pickering TG, Shepherd AM, Puddey I, Glasser DB, Orazem J, Sherman N, Mancia G.

Columbia University Medical College, New York, New York 10032, USA. tp2114 columbia.edu

BACKGROUND: Erectile dysfunction (ED) is common among men taking antihypertensive drugs to control blood pressure. We evaluated the safety and efficacy of sildenafil citrate for treating ED in men taking multiple antihypertensive medications in a randomized, double-blind, placebo-controlled trial. METHODS: A total of 568 men (> or =18 years) with ED and hypertension who were taking two or more antihypertensives were randomized to sildenafil (n = 281) or matching placebo (n = 287) for a 6-week double-blind trial followed by a 6-week open-label phase during which all patients received sildenafil. Primary efficacy variables were questions (Q) 3 and 4 (frequency of erections and penetration) of the International Index of Erectile Function (IIEF), and secondary efficacy variables were two global efficacy assessment (GEA) questions regarding improvement in erections and intercourse. RESULTS: A total of 562 men (mean age, 59 years) took > or =1 dose of study drug. At week 6, mean scores on both Q3 and Q4 improved significantly among sildenafil-treated compared with placebo-treated patients. In regard to Q3 and Q4 there were no differences between patients taking two and those taking three or more antihypertensive agents. In all, 71% and 69% of sildenafil-treated patients reported improved erections (GEA1) and intercourse (GEA2) compared with 18% and 20% of placebo-treated patients, respectively. By week 12, >80% of all patients (regardless of initial treatment group) had improved erections and intercourse. During double-blind treatment, 40% of sildenafil-treated and 25% of placebo-treated patients experienced adverse events; fewer than 2% in each group discontinued because of adverse events. CONCLUSIONS: Sildenafil was an effective and well tolerated treatment for ED in men receiving multiple antihypertensives. The results suggest that there were no additional safety risks associated with the use of sildenafil in these patients.

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Inhibition of cGMP-specific phosphodiesterase type 5 reduces sodium excretion and arterial blood pressure in patients with NaCl retention and ascites.

Thiesson HC, Jensen BL, Jespersen B, Schaffalitzky de Muckadell OB, Bistrup C, Walter S, Ottosen PD, Veje A, Skott O.

Department of Physiology and Pharmacology, University of Southern Denmark, Odense, Denmark; Department of Nephrology, Odense University Hospital, Odense, Denmark; Department of Gastroenterology, Odense University Hospital, Odense, Denmark.

In the present study we tested the hypothesis that inhibition of renal phosphodiesterase type 5 (PDE5) in patients with liver cirrhosis and ascites increases sodium excretion. The effect of sildenafil citrate was studied in a randomized double-blind placebo-controlled cross-over study. Diuretics were withdrawn and a fixed sodium diet (100 mmol/day) was given to the patients for five days prior to both study days. After a 60-min basal period, eight patients received either oral sildenafil (50 mg) or placebo. Glomerular filtration rate (GFR) and renal blood flow (RBF) were determined by (99m)Tc-diethylenetriamine-pentaacetate and (131)I-hippuran clearances. In human nephrectomy specimens PDE5 mRNA was expressed at similar levels in cortex (n=6) and inner medulla (n=4). Histochemical staining showed PDE5 immunoreactivity in collecting ducts and vascular smooth muscle. At baseline, cirrhotic patients exhibited elevated plasma concentrations of ANP, renin, ANG II and aldosterone that did not differ on the two study days. Basal sodium excretion was similar at the two study days (median 17 and 18 mmol, respectively) and patients were in positive sodium balance. Sildenafil increased heart rate, plasma renin activity, plasma angiotensin II and aldosterone concentrations significantly after 60 min. Plasma cGMP concentration was increased after 120 and 180 min and urinary sodium excretion and mean arterial blood pressure were decreased significantly at 120 min and 180 min. Plasma ANP concentration, GFR and RBF did not change after sildenafil. In patients with ascites and cirrhosis, inhibition of PDE5 did not promote natriuresis but led to increased plasma levels of the renin-angiotensin-aldosterone system.

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Sildenafil (Viagra) corrects DeltaF508-CFTR location in nasal epithelial cells from patients with cystic fibrosis.

Dormer RL, Harris CM, Clark Z, Pereira MM, Doull IJ, Norez C, Becq F, McPherson MA.

Department of Medical Biochemistry and Immunology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK. dormer cardiff.ac.uk

BACKGROUND: Most patients with cystic fibrosis (CF) have a DeltaF508 mutation resulting in abnormal retention of mutant gene protein (DeltaF508-CFTR) within the cell. This study was undertaken to investigate DeltaF508-CFTR trafficking in native cells from patients with CF with the aim of discovering pharmacological agents that can move DeltaF508-CFTR to its correct location in the apical cell membrane. METHOD: Nasal epithelial cells were obtained by brushing from individuals with CF. CFTR location was determined using immunofluorescence and confocal imaging in untreated cells and cells treated with sildenafil. The effect of sildenafil treatment on CFTR chloride transport function was measured in CF15 cells using an iodide efflux assay. RESULTS: In most untreated CF cells DeltaF508-CFTR was mislocalised within the cell at a site close to the nucleus. Exposure of cells to sildenafil (2 hours at 37 degrees C) resulted in recruitment of DeltaF508-CFTR to the apical membrane and the appearance of chloride transport activity. Sildenafil also increased DeltaF508-CFTR trafficking in cells from individuals with CF with a single copy DeltaF508 (DeltaF508/4016ins) or with a newly described CF trafficking mutation (R1283M). CONCLUSIONS: The findings provide proof of principle for sildenafil as a DeltaF508-CFTR trafficking drug and give encouragement for future testing of sildenafil and related PDE5 inhibitors in patients with CF.

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Oral sildenafil reduces pulmonary hypertension after cardiac surgery.

Trachte AL, Lobato EB, Urdaneta F, Hess PJ, Klodell CT, Martin TD, Staples ED, Beaver TM.

Department of Surgery, Division of Thoracic and Cardiovascular Surgery, University of Florida College of Medicine, Gainesville, Florida 32611, USA.

BACKGROUND: Treatment of postoperative pulmonary hypertension with intravenous (IV) pulmonary vasodilators is hampered by the lack of selectivity. Inhaled nitric oxide produces selective pulmonary vasodilation; however, it requires a special device, and weaning can cause rebound. Oral sildenafil is a phosphodiesterase type V inhibitor. Sildenafil can produce sustained pulmonary vasodilatation in patients with hypoxic or primary pulmonary hypertension; however, experience with postoperative pulmonary hypertension is limited. We report our initial experience with eight patients who received oral sildenafil as adjunctive therapy for postoperative pulmonary hypertension METHODS: We reviewed the charts of eight adult patients with postoperative pulmonary hypertension who received oral sildenafil (25 to 50 mg) to facilitate weaning of IV (milrinone, nitroglycerine, and sodium nitroprusside) and inhaled (nitric oxide) pulmonary vasodilators. Hemodynamic data were recorded before and 30 and 60 minutes after the initial dose of sildenafil. RESULTS: After the initial dose of sildenafil, mean pulmonary artery pressure was reduced by 20% and 22% at 30 and 60 minutes, respectively (p < 0.05). Pulmonary vascular resistance index decreased by 49% and 44% at 30 and 60 minutes, respectively (p < 0.05). Sildenafil had no clinically significant effects on cardiac index, mean arterial pressure, or systemic vascular resistance. Subsequent doses of sildenafil were administered at regular intervals, allowing successful weaning of concomitant pulmonary vasodilators. CONCLUSIONS: Oral sildenafil is an effective agent for treatment of postoperative pulmonary hypertension and can be used to facilitate weaning of inhaled and IV pulmonary vasodilators.

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Nuclear magnetic resonance investigation of the interaction of water vapor with sildenafil citrate in the solid state.

Apperley DC, Basford PA, Dallman CI, Harris RK, Kinns M, Marshall PV, Swanson AG.

Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, United Kingdom.

Solid-state carbon-13 ((13)C) and nitrogen-15 ((15)N) nuclear magnetic resonance (NMR) have been used to investigate how water interacts with sildenafil citrate. When the humidity is altered, the water concentration in the solid compound changes in a reversible manner. The proportion of occupied sites depends on the humidity, but the water concentration never reaches a rational (e.g., 1:1) stoichiometric ratio to form a true hydrate. The NMR spectra were obtained under several humidity-controlled conditions to determine what changes occur as the water content is varied and where the water is located in the crystal structure. Only one set of (15)N and (13)C signals is observed for each humidity level. This shows that water incorporated into the crystal lattice of sildenafil citrate is very mobile and exchanges rapidly on the NMR time scale between various sites. The (13)C data are consistent with formation of a hydrogen bond between a water molecule and one carbonyl of the citrate anion. The spectra also show that the water content affects the environment (perhaps influencing the average conformation) of the propyl group. Additionally, (15)N dipolar dephasing experiments show that the sildenafil molecule is only protonated in the piperazine ring. The work is supported by solution-state NMR. (c) 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:516-523, 2005.

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Dissociable effects of acetylcholinesterase inhibitors and phosphodiesterase type 5 inhibitors on object recognition memory: acquisition versus consolidation.

Prickaerts J, Sik A, van der Staay FJ, de Vente J, Blokland A.

Department of Psychiatry and Neuropsychology, Brain and Behavior Institute, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands. jprickae prdbe.jnj.com

RATIONALE: Phosphodiesterase enzyme type 5 (PDE5) inhibitors and acetylcholinesterase (AChE) inhibitors have cognition-enhancing properties. However, it is not known whether these drug classes affect the same memory processes. OBJECTIVE: We investigated the memory-enhancing effects of the PDE5 inhibitor sildenafil and AChE inhibitors metrifonate and donepezil in the object recognition task to find out whether acquisition or consolidation processes were affected by these drugs. METHODS: The object recognition task measures whether rats remembered an object they have explored in a previous learning trial. All drugs were given orally 30 min before or immediately after learning to study acquisition and consolidation, respectively. RESULTS: Sildenafil given immediately after the first trial improved the memory performance after 24 h and resulted in an inverted U-shaped dose-effect curve with the peak dose at 3 mg/kg. When given before the first trial, sildenafil also improved the memory performance. However, the dose needed for the best performance under this condition was 10 mg/kg, suggesting that the dose-effect curve shifted to the right. This can be explained by the metabolic clearance of the high dose of sildenafil. Donepezil had no memory improving effect when given after the first trial. However, when given before the first trial, a gradually increasing dose-effect curve was found which had its maximum effect at the highest dose tested (1 mg/kg). Likewise, only when metrifonate (30 mg/kg) was given before the first trial did rats show an improved memory performance. CONCLUSION: Our data strongly suggest that PDE5 inhibitors improve processes of consolidation of object information, whereas AChE inhibitors improve processes of acquisition of object information.

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