High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodiesterase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patients.

Weeks JL, Zoraghi R, Beasley A, Sekhar KR, Francis SH, Corbin JD.

1Department of Molecular Physiology and Biophysics, Vanderbilt University, School of Medicine, Nashville, Tennessee, USA.

The physiological role of phosphodiesterase (PDE)11 is unknown and its biochemical characteristics are poorly understood. We have expressed human His-tagged PDE11A4 and purified the enzyme to apparent homogeneity. PDE11A4 displays K(m) values of 0.97 muM for cGMP and 2.4 muM for cAMP, and maximal velocities were 4- to 10-fold higher for cAMP than for cGMP. Given the homology between PDE11 and PDE5, we have compared the biochemical potencies of tadalafil (Cialistrade mark, Lilly-ICOS), vardenafil (Levitratrade mark, Bayer-GSK), and sildenafil (Viagratrade mark, Pfizer Inc.) for PDE11A4 and PDE5A1. PDE5A1/PDE11A4 selectivities are 40-, 9300-, and 1000-fold for tadalafil, vardenafil, and sildenafil, respectively. This suggests that none of these three compounds is likely to crossreact with PDE11A4 in patients.International Journal of Impotence Research (2005) 17, 5-9. doi:10.1038/sj.ijir.3901283 Published online 11 November 2004.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15538396&dopt=Abstract sildenafil Viagra online



Overactive corpus cavernosum: a novel cause of erectile dysfunction.

Shafik A, Shafik I, El-Sibai O, Shafik AA.

Department of Surgery and Experimental Research, Faculty of Medicine, Cairo University, Cairo, Egypt. shafik ahmed-shafik.org

Our recording of the electromyographic (EMG) activity of the corpus cavernosum (CC) in 59 patients with erectile dysfunction (ED) revealed 18 patients who had elevated electric activity, which presumably points to heightened tone of the CC smooth muscles. We investigated the hypothesis that this elevated EMG activity and muscular tone of the CC could be the cause of ED. The study comprised the said 18 subjects with the hypertonic CC muscles as study group (42.6 +/- 5.3 SD years), 15 healthy volunteers (41.8 +/- 5.1 SD years) and 15 patients (41.6 +/- 5.5 SD years) with ED who had not recorded elevated tone of the CC muscles as control group. The EMG activity was registered in the flaccid, erectile and detumescent phases by two electrodes inserted into the CC. Electrocavernosography (ECG) of healthy volunteers recorded in the flaccid phase showed regular slow waves (SW) and random action potentials (APs). The wave variables declined significantly in the erection phase (P < 0.01). In the study group, the SW variables in the flaccid phase increased significantly (P < 0.05) compared with the healthy volunteers and the rhythm was irregular. Erection did not occur with sildenafil but with intracavernosal injection of papaverine, which led to decline of the SW variables (P < 0.05). The control ED group exhibited in the flaccid phase diminished SW variables (P < 0.05) compared with the healthy volunteers. On erection with sildenafil administration, the SW variables showed significant reduction (P < 0.05). CC hypertonicity or 'overactive CC' was identified as a possible cause of ED. An elevated EMG activity of the CC muscle fibres in the flaccid phase presumably denotes hypertonicity of these fibres and their failure to relax to effect erection. The cause of elevated CCEMG activity and presumed muscle hypertonicity is unknown and could be functional or organic. Erection was produced by intracavernosus injection of papaverine and not by sildenafil. This condition of 'overactive CC' should be considered in the diagnosis of ED. However, further studies in the pathogenesis of the condition are warranted.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15541054&dopt=Abstract sildenafil Viagra online



The influence of sildenafil on random skin flap survival in rats: an experimental study.

Sarifakioglu N, Gokrem S, Ates L, Akbuga UB, Aslan G.

Ankara Training and Research Hospital, Department of Plastic and Reconstructive Surgery, Cebeci, Ankara, Turkey. nsarifakioglu yahoo.com

Sildenafil (Viagra), a selective and specific inhibitor of cyclic guanosine monophosphate (cGMP) phosphodiesterases (PDEs), is currently marketed for the treatment of erectile dysfunction. Sildenafil is a potent and highly selective PDE-V inhibitor and enhances smooth muscle relaxation in human. Systemic arterial and venous smooth muscle cells contain PDE-V and nitric oxide (NO) which is a major mediator of relaxation of the smooth muscle cell. The aim of the present study is to investigate, in a rat model, the potential effect of sildenafil on survival of random pattern skin flaps. For this purpose, 32 Sprague-Dawley rats were used and a McFarlane-type caudally based skin flap was designed on the dorsum of the rat (2.5 x 8 cm). Rats were divided into four groups: One control (Group D), and three treatment groups (Groups A, B, C). Sildenafil was administered orally to the experiment groups; Group A: 3 mg/kg/single dose a day, Group B: 10 mg/kg/single dose a day and Group C: 10 mg/kg/twice dose a day. The areas of flap necrosis were measured in each group. The extent of viable flap areas were expressed as a percentage of total flap area, and differences were studied by Completely Randomised Experimental design. The areas of necrosis of skin flaps decreased depending on sildenafil dose, but viability of the flaps treated with 3 mg/kg/day was not different than the control group. The flaps receiving 2 x 10 mg/kg/day sildenafil gave the highest (P < 0.01) survival rate. As a conclusion, sildenafil may have a dose dependent effect to increase flap survival in random skin flaps.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15544775&dopt=Abstract sildenafil Viagra online



The effect of Sildenafil on human platelet secretory function is controlled by a complex interplay between phosphodiesterases 2, 3 and 5.

Dunkern TR, Hatzelmann A.

Department of Biochemistry Inflammation, ALTANA Pharma AG, Byk-Gulden-Str.2, Konstanz 78467, Germany. torsten.dunkern altanapharma.com

Human platelets contain the cyclic nucleotide-hydrolyzing phosphodiesterases (PDEs) 2, 3 and 5. The cGMP-PDE5 inhibitors Sildenafil and Zaprinast have been demonstrated to potentiate the anti-platelet aggregatory effect of NO donors like sodium nitroprusside (SNP) in vitro but the mechanisms of Sildenafil's action on the secretory function of human platelets have not been analysed in detail. In the present paper, we show (1) that both compounds potentiate the SNP-induced increase in cGMP in human platelets concentration-dependently. (2) However, whereas Sildenafil plus SNP treatment only partially inhibits thrombin-induced release of serotonin, the less selective Zaprinast plus SNP cause a complete inhibition. (3) The inhibition mediated by Sildenafil plus SNP is limited to low compound concentrations at which cAMP levels are increased, probably due to cGMP-mediated inhibition of PDE3. (4) High concentrations of Sildenafil (plus SNP) neither affect cAMP levels, likely due to the activation of PDE2, nor inhibits the release of serotonin. Thus, increases in both cyclic nucleotides seem to control platelet function. (5) Accordingly, treatment with increasing concentrations of Sildenafil plus SNP and a selective PDE2 inhibitor, which by its own has no effect, induced a concentration-dependent increase in cAMP and complete inhibition of platelet activation. In summary, our data indicate that Sildenafil inhibits secretory function of human platelets at least in part due to the cGMP-mediated effects on intracellular cAMP and that entire inhibition of serotonin release from thrombin-activated platelets is controlled by both cyclic nucleotides.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15567064&dopt=Abstract sildenafil Viagra online



Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension.

Hoeper MM, Faulenbach C, Golpon H, Winkler J, Welte T, Niedermeyer J.

Hannover Medical School, Dept of Respiratory Medicine, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. hoeper.marius mh-hannover.de

It has been proposed that targeted treatments should be combined for patients with idiopathic pulmonary arterial hypertension (IPAH) responding insufficiently to monotherapy. This study followed the clinical course of nine patients with severe IPAH, in whom the endothelin receptor antagonist bosentan caused transient clinical improvement, eventually followed by a decline in exercise tolerance, who received adjunct treatment with the phospodiesterase-5-inhibitor sildenafil. Measurements included the 6-min walk distance (6MWD) and cardiopulmonary exercise testing (CPET). The 6MWD at baseline was 346+/-66 m and improved to 403+/-80 m 3 months after introduction of bosentan treatment. However, this effect was not sustained and, after an interval of 11+/-5 months, the walk distance had declined to 277+/-80 m. At this point, sildenafil was added to bosentan. Three months later, the 6MWD had increased to 392+/-61 m and the patients remained stable throughout the median follow-up of 9 months (range 6-12). Measurement of the maximum oxygen uptake during CPET confirmed these results. The combination of bosentan and sildenafil was well tolerated by all patients. These preliminary data suggest that combining bosentan and sildenafil may be safe and effective in patients with idiopathic pulmonary arterial hypertension.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15572546&dopt=Abstract sildenafil Viagra online



Modulatory effect of cyclooxygenase inhibitors on sildenafil-induced antinociception.

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

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

Peripheral activation of the NO-cGMP pathway has been implicated in various nociceptive conditions. The antinociceptive effect of the PDE-5 inhibitor, sildenafil, alone or in combination with cyclooxygenase inhibitor diclofenac and nimesulide, was assessed in the different animal models of peripheral nociception. In the present study we investigated the possible interaction between cyclooxygenase and NO-cGMP pathway in writhing assay and carrageenan-induced hyperalgesia in mice and rats, respectively. Sildenafil [1-2 mg/kg, i.p. or 50-100 microg/paw, intraplantar (i.pl.)], nimesulide (1-2 mg/kg, i.p. or 25-50 microg/paw, i.pl.) and diclofenac (1-2 mg/kg, i.p. or 25-50 microg/paw, i.pl.) exhibited an antinociceptive effect in both the models. When ineffective doses of sildenafil (0.5 mg/kg, i.p and 25 microg/paw, i.pl.) were co-administered with ineffective doses of nimesulide (0.5 mg/kg, i.p. and 10 microg/paw, i.pl.) and diclofenac (0.5 mg/kg, i.p. and 10 microg/paw, i.pl.), there was a significant increase in the antinociceptive effect in both the models of peripheral nociception. Further, the potentiation of the effect was blocked by L-NAME (20 mg/kg, i.p., 100 microg/paw, i.pl.), a non-selective NOS inhibitor and methylene blue (1 mg/kg, i.p.), a guanylate cyclase inhibitor. L-NAME or methylene blue itself had little or no effect on both the models of hyperalgesia. These results suggest that cyclooxygenase, NO and cGMP are relevant in the combination-induced antinociception. In conclusion, sildenafil induced antinociception, and its potentiation of the effect of the cyclooxygenase inhibitors nimesulide and diclofenac was probably mediated through the activation of the NO-cGMP pathway and inhibition of cyclic GMP degradation. Copyright 2003 S. Karger AG, Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14624058&dopt=Abstract sildenafil Viagra online



Inhibition of angiotensin converting enzyme and phosphodiesterase type 5 improves endothelial function in heart failure.

Hryniewicz K, Dimayuga C, Hudaihed A, Androne AS, Zheng H, Jankowski K, Katz SD.

Angiotensin converting enzyme (ACE) inhibitors and phosphodiesterase type 5 (PDE5) inhibitors have each been reported to improve endothelial function in cardiovascular disease patients, but the comparative and combined effects of these two classes have not been previously studied. We sought to characterize the acute effects of ramipril alone, sildenafil alone, or their combination on endothelial function in patients with chronic heart failure (CHF). 64 CHF subjects were randomized to receive placebo, ramipril 10 mg alone, sildenafil 50 mg alone, or the combination of ramipril and sildenafil in a double-blind manner. Flow-mediated dilation (FMD) of the brachial artery was determined by high-resolution ultrasound imaging before and at 1, 2, and 4 hours after study drug. Ramipril alone increased FMD at 4 hours when compared with placebo (+2.3+/-1.3%, p=0.02). Sildenafil alone increased FMD at 1, 2 and 4 hours when compared with placebo (+3.9+/-1.4, +4.6+/-1.8, and +3.7+/-1.3% respectively, all p<0.02). Sildenafil in combination with ramipril increased FMD at 1, 2, and 4 hours when compared with placebo (+3.5+/-1.5, +4.5+/-1.8, and +4.8+/-1.3% respectively, all p< 0.03). Ramipril and sildenafil both acutely improved FMD in patients with CHF, with additive effects evident at 4 hours during combination therapy. Further work to characterize chronic effects of combined ACE and PDE5 inhibition on endothelial function are warranted.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15574127&dopt=Abstract sildenafil Viagra online



Marked improvement with sildenafil in a patient with primary pulmonary hypertension unresponsive to epoprostenol.

Kataoka M, Satoh T, Manabe T, Anzai T, Yoshikawa T, Mitamura H, Ogawa S.

Cardiopulmonary Division, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582.

We report a 48-year-old woman with right heart failure due to primary pulmonary hypertension. Continuous infusion of epoprostenol (prostaglandin I2) for 1.5 years failed to control her condition, but she was later successfully treated with additional sildenafil for a few months. Her mean pulmonary artery pressure was originally 57 mmHg, increased to 62 mmHg with epoprostenol, and decreased to 45 mmHg with sildenafil. Additional sildenafil may be an effective and life-saving agent in patients with primary pulmonary hypertension who show a poor response to epoprostenol, which is considered to be very powerful medical treatment for the disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15575245&dopt=Abstract sildenafil Viagra online