Sildenafil for treatment of severe pulmonary hypertension and commencing right-heart failure

Pulmonary hypertension (PHT) is mainly explained by four underlying pathophysiological phenomena: 1. Vasoconstriction, 2. reduction of pulmonary vascular bed, 3. reduction in vessel elasticity, and 4. obliteration of the vessel lumen by thrombotic material and subsequent cellular alterations of the vessel wall (vascular remodeling). Chronic right heart load is thus a consequence of increased pulmonary pressure and vascular resistance. Main targets of advanced therapeutic strategies are therefore first: resolution of chronically increased vascular tone by smooth muscle cell relaxation (vasodilators), second: reversal of vascular remodeling and third: prevention from pulmonary embolization and/or in-situ thrombosis (chronic anticoagulation). Long term administration of high dose calcium channel blockers (though operative only in a minority of 10 - 15 % of all patients), prostanoids (eg. prostacyclin, iloprost), and the recently approved unselective oral endothelin antagonist bosentan are regarded as established medical therapies for treatment of chronic PHT. However, applicability of these substances can be limited by potentially serious adverse events and/or necessity for elaborate parenteral application. Recent data are indicative for a strong pulmonary vasodilative potency of the selective phosphodiesterase-5 (PDE5) inhibitor sildenafil. Smaller clinical studies and numerous case reports underline the good tolerability of this orally applied substance in various form of PHT. Based on these encouraging results, the simple availability, and the low costs (in comparison to "established therapies") of the drug,Sildenafil Citrate (Viagra) is currently widely used in an "off-label" indication for treatment of PHT. Controlled randomized studies have to confirm the current findings, before general recommendations regarding the use ofSildenafil Citrate (Viagra) for treatment of PHT can be made

Protein kinase C plays an essential role in sildenafil-induced cardioprotection in rabbits.

Sildenafil Citrate (Viagra) is the most widely used pharmacological drug for treating Erectile Dysfunction in men. It has potent cardioprotective effects against ischemia-reperfusion injury via nitric oxide and opening of mitochondrial ATP-sensitive K(+) channels. We further investigated the role of protein kinase C (PKC)-dependent signaling pathway in sildenafil-induced cardioprotection. Rabbits were treated (orally) with Sildenafil Citrate (Viagra) (1.4 mg/kg) 30 min before index ischemia for 30 min and reperfusion for 3 h. The PKC inhibitor chelerythrine (5 mg/kg i.v.) was given 5 min before sildenafil. Infarct size (% of risk area) reduced from 33.65 +/- 2.17 in the vehicle (saline) group to 15.07 +/- 0.63 in sildenafil-treated groups, a 45% reduction compared with vehicle (mean +/- SE, P < 0.05). Chelerythrine abolished sildenafil-induced protection, as demonstrated by increase in infarct size to 31.14 +/- 2.4 (P < 0.05). Chelerythrine alone had an infarct size of 33.5 +/- 2.5, which was not significantly different compared with DMSO-treated group (36.8 +/- 1.7, P > 0.05). Western blot analysis demonstrated translocation of PKC-alpha, -, and -delta isoforms from cytosol to membrane after treatment with sildenafil. However, no change in the PKC-beta and -epsilon isoforms was observed. These data provide direct evidence of an essential role of PKC, and potentially PKC-alpha, -, and -delta, in sildenafil-induced cardioprotection in the rabbit heart

Erectile function after brachytherapy with external beam radiation for prostate cancer.

The effect of therapeutic modalities on sexual potency is an important consideration for patients choosing a treatment for prostate cancer. We assessed erectile function after iridium-192 (1r-192) high-dose rate (HDR) brachytherapy with external beam radiation therapy (EBRT), and examined the efficacy ofSildenafil Citrate (Viagra) after this treatment. Forty-two prostate cancer patients (T1c to T3bN0M0) were treated with 22Gy HDR brachytherapy with 36.8Gy EBRT without neoadjuvant hormone therapy. Erectile function was assessed using a 5-item version of the International Index of Erectile Function questionnaire (IIEF-5), pre, 3 and 12 months after treatment, Potency was defined as an IIEF-5 score > or = 11. Ten patients with potency before HDR brachytherapy with EBRT with or without neoadjuvant hormone therapy requestedSildenafil Citrate (Viagra) 3 months after treatment. The mean IIEF-5 score of all patients was 10.5 +/- 8.5, 4.5 +/- 5.3 (p < 0.001), and 3.8 +/- 4.7 (p < 0.001), pre, 3 and 12 months after treatment, respectively. Seventeen (40.4%) patients were potent before treatment. The mean IIEF-5 score of those patients was 15.8 +/- 3.2, 9.6 +/- 5.1 (p = 0.04), and 11.3 +/- 6.1 (p = 0.06), pre, 3 and 12 months after treatment, respectively. Ten of 17 (58.8%) patients maintained their potency 12 months after treatment. In 10 patients with potency before treatment who were treated with sildenafil, the mean IIEF-5 score increased from 6.2 +/- 3.5 at 3 months to 13.6 +/- 5.1 (p < 0.001) at 12 months after treatment. Eight of 10 (80%) patients treated withSildenafil Citrate (Viagra) had recovered 12 months after treatment. HDR brachytherapy with EBRT can be performed with favorable results for maintaining potency

Assessment of curative effect on Erectile Dysfunction of two drugs

OBJECTIVES: To further discuss the method of evaluating curative effect on Erectile Dysfunction (ED). METHODS: Clinical trials(Phase II) ofSildenafil Citrate (Viagra) and phentolamine were both 8-week-long, randomized, double-blind and placebo-controlled. Not only the curative effect between each treatment group and placebo group but also between the treatment groups were compared. The dosage ofSildenafil Citrate (Viagra) and phentolamine was respectively 50-100 mg and 40 mg. RESULTS: Efficiency, success rate of sexual intercourse and general curative effect inSildenafil Citrate (Viagra) and phentolamine groups were respectively 79.17%, 75.00%, 83.33% and 52.38%, 85.71%, 52.38%. The result revealed a statistically significant (P < 0.05) improvement over placebo. But no obvious differences were shown between the two treatment groups(P > 0.05). CONCLUSIONS: Most assessments of curative effect of ED drugs come from questionnaires answered subjectively by patients. The Lack of objective assessment criteria way lead to the non-conformity between trial results and clinical practices. So the curative effect of drugs shall be assessed more accurately and from more perspectives

Necessity for using evidence-based medicine in making clinical decisions based on the example of Erectile Dysfunction

The choice of the method to treat Erectile Dysfunction is often not easy. The evidence-based approach to the critical appraisal of the medical literature could help us to find the best way. All the available information was critically assessed in order to find the answer to the question: DsSildenafil Citrate (Viagra) effective in the treatment of Erectile Dysfunction in patients with diabetes mellitus? All sources of information have been analysed including medical text books and the sources from the university of Cochrane library. The result of the analysis was the following:Sildenafil Citrate (Viagra) is effective with a B degree of significance in the treatment of Erectile Dysfunction in patients with diabetes mellitus. This allows us to recommendSildenafil Citrate (Viagra) for treatment of Erectile Dysfunction in men with diabetes mellitus. The above algorithm of the critical assessment of the primary medical literature can be used for preparing standards of urological diseases treatment

Cross-regulation of intracellular cGMP and cAMP in cultured human corpus cavernosum smooth muscle cells.

The goal of this study was to assess the potential cross-regulation of cyclic nucleotides in human corpus cavernosum (HCC). Incubation of primary cultures of HCC smooth muscle cells with either the NO donor sodium nitroprusside (SNP, 10 microM) or the phosphodiesterase type 5 (PDE 5) inhibitorSildenafil Citrate (Viagra) (50 nM) produced little or no changes in the intracellular cGMP levels. Incubation with both SNP andSildenafil Citrate (Viagra) produced marked increases in cGMP. Interestingly, incubation of cells with 10 microM of forskolin or PGE(1) produced significant enhancement of cGMP accumulation. These increases were not further enhanced by the addition of SNP and sildenafil. Kinetic analyses of cGMP hydrolysis by PDE 5 showed that high concentrations of cAMP reversibly inhibited the enzyme with a K(i) of 258 +/- 54 microM. The increase in cGMP levels in response to cAMP generating agents is not due to assay artifact since cAMP did not cross-react with cGMP antibody. Our data suggest that cAMP up-regulates intracellular levels of cGMP, in part, by inhibition of PDE 5. We also noted that cGMP down-regulates cAMP synthesis via a mechanism requiring G-protein coupling of adenylyl cyclase. These observations may have important implications in the utility of pharmacotherapeutic agents targeting cyclic nucleotide metabolism for the treatment of Erectile Dysfunction.

Pilot assessment of the response of several pulmonary hemodynamic variables to sublingualSildenafil Citrate (Viagra) in candidates for heart transplantation.

OBJECTIVE: To determine the acute vasodilator effect of sublingualSildenafil Citrate (Viagra) in heart transplant candidates with severe pulmonary hypertension due to severe left ventricular dysfunction (LVD). BACKGROUND: Pulmonary hypertension confers an increased risk of early graft failure. PATIENTS AND METHODS: Seven patients, (mean age of 53+/-8) with severe LVD (mean EF: 19+/-1.7%, functional class III-IV) due to coronary artery disease, dilated cardiomyopathy and valvulopathy were evaluated for heart transplant. All patients presented a mean transpulmonary gradient >12 mmHg and pulmonary vascular resistances >2.5 W.U., despite full treatment for advanced heart failure. The following hemodynamic data were obtained at basal state and then 15, 30 and 45 min after administration of 100 mg of sublingual sildenafil: right atrial, mean pulmonary artery pressure (mPAP), mean pulmonary capillary wedge pressures, mean transpulmonary gradient (mTPG), blood pressure, cardiac output, pulmonary vascular resistances (PVR) and systemic vascular resistances. SublingualSildenafil Citrate (Viagra) was given without changing the previous treatment of heart failure. RESULTS: After 30 min of sublingual sildenafil, mPAP decreased from 37 (28-61) to 30 (16-42) mmHg and PVR decreased from 5.2 (1.9-13.8) to 2.5 (1.4-3.9) W.U. after 45 min. Mean TPG decreased from 19 (16-33) to 12 (8-14) mmHg at 45 min. Mean pulmonary capillary wedge pressure, cardiac output, systemic vascular resistances and mean blood pressure were unchanged. SublingualSildenafil Citrate (Viagra) was well tolerated, with only transient facial flushing in 4 patients and mild headache in 2. CONCLUSIONS: Based on this initial study, sublingualSildenafil Citrate (Viagra) may be a useful alternative drug to perform acute vasodilator test in heart transplant candidates with significant pulmonary hypertension due to severe LVD. Nevertheless, further studies are warranted to confirm our results

Interactions between cGMP- and cAMP-pathways are involved in the regulation of penile smooth muscle tone.

Nitric oxide (NO)/cyclic GMP (cGMP)-mediated mechanisms have a pivotal function in reducing the tone of the penile smooth musculature during normal erectile responses. The cyclic AMP (cAMP) signaling pathway is also involved in the adjustment of smooth muscle contractility, and suggestions for interactions between cGMP- and cAMP-mediated mechanisms have been presented. Using activators of the cGMP- or the cAMP-pathway, as well as inhibitors of protein kinase A (PKA; cAMP-dependent kinase) and protein kinase G (PKG; cGMP-dependent kinase), the present study was undertaken to further delineate the functional relation between these pathways in the penis. In addition, the distribution of PKA and some cAMP-binding phosphodiesterases (cAMP-PDEs) were investigated in human erectile tissue. Functional experiments were performed on isolated human corpus cavernosum (HCC). The effects of an inhibitor of the PKA, Rp-8CPT-cAMPS (10 microM), or the PKG, Rp-8-pCPT-cGMPS (10 microM), on relaxation induced by the cumulative administration of sodium nitroprusside (SNP), forskolin,Sildenafil Citrate (Viagra) or tadalafil (IC351) were studied in preparations of HCC precontracted with 1 microM norepinephrine (NE). Using immunohistochemical procedures, the presence of immunoreactivity for cAMP-PDEs PDE3, PDE4, and PDE4A, as well as for PKA was investigated in specimens of HCC from which preparations were also used in the functional experiments. Forskolin, SNP, sildenafil, and IC 351 dose-dependently reversed NE-induced tension of isolated HCC preparations. The relaxing effects of SNP were significantly attenuated by Rp-8-pCPT-cGMPS, but not by Rp-8CPT-cAMPS. In contrast, relaxation induced by forskolin,Sildenafil Citrate (Viagra) and tadalafil were significantly reversed by both Rp-8-pCPT-cGMPS and Rp-8CPT-cAMPS. Abundant immunoreactivity for PDE3 and PKA was observed in the corpus cavernosum smooth muscle cells. Immunoreactivity for PDE4 was also detected in the smooth musculature and in the cytoplasm of endothelial cells lining the cavernous sinusoids, as well as in nerve fibres interspersing the trabecular stroma. The present results support the hypothesis of interactions between cGMP- and cAMP-mediated signals in the HCC, and suggest that the effects of inhibitors of PDE5 on isolated erectile tissue may also partly or indirectly include actions of the cAMP second messenger system. The exact mechanism by which such an interaction occurs is not clear, but it may involve altered activity of the cGMP-inhibited PDE3 brought about by a change in the intracellular levels of cGMP by the inhibition of PDE5. This will in turn lead to increasing levels of cAMP, facilitating the interaction of cAMP with the PKA. The immunoreactivity specific for PDE3, PDE4, PDE4A and PKA registered in HCC section is also in support of an important role for the cAMP/PKA-system for penile smooth muscle function