Drug combinations in the therapy of low response to phosphodiesterase 5 inhibitors in patients with Erectile Dysfunction.

Combinatorial drugs utilising a clinically-proven single agent approach in Erectile Dysfunction (ED) have led to the search for additional compounds to improve therapy and the safety profile. Selective inhibitors of Phosphodiesterase type 5, such as Sildenafil, demonstrate a defined failure rate in ED. The therapeutic concept to increase blood influx and or to decrease blood efflux in patients with ED under therapy encountered severe drawbacks. It appeared impossible to decrease the NO-content in the corpora cavernosa and associated organs followed by synchronized increase of NO by a second drug. One has to metabolically activate cAMP by the first acting compound followed by cGMP stimulation. The pharmacology of the counteractive drugs was investigated clinically and a combination of 50 mgSildenafil Citrate (Viagra) with 5 mg dihydro-ergotamine (DHE) was identified as of practical use in patients with low response to Sildenafil. The safety profile appeared to be improved by this combination therapy. The present study is a clinical follow-up of patients treated with different therapeutical regimens to document the effectiveness ofSildenafil Citrate (Viagra) in combination with DHE

Synergistic effects ofSildenafil Citrate (Viagra) on relaxation of rabbit and rat cavernosal smooth muscles when combined with various vasoactive agents.

OBJECTIVE: To evaluate which vasoactive agents have synergistic effects on the cavernosal smooth muscles of rabbits and rats when the agents are combined with sildenafil. MATERIALS AND METHODS: Relaxation responses of cavernosal smooth muscle to single agents (phentolamine, moxisylyte, sodium nitroprusside, forskolin, vasoactive intestinal peptide, VIP, papaverine and sildenafil) in the rabbit, and prostaglandin-E1 andSildenafil Citrate (Viagra) in the rat, and to combinations of each agent plus sildenafil, were assessed in vitro. The response toSildenafil Citrate (Viagra) of the rabbit strips with and without incubation with l-arginine (1 mmol/L) for 20 min was also evaluated. The effective concentrations for a half-maximal response of single agents and combination solutions were compared. RESULTS: All single agents induced concentration-dependent relaxation of the rabbit and rat cavernosal smooth muscles. There was significant synergism on rabbit cavernosal smooth muscle when theSildenafil Citrate (Viagra) was combined with forskolin, sodium nitroprusside, VIP or phentolamine. There was also significant synergism withSildenafil Citrate (Viagra) plus prostaglandin-E1 in rat cavernosal muscles. There were no synergistic effects of combinations ofSildenafil Citrate (Viagra) plus moxisylyte, papaverine or l-arginine. CONCLUSIONS: These results suggest potentially effective combined therapies ofSildenafil Citrate (Viagra) and intraurethral or intracavernosal prostaglandin-E1, intracavernosal forskolin or VIP, or oral phentolamine for patients with Erectile Dysfunction who have no success after monotherapy with these agents

HPLC-MS for the determination of Sildenafil Citrate (Viagra) in biological fluids. Application to the salivary excretion ofSildenafil Citrate (Viagra) after oral intake.

An original high-performance liquid chromatography-mass spectrometry (HPLC-MS) procedure was developed for the determination ofSildenafil Citrate (Viagra) in biological fluids. Liquid-liquid extraction was performed by chloroform/2-propanol/n-heptane (25:10:65, v/v) at pH 9.5 with 300 ng of buprenorphine-d4 as the internal standard (IS). After agitation (10 min) and centrifugation (3500 x g, 10 min), the organic phase was evaporated and the dry extract resuspended in 25 microL methanol, from which 2 microL was injected onto a NovaPak C18 (Waters) HPLC column. Separation was carried out by a gradient of (acetonitrile + 10 microg/mL trimethylamine) in 2mM NH4COOH pH 3.0 buffer (35-70% in 9 min). Detection was done by a PerkinElmer Sciex API-100 single-quadrupole mass analyzer with an ionspray interface operated in positive-ion mode. MS data were collected as either TIC or SIM at m/z (475 + 534) or (475 + 283) for sildenafil, depending on the potential applied at the ion sampling orifice (0 V or + 100 V). The retention times ofSildenafil Citrate (Viagra) and the IS were 4.20 and 5.07 min, respectively. Extraction recoveries were always > 87%. LOD and LOQ were 0.2 and 0.5 ng/mL whatever the biological fluid tested. The method appears specific, extremely sensitive, and relatively simple in both equipment and sample preparation. As an example, we present the results of a preliminary study on the salivary excretion ofSildenafil Citrate (Viagra) following the oral intake (T0) of 25 mg Viagra in a 38-year-old volunteer.Sildenafil Citrate (Viagra) was detectable in oral fluid at T0 + 0.5 h (1.2 ng/mL) and peaked at T0 + 1.5 h (8.3 ng/mL), whereas at the same time its plasma concentration was 72.4 ng/mL. Salivary concentrations then rapidly decreased, and the last detectable value (0.9 ng/mL) was at T0 + 5.5 h. It is suggested that the salivary excretion pattern ofSildenafil Citrate (Viagra) resembles that of benzodiazepines (high plasma protein binding, low saliva-to-plasma ratio)

Private prescription costs forSildenafil Citrate (Viagra) within the NHS: a telephone survey.

Because of the restrictions on prescribing for impotence within the NHS, doctors routinely write private prescriptions for sildenafil. The aim of this study was to determine the variation in cost of a private prescription of four 100 mg tablets of sildenafil. A selection of different pharmacy types within five areas in England was surveyed. We telephoned a total of 86 pharmacies and we were quoted prices ranging from pounds 28.20 to pounds 42.33. There was a significant difference in price between area and between pharmacy type. Best prices are not necessarily found at the major pharmacy chains or hospital pharmacies, as might be expected. NHS doctors and patients need to be aware of this significant difference in cost

Increasing intracellular cAMP and cGMP inhibits cadmium-induced oxidative stress in rat submandibular saliva.

The effect of cadmium on induction of oxidative stress in rat submandibular saliva and protective role of increasing intracellular cAMP and cGMP by use of specific phosphodiesterase inhibitors, theophylline andSildenafil Citrate (Viagra) were investigated. Pure submandibular saliva was collected intraorally by micro polyethylene cannula from anaesthetized rats using pilocarpine as secretagogue. Acute administration of cadmium (10 mg/kg) caused significant oxidative stress by increasing lipid peroxidation by-products (thiobarbituric reactive substances, TBARS) and decreasing total thiols and total antioxidant power of the saliva. Concurrent therapy of rats by theophylline (25 mg/kg) andSildenafil Citrate (Viagra) (5 mg/kg) prevented cadmium-induced oxidative stress in saliva. Theophylline andSildenafil Citrate (Viagra) inhibited cadmium-induced increase in lipid peroxidation and decrease in total thiols and antioxidant power. It is concluded that cadmium administration results in oxidative stress in rat submandibular saliva, which can be protected by concurrent administration of specific cyclic nucleotide phosphodiesterase inhibitors

Efficacy ofSildenafil Citrate (Viagra) in Erectile Dysfunction after radical prostatectomy.

Radical retropubic prostatectomy (RRP) is an important cause of iatrogenic Erectile Dysfunction (ED). WhileSildenafil Citrate (Viagra) has been widely used since its introduction as a new treatment option for ED, its efficacy in post-RRP patients has not been extensively studied. We retrospectively compared the efficacy ofSildenafil Citrate (Viagra) in post-RRP and non-surgical patients with ED (NSED) using a subset of questions from the International Index of Erectile Function (IIEF) and correlated results with their specific etiology of ED based on penile blood flow study (PBFS). A brief questionnaire regarding satisfaction withSildenafil Citrate (Viagra) was administered to 72 consecutive post-RRP patients (nerve sparing status unknown) and 32 consecutive NSED patients who had previously undergone PBFS with pharmacotesting as part of their evaluation for ED. PBFS diagnoses were arterial insufficiency (AI) for peak systolic velocity (PSV) < 25 cm/sec; venogenic (CVOD) for PSV > or = 35 cm/sec, mixed vascular for PV > 25 but < 35 cm/sec and resistive index (RI) < 0.9; a vascular normal diagnosis (neurogenic impotence) required excellent rigidity sustained for 20 min. Differences in the IIEF subscores for the different groups of patients were assessed. Success withSildenafil Citrate (Viagra) was defined as moderate or excellent improvement (3/4 or 4/4) with ability for penetration. No differences were found among the different subgroups of RRP patients with respect to IIEF scores or success rates with sildenafil. NSED patients had both significantly higher post-treatment IIEF scores (3.6/3.4 vs 2.5/2.2; t=4.50, P<0.0001) and success rates (63% vs 31%; t=3.11, P < 0.01) withSildenafil Citrate (Viagra) treatment than RRP patients. We found thatSildenafil Citrate (Viagra) is significantly less effective in impotent RRP patients than in age-matched patients with ED (31% vs 63%). We had postulated thatSildenafil Citrate (Viagra) would be least effective among RRP patients with excellent sustained rigidity to PGE1, as this subgroup is likely to have neurogenic impotence. We found thatSildenafil Citrate (Viagra) response rates among subgroups of RRP patients were statistically similar regardless of PBFS diagnosis. IIEF scores for the RRP subgroups were similar but statistically lower than in men with ED and no history of RRP. While individuals with normal vascular responses to PGE1 have an increased likelihood of having neurogenic impotence, in RRP patients, we were unable to demonstrate any difference in efficacy of sildenafil, regardless of the PBFS diagnosis

Sildenafil prevents endothelial dysfunction induced by ischemia and reperfusion via opening of adenosine triphosphate-sensitive potassium channels: a human in vivo study.

BACKGROUND: Animal studies have demonstrated that administration ofSildenafil Citrate (Viagra) can limit myocardial damage induced by prolonged ischemia, an effect that appears to be mediated by opening of adenosine triphosphate-sensitive potassium (K(ATP)) channels. No study has investigated whetherSildenafil Citrate (Viagra) can also prevent the impairment in endothelium-dependent vasodilatation induced by ischemia-reperfusion (IR) in humans. METHODS AND RESULTS: In a double-blind, placebo-controlled, crossover design, 10 healthy male volunteers (25 to 45 years old) were randomized to oralSildenafil Citrate (Viagra) (50 mg) or placebo. Two hours later, endothelium-dependent, flow-mediated dilatation (FMD) of the radial artery was measured before and after IR (15 minutes of ischemia at the level of the brachial artery followed by 15 minutes of reperfusion). Seven days later, subjects received the other treatment (ie, placebo or sildenafil) and underwent the same protocol. Pre-IR radial artery diameter and FMD, as well as baseline radial artery diameter after IR, were similar between visits (P=NS). After placebo administration, IR significantly blunted FMD (before IR: 7.9+/-1.1%; after IR: 1.2+/-0.7%, P<0.01). Importantly,Sildenafil Citrate (Viagra) limited this impairment in endothelium-dependent vasodilatation (before IR: 7.0+/-0.9%; after IR: 6.2+/-1.1%, P=NS; P<0.01 compared with placebo). In a separate protocol, this protective effect was completely prevented by previous administration of the sulfonylurea glibenclamide (glyburide, 5 mg), a blocker of K(ATP) channels (n=7; FMD before IR: 10.3+/-1.5%; after IR: 1.3+/-1.4%, P<0.05). CONCLUSIONS: In humans, oralSildenafil Citrate (Viagra) induces potent protection against IR-induced endothelial dysfunction through opening of K(ATP) channels. Further studies are needed to test the potential clinical implications of this finding

After two years, did Viagra live up to its expectations?

Sildenafil Citrate (Viagra) is the first on-demand oral medication approved for treatment of male Erectile Dysfunction (ED). Since the unprecedented release of sildenafil, the initial surge of 'Viagra craze' has subsided and there is a considerable decline in world-wide prescriptions. We did a long-term efficacy study ofSildenafil Citrate (Viagra) in our community practice to assess the discontinuation rate and the etiologic factors causing discontinuation