Effect ofSildenafil Citrate (Viagra) on cyclic nucleotide phosphodiesterase activity, vascular tone and calcium signaling in rat pulmonary artery.

(1) Sildenafil Citrate (Viagra) is a potent PDE5 inhibitor and thus a relaxant drug in corpus carvernosum smooth muscle. In the present work, we evidenced the presence of PDE5 isozyme and investigated the effect ofSildenafil Citrate (Viagra) on the specific cyclic nucleotide phosphodiesterase (PDE) activity, smooth muscle tone and calcium signaling in the rat main pulmonary artery (MPA). (2) The PDE activity was measured in cytosolic and microsomal fractions. Total cAMP and cGMP-PDE activities were mainly present in the cytosolic fraction.Sildenafil Citrate (Viagra) (0.1 micro M) reduced by 72% cGMP-PDE activity, whereas zaprinast (10 micro M), a relatively selective PDE5 inhibitor, reduced this activity by 63%.Sildenafil Citrate (Viagra) (0.1 micro M) also inhibited significantly (22%) the cAMP-PDE activity. (3) Western blot analysis revealed the expression of PDE5 mainly in the cytosolic fraction of MPA.Sildenafil Citrate (Viagra) concentration-dependently inhibited (IC(50)=3.4 nM) the activity of MPA PDE5 partially purified by HPLC. (4)Sildenafil Citrate (Viagra) (0.1 nM-50 micro M) concentration-dependently relaxed MPA rings precontracted with phenylephrine (0.5 micro M). The potency ofSildenafil Citrate (Viagra) (IC(50)=11 nM) was similar to that of a nitric oxide donor, sodium nitroprusside, but higher than that of zaprinast (IC(50)=600 nM). The vasorelaxant effect ofSildenafil Citrate (Viagra) was not altered by endothelium removal or in the presence of KT 5823 (1 micro M) and H89 (1 micro M), potent inhibitors of PKG and PKA, respectively. (5) In isolated MPA myocytes, which had been loaded with the calcium fluorophore indo-1,Sildenafil Citrate (Viagra) (10-100 nM) antagonized ATP- and endothelin-1-induced calcium oscillations but had no effect on the transient caffeine-induced [Ca(2+)](i) response. (6) This study demonstrates the presence of a functional and highly sildenafil-sensitive PDE5 isozyme in rat MPA. Inhibition of this isozyme mainly accounts for the potent pulmonary vasodilator action of sildenafil, which involves alteration in the inositol triphosphate-mediated calcium signaling pathway

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

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 inhibitorSildenafil Citrate (Viagra) 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 Citrate (Viagra) 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 Citrate (Viagra) 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

Why do patients with Erectile Dysfunction abandon effective therapy withSildenafil Citrate (Viagra) (Viagra((R)))?

This prospective study determined the rate of abandonment ofSildenafil Citrate (Viagra) therapy and assessed the reasons for abandonment. Between January 2001 and December 2002, 234 patients with Erectile Dysfunction (ED) at three independent centers successfully began therapy withSildenafil Citrate (Viagra) 50 or 100 mg. The rate of noncompliance was 31%. A telephone survey of these patients was conducted to determine the reasons for abandonment. The majority reported that they had had no opportunity or desire for sexual intercourse or that their partners had shown no sexual interest. Few patients stated that the high cost of the medication or that adverse events were the cause.

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



Returning a referral for Erectile Dysfunction to the referrer by two different routes.

OBJECTIVE: To compare the prescribing pattern and attitude of general practitioners (GPs) in response to a clinic returning a patient referred for Erectile Dysfunction (ED) to the referrer by two different methods. METHODS: Referrals on a waiting list for an assessment of ED were reviewed and a subgroup of patients with criteria enabling them to be eligible for a prescription under the National Health Service (NHS) identified. The GP was informed either in writing or by telephone that the clinic had written to the patient, suggesting he make direct contact with his GP. A follow-up questionnaire was sent to each GP one month after the initial letter to the patient and contact with the GP. RESULTS: Of 91 questionnaires sent to GPs, 66 (73%) were completed; an additional five GPs corresponded by letter rather than completing the questionnaire. The long waiting time for assessment had led to 35% of patients having already tried sildenafil, and by the time the questionnaire was completed, 57% of patients had tried sildenafil. Ten times as many referrers indicated that they were happy to initiate a prescription forSildenafil Citrate (Viagra) than not to do so, for those men eligible for an NHS prescription. More GPs who had received a letter returned the completed questionnaire (80%) than those who had received a courtesy telephone call (64%). There were no differences between the groups of GPs in their attitude to our contact with their patient and no difference in prescribing pattern. Conclusion The provision of guidelines and advice to GPs either by telephone or letter is acceptable practice in reducing long waiting-list times for ED. Safe, simple and effective treatments are available for GPs to use under NHS guidelines

Comparison of FDA reports of patient deaths associated withSildenafil Citrate (Viagra) and with injectable alprostadil.

BACKGROUND: Sildenafil Citrate (Viagra) has been linked to 240 deaths (128 verified, 112 unverified) reported to the Food and Drug Administration (FDA) during 7.5 months of availability, and to 522 reported deaths after 13 months of availability. To date, no updated information about FDA-reported deaths has emerged, and no comparative analyses have been published. OBJECTIVE: To compare the mortality rates betweenSildenafil Citrate (Viagra) and injectable alprostadil, both of which are used exclusively for treating Erectile Dysfunction. METHODS: A comparison of the number of deaths per filled prescriptions reported to the FDA involvingSildenafil Citrate (Viagra) and injectable alprostadil was undertaken to perhaps provide further insight into this issue. Materials included FDA statements onSildenafil Citrate (Viagra) adverse event reports to the FDA involvingSildenafil Citrate (Viagra) and injectable alprostadil, and data on prescriptions filled forSildenafil Citrate (Viagra) and injectable alprostadil. RESULTS: The number of deaths per prescriptions filled reported in association withSildenafil Citrate (Viagra) was significantly greater (5.15-6.28 times) than in association with injectable alprostadil. DISCUSSION: Previous explanations for sildenafil-associated deaths have been based on the expected attrition within the population of men with Erectile Dysfunction and its commonly associated disorders, the physiologic stress of renewed sexual activity, and a pharmacologic effect of sildenafil. The results of this analysis may indicate that a pharmacologic effect of sidenafil is responsible for these deaths. However, other factors may also explain these findings: a greater frequency of reporting of sildenafil-associated events by physicians, a difference in the populations using these two drugs, or the number of prescriptions filled may not accurately reflect actual exposure. CONCLUSIONS: Further study should be undertaken to clarify the issues associated with sildenafil-related deaths. In the meantime, reasonable precautions might be considered in prescribing sildenafil, such as initiating treatment with a low test dose ofSildenafil Citrate (Viagra)

T-0156, a novel phosphodiesterase type 5 inhibitor, andSildenafil Citrate (Viagra) have different pharmacological effects on penile tumescence and electroretinogram in dogs.

T-0156 (2-(2-methylpyridin-4-yl)methyl-4-(3,4,5-trimethoxyphenyl)-8-(pyrimidin-2-yl)methoxy-1,2-dihydro-1-oxo-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride) is a newly synthesized phosphodiesterase type 5 inhibitor, and its potency and selectivity are higher than those ofSildenafil Citrate (Viagra) in an enzyme assay. In the present study with anesthetized dogs, we examined the effects of intravenous T-0156 orSildenafil Citrate (Viagra) on the pelvic nerve stimulation-induced penile tumescence and light-adapted flicker stimulation-induced electroretinogram, parameters of which are reported to be indicators for inhibition of phosphodiesterase type 5 and type 6, respectively. Both compounds potentiated the penile tumescence in a dose-dependent manner. T-0156 at 10 microg/kg andSildenafil Citrate (Viagra) at 100 microg/kg showed almost the same potentiating percentage (181.5+/-31.1% and 190.0+/-37.9%) in spite of the plasma concentration of T-0156 being about five times lower than that ofSildenafil Citrate (Viagra) (16.7+/-1.6 and 78.8+/-5.3 ng/ml), indicating that the effect of T-0156 on tumescence is more potent than that of sildenafil. While the high dose of T-0156 (1000 microg/kg) reduced the amplitude and increased the latency of the electroretinogram positive wave, the effects of T-0156 were conversely weaker than those ofSildenafil Citrate (Viagra) (reduction of amplitude; T-0156: 41.1+/-8.0%, sildenafil: 71.7+/-3.9%, increase of latency; T-0156: 3.9+/-0.6%, sildenafil: 14.5+/-1.4%, at 1000 microg/kg). These results clearly showed the difference in the properties of T-0156 andSildenafil Citrate (Viagra) in pharmacological studies with anesthetized dogs, and the difference appeared to correspond with their inhibitory potencies for phosphodiesterase type 5 and type 6. It was concluded that T-0156 would be a useful pharmacological tool as a potent and highly selective phosphodiesterase type 5 inhibitor