Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DA-8159, a new phosphodiesterase 5 inhibitor, was assessed for its erectogenic potential by a penile erection test in rats, the relaxation of isolated rabbit corpus cavernosum (CC), and estimation of the intracavernous pressure (ICP) in the anesthetized dog. Oral administration of DA-8159 (0.3 to 1 mg/kg) increased the number of erections in rats with increasing dosage, with the highest penile erection index at 10 mg/kg. DA-8159 induced the relaxation of phenylephrine (PHE)-induced contractions in the rabbit CC and decreased the IC50 of the nitric oxide donor sodium nitroprusside (SNP) in a dose-dependent fashion. In pentobarbital-anesthetized dogs, the intravenous administration of DA-8159 (1 approximately 300 g/kg) potentiated the increase in ICP induced by the intracavernosal SNP in a dose-related manner. These findings suggest that DA-8159 has significant therapeutic potential in the treatment of erectile dysfunction.
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PMID:Erectogenic effect of the selective phosphodiesterase type 5 inhibitor, DA-8159. 1105 26

The past few years have witnessed major developments in the management of male sexual dysfunction. The introduction of the first efficacious and safe oral medication (sildenafil) resulted in the expansion of the patient base and, the change in health care delivery, with erectile dysfunction (ED) entering the primary care physician's practice. New guidelines for the diagnosis and treatment of ED have been developed, including the Process of Care in the USA and the 1st International Consultation on ED sponsored by the World Health Organization. Well-defined algorithms for diagnosis and treatment have been adopted. These recent developments have brought up challenging issues, including the cardiovascular safety of sexual activity, societal changes, internet prescriptions, definition of the patient, expansion of clinical and laboratory research, rise of interest in female sexual dysfunction, and a significant economic impact. The recent developments in male sexual dysfunction continue with the study of new oral medications. Some of these new medications, such as sublingual apomorphine, have a central mode of action, whereas others, such as the phosphodiesterase inhibitor IC351, have a selective peripheral vasodilation-enhancing action.
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PMID:Recent developments in male sexual dysfunction. 1112 55

Erectile dysfunction (ED) is common in men with cardiovascular disease. The introduction of sildenafil citrate, the first oral agent for the treatment of this disorder, has increased awareness about the risks of sexual activity in cardiac patients and raised concerns about the safety of sildenafil in patients being treated for coronary disease. Sildenafil is a potent and selective inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). Sildenafil acts along the same general pathway as nitric oxide donors to increase cGMP levels and enhance erections. Sildenafil is a modest vasodilator that causes small decreases in systemic arterial pressure and mild preload and afterload reductions. It does not cause major decreases in blood pressure when administered with one or more standard antihypertensive agents. Because PDE5 is also present in small amounts in the systemic vasculature, sildenafil can cause a synergistic and major decrease in pressure when combined with organic nitrates. Use of organic nitrates is the only contraindication to sildenafil use. Data on sildenafil in patients with recent (less than 6 months) myocardial infarction (MI), unstable angina, stroke, and recent life-threatening arrhythmias are not available, so the drug should be used with caution in patients with unstable cardiac conditions. Placebo-controlled and open-label phase 2/3 trials including men with ischemic heart disease did not show an increase in MI or serious cardiovascular events in patients treated with sildenafil versus placebo. None of the serious cardiovascular events reported in these trials were considered treatment related by the investigators. There is a small but finite increased risk of developing ischemia or infarction with sexual activity. Therefore, before prescribing sildenafil or any current or future treatment for ED to patients with known cardiac disease or multiple cardiovascular risk factors, physicians should discuss the potential cardiac risk of sexual activity and perform a complete medical assessment, including an exercise stress test if appropriate.
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PMID:Sex and the patient with cardiovascular risk factors: focus on sildenafil. 1113 98

Phosphodiesterase 5 terminates the cellular actions of the second messenger molecule cyclic GMP; inhibitors of phosphodiesterase 5 will therefore increase and prolong the actions of endogenous substances that signal via the cyclic GMP pathway, including nitric oxide released as a neurotransmitter from nitrergic nerves. To date, the most widely used phosphodiesterase 5 inhibitors, zaprinast and sildenafil, have proved vital in the elucidation of the widespread role of cyclic GMP in nitrergic transmission and, specifically in the case of sildenafil, have provided a major breakthrough in the treatment of erectile dysfunction in men. Although still a matter of debate, early evidence indicates that sildenafil may also be of benefit in some forms of sexual dysfunction in women. The remarkable clinical success of sildenafil has prompted the search for further novel phosphodiesterase 5 inhibitors which might be used to enhance nitrergic function in other disease states.
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PMID:Phosphodiesterase 5 inhibitors and nitrergic transmission-from zaprinast to sildenafil. 1113 52

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) inhibitor sildenafil (50 nM) produced little or no changes in the intracellular cGMP levels. Incubation with both SNP and sildenafil 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.
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PMID:Cross-regulation of intracellular cGMP and cAMP in cultured human corpus cavernosum smooth muscle cells. 1115 21

Presentations at the William Harvey Research Conference on PDE Inhibitors described the molecular biology, biochemical regulation. pharmacology, and therapeutic utility of inhibitors of cyclic nucleotide phosphodiesterases (PDEs). Most of the talks focused on PDE4 and PDE5. two members of the 11-member PDE family that have attracted much interest over the last several years. These enzymes have been shown to be targets for drugs with wide-ranging clinical utility, including treatment of inflammation, depression, and male erectile dysfunction. The continued investigation of PDEs and the development of potent and selective inhibitors should provide even more therapeutic agents in years to come.
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PMID:William Harvey Research Conference on PDE inhibitors: drugs with an expanding range of therapeutic uses. 1120 90

Sildenafil (Viagra, Pfizer, Inc.) is a new orally effective therapy for the treatment of men with erectile dysfunction (ED). It is a specific and selective inhibitor of phosphodiesterase Type 5 (PDE5), an enzyme which is an important modulator of smooth muscle relaxation in the corpus cavernosum. In the presence of a sexual stimulus, inhibition of PDE5 results in improved smooth muscle relaxation within the sinusoids of the corpus cavernosum and the penile arteries. This results in improved erections in men with ED. In clinical trials, sildenafil has been found to be effective in improving the erections of large numbers of men with ED secondary to a range of causes. The presence of PDE5 in other tissues such as vascular smooth muscle results in side effects such as headache, flushing, indigestion and nasal congestion. These side effects are dose-dependent and well-tolerated. The introduction of sildenafil in many countries around the world has revolutionised the assessment and treatment of men with ED.
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PMID:Sildenafil. 1124 56

Based on the increasing knowledge of intracellular signal propagation in cavernous smooth muscle tone regulation, which is of major importance to the understanding of both the physiology of erection and the pathophysiology of erectile dysfunction, selective phosphodiesterase (PDE) inhibitors have recently been introduced in the treatment of erectile dysfunction. The first promising clinical data on the use of the orally active PDE5 inhibitor Sildenafil in the treatment of erectile dysfunction were accompanied by boosting research activities on cavernous intracellular signal transduction and phosphodiesterase characterization with the aid of molecular biology and protein chemistry. The presence of mRNA transcripts specific for 14 different human phosphodiesterase isoenzymes and isoforms in human cavernous tissue was shown by RT-PCR: Three isogenes of PDEI, PDE2A and 10A, which hydrolyse cAMP as well as cGMP, the cAMP-specific PDE3A, four isogenes of PDE4, PDE7A and PDE8A, as well as cGMP-specific PDEs PDE5A and PDE9A. Using anion exchange chromatography, the activities of PDE isoenzymes 2, 3, 4, and 5 were detected in cytosolic supernatants of human cavernous smooth muscle. To date, the efficacy and safety of several next generation PDE5 inhibitors for use in the treatment of male erectile dysfunction are under evaluation in vitro and in vivo. Further research will possibly allow identification of diagnostic tools for erectile dysfunction and of even more selective drugs in its therapy.
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PMID:Phosphodiesterase isoenzymes as pharmacological targets in the treatment of male erectile dysfunction. 1128 65

An experimental study was done to examine a potential role of phosphodiesterase (PDE) inhibitors in the treatment of diabetic erectile dysfunction. Relaxant effect of specific PDE inhibitors were measured in strips of corpus cavernosum smooth muscle taken from control and diabetic groups. Diabetes mellitus was induced in New Zealand white rabbits using alloxan. Penises excised from diabetic rabbits 8 weeks after the induction of diabetes mellitus. In the organ bath strips from control and diabetic rabbit corpus cavernosum were precontracted and increasing doses of several PDE inhibitors were added. In the precontracted rabbit cavernous tissue, sulmazole and zaprinast specific PDE V inhibitors were equally potent and efficacious in vitro but amrinone, a specific PDE III inhibitor, exhibits low relaxant effects. All PDE inhibitors tested showed a similar relaxation effect on corpus cavernosum smooth muscle from control and 8-week diabetic rabbits. The present study provides the possibility of using selective PDE III and V inhibitors in the treatment of diabetic impotence.
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PMID:Effects of the specific phosphodiesterase inhibitors on alloxan-induced diabetic rabbit cavernous tissue in vitro. 1131 37

Sildenafil is an oral treatment for erectile dysfunction (ED). It acts as an inhibitor of 3',5'-cyclic guanosine monophosphate-phosphodiesterase type 5. An effective treatment for ED is required to produce an erectile response sufficient for satisfactory sexual performance. This has been documented for sildenafil in men with ED of differing aetiologies and baseline severity in various types of clinical trials. Sildenafil treatment is characterised by a good tolerability profile and low treatment digcontinuation rate caused by treatment-related adverse effects. Most of the adverse effects associated with sildenafil are extensions of the pharmacological action of the drug. There is no significant difference in the adverse effect profile (headache, flushing, dyspepsia, nasal congestion and abnormal vision) of this agent as assessed by clinical data obtained either in the pre- and postlaunch periods. Because of its acceptable risk-benefit ratio, sildenafil can be prescribed to a very large group of patients with ED. The reports of serious cardiovascular events associated with the use of sildenafil (including anecdotal reports of deaths) have been very thoroughly analysed. A number of studies have not shown any difference in the risk of serious cardiovascular events in sildenafil- and placebo-treated patients. However, when making a risk-benefit evaluation, certain subgroups of patients need to be considered separately. In particular, sildenafil is contraindicated in patients receiving nitrate therapy. In some other subgroups of patients, the risks and benefits of treatment need to be assessed on an individual basis and it is hoped that additional data will clarify any possible risks associated with sildenafil administration such patients. It is helpful to compare the risk-benefit profile of sildenafil with the characteristics of other oral drugs for ED. According to the preliminary data, apomorphine and phentolamine are possible future options for the treatment of ED; however, there needs to be further clinical evaluation of these agents. Initial data have shown that sildenafil can be successfully combined with intracavernosal injection in patients nonresponders to either therapy. In conclusion, favourable characteristics make sildenafil suitable for the first-line therapy for a substantial proportion of patients with ED.
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PMID:A risk-benefit assessment of sildenafil in the treatment of erectile dysfunction. 1133 Jun 55


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