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)

Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE5), which has been shown to be a clinically effective treatment for erectile dysfunction. Its action results from increased levels of cyclic guanosine monophosphate (cGMP), which is normally degraded by PDE5. This cyclic nucleotide is a second messenger for nitric oxide, which is involved in the regulation of numerous functions, including vascular smooth muscle tone. In an attempt to better predict the effects of sildenafil on cardiovascular function, the distribution of PDE activity was determined with anti-PDE1 and anti-PDE5 antibodies in the human cardiac ventricle and saphenous vein, and in vitro studies were performed on the isolated human cardiac ventricle, corpus cavernosum, saphenous vein, and mesenteric artery as well as on rabbit aorta, dog coronary artery, dog trabecular tissue, and rabbit and human platelets. The major PDE activity in the human cardiac ventricle was shown to be calcium/calmodulin-dependent PDE1, but there was no detectable level of PDE5. In contrast, the human saphenous vein contained PDEs 1, 4, and 5, and the human mesenteric artery contained PDEs 1, 2, 3, 4, and 5. The distribution of PDE5 in the cardiovascular system is consistent with the observed pharmacodynamic and clinical effects of sildenafil. Sildenafil, unlike milrinone, a selective PDE3 inhibitor, had no effect on the isolated trabeculae carneae; this is consistent with the lack of PDE5 expression in cardiac myocytes. Sildenafil selectively increased cGMP levels in coronary vascular smooth muscle tissue but produced no change in cyclic adenosine monophosphate (cAMP) levels, which is consistent with the drug's selectivity for PDE5. In phenylephrine-contracted isolated rabbit aortic rings, sildenafil enhanced the relaxation induced by the nitric oxide donor glyceryl trinitrate, suggesting that sildenafil may potentiate the hypotensive effects of nitric oxide donor agents on the vasculature, an effect that has been observed clinically. Human platelets were found to contain PDE5, which was inhibited by 50% (IC50) by sildenafil at a concentration of 6.3 nM, consistent with the IC50 value in the corpus cavernosum. Sildenafil alone had no direct effect on platelet function, but it potentiated the in vitro antiaggregatory activity of sodium nitroprusside on rabbit and human platelets. The pharmacodynamic and adverse event profiles observed in clinical trials with sildenafil are consistent with the in vitro profile of the tissue distribution of PDE5 and its known mechanism of action as a selective inhibitor of PDE5.
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PMID:Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. 1007 37

Nitric oxide (NO) induces the formation of intracellular cyclic guanosine monophosphate (cGMP) by guanylate cyclase. Sildenafil, which selectively inhibits phosphodiesterase type 5 (PDE5) found predominantly in the corpora cavernosa of the penis, effectively blocks the degradation of cGMP and enhances erectile function in men with erectile dysfunction. The NO-cGMP pathway also plays an important role in mediating blood pressure. It is, therefore, possible that the therapeutic doses of sildenafil used to treat erectile dysfunction may have clinically significant effects on human hemodynamics. Three studies were undertaken to assess the effects of intravenously, intra-arterially, and orally administered doses of sildenafil on blood pressure, heart rate, cardiac output, and forearm blood flow and venous compliance in healthy men. A fourth study evaluated the hemodynamic effects of intravenous sildenafil in men with stable ischemic heart disease. In healthy men, significant (p <0.01) decreases in supine systolic and diastolic blood pressures were observed with intravenous sildenafil (20, 40, and 80 mg) at the end of the infusion period when plasma levels of sildenafil were highest (mean decreases from baseline of 7.0/6.9 and 9.2/6.7 mm Hg, for the 40- and 80-mg doses, respectively). These changes were transient and not dose related. Modest reductions in systemic vascular resistance also were observed (maximum decrease 16%), although heart rate was not affected by sildenafil administration when compared with placebo. Single oral doses of sildenafil (100, 150, and 200 mg) produced no significant changes in cardiac index from 1-12 hours postdose between placebo- and sildenafil-treated subjects. The approved dosage strengths of sildenafil citrate are 25 mg, 50 mg, and 100 mg. The 80-mg intravenous dose and the 200-mg oral dose of sildenafil produced comparable plasma levels at twice the maximum therapeutic dose (recommended range, 25-100 mg). After brachial artery infusion of sildenafil (up to 300 microg/min), there was a modest vasodilation of resistance arteries and a reversal of norepinephrine-induced preconstriction of forearm veins. These hemodynamic effects were similar to but smaller in magnitude than those of nitrates. In a small pilot study of men with ischemic heart disease, decreases from baseline in pulmonary arterial pressure (-27% at rest and -19% during exercise) and cardiac output (-7% at rest and -11% during exercise) were observed after 40-mg intravenous doses of sildenafil. Sildenafil was well tolerated by subjects and patients in all studies, with headache and other symptoms of vasodilation the most commonly reported adverse effects of treatment. Modest, transient hemodynamic changes were observed in healthy men after single intravenous or oral doses of sildenafil even at supratherapeutic doses. In men with stable ischemic heart disease, sildenafil produced modest effects on hemodynamic parameters at rest and during exercise.
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PMID:Effects of sildenafil citrate on human hemodynamics. 1007 38

Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), is a well-tolerated and highly effective treatment for erectile dysfunction. The mechanism of action of sildenafil depends on activation of the nitric oxide (NO)-cGMP pathway during sexual stimulation, which results in corpus cavernosal smooth muscle relaxation and penile erection. Endogenously derived NO is also involved in blood pressure regulation through its effect on basal vascular tone, which is mediated by cGMP levels. Organic nitrates and NO donors exert their therapeutic effects on blood pressure and vascular smooth muscle by the same mechanism as endogenous NO. Since both sildenafil and organic nitrates exert their pharmacologic effects via increases in cGMP concentrations, a double-blind, placebo-controlled, crossover study was undertaken to investigate the effects of sildenafil coadministered with glyceryl trinitrate on blood pressure and heart rate in healthy male subjects. The hemodynamic effects of sildenafil were also evaluated in a second placebo-controlled crossover study in men with hypertension who were taking the calcium antagonist amlodipine, which has a mechanism of action that does not involve the cGMP pathway. In the first crossover study, subjects were treated with oral sildenafil (25 mg, 3 times a day for 4 days) or placebo and then challenged on day 4 with a 40-minute, stepwise, intravenous infusion of glyceryl trinitrate (0.5 mg/mL in 5% dextrose at an initial infusion rate of 2.5 microg/min and doubling every 5 minutes to a maximum rate of 40 microg/min) 1 hour after taking sildenafil or placebo. On day 5, subjects received a sublingual glyceryl trinitrate tablet (500 microg) 1 hour after taking 25 mg of sildenafil or placebo. During sildenafil treatment, the subjects were significantly less tolerant of intravenously administered glyceryl trinitrate than during placebo treatment, based on the occurrence of a >25 mm Hg decrease in blood pressure or the incidence of symptomatic hypotension (p <0.01). When a sublingual glyceryl trinitrate tablet was administered on day 5, a 4-fold greater decrease in systolic blood pressure was observed for the subjects during the sildenafil treatment period than during the placebo treatment period. The changes in heart rate were negligible during both glyceryl trinitrate challenges. In conclusion, sildenafil potentiated the hypotensive effects of glyceryl trinitrate, an organic nitrate. Thus, sildenafil administration to patients who are using organic nitrates, either regularly and/or intermittently, in any form is contraindicated. In the second crossover study, men with hypertension, who were taking 5 or 10 mg/day of amlodipine, received a single oral dose of 100 mg sildenafil or placebo. Coadministration of sildenafil did not significantly affect the pharmacokinetics of amlodipine. In the 4 hours after dosing, differences in the mean maximum change from baseline in supine systolic and diastolic blood pressures between the sildenafil plus amlodipine and the placebo plus amlodipine treatment periods were -8 mm Hg and -7 mm Hg, respectively (p < or =0.002). The mean maximum supine heart rate increased 2.1 beats/min during sildenafil plus amlodipine treatment and decreased 1.5 beats/min during placebo plus amlodipine treatment (p <0.02). The adverse events in this study were predominantly mild or moderate and did not cause discontinuation of treatment. Adverse events considered to be related to sildenafil treatment included headache, nausea, and dyspepsia. In patients with hypertension who were taking amlodipine therapy, sildenafil produced additive, but not synergistic, reductions in blood pressure. The difference in the mean maximum change from baseline in blood pressure between sildenafil plus amlodipine and placebo plus amlodipine was comparable to the decrease in blood pressure reported for healthy men taking sildenafil alone. (ABSTRACT TRUNCATED)
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PMID:Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. 1007 39

Erectile dysfunction is a common condition in men with cardiovascular disease, probably as a result of shared factors that impair hemodynamic mechanisms in the penile and ischemic vasculature. Sildenafil citrate, an orally active, selective inhibitor of phosphodiesterase type 5 (PDE5), has demonstrated excellent efficacy and safety profiles in men with erectile dysfunction of various etiologies. Sildenafil administration is contraindicated in patients who are taking nitrates or nitric oxide donors. This retrospective subanalysis of data from double-blind, placebo-controlled studies assessed the efficacy (9 studies) and safety (11 studies) of sildenafil in patients with erectile dysfunction and ischemic heart disease who were not taking nitrates. Of 3,672 patients randomized to receive sildenafil (5-200 mg) or placebo for 4-24 weeks in 11 double-blind, placebo-controlled studies, 357 (10%) reported a history (past or present) of ischemic heart disease and were not taking nitrates. Efficacy was assessed using end-of-treatment responses to Question 3 (ability to achieve an erection) and Question 4 (ability to maintain an erection) of the International Index of Erectile Function (IIEF), scores for the 5 domains of male sexual function assessed by the IIEF (erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction), and responses to a global efficacy question ("Did the treatment improve your erections?"). The responses to the 2 IIEF questions were graded on a scale of 1 (almost never or never) to 5 (almost always or always), with a score of 0 indicating no attempt at sexual intercourse. At the end of treatment, the mean scores for Question 3 and Question 4 of the IIEF for patients with erectile dysfunction and ischemic heart disease were significantly higher for the sildenafil group than for the placebo group (p <0.0001). Mean end-of-treatment scores for the IIEF domains also demonstrated significant increases for sildenafil-treated patients compared with those receiving placebo (p <0.05). At the end of treatment, improved erections were reported by 70% of patients who received sildenafil and by 20% of those in the placebo group p <0.0001). For the sildenafil group, the incidences of the most common adverse events (headache 25%, flushing 14%, and dyspepsia 12%) for patients with ischemic heart disease were similar to those in patients without this concomitant illness (21%, 15%, and 10%, respectively). Moreover, the overall incidence of cardiovascular adverse events other than flushing was comparable in patients with and without ischemic heart disease for both treatment groups. Since there is a degree of cardiac risk associated with sexual activity, clinicians should consider the patient's cardiovascular status before initiating any treatment for erectile dysfunction. Physicians should be aware that patients with underlying cardiovascular disease could be adversely affected by the vasodilator effects of sildenafil, especially in combination with sexual activity. The results of the present subanalysis indicate that oral sildenafil significantly improves erectile function and is well tolerated in patients with erectile dysfunction and ischemic heart disease who are not taking nitrate therapy.
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PMID:Efficacy and safety of sildenafil citrate in the treatment of erectile dysfunction in patients with ischemic heart disease. 1007 40

Sildenafil, a selective inhibitor of phosphodiesterase type 5 (PDE5), is the first in a new class of orally effective treatments for erectile dysfunction. During sexual stimulation, the cavernous nerves release nitric oxide (NO), which induces cyclic guanosine monophosphate (cGMP) formation and smooth muscle relaxation in the corpus cavernosum. Sildenafil facilitates the erectile process during sexual stimulation by inhibiting PDE5 and thus blocking the breakdown of cGMP. Sildenafil alone can cause mean peak reductions in systolic/diastolic blood pressure of 10/7 mm Hg that are not dose related, whereas the heart rate is unchanged. Sildenafil and nitrates both increase cGMP levels in the systemic circulation but at different points along the NO-cGMP pathway. The combination is contraindicated because they synergistically potentiate vasodilation and may cause excessive reductions in blood pressure. Erectile dysfunction is a significant medical condition that shares numerous risk factors with ischemic heart disease, and hence a substantial overlap exists between these patient groups. From extensive clinical trials, the most commonly reported cardiovascular adverse events in patients treated with sildenafil were headache (16%), flushing (10%), and dizziness (2%). The incidences of hypotension, orthostatic hypotension, and syncope and the rate of discontinuation of treatment due to adverse events were <2% and were the same in patients taking sildenafil and those taking placebo. Retrospective analysis of the concomitant use of antihypertensive medications (beta blockers, alpha blockers, diuretics, angiotensin-converting enzyme inhibitors, and calcium antagonists) in patients taking sildenafil did not indicate an increase in the reports of adverse events or significant episodes of hypotension compared with patients treated with sildenafil alone. In clinical trials, the incidence of serious cardiovascular adverse events, including stroke and myocardial infarction, was the same for patients treated with sildenafil or placebo. Concurrent disease states, such as renal or hepatic impairment, or concomitant use of inhibitors of the cytochrome P450 isozyme CYP3A4 could increase systemic exposure to sildenafil. Since the US market launch in April 1998, monitoring of spontaneous adverse event reports in association with sildenafil has demonstrated a pattern that is generally consistent with the experience observed during clinical development, with the exception of infrequent reports of priapism. In conclusion, extensive clinical testing has shown that overall treatment with sildenafil for up to 1 year is well tolerated and is associated with a low incidence of adverse events that result in discontinuation of treatment in <3% of patients.
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PMID:Overall cardiovascular profile of sildenafil citrate. 1007 41

Sildenafil (Viagra) from Pfizer (UK-92,480) is a competitive and selective inhibitor of cyclic GMP specific type 5 phosphodiesterase. Male erectile dysfunction is defined as "the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance". Sildenafil (Viagra) is effective in a significant proportion of patients with erectile dysfunction. Patients should be instructed to take a dose from 25 to 100 mgrs approximately 30 to 60 minutes before sexual activity, but no more than once daily. Sexual stimulation is necessary to produce erectile reaction. The safety and tolerance of sildenafil have been demonstrated. However, prior to initiating treatment with sildenafil, physicians should consider the cardiovascular status of their patients, particularly for patients with unstable coronary heart disease or concomitant treatment with nitrates.
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PMID:[Drug of the month. Sildenafil (Viagra)]. 1008 14

Phosphodiesterases are enzymes that catalyze the degradation of the cyclic nucleotides, cyclic AMP and cyclic GMP, to the corresponding 5' nucleotide monophosphates. Ten different phosphodiesterase families have been described to date. These enzymes exist as homodimers and there is structural similarity between the different families. However, they differ in several respects like selectivity for cyclic nucleotides, sensitivity for inhibitors and activators, physiological roles and tissue distribution. Interest in these enzymes has increased tremendously, both within the medical community and in the general public as a consequence of sildenafil (Viagra), the medication recently introduced for the treatment of erectile dysfunction. Sildenafil mediates its effects by inhibiting phosphodiesterase 5. Some biochemical and molecular biological aspects of this enzyme are presented here. To achieve satisfactory erection, normal penile innervation is required. Nitrogen monoxide, the transmitter substance in these nerves, activates guanylyl cyclase, thereby increasing cyclic GMP production. The increased levels of cyclic GMP cause relaxation of smooth muscles in penile vessels and this leads to an erection. Erection is dependent on elevated levels of cyclic GMP and sildenafil mediates its effects by inhibiting the degradation of cyclic GMP. Other functions that are mediated by the phosphodiesterases explain visual disturbances, flushing and decreased blood pressure that are some of the side effects seen with sildenafil treatment. Furthermore, the potentially fatal consequence of combining sildenafil and nitrovasodilators is discussed.
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PMID:[Phosphodiesterase 5--the enzyme inhibited by sildenafil (Viagra)]. 1021 Sep 55

Sildenafil is the first orally administered available treatment for erectile dysfunction. It produces a selective vasodilatation of corpus carvernosum, mediated by the inhibition of phosphodiesterase 5, an enzyme that degrades GMPc. Its therapeutic efficacy has been demonstrated in organic as well as psychogenic or mixed erectile dysfunction. Most of its adverse effects, such as headache, flushing, gastroesophageal reflux and color vision disturbances, are related to the mechanism of action. Its interactions with other medications, can have severe adverse consequences. The concomitant use of sildenafil with drugs that release nitric oxide in their molecule, can produce severe hypotension. In patients with coronary heart disease or cardiac failure, this interaction can cause death. Sildenafil is metabolized in the liver through cytochrome P-450. This enzymatic system can be inhibited by cimetidine, ketoconazole or erythromycin. These drugs can increase plasma concentrations of sildenafil. We must identify the groups of patients that will have a better response to the drug and those in whom the drug will be useless. We must also know more about the security profile of the drug. With time, we will know the real role of sildenafil in the treatment of erectile dysfunction.
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PMID:[Sildenafil (viagra) at the time of warnings]. 1034 69

The recent introduction of sildenafil has revolutionized the treatment of erectile dysfunction (ED). The availability of sildenafil, the first effective oral agent for ED, has also expanded the field of sexual healthcare to include general and primary care practitioners and other nonurology specialists. A new process-of-care algorithm has been developed to facilitate the evaluation and treatment of ED in these nonurology settings. Sildenafil has been demonstrated to be safe and effective in randomized, double-blind, placebo-controlled trials involving >3,000 men ages 19-87 years. Sildenafil is effective across a broad range of etiologies including diabetes. For patients in whom first-line treatment with sildenafil fails or ceases to be effective, second-line interventions with intracavernosal self-injection therapy or transurethral alprostadil may be indicated. In addition to sildenafil, other oral agents such as oral phentolamine and sublingual apomorphine are now in clinical trials. Drugs under development include second-generation phosphodiesterase type 5 (PDE5) inhibitors, endothelin antagonists, and agents that offer specific molecular targeting. Clinical studies are also being planned to examine the efficacy of combination oral drug regimens for ED.
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PMID:A new era in the treatment of erectile dysfunction. 1050 72

Sildenafil citrate (Viagra) is a new oral medication that inhibits phosphodiesterase-5 (PDE5) in the corpus cavernosum to facilitate penile erection for the treatment of male impotence. The drug also has a mild inhibitory effect on PDE6, which controls the level of cyclic guanosine monophosphate in the retina, and it may cause a perception of bluish haze or increased light sensitivity in some patients. Long-term retinal damage has not been reported, but long-term electroretinographic studies have not been performed. Sildenafil causes a mild lowering of blood pressure and is absolutely contraindicated in patients taking any form of nitrate medication. A number of cardiovascular deaths and retinal vascular events in patients taking sildenafil have been reported, but so far the rate of these complications does not exceed expectation for an elderly population. Ophthalmologists should alert patients to the ocular side effects and potential risks of this new drug until further clinical experience has been obtained.
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PMID:Sildenafil (Viagra) and ophthalmology. 1054 Nov 53


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