Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013395 (dyspepsia)
 4,879 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sildenafil citrate, an oral therapy for erectile dysfunction, is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), the predominant isozyme metabolizing cGMP in the corpus cavernosum. Chemically, it is a compound of the pyrazolo-pyrimidinyl-methylpiperazine class. Sildenafil has no direct relaxant effect on human corpus cavernosum but enhances the relaxant effect of nitric oxide (NO) on the corpus cavernosum by inhibiting PDE5, which is responsible for degradation of cGMP in this tissue. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil increases concentrations of cGMP in the corpus cavernosum, causing smooth muscle relaxation and blood flow into the penis, resulting in an erection. Sildenafil at recommended doses has no effect in the absence of sexual stimulation. The drug is rapidly absorbed after oral administration, with absolute bioavailability of 40%. Its pharmacokinetics are dose proportional over the recommended dosage range. Maximum plasma concentrations are reached within 30 to 120 minutes after oral dosing in the fasting state. Sildenafil is cleared predominantly by the hepatic microsomal isoenzymes CYP3A4 (major route) and CYP2C9 (minor route). Clinical studies assessed the effect of sildenafil on the ability of men with erectile dysfunction to engage in sexual activity and, specifically, to achieve and maintain an erection sufficient for satisfactory sexual intercourse. Sildenafil was evaluated at doses of 25, 50, and 100 mg in randomized, double-masked, placebo-controlled clinical trials of up to 6 months' duration. The drug was administered to hundreds of patients aged 19 to 87 years having erectile dysfunction of various etiologies for a mean duration of 5 years. Sildenafil was associated with statistically significant improvement in erectile function compared with placebo. Adverse effects reported at a rate of >2% were headache, flushing, dyspepsia, nasal congestion, urinary tract infection, abnormal vision, diarrhea, dizziness, and rash. No cases of priapism were reported. The use of sildenafil is contraindicated in men who are taking organic nitrates, because of the potential for a precipitous decrease in blood pressure. Postmarketing reports and surveillance have revealed at least 39 deaths with sildenafil use in men having a history of heart disease, men taking nitrate medications, and men in poor physical health due to lack of exercise. Many of the men who experienced serious adverse effects or death had a variety of concomitant diseases and were taking multiple medications.
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PMID:Safety and efficacy of sildenafil citrate in the treatment of male erectile dysfunction. 991 1

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

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

Safety data from 546 men with erectile dysfunction (ED) enrolled in three double-blind, placebo-controlled studies conducted in distinct regions of Latin America were pooled and analyzed. The most commonly reported adverse events of all causalities associated with sildenafil treatment were headache (19%), flushing (14%), dyspepsia (6%), and nasal congestion (4%), reflecting the inhibitory effects of sildenafil on cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) in the peripheral vasculature, gastroesophageal sphincter, and nasal mucosa. Visual symptoms were reported in 5.5%, reflecting sildenafil's minor inhibitory effects on cGMP-specific PDE6 in the retina. These adverse events were generally transient and mild, and rarely resulted in discontinuation of sildenafil therapy. Thus, in this representative sample of Latin American men with ED, including those with concomitant stable cardiovascular disease, sildenafil treatment was well tolerated with an incident rate of adverse events similar to reports from other patient populations.
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PMID:Tolerability and safety profile of sildenafil citrate (Viagra) in Latin American patient populations. 1216 69

Erectile dysfunction (ED) (impotence) is a widespread, age-related problem, which affects 52% of men between 40 and 70 years of age. It is classified as psychogenic, organic, or mixed psychogenic and organic. ED is not a problem only of men, because the relationship between partners can also be disturbed. Therefore, adequate treatment of ED is needed and the most convenient and simplest way is oral drug therapy. Sildenafil, phosphodiesterase-(PDE)-5-selective inhibitor has been the drug of choice for patients with ED since it has been launched in March 1998. The results of various studies have confirmed the efficacy of the drug in men with ED of various etiologies, as well as the positive effect of sildenafil on the quality of a partnership. The most frequent adverse effects documented with sildenafil usage are headache, flushes, dyspepsia, visual disturbances and nasal congestion/rhinitis. These adverse effects are dose-related, usually transient and mild, with low withdrawal rate. Several studies performed recently have shown that sildenafil is a safe and effective treatment of ED in patients with cardiovascular disease, who do not take nitrates or nitrate donors concomitantly. Other oral medications for ED include apomorphine, phentolamine, yohimbine, trazodone, testosterone and new PDE-5 inhibitors in Phase III clinical trials, such as vardenafil and tadalafil. It is obvious, according to recent data, that the concept of PDE-5 inhibition has a central position in oral pharmacotherapy of ED. However, larger clinical studies of efficacy and safety should be carried out using most of the other above-mentioned oral agents and these may also gain a place in the therapy of ED. There are no studies directly comparing sildenafil and other treatments of ED or assessing its role in combination with other therapies. According to the present knowledge, the quality of life, not only of patients but also of their sexual partners, will be improved significantly with sildenafil usage and this is an important precondition for overall health ofboth. Sildenafil is thus a highly effective peroral treatment for ED in patients without contraindications for its use, which can be considered as the firstline therapy with an acceptable risk-benefit ratio.
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PMID:Erectile dysfunction: oral pharmacotherapy options. 1235 56

Potential vasodilator side effects of sildenafil such as headache, flushing, dyspepsia, heartburn, nasal congestion, dizziness and visual changes have been frequently observed. We report a 79-year-old man who developed severe vestibular neuritis-like symptoms (horizontal nystagmus with rotatory components and vomiting) two hours after taking 50 mg sildenafil. Additionally, the patient complained of tinnitus in both ears. Internal and neurological examination revealed no pathological findings and the patient had no history of cardiovascular disease. The symptoms lasted for 24 hours and then resolved completely. All of the patient's complaints indicated a drug-related phenomenon. This drug related adverse reaction should be included in the long list of potential side effects of sildenafil.
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PMID:Vestibular symptoms as a complication of sildenafil: a case report. 1240 37

The objectives of this study were to evaluate the efficacy and tolerability of high dose sildenafil as a salvage therapy for patients refractory to the maximum recommended dose of sildenafil. Fifty four fully evaluated patients with chronic erectile failure (ED) who had previously failed to respond to a home trial of sildenafil (100 mg) with erections suitable for sexual intercourse were studied. Each man was treated at home with sildenafil at escalating doses of up to 200 mg until either maximal response or intolerable adverse effects occurred. Erectile function was quantified using the erectile function domain of the International Index of Erectile Function (IIEF) before treatment, with sildenafil 100 mg and with maximal dose of sildenafil and a global efficacy question after 4 weeks of treatment. The mean age of the study group was 59.6+/-11.2 y. 13/54 (24%) had arteriogenic ED, 16/54 (30%) had mixed vasculogenic ED, 9/54 (17%) had cavernosal veno-occlusive dysfunction, 11/54 (20%) had post radical retropubic prostatectomy ED and 5/54 (9%) had psychogenic ED. 13/54 (24.1%) responded to sildenafil at a median maximal dose of 200 mg, 4/13 required 150 mg and 9/13 required 200 mg. 41/54 (76%) failed to respond to sildenafil. Mean IIEF question 3 and 4 scores were 1.5 and 1.4 at baseline, 2.2 and 1.9 with sildenafil 100 mg, 2.8 and 2.5 with sildenafil 150 mg and 3.0 and 2.9 with sildenafil 200 mg, respectively. After 4 weeks, treatment was regarded as having improved their erections by 37%, 46.3% and 68% of patients with sildenafil 100 mg, 150 mg and 200 mg, respectively. 34/54 (63%) reported adverse effects with maximal dose sildenafil comprising headache (19), facial flushing (32), dyspepsia (14), nasal congestion (11), dizziness (5) and visual disturbances (5). 4/13 (31%) responders refused to continue treatment due to adverse effects.In conclusion, sildenafil at doses of up to 200 mg is an effective salvage therapy for 24.1% of previous sildenafil non-responders but is limited by a significantly higher incidence of adverse effects and a 31% treatment discontinuation rate.
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PMID:High dose sildenafil citrate as a salvage therapy for severe erectile dysfunction. 1460 83

The mechanism of action of the phosphodiesterase type 5 (PDE5) inhibitors (i.e., sildenafil, tadalafil, and vardenafil) involves inhibition of the PDE5 isoenzyme located in penile vascular smooth muscle cells. Sexual stimulation triggers the release of nitric oxide (NO), stimulating the release of guanylyl cyclase, leading to an increase in intracellular cyclic guanosine monophosphate (cGMP) concentrations, a decrease in intracellular calcium, and ultimately relaxation of the vascular smooth muscle in the corpus cavernosum and penile erection. The PDE5 inhibitors have no effect on the penis in the absence of sexual stimulation. Although the various PDE5 inhibitors differ with respect to selectivity and pharmacokinetic profiles, efficacy and safety of these agents are comparable in broad populations of men with erectile dysfunction (ED), including those with diabetes or those taking multiple antihypertensive agents. The most frequently reported adverse events of the PDE5 inhibitors are related to their mild vasodilatory effects and include headache, flushing, dyspepsia, and nasal congestion or rhinitis. Side effects are generally reversible and tend to diminish during continued treatment. Differences in pharmacokinetic properties among the PDE5 inhibitors include the fact that sildenafil and vardenafil have a shorter duration of action (approximately 4 h) compared with the longer period of responsiveness observed with tadalafil (up to 36 h). In addition, in the presence of high-fat food, absorption of sildenafil and vardenafil may be delayed; however, the rate and extent of tadalafil absorption are unaffected by high-fat food.
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PMID:Phosphodiesterase type 5 inhibitor differentiation based on selectivity, pharmacokinetic, and efficacy profiles. 1511 91

Erection is a neurovascular event that involves spinal and supra spinal pathways. The final common pathway involves the release of nitric oxide (NO) from both endothelial cells and neurons, which acts as a vasodilator causing penile engorgement and erection. NO is degraded by the enzyme phosphodiesterase (PDE) type 5 in the penis. Erectile dysfunction (ED), defined as the persistent inability to achieve and/or maintain an erection sufficient for satisfactory sexual performance, results when the neurovascular pathway is interrupted by medical conditions or drugs. A 15-item self-administered questionnaire, the International Index of Erectile Function (IIEF), is one of the most useful tools to evaluate erectile function (EF) in clinical trials, although of much less use in routine clinical practice. The MMAS (Massachusetts Male Aging Study) was the first major epidemiological investigation to study the prevalence of ED. The study found that ED was three times more common in patients with diabetes mellitus. The aetiopathogenesis of ED in diabetes is multifactorial, with vascular and neural factors being equally implicated. Hyperglycaemia is believed to give rise to biochemical perturbations that lead to these microvascular changes. In the MMAS, ED in diabetes was strongly correlated with glycaemic control, duration of disease and diabetic complications. The incidence increased with increasing age, duration of diabetes and deteriorating metabolic control, and was higher in individuals with type 2 diabetes than those with type 1.ED in men with diabetes often affects their quality of life and, as patients are often reluctant to come forward with their symptoms, a carefully taken history is one of the most useful approaches in identifying affected individuals. The PDE inhibitors have revolutionised the management of ED and oral drug therapy is currently first-line therapy for the condition. These agents act by potentiating the action of intracavernosal NO, thereby leading to a more sustained erection. Sildenafil was the first PDE5 inhibitor to undergo evaluation and has been studied extensively. More recently two other agents, vardenafil and tadalafil, have been introduced. All the drugs have been shown to be effective across a wide range of aetiologies of ED, including diabetes. The drugs have been shown to improve EF domain scores, penetration and maintenance of erection, resulting in more successful intercourse. Their effects are greater at higher doses. Sildenafil and vardenafil are shorter-acting agents, while tadalafil has a longer half-life allowing the user more flexibility in sexual activity. Common adverse effects include headache, nasal congestion and dyspepsia, all actions related to inhibition of PDE5. The drugs are generally well tolerated and withdrawal from the clinical studies as a result of drug-related adverse effects were rare. The use of PDE5 inhibitors in the presence of oral nitrates is absolutely contraindicated. The clinical studies to date have not evaluated the use of one drug in the case of treatment failure with another agent. Sublingual apomorphine, which stimulates central neurogenic pathways, is a new agent and may be a suitable alternative in those patients in whom PDE5 inhibitors are ineffective or contraindicated. In clinical trials, all IIEF domains except sexual desire were found to have improved after apomorphine. The median times to erection in these studies were 18.9 and 18.8 minutes for the 2 and 3mg doses, respectively. Intraurethral and intracavernosal alprostadil may be a useful alternative when oral drug therapy is ineffective or contraindicated. The management of ED in the diabetic patient may often involve a multidisciplinary approach where psychosexual counselling and specialist urologist advice is required in addition to the skills and expertise of the diabetologist. Finally, the introduction of the new oral agents have completely revolutionised the management of ED and allowed more individuals to come forward for treatment.
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PMID:New treatment options for erectile dysfunction in patients with diabetes mellitus. 1553 69

Inhibition of phosphodiesterase-5 (PDE5) reduces the degradation of cyclic guanosine monophosphate, which allows erectile function to occur by relaxation of penile smooth muscle. Three PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) in a range of doses are available. PDE5 therapy, compared with placebo, significantly improves scores on the International Index of Erectile Function and has been found to be effective in special clinical populations, such as those with prostate cancer, diabetes, and cardiovascular disease. Sildenafil and vardenafil show some interaction with food intake. Time to onset of action is usually 30-120 minutes, but there are reports of shorter times to onset of action. The duration of action of sildenafil and vardenafil is about 4 hours, whereas that of tadalafil is about 36 hours. The overall safety of the treatments is good, even in patients with a history of cardiovascular disease. However, there is a risk of hypotension if nitrates are given concurrently. Increased QTc intervals have been reported, the longest with vardenafil, shortest with tadalafil, and intermediate with sildenafil. Priapism and prolonged erection are rare adverse events. Common side-effects include headache, facial flushing, nasal congestion, and dyspepsia. There may be interactions with other medications metabolized in a similar way, such as erythromycin and HIV protease inhibitors.
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PMID:The efficacy and safety of PDE5 inhibitors. 1615 23


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