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: UMLS:C0027497 (nausea)
23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

This prospective open-label extension study was carried out to evaluate the effectiveness of sildenafil (Viagra) in the treatment of male erectile dysfunction in Nairobi, Kenya. A total of 219 adult male patients with erectile dysfunction were instructed to take 50 mg, 25 mg, or 100 mg of sildenafil orally 1 hour prior to planned sexual activity, but not more than once every 24 hours. Patients were reviewed at 4-week intervals for 16 weeks to assess the efficacy and adverse effects of the drug. The age range was 33-80 years with a mean of 62.5 years and a peak incidence in the 60-69 year age group. The causes of erectile dysfunction were organic (n = 119, 54.34%), psychogenic (n = 85, 38.81%), and mixed (n = 15). 200 patients (91.32%) had improved sexual function after treatment with Viagra. This improvement included improved erectile and orgasmic functions and overall sexual satisfaction. 157 patients responded to the 50-mg treatment regimen; 40, to the 25-mg regimen; and 3, to the 100-mg regimen. No improvement in sexual function was reported in 19 patients (8.68%) after Viagra administration. In addition, 7 patients reported mild and transient adverse effects of the drug, including mild headache, dyspepsia, facial flushing, nausea, and vomiting. In conclusion, oral sildenafil (Viagra) is an effective well-tolerated and simple treatment for male erectile dysfunction in the majority of cases. However, the cost of treatment may prohibit and limit its wide use by many deserving patients in this area.
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PMID:Sildenafil (Viagra) in the treatment of male erectile dysfunction in Nairobi. 1077 79

Apomorphine SL (TAP Holdings, Deerfield, IL) is a centrally acting treatment for erectile dysfunction (ED) that has been undergoing phase III trials. Over 3000 men have received apomorphine SL and over 75,000 doses have been taken. In the first three phase III parallel arm cross-over double-blind studies 854 patients were given a total of 8263 tablets of apomorphine SL in 2 and 4 mg doses. The patients were between 18 and 70 y old and outcome measures included per attempt rates of intercourse and erections firm enough for intercourse as well as psychometric instruments and partner responses. The majority (74.1%) had moderate and severe grades of ED on admission to the studies, 31% had hypertension, 16% had documented coronary artery disease, 16% had dyslipidemia and 16% had diabetes. Erections occurred rapidly (10-25 min) and in 54.4% of attempts at 4 mg (vs 33.8% placebo). A majority of the attempts at intercourse (50.6%) were successful at 4 mg in patients when recorded on a per-attempt basis. The most common but infrequent and mild side effect of nausea decreases with use. The phase III trials of apomorphine SL show that there is a clinically important restoration of erectile function from this new formulation of apomorphine. It has a rapid and safe effect through action in the central nervous system. Apomorphine SL brings a new choice to the management of ED that will further benefit the millions of couples affected. International Journal of Impotence Research (2000) 12, Suppl 4, S67-S73.
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PMID:Apomorphine: an update of clinical trial results. 1103 90

We review our experience with Melanotan II, a non-selective melanocortin receptor agonist, in human subjects with erectile dysfunction (ED). Melanotan II was administered to 20 men with psychogenic and organic ED using a double-blind placebo-controlled crossover design. Penile rigidity was monitored for 6 h using RigiScan. Level of sexual desire and side effects were reported with a questionnaire. In the absence of sexual stimulation, Melanotan II led to penile erection in 17 of 20 men. Subjects experienced a mean of 41 min Rigiscan tip rigidity>80%. Increased sexual desire was reported after 13/19 (68%) doses of Melanotan II vs 4/21 (19%) of placebo (P<0.01). Nausea and yawning were frequently reported side effects due to Melanotan II; at a dose of 0.025 mg/kg, 12.9% of subjects had severe nausea. We conclude that Melanotan II is a potent initiator of penile erection in men with erectile dysfunction. Our findings warrant further investigation of melanocortin agonists and antagonists on penile erection. International Journal of Impotence Research (2000) 12, Suppl 4, S74-S79.
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PMID:Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with Melanotan II. 1103 91

The central nervous system has the capacity to enhance the activity of dysfunctional penile tissue in men with erectile dysfunction (ED). Phase III clinical trials have been conducted using Apomorphine SL (TAP Pharmaceuticals, Deerfield, IL) as a centrally acting treatment for ED. Apomorphine SL has been administered to over 3,000 men in over 75,000 doses. In three phase III crossover double blind studies 854 patients were given a total of 8,263 tablets of apomorphine SL in 2 and 4 mg doses. The patients were between 18 and 70 years old and had multiple co-morbid conditions. Outcome measures included intercourse rates and erection rates on a per attempt basis as well as psychometric instruments and partner response evaluations. The results show that 74.1% of patients had moderate or severe grades of ED on inclusion into the studies, 31% had hypertension, 16% had documented coronary artery disease, 16% had dyslipidemia, and 16% had diabetes. Erections occurred rapidly (10-25 min). In 54.4% of attempts at 4 mg (vs 33.8% placebo, P < 0.001) erections suitable for intercourse were documented. A majority of the attempts at intercourse (50.6%, P < 0.001) were successful at 4 mg a doubling of baseline rates. Mild nausea was the most common but infrequent side effect and the rare occurrence of syncope was the most significant. No cardiac deaths were attributed. It is concluded that the clinical trials of apomorphine SL demonstrate a safe and significant rate of restoration of erectile function by means of a central mode of action. Efficacy has been shown in men with cardiovascular disease and severe grades of ED.
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PMID:Key issues from the clinical trials of apomorphine SL. 1128 67

This paper reviews laboratory and clinical data concerning oral phentolamine mesylate, Vasomax, an alpha-1, alpha-2 adrenergic receptor antagonist developed specifically for treatment of erectile dysfunction. A contemporary view of the neurovascular mechanisms in penile erection includes the effects of both smooth muscle relaxation and contraction. Contraction of the cavernosal arteries and trabecular smooth muscle appears to be predominantly under the control of alpha-adrenergic innervation. Conversely, adrenergic blockade of alpha-1 and alpha-2 receptors has been shown to facilitate penile erection in both animal and human models. The pharmacokinetic profile of Vasomax appears well suited for an oral erectogenic agent. Vasomax is rapidly absorbed and eliminated in normal males. Peak plasma concentrations are achieved in 30-60 min, and the half-life approximates 5-7 h. Food decreases the rate, but not the extent of bioavailability. Vasomax has low protein binding and is excreted primarily via urine and feces. There is a strong dose-response relationship in maximum plasma concentration (Cmax) and area under the curve (AUC), and there are no clear age-related differences in absorption or elimination rates. Efficacy of Vasomax has been systematically evaluated in two (ZON300, ZON301) large-scale, placebo-controlled trials, in addition to two long-term open-label studies. In both studies, Vasomax was associated with significant improvements in the erectile function domain scores of the International Index of Erectile Function (IIEF). Further improvements were noted as the duration of treatment and dose level were increased. The percentage of successful penetration attempts was also significantly improved with Vasomax compared to placebo. For patients who continued in open-label treatment with Vasomax, efficacy was generally well maintained. Vasomax was well tolerated by the majority of patients. The most common side effects observed were nasal congestion (10%), headache (3%), dizziness (3%), tachycardia (3%) and nausea (1%). Side effects were generally dose-related and in the mild-to-moderate range in all three studies. Furthermore, side effects seldom resulted in treatment discontinuation. Very few serious adverse events were observed in these trials. In summary, Vasomax appears to be effective in the treatment of male erectile dysfunction and well-tolerated by the majority of patients. The drug has a satisfactory side effect profile, without significant risk of cardiovascular effects. Results of clinical trials with Vasomax support the concept of adrenergic-blockade as a clinically relevant mechanism in the control of penile erection.
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PMID:Vasomax for the treatment of male erectile dysfunction. 1128 71

Sublingual (SL) apomorphine (2 to 6 mg) has been shown to be effective for treatment of male erectile dysfunction. Many patients with erectile dysfunction are also being treated for systemic hypertension and/or cardiovascular disease. In a double-blind, randomized, placebo-controlled, crossover trial, SL apomorphine 5 mg and placebo were administered on alternate days to 162 men who were on long-term therapy (> or =4 weeks) with angiotensin-converting enzyme inhibitors, beta blockers, diuretics, calcium channel blockers, alpha(1) blockers, or short- or long-acting nitrates. Blood pressure and heart rate were measured before and after dosing; cardiac rhythm was recorded by 4-hour Holter monitoring. The only potentially clinically significant interactions between SL apomorphine and the antihypertensive agents or short-acting nitrates were greater orthostatic decreases in systolic blood pressure in the alpha-blocker and calcium channel blocker groups (-10 and -6 mm Hg vs placebo, respectively). Administration of SL apomorphine after dosing with long-acting nitrates resulted in significant decreases in blood pressure when patients were standing (mean systolic change, -5 to -9 mm Hg 30 to 60 minutes postdose, p <0.05; mean diastolic change, -3 to -4 mm Hg 50 to 60 minutes postdose, p <0.05). The most common adverse events with SL apomorphine were dizziness, nausea, and headache. Syncope occurred in 1 patient in the beta-blocker group; symptomatic hypotension occurred in 2 patients each in the short- and long-acting nitrate groups. Thus, in patients receiving common antihypertensive agents and short-acting nitrates, as well as in most patients receiving long-acting nitrates, SL apomorphine at higher than recommended doses produced no clinically significant changes in heart rate or blood pressure greater than changes seen with SL apomorphine alone.
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PMID:Cardiovascular safety of sublingual apomorphine in patients on stable doses of oral antihypertensive agents and nitrates. 1158 43

Apomorphine SL (Ixense, Uprima) is a new oral medication shown to be effective in the treatment of erectile dysfunction. This compound is a dopaminergic agonist with affinity for dopamine receptor sites - mostly D(2) - within the brain known to be involved in sexual function. Apomorphine induces selective activation in the nucleus paraventricularis leading to erectogenic signals. More than 5,000 men with erectile dysfunction participated in phase II/III clinical trials assessing the safety and efficacy of doses ranging from 2 to 6 mg. The most favorable risk/benefit ratio is seen with a dose-optimization regimen of 2-3 mg: the 3-mg dose provides efficacy comparable to that of 4 mg but with fewer side effects. Consequently, review of clinical studies focuses on data with the 2- to 3-mg dose, the registered dose for use in clinical practice. The primary efficacy endpoint in most clinical trials with apomorphine SL was the percentage of attempts resulting in erections firm enough for intercourse - one of the most rigorous endpoints used in ED trials to date. These data were collected from both patients and their partners by reviewing entries in patient diaries and partner BSFI questionnaires. Secondary endpoints included percentage of attempts resulting in intercourse and improvement in ED severity based on the International Index of Erectile Function (IIEF). The proportion of attempts resulting in erections firm enough for intercourse was 49.4% with 3 mg compared with the baseline value of 24.3%. Partner evaluations corresponded with those of the patients. Erections occurred between 18 and 19 min after taking apomorphine SL 2 or 3 mg. The most common side effect was nausea which declined with continued use. Vasovagal syncope was reported in <0.2% of men, and was preceded by clear prodromal symptoms. Thus, apomorphine SL is an effective, well-tolerated drug for erectile dysfunction.
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PMID:Oral treatment of erectile dysfunction with apomorphine SL. 1174 Nov 26

(1) When drug treatment is indicated for erectile dysfunction, sildenafil is the first line oral treatment. Overall, about half of patients with erectile dysfunction can achieve satisfactory penetrative sex with sildenafil. (2) Apomorphine, a dopamine agonist, is now licensed in France for treatment of erectile dysfunction. It is available as sublingual tablets of 2 mg and 3 mg. (3) The evaluation dossier contains no data comparing apomorphine with sildenafil. Dose-finding studies and placebo-controlled trials in patients without a serious organic disorder show that about 90% consider the 2 mg dose of apomorphine to be insufficient. The 3-mg tablets are hardly more effective. Nearly 90% of patients prefer a dose of at least 4 mg. (4) The main side effects of sublingual apomorphine are nausea, dizziness, severe sweating and drowsiness. These effects are dose-dependent. Syncope and hypotension are also relatively common. Serious consequences of these side effects were reported during some clinical trials. (5) The safety profile of sublingual apomorphine is no better than that of sildenafil. Both drugs interact with nitrates, increasing the risk of hypotension. (6) In practice, sildenafil remains the first line treatment for men with erectile dysfunction.
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PMID:Sublingual apomorphine: new preparation. In erectile disorders: a narrow therapeutic margin. 1206 41

This open-label, multi-center study from Mexico compared the efficacy and safety of oral sildenafil and phentolamine in men with erectile dysfunction. Patients received sildenafil (25-100 mg; n=123) or phentolamine (40 mg; n=119) for 8 weeks, and efficacy was assessed using the International Index of Erectile Function (IIEF) as well as two global efficacy questions. Mean scores for the erectile function domain of the IIEF were significantly higher for sildenafil (27.23 +/- 0.62; P=0.0001) than for phentolamine (19.35 +/- 0.66). Approximately twice as many men receiving sildenafil had successful attempts at sexual intercourse (88% vs 42%), improved erections (95% vs 51.1%), and improved ability to have sexual intercourse (94.4% vs 46.4%) compared with phentolamine. The most common adverse events included rhinitis, headache, tachycardia, and nausea, with a higher frequency reported in patients receiving phentolamine than sildenafil (41% vs 33%), with the exception of headache, which was reported more frequently in sildenafil users. Overall, sildenafil was more effective and appeared to be better tolerated than phentolamine for the treatment of erectile dysfunction.
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PMID:Comparison of the efficacy and safety of sildenafil citrate (Viagra) and oral phentolamine for the treatment of erectile dysfunction. 1216 68


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