Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cilostazol (Pletal), a quinolinone derivative, has been approved in the U.S. for the treatment of symptoms of intermittent claudication (IC) since 1999 and for related indications since 1988 in Japan and other Asian countries. The vasodilatory and antiplatelet actions of cilostazol are due mainly to the inhibition of phosphodiesterase 3 (PDE3) and subsequent elevation of intracellular cAMP levels. Recent preclinical studies have demonstrated that cilostazol also possesses the ability to inhibit adenosine uptake, a property that may distinguish it from other PDE3 inhibitors, such as milrinone. Elevation of interstitial and circulating adenosine levels by cilostazol has been found to potentiate the cAMP-elevating effect of PDE3 inhibition in platelets and smooth muscle, thereby augmenting antiplatelet and vasodilatory effects of the drug. In contrast, elevation of interstitial adenosine by cilostazol in the heart has been shown to reduce increases in cAMP caused by the PDE3-inhibitory action of cilostazol, thus attenuating the cardiotonic effects. Cilostazol has also been reported to inhibit smooth muscle cell proliferation in vitro and has been demonstrated in a clinical study to favorably alter plasma lipids: to decrease triglyceride and to increase HDL-cholesterol levels. One, or a combination of several of these effects may contribute to the clinical benefits and safety of this drug in IC and other disease conditions secondary to atherosclerosis. In eight double-blind randomized placebo-controlled trials, cilostazol significantly increased maximal walking distance, or absolute claudication distance on a treadmill. In addition, cilostazol improved quality of life indices as assessed by patient questionnaire. One large randomized, double-blinded, placebo-controlled, multicenter competitor trial demonstrated the superiority of cilostazol over pentoxifylline, the only other drug approved for IC. Cilostazol has been generally well-tolerated, with the most common adverse events being headache, diarrhea, abnormal stools and dizziness. Studies involving off-label use of cilostazol for prevention of coronary thrombosis/restenosis and stroke recurrence have also recently been reported.
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PMID:Cilostazol (pletal): a dual inhibitor of cyclic nucleotide phosphodiesterase type 3 and adenosine uptake. 1183 Jul 53

IC351 (tadalafil, trade name Cialis) is a new representative compound of the second generation of selective phosphodiesterase 5 (PDE-5) inhibitors. The selectivity ratio vs PDE-5 is more than 10 000 for PDE-1 through PDE-4 and PDE-7 through PDE-10 and 780 for PDE-6. In the European daily-dosing trial, the efficacy rates were up to 93% for successful intercourses with completion in the 50-mg dose in patients with mild to moderate erectile dysfunction (ED). In two different dose-ranging studies with 2-25 mg taken as needed, efficacy rates of up to 88% improvement in erections and up to 73% successful intercourses with completion were achieved. In a placebo-controlled, fixed-dose (10- and 20-mg) trial in diabetic patients, improved erections of 56% and 64% were reported compared with 25% after placebo. Drug-related adverse effects, with headache in up to 23% of patients (placebo, up to 17%), dyspepsia in up to 11% (placebo, up to 7%), back pain in up to 4.7% (placebo, 0%), and myalgia in up to 4.1% (placebo, up to 2.4%), were mostly mild to moderate. Neither drug-related serious cardiovascular adverse events nor color vision disturbances were encountered. The long half-life (>17 h), with a comfortably long window of opportunity, releases couples from the need to plan sexual activities and therefore provides the highest amount of spontaneity for sexual activities.
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PMID:IC351 (tadalafil, Cialis): update on clinical experience. 1185 Jul 37

Vardenafil selectively inhibits phosphodiesterase type 5 (PDE5), an enzyme which hydrolyses cyclic guanosine monophosphate in the cavernosum tissue of the penis. Inhibition of PDE5 results in increased arterial blood flow leading to enlargement of the corpus cavernosum. Because of the increased tumescence, veins are compressed between the corpus cavernosum and the tunica albuginea, resulting in an erection. Vardenafil has a high bioavailabilty and is rapidly absorbed. An erection of >60% rigidity was maintained for approximately twice as long following visual stimulation in patients treated with vardenafil 10 or 20mg than in recipients of placebo. In a large, placebo-controlled trial in patients with mild to severe erectile dysfunction (ED), vardenafil 5, 10 or 20mg taken as needed over a 12-week period significantly improved the scores in questions 3 and 4 of the International Index of Erectile Function (IIEF). The rate of successful attempts at intercourse with ejaculation was also significantly higher with vardenafil (71 to 75%) than in the placebo group (39.5%), and significantly more patients treated with vardenafil than placebo responded 'yes' to a Global Assessment Question (GAQ) asking if treatment had improved erections. In a 26-week trial in 736 men with ED of varied aetiologies and severity patients receiving vardenafil 5, 10 or 20mg experienced significantly improved erections with 85% of vardenafil 20mg recipients reporting improved erectile function (assessed using the GAQ) compared with 28% of placebo recipients. Treatment with vardenafil also significantly improved scores in response to questions 3 and 4 of the IIEF compared with placebo. A 12-week trial in 452 men with ED associated with diabetes mellitus demonstrated that treatment with vardenafil 20mg compared with placebo significantly improved IIEF erectile function domain scores and the rate of positive responders to the erectile improvement GAQ. Similar results were reported in a placebo-controlled trial of vardenafil 10 to 20mg involving 440 patients with ED after radical prostatectomy. Adverse events associated with vardenafil were those commonly associated with PDE5 inhibitors: headache, flushing, dyspepsia and rhinitis. These were mostly dose-dependent and mild to moderate in intensity.
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PMID:Vardenafil. 1202 79

Levosimendan is one of the first agents of a new class of drugs known as calcium sensitizers. These drugs are believed to increase cardiac contractility by sensitizing cardiac myofibrils to calcium, and may therefore be of clinical benefit in the treatment of low-cardiac output states, particularly congestive heart failure. In addition to sensitizing troponin to intracellular calcium, levosimendan has been shown to inhibit phosphodiesterase III, which may contribute to its positive inotropic effect, and open adenosine triphosphate (ATP)-sensitive potassium channels (K(ATP)), which may produce vasodilation. Unlike currently available intravenous inotropes, levosimendan does not increase myocardial oxygen utilization, has not been shown to be proarrhythmic, and has been used effectively in the presence of beta-blocking medications. Levosimendan also has not been shown to impair ventricular relaxation, which was an initial concern with this class of drugs. Clinical studies of levosimendan have demonstrated short-term hemodynamic benefits of levosimendan over both placebo and dobutamine. While large-scale, long-term morbidity and mortality data are scarce, the Levosimendan Infusion versus Dobutamine in severe low-output heart failure (LIDO) study suggested a mortality benefit of levosimendan over dobutamine up to 180 days after treatment. Clinical studies comparing levosimendan with other positive inotropes, namely milrinone, are lacking. Levosimendan treatment appears to be well-tolerated, with the primary adverse events being headache and hypotension. No clinically significant drug-drug interactions have been reported with levosimendan to date. The clinical future of levosimendan will depend on the results of larger, ongoing clinical trials.
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PMID:Levosimendan: a unique approach to the treatment of heart failure. 1214 86

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

Cyclic nucleotides are important hemodynamic regulators in many tissues. Glyceryl trinitrate markedly dilates large cerebral arteries and increases cGMP. Here, the authors study the effect of sildenafil, a selective inhibitor of cGMP-hydrolyzing phosphodiesterase 5 on cerebral hemodynamics and headache induction. Ten healthy subjects were included in a double-blind, placebo-controlled crossover study where placebo or sildenafil 100 mg (highest therapeutic dose) were administered on two separate days. Blood velocity in the middle cerebral artery (Vmca) was recorded by transcranial Doppler, and regional cerebral blood flow in the perfusion area of the middle cerebral artery (rCBFmca) was measured using single photon emission computed tomography and xenon inhalation. Radial and temporal artery diameters were studied using high-frequency ultrasound. Blood pressure and heart rate were recorded repeatedly. Headache responses and tenderness of pericranial muscles were scored verbally. Sildenafil caused no significant changes in rCBFmca, Vmca, or in temporal or radial artery diameter, but heart rate increased and diastolic blood pressure decreased significantly compared to placebo. Despite the lack of cerebral arterial dilatation, sildenafil caused significantly more headache than placebo. The present results show that sildenafil 100 mg does not dilate cerebral or extracerebral arteries but nevertheless causes headache, which may be attributed to nonvascular mechanisms.
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PMID:The phosphodiesterase 5 inhibitor sildenafil has no effect on cerebral blood flow or blood velocity, but nevertheless induces headache in healthy subjects. 1221 18

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

Migraine is considered a neurovascular disease involving dilatation of cerebral arteries. Nitric oxide (NO) donors induce dilatation of cerebral and extracranial arteries and migraine, but NO has several mechanisms of action in addition to its cyclic guanosine monophosphate (cGMP)-mediated vasodilatation. We examined whether sildenafil (Viagra), a selective inhibitor of cGMP-hydrolysing phosphodiesterase 5 (PDE5), which acts exclusively by increasing cGMP, can induce migraine and dilatation of cerebral arteries. We included 12 patients with migraine without aura in this double-blind, placebo-controlled crossover study, in which placebo or sildenafil 100 mg was administered orally on two separate days. Blood flow velocity in the middle cerebral artery (V(mca)) was recorded by transcranial Doppler ultrasonography and regional cerebral blood flow in the territory of the middle cerebral artery (rCBF(mca)) was measured using SPECT (single photon emission computed tomography) and xenon 133 inhalation. Radial and temporal artery diameters were studied using high-frequency ultrasonography. Headache response, tenderness of pericranial muscles, blood pressure and heart rate were measured repeatedly. We found that migraine attack was induced by sildenafil in 10 of 12 migraine patients and by placebo in two of 12 patients (P = 0.01). V(mca) (P = 0.1) and rCBF(mca) (P = 0.93) remained unchanged after sildenafil. Temporal (P = 0.47) and radial (P = 0.87) artery diameter and pericranial tenderness (P = 0.16) were unaffected by sildenafil. Systolic and diastolic blood pressures were unchanged but heart rate increased from a mean of 62 +/- 2 to 74 +/- 3 beats/min (P = 0.01) after sildenafil. Our results demonstrate that migraine may be induced via a cGMP-dependent mechanism, and we show for the first time that this occurs without initial dilatation of the middle cerebral artery. We propose that triggering mechanisms may reside within the perivascular sensory nerve terminals or the brainstem. However, other sites of action may also be possible and future studies are needed to elucidate this. In the clinical use of sildenafil, patients who have migraine should be informed about the risk of migraine attacks.
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PMID:Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. 1247 10

We examined the effect of cilostazol, a type III phosphodiesterase inhibitor, on pain-free and maximal walking distance and quality of life measures. The present study examined adverse effects in 2,702 patients with stable, moderate to severe claudication enrolled in 8 randomized, double-blind, placebo-controlled trials. Treatment duration ranged from 12 to 24 weeks. Cilostazol therapy increased maximal and pain-free walking distances by 50% and 67%, respectively. In subgroup analysis, cilostazol increased pain-free and maximal walking distance similarly in men and women, in older (>/=65 years) and younger patients, and in patients with and without diabetes. Quality-of-life assessments revealed enhanced scores for physical well-being. Cilostazol-treated patients reported a higher incidence of headache, bowel complaints, and palpitations than patients given placebos. Cilostazol decreased triglycerides by 15.8% and increased high-density lipoprotein cholesterol by 12.8%, but there were no deleterious effects on any hematologic or serum markers. We conclude that cilostazol significantly increases walking distance and quality-of-life measures in patients with claudication without major adverse effects.
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PMID:Meta-analysis of results from eight randomized, placebo-controlled trials on the effect of cilostazol on patients with intermittent claudication. 1248 40

black triangle Tadalafil is a selective phosphodiesterase type 5 inhibitor that is effective in men with mild-to-severe erectile dysfunction (ED), including those with diabetes mellitus. black triangle The improvement in the erectile function domain score on the International Index of Erectile Function (IIEF) and the percentage of sexual intercourse attempts marked by successful vaginal penetration and completion was significantly greater with on-demand (not more than once daily) tadalafil 10 or 20 mg than placebo in trials of 12 weeks' duration. Improvement in scores on other domains of the IIEF and the percentage of positive responses to a Global Assessment Question measuring erection improvement were also significantly greater with on-demand tadalafil than placebo. black triangle The adverse events associated with tadalafil were generally mild to moderate and decreased in frequency with continued administration. The most commonly reported adverse events were headache and dyspepsia. The incidence of cardiovascular adverse events was not significantly different in tadalafil or placebo recipients.
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PMID:Tadalafil. 1449 56


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