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, an inhibitor of phosphodiesterase (PDE) type 3, is used clinically in peripheral artery disease. PDE3 inhibitors may be clinically useful in the treatment of delayed cerebral vasospasm after subarachnoid hemorrhage. The authors present the first results on the effect of cilostazol on cerebral hemodynamics in normal participants. In this double-blind, randomized, crossover study, 200 mg cilostazol or placebo was administered orally to 12 healthy participants. Cerebral blood flow was measured using 133Xe inhalation and single photon emission computerized tomography. Mean flow velocity in the middle cerebral arteries (VMCA) was measured with transcranial Doppler, and the superficial temporal and radial arteries diameters were measured with ultrasonography. During the 4-hour observation period, there was no effect on systolic blood pressure (P = 0.28), but diastolic blood pressure decreased slightly compared with placebo (P = 0.04). VMCA decreased 21.5 +/- 5.7% after cilostazol and 5.5 +/- 12.2% after placebo (P = 0.02, vs. placebo), without any change in global or regional cerebral blood flow. The superficial temporal artery diameter increased 17.6 +/- 12.3% (P < 0.001 vs. baseline) and radial artery diameter increased 12.6 +/- 8.6% (P < 0.001 vs. baseline). Adverse events, especially headache, were common. The findings suggest that cilostazol is an interesting candidate for future clinical trials of delayed cerebral vasospasm.
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PMID:The phosphodiesterase 3 inhibitor cilostazol dilates large cerebral arteries in humans without affecting regional cerebral blood flow. 1562 9

Inhibitors of phosphodiesterase type 5 (PDE-5) are well established as an oral treatment for the majority of patients with erectile dysfunction (ED). PDE-5 is found in high concentration in smooth muscle cells of the corpora cavernosa. However, enzymes of the PDE family are also expressed in various other tissues, including the brain. Little is known about its effects on the central nervous system (CNS), although it has been suggested that PDE-5 inhibitors might cross the blood-brain barrier. Side effects, such as headache, nasal congestion, flushing, nausea, are much more common. We describe a patient who had a transient global amnesia (TGA) after his first-ever use of tadalafil, a potent PDE-5 inhibitor. Despite the fact that the aetiology of TGA has not entirely been clarified at present, we consider the hypothesis of a causal relationship as tempting with respect to the current hypotheses of TGA pathophysiology. This case, together with others, suggests that PDE-5 inhibitors might be capable of exerting adverse effects in the CNS. Physicians should be aware of the possibility of neurological disturbances when prescribing PDE-5 inhibitors for ED.
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PMID:Transient global amnesia after intake of tadalafil, a PDE-5 inhibitor: a possible association? 1567 2

Erectile dysfunction (ED) affects up to 50% of men, between 40 and 70 years of age. In the first major trial of sildenafil in ED, at 24 weeks, improved erections were reported by 77 and 84% of men taking sildenafil 50 and 100mg, respectively. Subsequently, sildenafil has been reported to be effective in men with ED associated with diabetes and prostate cancer, and in psychogenic ED. Sildenafil is safe in men with coronary artery disease, provided it is not used with the nitrates (a contraindication). The most commonly reported adverse effects with sildenafil are headache, flushing and dyspepsia. Vardenafil is more potent and more selective than sildenafil at inhibiting phosphodiesterase-5. Vardenafil is similarly effective to sildenafil in the treatment of ED. The only advantage that vardenafil has over sildenafil is that it does not inhibit phosphodiesterase-6 to alter colour perception, a rare side effect which sometimes occurs with sildenafil. Tadalafil has a longer duration of action than sildenafil and vardenafil. Tadalafil is similarly effective as sildenafil in the treatment of ED. In comparison studies, tadalafil is preferred to sildenafil (50/100mg) by men with ED, possibly because of its longer duration of action. Of the phosphodiesterase inhibitors, tadalafil may displace sildenafil as the drug of choice among men with ED.
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PMID:Comparison of clinical trials with sildenafil, vardenafil and tadalafil in erectile dysfunction. 1570 77

Levosimendan is a new calcium sensitizer developed for the treatment of congestive heart failure. Experimental studies indicate that levosimendan increases myocardial contractility and dilates both the peripheral and coronary vessels. Its positive inotropic effect is based on calcium-dependent binding of the drug to cardiac troponin C. It also acts as an opener of ATP-dependent potassium channels in vascular smooth muscle, thus inducing vasodilation. Although levosimendan acts preferentially as a calcium sensitizer it has also demonstrated selective phosphodiesterase III inhibitory effects in vitro. However, this selective inhibition does not seem to contribute to the positive action at pharmacologically relevant concentrations. Levosimendan has an active metabolite, OR-1896. Similarly to levosimendan, the metabolite exerts its positive inotropic and vasodilatory effects on myocardium and vasculature. The elimination half-life of levosimendan is about 1 hour. Thus, with intravenous administration, the parent drug rapidly disappears from the circulation after the infusion is stopped. The active metabolite, however, has a half-life of approximately 80 hours, and can be detected in circulation up to 2 weeks after stopping a 24-hour infusion of levosimendan. The intravenous formulation of levosimendan has been studied in several randomized comparative studies in patients with decompensated heart failure. Both patients with ischemic and non-ischemic etiology have participated in the studies. Levosimendan produces significant, dose-dependent increases in cardiac output, stroke volume and heart rate, and decreases in PCWP, mean blood pressure, mean pulmonary artery pressure, mean right atrial pressure and total peripheral resistance. With a loading dose, the effects on PCWP and cardiac ouput are seen within few minutes. There is no sign of development of tolerance even with a prolonged infusion up to 48 hours. Cardiac performance is improved with no significant increases in oxygen consumption or potentially malignant rhythm disorders. Due to the formation of an active metabolite, the hemodynamic effects are maintained up to several days after stopping levosimendan infusion. Compared to dobutamine, levosimendan produces similar increase in cardiac output but profoundly greater decrease in pulmonary capillary wedge pressure. On the contrary to dobutamine, the hemodynamic effects are not attenuated with concomitant beta-blocker use. Levosimendan has been shown to have favourable effects on symptoms of heart failure superior to placebo and at least comparable to dobutamine. Mortality and morbidity in levosimendan treated patients has been shown to be significantly lower when compared to dobutamine or placebo treated patients. The most common adverse events associated with levosimendan treatment are headache and hypotension, as a likely consequence of the vasodilating properties of the compound. In conclusion, levosimendan offers a new effective option for the treatment of acutely decompensated heart failure. Unlike traditional inotropes, levosimendan seems also to be safe in terms of morbidity and mortality.
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PMID:Levosimendan: a new inodilatory drug for the treatment of decompensated heart failure. 1572 64

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

Sildenafil (Viagra), a selective inhibitor of phosphodiesterase 5 (PDE5), induces headache and migraine. Although previously supposed to be a "vascular" headache, no significant cerebral artery dilatation was found in vivo. Thus, we hypothesised that PDE5 may not be present or that sildenafil is less effective on the cGMP hydrolysis in cerebral arteries, and that sildenafil may not be an effective dilator of cerebral arteries under baseline conditions. We evaluated the presence of PDE5 mRNA and protein in human arteries. Furthermore, the effects of two selective PDE5 inhibitors, sildenafil and UK-114,542, and a PDE1 inhibitor UK-90,234 on cGMP hydrolysis were investigated in human and guinea pig cerebral arteries. The vasoactive responses of the compounds were evaluated in guinea pig basilar arteries in vitro, with concomitant measurements of cAMP and cGMP. PDE5 was found in human middle cerebral arteries. Sildenafil and UK-114,542 inhibited cGMP hydrolysis concentration-dependently in both species. In guinea pig arteries, sildenafil induced an endothelium-dependent vasodilatation only at concentrations above 10 nM, which was augmented by sodium nitroprusside and attenuated by reduction of cGMP, but was cGMP independent at high concentrations. UK-114,542 was more and UK-90,234 was less potent than sildenafil. In conclusion, PDE5 is present in human and guinea pig cerebral arteries, and is inhibited by sildenafil at micromolar levels. Sildenafil in vitro is a poor dilator of guinea pig cerebral arteries unless a nitric oxide donor is co-administered, corresponding to the previous findings in vivo.
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PMID:Phosphodiesterase 5 and effects of sildenafil on cerebral arteries of man and guinea pig. 1618 82

Roflumilast is an inhibitor of phosphodiesterase- IV (PDE4), a cellular enzyme that is linked to airway inflammation in asthma and chronic obstructive pulmonary disease (COPD). In clinical trials, roflumilast produced significant improvements in FEV1 (forced expiratory volume in one second) and PEF (peak expiratory flow) compared with low-dose inhaled beclomethasone in asthma patients, and compared with placebo in COPD patients. Roflumilast reduced the use of rescue medication in both populations. COPD patients on roflumilast experienced fewer exacerbations. The most common adverse effects reported in roflumilast trials were diarrhea, nausea, headache, and abdominal pain. Evidence is only available in non-peer-reviewed format abstracts. Most of the measures used are markers of clinical effects as opposed to clinical outcomes. More studies are needed to determine the role of roflumilast in the treatment of asthma and COPD.
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PMID:Roflumilast for asthma and chronic obstructive pulmonary disease. 1631 27

Activation of the trigeminovascular pain signalling system appears involved in migraine pathophysiology. However, the molecular mechanisms are only partially known. Stimulation of cAMP and cGMP production as well as inhibition of their breakdown induce migraine-like headache. Additionally, migraine may be associated with mutations in ion channels. The aim of the present study was to describe the expression of phosphodiesterase 3 (PDE3) and 5 (PDE5) and cyclic nucleotide-gated ion channels (CNG) in cerebral arteries, meninges, and the trigeminal ganglion. mRNA for PDE and CNG was determined in the rat middle cerebral artery, basilar artery, trigeminal ganglion, and dura mater using real-time PCR. PDE and CNG proteins were identified using Western blot. For comparison, rat aorta and mesenteric artery were analysed. PDE3A, PDE3B, and PDE5A mRNA were detected in all tissues examined except for PDE3A mRNA in dura mater and the trigeminal ganglion. PDE5A and PDE3A protein expression was present in both cerebral and peripheral arteries, whereas PDE3B protein was present only in the cerebral arteries. The CNGA4 and B1 subunit mRNAs were detected in cerebral arteries and CNGA2 also in the mesenteric artery. CNGA2 and A3 proteins were found in cerebral arteries and dura and CNGA1, CNGA2 and CNGA3 in the trigeminal ganglion. In conclusion, PDE3A, PDE3B, PDE5A, and five CNG subunits were expressed in several components of the trigeminovascular system of the rat. This suggests that modulation of cAMP and cGMP levels by PDE and activation of CNG may play a role in trigeminovascular pain signalling leading to migraine headache.
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PMID:Phosphodiesterase 3 and 5 and cyclic nucleotide-gated ion channel expression in rat trigeminovascular system. 1680 96

Dipyridamole inhibits phosphodiesterase 5 (PDE5) and adenosine re-uptake. The most prominent side-effect is headache. We examined the migraine-generating effects of dipyridamole as well as the cerebral blood velocity response in a single-blind study, including 10 patients with migraine without aura and 10 healthy subjects. Dipyridamole 0.142 mg/kg per min was administered intravenously. Headache intensity was scored on a verbal rating scale along with pain characteristics and accompanying symptoms. Blood velocity in the middle cerebral artery (V(mca)), blood pressure and heart rate were recorded repeatedly. Headache was induced in all migraine patients and in eight of 10 healthy subjects (P = 0.47) with no significant difference in headache intensity (P = 0.53). However, five patients but only one healthy subject experienced the symptoms of migraine without aura, according to ICHD-2 criteria, within 12 h (P = 0.14). Four patients reported photophobia after dipyridamole compared with no healthy subjects (P = 0.087). V(mca) decreased (P < 0.001) during and after dipyridamole infusion with no difference between groups (P = 0.15) coinciding with initiation, but not cessation of immediate headache. Thus, dipyridamole induces symptoms of migraine and an initial decrease in V(mca) in migraine patients, but not significantly more than in healthy subjects. This relatively low frequency of migraine induction, compared with nitric oxide donors and sildenafil, is probably due to the less specific action of dipyridamole on the cGMP signalling pathway as well as a possible bidirectional effect of adenosine on migraine induction.
Cephalalgia 2006 Aug
PMID:Dipyridamole may induce migraine in patients with migraine without aura. 1688 28

Nitrates are very effective antianginal and anti-ischaemic agents. Provision of a long nitrate-free interval or low plasma nitrate levels prior to the morning dose prevents the loss of clinical efficacy by preventing the development of tolerance. However, side effects during nitrate therapy are common. Headache is the most common side effect of nitrates; often dose-related and reported by up to 82% of patients in placebo-controlled trials. Nearly 10% of patients are unable to tolerate nitrates due to disabling headaches or dizziness. In others, headaches are mild-to-moderate in severity and either resolve or diminish in intensity with continued nitrate therapy. Nitrate-induced hypotension is common, but often asymptomatic. In rare instances, nitrate-induced hypotension is severe and accompanied by marked slowing of the heart rate and syncope. Use of nitrates in patients who experience syncope after administration of nitrates is contraindicated. Nitrates rarely cause coronary steal and myocardial ischaemia. Nitrate rebound may occur and patients may experience nocturnal anginal episodes during intermittent therapy with nitroglycerin patches. Administration of nitrates is contraindicated with concomitant use of phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction, as combination therapy may lead to profound hypotension and even death. There are disturbing observational reports in the literature that continuous, prolonged use of nitrates may lead to increased mortality and recurrent myocardial infarctions. Large, randomised, placebo-controlled studies are needed to confirm or refute these reports; until then, the use of nitrates to treat angina is here to stay.
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PMID:Side effects of using nitrates to treat angina. 1690 56


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