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)

The major finding of this analysis is that acute anti-migraine agents (e.g., ergots, sumatriptan) share high affinity for 5-HT1D receptors. This receptor appears to be present in certain intracranial blood vessels. It is also found on nerve terminals where it inhibits the release of 5-HT and other neurotransmitters. Theoretically, 5-HT1D receptor agonists may acutely inhibit the release of vasoactive and/or pain-inducing substances in the perivascular space. Conceivably, drugs acting at this receptor would stop the progression of this perivascular process. In contrast, a number of prophylactic anti-migraine drugs share a relatively high affinity for 5-HT2 receptors in human brain. Although this receptor is also found in certain blood vessels, it is present throughout the nervous system. The receptor appears to mediate neuronal depolarizations at the cellular level. No hypothesis, at present, readily explains the effectiveness of prophylactic anti-migraine drugs based on this receptor. These data offer a novel approach to the analysis of anti-migraine agents. Drugs could be selected for use in clinical migraine studies based on their selectivity for a specific 5-HT receptor subtype. "Pure" drugs could be chosen which would essentially limit the number of possible sites of action for the drugs. For example, an agent which displays both high affinity and selectivity for 5-HT1D receptors could be clinically evaluated. Its effectiveness, or lack thereof, would indicate the importance of the specific 5-HT receptor site in the pathogenesis of migraine. Further attempts to determine a common mechanism of action for effective anti-migraine agents should facilitate the elucidation of the pathogenesis of this neurological syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)
Headache 1990 Jan
PMID:The pharmacology of current anti-migraine drugs. 196 55

The results of recent investigations designed to elucidate the neuroeffector functions of sensory fibres, the cause of migraine headache and the mechanism of action of antimigraine drugs are reviewed and discussed. Neurogenic inflammation (vasodilatation and neurogenic plasma extravasation) is one explanation for the development of headaches and the blood flow changes which occur during migraine headache. Numerous studies have recently been carried out on rats and guinea-pigs into the effects of antimigraine agents, including ergot alkaloids, sumatriptan and non-steroidal anti-inflammatory drugs (NSAIDs), on neurogenic plasma protein extravasation in the dura mater induced by electrical stimulation of trigeminal ganglia or systemic administration of capsaicin. It is known that the dura mater is able to produce headaches in man. Ergot alkaloids have been shown to block neurogenic inflammation via a C-fibre dependent neuronal mechanism. Sumatriptan appears to act fairly similarly although, whereas the ergot alkaloids are non-selective for either 5-hydroxytryptamine (5-HT; serotonin) receptors or 5-HT1, sumatriptan is selective for 5-HT1 receptors. The antimigraine action of NSAIDs may be via either an effect on blood vessels or an effect on the nerve fibre. The antimigraine effects of ergot alkaloids, sumatriptan and NSAIDs are discussed in the light of the common vasoconstrictor actions of these agents and knowledge that vasodilatation is apparently not responsible for migraine headache pain in most cases.
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PMID:Neuroeffector functions of sensory fibres: implications for headache mechanisms and drug actions. 204 26

5-Hydroxytryptamine (5-HT; serotonin) has long been implicated in the aetiology of migraine but the evidence remains circumstantial and certainly not definitive. Numerous papers have reviewed the background which is briefly outlined here. Although the continued belief in the primary involvement of 5-HT in the genesis of a migraine attack has recently been questioned, many antimigraine drugs undeniably interact potently with 5-HT receptors. It can be argued, however, that their modest clinical benefit results from their pharmacological effects, be they mediated through 5-HT receptors or otherwise, independently of any pathophysiological involvement of endogenous 5-HT. Nevertheless, there seems convincing evidence that central release of 5-HT by various drug mechanisms causes migraine-like headache in migraineurs. It remains to be seen whether these drugs mimic the pathological event initiating the spontaneous migraine attack. Regardless of these considerations, the focus of research on 5-HT and migraine has proved to be enormously profitable over several decades, culminating recently in the identification of a novel, potentially important, antimigraine drug for the treatment of the acute attack. This drug, sumatriptan, is a selective cranial vasoconstrictor which mediates this effect by specifically activating a particular 5-HT1 receptor subtype. Undoubtedly a precise understanding of its clinical mechanism of action, which is currently being studied by a number of groups, will lead to a better understanding of the pathogenesis of migraine. Perhaps this in turn will help in finally determining whether migraine is a vascular disease and whether or not a disturbance of 5-HT is just epiphenomenal or is truly the primary initiating pathological event.
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PMID:5-Hydroxytryptamine and the pathophysiology of migraine. 204 30

Emesis in chemotherapy containing Cisplatinum (DDP) is still a therapeutical dilemma. Emesis and nausea cause the cessation of a potential curative therapy in up to 10% of patients treated with DDP. We studied the antiemetic effectiveness of the selective Serotonin (5HT3)-receptor-antagonist Ondansetron (GR 38032F, Glaxo) in patients receiving high dose platinum chemotherapy. All patients suffered from severe emesis and were refractory to any standard antiemetic regimen (Metoclopramid). We studied the efficacy of the new drug against acute and delayed emesis following platinum chemotherapy. All adverse events are listed. Thirty four courses (n = 17 patients) of a platinum-containing regimen were analyzed so far. A sufficient antiemetic efficacy was observed in 56% of the courses. In 32 of 34 course (94%) the patients preferred the new drug compared with the standard antiemetic regime (Metoclopramid). In most cases only minor adverse events--which do not require any medical therapy--occurred. The most common adverse events were headache, constipation, dry mouth, abdominal discomfort and elevation of liver enzyme level without any clinical symptoms. One patient needed bowel surgery for severe constipation based on widespread intra-abdominal carcinosis.
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PMID:[Refractory vomiting with cisplatin therapy. Prospective study with the serotonin receptor antagonist GR 38032F]. 215 May 51

Consumption of monosodium glutamate has long been considered to precipitate headaches in susceptible patients. In this study the direct effects of glutamate and its metabolite, glutamine, on arterial contractility were examined using rings of rabbit aorta. In a high concentration glutamate caused significant concentration-dependent contractions (EC50, 10(-1)M; maximum tension, 188.4 +/- 33.3 mg wt tension/mg tissue). Agonists and antagonists for alpha-adrenergic, histaminergic, serotonergic, cholinergic, and GABA-nergic receptors as well as inhibition of prostaglandin synthesis failed to influence glutamate contractions. At high concentrations (10(-5)M) the calcium channel blocker, verapamil, inhibited the glutamate response. Glutamate and glutamine both exhibited concentration dependent relaxation of norepinephrine (NE), phenylephrine (PE), histamine, serotonin (5-HT), and prostaglandin F2 alpha (PGF2 alpha)-induced contractions. Kainic acid (10(-4)M), an agonist of one subpopulation of central glutamate receptor, potentiated glutamate-induced vasoconstriction; a higher concentration (10(-3)M) produced an irreversible inhibition of glutamate contractility. Only the central glutamate receptor antagonist, ketamine (10(-4)-10(-2)M), induced a reversible, concentration dependent inhibition of glutamate-induced contractions. Glutamate contractility was not dependent on extracellular calcium, an intact endothelium or neuronal function. These results demonstrate a direct effect of glutamate on peripheral arterial tone. Dietary consumption of large quantities of MSG may represent a serious health hazard to certain individuals with pre-existing vascular disease.
Headache 1990 Sep
PMID:Vasospasm contributes to monosodium glutamate-induced headache. 226 10

In spite of recent theories about the aetiopathogenesis of migraine, serotonin continues to play a central role, explaining the efficacy of almost all migraine prophylactic drugs. In migraineurs with and without aura we measured (by HPLC-EC) the serum serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels between as well as during headache attacks. Between attacks of migraine with aura and at the beginning of attacks of both types of migraine the serum 5-HT and 5-HIAA concentration was significantly increased. These results were corroborated by 3H-spiperone binding to platelet membranes: in migraineurs with aura in the attack-free interval, there was a significant decrease in its Bmax, which suggests down-regulation of 5-HT2 receptors. In conclusion, we have verified that migraine with aura differs biochemically from migraine without aura.
Cephalalgia 1990 Oct
PMID:Migraine, serum serotonin and platelet 5-HT2 receptors. 227 90

Serotonin (5HT) binds in a saturable and specific manner to high affinity binding sites present on the surfaces of human lymphocytes and monocytes. We reported that migraine patients have an increase in 5HT binding parallel to the progression of the attack, with the appearance of a subsequent phenomenon of cellular deactivation. The same experiment previously carried out in cluster headache patients revealed a lack of high affinity binding sites, independently of the pain period. Low levels of plasma 5HT were recently described by Anthony in chronic tension-type headache. The implication of 5HT in tension headache was also hypothesized by Shukla with the demonstration of an increased 5HT uptake by platelets. We studied the 5HT binding on surfaces of lymphocytes and monocytes in 26 tension-type headache patients (16 affected by chronic form (CTH) of the disease and 10 by episodic form (ETH]. Fourteen clinically healthy subjects were used as controls. Circulating lymphocytes and monocytes were tested for their ability to specifically bind 5HT, using (3H) labeled 5HT. The "in vitro" 5HT binding curves to lymphocytes and monocytes of tension-type headache patients show a constant trend; during headaches, both CTH and ETH patients present a desensitization phenomenon with a complete loss of high affinity binding sites for 5HT. The 5HT binding curve observed in controls is indistinguishable from that of ETH patients studied outside the attack period. The total amount of 5HT bound appeared to be more markedly raised in CTH patients than in ETH patients when compared to control values.(ABSTRACT TRUNCATED AT 250 WORDS)
Headache 1990 Mar
PMID:Impairment of 5HT binding to lymphocytes and monocytes from tension-type headache patients. 233 75

In a double-blind clinical trial comprising 29 depressed patients citalopram, a highly selective 5-HT re-uptake inhibitor and maprotiline, a specific NA re-uptake inhibitor, were compared. Allowing for the small sample and taking into consideration that both groups consisted of severely ill, hospitalized patients, it is notable that half of them appeared to respond to treatment. Comparison of the clinical efficacy of the two drugs showed no significant difference, but the profiles of the side-effects appeared to be different. The patients treated with citalopram showed increased sweating, drowsiness, restlessness and headache. These side-effects were almost entirely reported by the non-responders. The maprotiline patients had anticholinergic symptoms, such as dryness of mouth and constipation, side-effects which were also reported by the responders. No correlation was found between plasma steady-state levels of either drug and clinical outcome. The Dexamethasone Suppression Test (DST) appeared to show some predictive value as regards treatment response. There was a tendency towards better overall treatment results in the non-suppressor group. Determination of post-probenecid 5-HIAA, HVA and MHPG concentrations in lumbar-CSF was made in 22 patients. There was a significant negative correlation between HVA and the severity of depression, as well as a significant negative correlation of MHPG with the Newcastle score. The 5-HIAA concentration was found to be correlated with HVA, but not with MHPG. Rather surprisingly significant negative correlation between 5-HIAA and treatment results with maprotiline was found, but no correlation with MHPG. The lumbar-CSF MHPG and HVA values did not appear to have any predictive value as regards treatment response to citalopram or maprotiline. As expected the serotonin (5-HT) concentration in blood and thrombocytes in patients treated with citalopram showed a highly significant reduction after 2 and 4 weeks of treatment.
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PMID:A double-blind comparative clinical trial of citalopram vs maprotiline in hospitalized depressed patients. 244 51

To investigate systemic serotonin (5-HT) metabolism in migraine, we determined platelet and platelet-free plasma concentrations of 5-HT, its precursors tryptophan and 5-hydroxytryptophan, and its main metabolite 5-hydroxyindoleacetic acid (5-HIAA), as well as the activities of the platelet enzymes monoamine oxidase and phenolsulfotransferase in classic and common migraineurs. Between attacks, migraineurs had lower plasma 5-HT and higher 5-HIAA levels than did healthy controls and patients with tension headache. During migraine attacks, plasma 5-HT levels were substantially higher than during attack-free periods, while 5-HIAA concentrations and platelet enzyme activities were lower. Platelet 5-HT was reduced only during common, but not classic, migraine attacks. We hypothesize that systemic 5-HT metabolism is enhanced in migraineurs during headache-free periods and transiently decreases during attacks, presumably due to a fall in enzymatic degradation. Furthermore, platelet behavior differs during migraine attacks with and without aura, and release of platelet 5-HT cannot (exclusively) be held accountable for the rise of plasma 5-HT during migraine attacks.
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PMID:Serotonin metabolism in migraine. 247 21

GR43175 is a selective 5-HT 1-like receptor agonist which is effective in the acute treatment of migraine. Rats and dogs were dosed intravenously (iv) and orally (po) with 1 mg 14C-GR43175 base (as succinate salt)/kg bodyweight. GR43175 is rapidly absorbed after oral dosing. In dog, 95-100% of the dose is absorbed, but less (25-30%) is absorbed by the rat. The bioavailability is greater than 54% in dog, but lower in rat. Except for the CNS, drug-related material is widely distributed after iv dosing, but is mainly concentrated in the gastrointestinal tract and excretory organs after oral dosing. GR43175 is eliminated from plasma by a combination of renal and metabolic clearance. Some first-pass metabolism occurs in both species. In dog the major route of excretion is in urine (78-83% of the dose) after either route of administration. In rat, urine is also the major route of excretion (71%) after iv dosing. After oral dosing to the rat the major route of excretion is in the faeces (83%). GR43175 is extensively metabolized, after either route of administration, in both species. GR49336, the indole acetic acid derivative of GR43175, is the major metabolite in dog and a major metabolite in rat.
Cephalalgia 1989
PMID:The kinetics of 14C-GR43175 in rat and dog. 254 84


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