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: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypotheses that defective platelet structure and function is the basis for migraines is presented, with evidence explaining the biochemical, clinical, pathological, and pharmacological aspects of migraine. Platelets undergo 2 types of reaction, a shape change and a granule release reaction, releasing adenosine diphosphate (ADP) serotonin 5-hydroxy-tryptamine (5-HT), and thromboglobulin in response to collagen and thrombin. Platelets from migraine suffers contain more ADP, have more dense granules, and show some qualitative differences in their release reaction. Their platelets aggregate more readily when exposed to 5-HT, their platelet fibrinogen receptors have greater affinity, and their platelet membranes show altered viscosity. Some drugs that inhibit platelet aggregation, such as methysergide, aspirin, and amitryptylline, are beneficial in cases of migraine. Some migraine triggers, such as tyramine and catecholamines, are known to be vasoactive. The release by platelets of 5-HT may account for the visual aura or prodrome that migraine patients experience. Some migraine precipitating factors, such as stress, fatigue, hunger, certain foods, and hormones, may stimulate 5-HT release by platelets. Alterations in hormones, notably puberty, menstruation, oral contraceptive use, and menopause, are characterized by altered platelet aggregation and by onset of migraine in previously healthy people. Other arguments in favor of the platelet hypothesis involve prostacyclin deficit during menstruation and migraine associated with sudden decline in platelet numbers in cases of thrombocytopenic purpura and essential thrombocythemia.
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PMID:Migraine: the platelet hypothesis after 10 years. 270 Dec 86

We investigated some ultrastructural aspects of platelet activity in patients with classic migraine during an attack-free period. We focused on the production of malondialdehyde (MDA), the intracellular concentration of Ca++ and the membrane phospholipid structure using a DPH (1,6 diphenyl-1,3,5 hexatriene) fluorescent probe. Our study comprised 20 patients with classic migraine and 5 healthy controls, from whom 10 cc samples of blood were collected in test tubes containing sodium citrate (1/9 cc). We found no significant differences in MDA production between migraineurs and controls either before or after stimulation with thrombin. The same applies to the concentration of intracellular Ca++ (Ca++i). The membrane lipid composition assessed by DPH fluorescent probe was normal both in migraineurs and in controls. Our findings suggest no intrinsic activation of platelet aggregation.
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PMID:Platelet changes in classic migraine. 831 73

We prospectively studied the prevalence of lupus anticoagulant, anticardiolipin antibodies (aCL) and various haemostatic parameters in 71 patients with migraine and compared the results with a control group of 32 subjects with back pain never having experienced migraine. The patients with migraine were divided into two groups: group I with migraine without (n = 18) and with aura lasting less than 60 min (n = 24) and group II with migraine with prolonged aura or migrainous infarction (complicated migraine, n = 29). The following results were obtained: a) no difference in aCL positivity was noted between migrainous patients and controls and between common migraine and complicated migraine patients and b) no statistically significant difference in haemostatic parameters (except for thrombin-antithrombin III complexes) was found between the two groups of migraine and between aCL positive and negative migrainous patients. These data suggest that anticardiolipin antibodies are not involved in the pathogenesis of migraine complications.
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PMID:Lack of association between antiphospholipid antibodies and migraine. 832 62

Ergotamine and analgesic misuse are now recognized as causes of chronic daily headache and the condition responds well to drug withdrawal with reduced headache frequency. In this study, we have investigated whether medication misuse is associated with an alteration in membrane transduction which is sensitive to drug withdrawal. This was carried out by assay of the thrombin-stimulated generation of inositol phosphates in platelets from 12 migraine patients with chronic daily headache and analgesic misuse, 7 migraine patients with chronic daily headache and ergotamine misuse and 7 control subjects. After drug withdrawal, a significant decrease in headache frequency was seen at one month in both patient groups. Withdrawal of analgesics produced a significant decrease in thrombin-stimulated inositol phosphate production at one month; this was further decreased a month later with a reduction in Bmax of 60% and no significant change in KD. A similar pattern was obtained in ergot misuse patients, with the KD value decreasing by 56% one month after drug withdrawal. These results provide evidence of an adaptation in transduction with misuse of analgesics and ergotamine which correlates with headache frequency.
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PMID:Cellular adaptation in migraineurs with chronic daily headache. 839 71

1. m-Chlorophenylpiperazine (m-CPP), a 5-HT1c-receptor agonist, induces migraine-like headaches when taken orally by migraine sufferers. The present study was undertaken to see what effects m-CPP had on 5-HT function in platelets. 2. Platelets from healthy male volunteers were loaded with [3H]-5-HT and continuously perfused in vitro with carboxygenated Krebs solution at 37 degrees C. After 30 min washout the effects of m-CPP, thrombin, 5-HT and ADP on the efflux of [3H]-5-HT were recorded. 3. m-CPP (0.5-500 microM) did not evoke an increase in the efflux of [3H]-5-HT over that occurring spontaneously whereas thrombin, unlabelled 5-HT and ADP did. The effects of 5-HT were potentiated by ADP. The results were identical whether or not the 5-HT reuptake blocker paroxetine (1 microM) was present. 4. m-CPP inhibited the increase in the efflux of [3H]-5-HT evoked by different concentrations of unlabelled 5-HT in the presence of ADP (2.5 microM) and displaced the 5-HT log concentration response curve to the right. A similar result was obtained with the 5-HT2-receptor antagonist ketanserin. 5. We conclude that m-CPP is a 5-HT2-receptor antagonist on human platelets, which is unlikely to account for its headache-inducing property, as many drugs effective in migraine prophylaxis have this action.
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PMID:The effects of 5-HT and m-chlorophenylpiperazine (m-CPP) on the efflux of [3H]-5-HT from human perfused platelets. 851 59

Endothelin-1 is a recently discovered peptide mainly released from endothelial cells. Hypoxia and ischemia as well as numerous factors such as angiotensin 11, thrombin and transforming growth factor beta 1 stimulate the formation of the peptide. On the other hand the synthesis of endothelin is inhibited by nitric oxide and atrial natriuretic peptide via the formation of cyclic guanosine monophosphate. Released from endothelial cells endothelin-1 mediates transient vasodilation followed by a profound and longlasting vasoconstriction. Endothelin is also a mitogen for smooth muscle proliferation. Endothelins exert their biological effects via activation of specific receptors. Two different receptors have been cloned from mammalian tissues (ET(A) and ET(B) receptors). On vascular smooth muscle cells both receptors mediate contractions. Endothelial cells only express ET(B) receptors linked to the formation of nitric oxide and/or prostacyclin formation. Increased plasma concentrations of endothelin-1 have been described in a variety of diseases such as pulmonary hypertension, arteriosclerosis, renal failure, acute coronary syndromes, heart failure, migraine and vascular diseases. Recently an increasing number of endothelin receptor antagonists have been synthetized, which have been shown to inhibit endothelin-mediated vasoconstriction. Clinical studies are now ongoing to elucidate the pathophysiologic role of endothelin and the potential benefit of the blockade of the system in different disease states.
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PMID:Endothelin and endothelin antagonists: potential role in cardiovascular and renal disease. 873 56

We reported a family with early onset cerebrovascular disease. Patient 1 (a 36-year-old man) demonstrated a combination of livedo reticularis and cerebral infarction as previously described as Sneddon syndrome. He also showed transient focal neurologic symptoms and mild dementia. Patient 2 (an elder sister of Patient 1) was suffering from migraine. Their father and paternal uncle died of cerebral infarction, which had developed in their thirties or forties. Patients 1 and 2 showed MRI findings compatible with encephalopathy with Binswanger-type. Contrary to the previous reports on Binswanger-type encephalopathy, both of these patients demonstrated decreased levels of fibrinogen as well as those of factor V, together with negative antiphospholipid antibody. Thus, juvenile onset, autosomal dominant inheritance, the diversity of clinical findings and the coagulopathy in this family were characteristic features. The level of thrombin-antithrombin III complex (TAT) was markedly increased in Patient 1. Treatment with antithrombin (argatroban 20mg i.v. everyday for 28 days) not only reduced the level of TAT but also improved the livedo reticularis and neurological findings. Although gene analysis has not been performed yet on this family, this condition is similar to cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL), which involve juvenile cerebral infarction and dementia as well as migraine.
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PMID:[Familial Binswanger-type encephalopathy with Sneddon syndrome]. 875 90

Cyclandelate inhibits calcium-induced contraction of vascular smooth muscle cells, platelet aggregation induced by thrombin, platelet-activating-factor and adenosine, and also suppresses a provoked 5HT release from platelets. This pharmacological profile suggests that cyclandelate may have a potential prophylactic effect in migraine. To test this hypothesis, a double-blind multicentre study was performed in 214 patients to investigate the efficacy and tolerability of cyclandelate compared to placebo and propranolol. After a 4-week baseline period, eligible patients (randomization 3:2:3) were treated for 12 weeks with daily doses of 1.200 mg cyclandelate (n = 81), placebo (n = 55) or 120 mg propranolol (n = 78). The number of migraine attacks (> or = 50% responders) and the migraine duration/month were compared based on the difference between baseline and the last 4 weeks of prophylactic treatment. The percentage of patients with a reduction in migraine attacks of > or = 50% treated with cyclandelate (37.0%) or propranolol (42.3%) was not significantly superior to placebo (30.9%; p > 0.025). The mean duration of migraine in hours (h) per month decreased in both active treatment groups (cyclandelate: 36.8 h, p = 0.046; propranolol: 34.4 h, p = 0.039) compared to placebo (13.7 h) without reaching statistical significance (alpha/2 = 0.025). The clinical efficacy of cyclandelate and propranolol was comparable. Adverse experiences were reported by 13 patients (16.0%) treated with cyclandelate, by 5 patients (9.1%) treated with placebo and by 19 patients (24.4%) treated with propranolol. These were drug-related in 7.1% (n = 6) of patients treated with cyclandelate and in 9% (n = 7) of patients treated with propranolol. In summary, cyclandelate has a comparable efficacy to that of propranolol, an established drug of first choice in the prophylaxis of migraine. Both drugs were better than placebo, but not significantly so. Both active treatments were well tolerated.
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PMID:Cyclandelate in the prophylaxis of migraine: a randomized, parallel, double-blind study in comparison with placebo and propranolol. The Study group. 890 55

The aim of this study is to investigate whether oxidative stress may represent a pivotal determinant of the altered functional features of platelets in migraineurs during the headache-free period. Twenty-three patients with migraine with aura, free of attack, and 23 healthy volunteers were enrolled for the study. The involvement of an oxidative condition appears confirmed by the statistically significant increase (p < 0.001) of plasma levels of thiobarbituric acid-reactive substances which may be considered a marker for oxidative stress and themselves strong-pro-oxidants. Such oxidative status seems to induce in platelets of migraineurs increased membrane rigidity (p < 0.001), reduced cytosolic calcium in the resting condition and after thrombin stimulation (p < 0.001), and decreased aggregatory responses to ADP and collagen. These findings indicate that the "in vitro" anomalous platelet behavior in migraineurs, observed in headache-free periods, may be considered as the transient expression of the exhausted platelets to "in vivo" stimulation and probably related to an increased vulnerability to oxidative stress.
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PMID:Oxidative stress and platelet responsiveness in migraine. 925 72

Migraine with aura has been shown to be an independent risk factor for stroke. Although the precise mechanism of migraine-related stroke is not known, risk factors for hypercoagulability have been found in migraineurs. Prothrombin factor 1.2 (F1.2) is a cleavage product of prothrombin. Elevated plasma F1.2 has been shown to be a sensitive and a specific marker of ongoing thrombin generation, and thus may serve as an indicator of hypercoagulability. In this study we determined plasma F1.2 levels in 35 patients with migraine (22 with aura and 13 without aura) and in 24 healthy age- and sex-matched volunteers. Elevated F1.2 levels were found in 11 of 22 (50%) patients with migraine with aura (1.25-3.5 nmol/l). None of the patients with migraine without aura nor any of the healthy volunteers had elevated plasma F1.2 levels (normal < 1.1 nmol/l). We conclude that prothrombin F1.2 levels are elevated in a significant number of patients with migraine with aura but not in patients with migraine without aura. This finding suggests that there is activation of the clotting system in certain patients with migraine with aura.
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PMID:Evidence for activation of the coagulation system in migraine with aura. 1142 96


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