ozagrel and Cerebral-Infarction

Topics: Acute Disease; Cerebral Infarction; Clinical Trials as Topic; Enzyme Inhibitors; Fibrinolytic Agents; Humans; Methacrylates

Topics: Cerebral Infarction; Dilazep; Humans; Methacrylates; Thromboxane-A Synthase; Vasodilator Agents

Measurements of platelet reactivity and assessment of the efficacy of antiplatelet drugs are widely recognized as pre-requisite for the diagnosis and treatment of stroke patients. A recently established shear-induced platelet reactivity test using non-anticoagulated blood (the Global Thrombosis Test) has facilitated measurements of physiologically relevant platelet function and thrombolytic activity. 195 healthy volunteers, not taking antiplatelet drugs or anticoagulants, and 185 patients with acute cerebrovascular diseases were enrolled. The effect of antiplatelet drugs on platelet function and thrombolytic activity was assessed using the Global Thrombosis Test after 14 days of medication. The occlusion time (OT), an index of platelet reactivity, in healthy controls was 284.9 ± 92.2 s. The lysis time (LT), an index of thrombolytic activity, in healthy controls was 2,231 ± 1,223 s. Both times had no significant difference between males and females. The OT of all stroke patients was 210.3 ± 140.8 s and was shorter than that of the healthy controls (284.9 ± 92.2, p < 0.0001). The LT of all stroke patients was 3,159 ± 1,549 s and was longer than that of the controls (2,231 ± 1,223, p < 0.0001). Medication significantly prolonged the OT from 184.5 ± 150.6 s (before) to 295.3 ± 208.1 s (after) in all patients, indicating a reversal of the hyper-platelet reactivity. In addition, medication shortened the LT from 3,924 ± 1,718 s (before) to 3,107 ± 1,794 s (after) in all patients. A prothrombotic state exists in stroke patients due to enhanced platelet function and suppressed thrombolytic activity. Medication improved these physiological parameters of haemostasis.

Topics: Adult; Aged; Anticoagulants; Aspirin; Blood Coagulation; Blood Platelets; Cerebral Infarction; Female; Fibrinolytic Agents; Humans; Male; Methacrylates; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Stroke; Young Adult

The clinical effects were compared between a thrombolytic agent (urokinase) and a thromboxane synthetase inhibitor (sodium ozagrel) in patients with acute lacunar infarction. All patients had some degree of neurological deficits, which corresponded to the lesions on computerized tomography or magnetic resonance imaging. Urokinase of 420,000 units was given over two days in 11 patients, 160 mg/day of sodium ozagrel was administered for two weeks in 23 patients. The study was followed up to one month after the onset. Urokinase treatment improved motor paresis in 45.5-62.5% of the patients, sodium ozagrel in 68.4-86.7%. Using the combined score of motor paresis and conscious disorder, urokinase group revealed 44.4-45.5% improvement, but sodium ozagrel group 81.0-89.5% (p < 0.05). The rates of suppressive effect in progressing stroke and complete recovery were higher in sodium ozagrel group. Sodium ozagrel was clinically more efficient than urokinase in patients with lacunar infarction.

Topics: Acute Disease; Cerebral Infarction; Fibrinolytic Agents; Humans; Methacrylates; Plasminogen Activators; Thromboxane-A Synthase; Urokinase-Type Plasminogen Activator

The effects of thromboxane A2 synthetase inhibitor and hyperdynamic therapy on delayed cerebral ischaemia following aneurysmal subarachnoid haemorrhage were evaluated in a series of twenty eight patients, who underwent aneurysmal clipping with 72 hours after subarachnoid haemorrhage. Postoperatively, 13 patients were treated with thromboxane A2 synthetase inhibitor, Xanbon [sodium (E)-3-[p-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoate]. Hyperdynamic therapy with dobutamine was given to the remaining 15 patients. Of the 13 patients treated with Xanbon, nine patients (69%) developed delayed cerebral ischaemia and cerebral infarcts occurred in eight patients (62%). On the other hand, of the 15 patients treated with hyperdynamic therapy, only three patients (20%) manifested delayed cerebral ischaemia and two patients (13%) developed cerebral infarcts. In the present study, the patients treated with hyperdynamic therapy met an expected incidence of ischaemic events after subarachnoid haemorrhage by today's standards, while those treated with thromboxane A2 synthetase inhibitor did not.

Topics: Adult; Aged; Cerebral Infarction; Cisterna Magna; Dobutamine; Drainage; Female; Humans; Infusions, Intravenous; Intracranial Aneurysm; Ischemic Attack, Transient; Male; Methacrylates; Middle Aged; Neurologic Examination; Postoperative Complications; Subarachnoid Hemorrhage; Thromboxane-A Synthase

A double-blind study was conducted at 48 neurosurgical services in Japan to investigate the usefulness of OKY-046, an imidazole derivative and a thromboxane synthetase inhibitor, on cerebral vasospasm and cerebral ischaemic symptoms in patients with ruptured cerebral aneurysms. OKY-046 was administered in two daily doses of 80 mg (L group) and 400 mg (H group), and compared with a group given a placebo (P group). The following results were obtained: the occurrence of cerebral vasospasm was significantly lower in the L group than in the P group; the development of low density area (LD) in CTs was significantly lower in both the L and H groups than in the P group; motor paralysis in the L group improved significantly sooner, and that in the H group tended to improve sooner than that in the P group; in subjects with severe vasospasm, the incidence of LD was significantly lower, with better functional prognosis, in the L group than in the P group; in subjects with severe grades on the Glasgow Coma Scale (GCS), Japan Coma Scale (JCS) or High Density (HD) Score the functional prognosis at 1 month after the aneurysmal rupture was significantly better in the L group than in the P group, though no significant differences were seen in the overall investigation; there were no significant differences among the three groups in the development of either laboratory-determined abnormality or of adverse reactions. It is thus concluded that OKY-046 is clinically useful at a dose of 80 mg/d for cerebral vasospasm and cerebral ischaemic symptoms after subarachnoid haemorrhage (SAH) caused by aneurysmal rupture.

Topics: Acrylates; Adult; Aged; Angiography; Cerebral Infarction; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Infusions, Intravenous; Intracranial Aneurysm; Ischemic Attack, Transient; Male; Methacrylates; Middle Aged; Multicenter Studies as Topic; Muscles; Paralysis; Prognosis; Random Allocation; Rupture, Spontaneous; Statistics as Topic; Subarachnoid Hemorrhage; Thromboxane-A Synthase; Tomography, X-Ray Computed

The free radical scavenger edaravone has been reported useful for improvement in activities of daily living and for prevention of recurrent stroke in the edaravone versus sodium ozagrel in acute noncardioembolic ischemic stroke (EDO) trial. The aim of this report was to evaluate the cost-effectiveness of edaravone compared to the intravenous antiplatelet drug ozagrel sodium (ozagrel) for noncardioembolic stroke (non-CES) based on the EDO trial data.. A cost-effectiveness analysis was performed using the Markov model, which also incorporated the long-term course after the acute stage of non-CES. From the perspective of a health care payer, direct medical costs and nursing care costs were taken into account in the cost analysis. The quality-adjusted life year (QALY) served as an indicator of effectiveness. Simulation at 5 and 10 years after the onset of non-CES was carried out. The study involved 68-year-old patients with non-CES, selected against the EDO trial subject selection criteria. A 14-day treatment with edaravone 60 mg/day or ozagrel 160 mg/day was assumed as acute treatment for non-CES.. The use of edaravone was associated with a reduction in total costs (0.51 million yen [$6,374] at 5 years and 0.64 million yen [$8,039]) at 10 years after the onset of non-CES) and improvement in QALYs (0.23 at 5 years and 0.38 at 10 years). Compared to ozagrel therapy, edaravone therapy was a cost-saving strategy for treating non-CES.. Compared to ozagrel therapy, edaravone therapy for non-CES is not only useful from a clinical viewpoint, but also valuable from a socioeconomic perspective.

Topics: Aged; Antipyrine; Cerebral Infarction; Computer Simulation; Cost Savings; Cost-Benefit Analysis; Drug Costs; Edaravone; Female; Free Radical Scavengers; Hospital Costs; Humans; Intracranial Embolism; Male; Markov Chains; Methacrylates; Models, Economic; Neuroprotective Agents; Platelet Aggregation Inhibitors; Quality-Adjusted Life Years; Secondary Prevention; Time Factors; Treatment Outcome

Rho kinase (ROCK), one of the serine/threonine kinases, is involved in pathologic conditions, and its activation causes neuronal cell death. Fasudil, a selective ROCK inhibitor, has been reported to cause increased cerebral blood flow (CBF) in the ischemic brain and protect against neuronal cell death by inhibiting ROCK. Ozagrel, a thromboxane A(2) synthase inhibitor, inhibits platelet aggregation and causes vasodilatation, thereby increasing CBF in cerebral thrombosis. The present study evaluates the combination therapy of fasudil and ozagrel on focal brain ischemia induced by middle cerebral artery occlusion (MCAO) in mice. Each monotherapy of fasudil at 10 mg/kg i.p. and ozagrel at 30 mg/kg i.p. significantly reduced cerebral infarction. The combination therapy of fasudil (3 mg/kg i.p.) and ozagrel (10 mg/kg i.p.), which are noneffective doses, resulted in reduction of cerebral infarction, and the protective effect was observed up to 5 min, but not 3 h, after reperfusion. Regional CBF after MCAO and phosphorylation of endothelial nitric-oxide synthase (NOS) significantly increased in response to the combination therapy, whereas these effects were not observed with monotherapy of either drug. The protective effect of combination treatment was antagonized by the treatment of a NOS inhibitor, nitro-l-arginine methyl ester hydrochloride. These findings indicate that the combination treatment of fasudil and ozagrel exhibits additive effects for neuroprotection after MCAO. These findings indicate that the combination treatment of fasudil and ozagrel may be useful as a potential therapeutic strategy for the treatment of stroke.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Cells, Cultured; Cerebral Infarction; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endothelium, Vascular; Humans; Infarction, Middle Cerebral Artery; Male; Methacrylates; Mice; Neuroprotective Agents; Random Allocation

A 69-year-old man presented with a rare case of retinal artery embolization, which occurred as a complication of carotid angioplasty and carotid artery stenting performed for recurrent cerebral infarction. Magnetic resonance imaging and angiography showed right internal carotid artery stenosis with ulceration. Carotid angioplasty and carotid artery stenting were performed using the distal protection system with the PercuSurge GuardWire. However, just after dilation, the patient complained of ocular pain and blurred vision on the right, which was subsequently diagnosed as retinal artery embolization. Heparin was given for 15 hours after stenting, and aspirin and ticlopidine medication were continued. The patient received hyperbaric oxygen therapy for 1 week. The patient's blurred vision gradually improved, but visual field defect remained. Debris was probably flushed into the external carotid artery, and passed through an anastomosis into the ophthalmic artery, resulting in retinal artery embolization.

Topics: Aged; Angioplasty, Balloon; Anticoagulants; Antipyrine; Aspirin; Carotid Artery, External; Carotid Stenosis; Cerebral Infarction; Combined Modality Therapy; Drug Therapy, Combination; Edaravone; Embolism; Heparin; Humans; Hyperbaric Oxygenation; Intraoperative Complications; Male; Methacrylates; Ophthalmic Artery; Recurrence; Retinal Artery Occlusion; Stents; Ticlopidine

Intracranial dissecting aneurysms cause ischemia, but anticoagulation or antiplatelet agents are administered to most ischemic patients without angiographical investigation. A 55-year-old woman succumbed to a subarachnoid hemorrhage (SAH) during antiplatelet therapy for ischemia caused by a dissecting aneurysm at the anterior cerebral artery, which was identified by conventional angiography on day 11 after admission. The authors emphasize that all dissecting aneurysms manifesting ischemic attack can cause hemorrhage. Therefore, emergency angiography is recommended for patients with ischemia complaining of a headache. If dissection is identified, it may be better to regulate the blood pressure of the patient strictly without anticoagulation or antiplatelet therapy.

Topics: Aortic Dissection; Cerebral Angiography; Cerebral Infarction; Fatal Outcome; Female; Fibrinolytic Agents; Humans; Intracranial Aneurysm; Methacrylates; Middle Aged; Neurosurgical Procedures; Platelet Aggregation Inhibitors; Subarachnoid Hemorrhage; Tomography, X-Ray Computed

Sodium ozagrel (ozagrel), a selective thromboxane A2 synthetase inhibitor, has been used for the treatment of various types of acute ischemic stroke, except cardioembolic stroke. Recently, edaravone, a novel free radical scavenger, has been approved for the treatment of acute ischemic stroke within 24 hours after onset. Since these two drugs differ in mode of action, we hypothesized that combination of both drugs would yield further improvement of the outcome of patients with acute ischemic stroke. The clinical efficacy of combination therapy with edaravone and ozagrel for acute ischemic stroke was studied retrospectively, and compared with that of ozagrel alone. A total of 62 patients who suffered acute ischemic stroke within 24 hours after onset during the 10-month period from June 2001 to March 2002, were treated with both edaravone and ozagrel (E-O group), while 76 patients during August 2000 to May 2001, were treated with ozagrel alone (O group). The rate of modified Rankin Scale (MRS) 0 and 1 at discharge in the total ischemic stroke and atherothrombotic stroke, was significantly higher in the E-O group than in the O group. The improvement in MRS also differed between E-O group and O group in total. The difference was significant in patients with atherothrombotic stroke but not in those with lacunar stroke. These results indicate that combination therapy with edaravone and ozagrel is more effective than mono-therapy with ozagrel for the treatment of acute ischemic, especially of atherothrombotic stroke.

Topics: Aged; Antipyrine; Cerebral Infarction; Drug Therapy, Combination; Edaravone; Female; Fibrinolytic Agents; Free Radical Scavengers; Humans; Male; Methacrylates; Middle Aged; Treatment Outcome

The therapeutic efficacy of ozagrel sodium (ozagrel), alone and in combination with heparin, and its therapeutic time window were studied in a photochemically induced thrombotic cerebral infarction rat model. Cerebral artery thrombosis was induced by irradiating the brain with green light through intact skull using rose bengal as the photosensitizing dye. One set of animals was treated immediately after thrombosis with (1) vehicle, (2) 10 mg/kg ozagrel in saline, intravenously (i.v.), (3) 150 U/kg unfractioned heparin, subcutaneously (s.c.), or (4) ozagrel, i.v. plus heparin, s.c. Infarct volume was significantly smaller and edema was reduced in the ozagrel-treated groups compared to the vehicle-treated group; heparin did not convey additional benefit. In another set of animals, rats were given either vehicle or 10 mg/kg ozagrel in saline, i.v., 60 min or 120 min after induction of thrombosis. Ozagrel reduced infarct volume, but its effect diminished with delayed administration. The therapeutic window was determined to be less than 60 minutes after induction of thrombosis.

Topics: Animals; Cerebral Arteries; Cerebral Infarction; Disease Models, Animal; Drug Therapy, Combination; Fibrinolytic Agents; Heparin; Image Processing, Computer-Assisted; Injections, Intravenous; Injections, Subcutaneous; Intracranial Thrombosis; Light; Male; Methacrylates; Rats; Rats, Sprague-Dawley; Thromboxane-A Synthase; Time Factors; Treatment Outcome

We reported a 31 year-old man with repeated episodes of migraine at a frequency of about once a week on and after January, 2000. In January 2001, scintillating scotoma and pulsating headache appeared followed by left hemianopsia. His platelet count decreased to 80,000/microliter and high intensity areas were observed in the right occipital lobe and hippocampal gyrus on the FLAIR image of brain MRI. Subsequently performed brain MRA and vertebral angiography revealed segmental stenosis and obstruction in the right posterior cerebral artery. Under the diagnosis of migrainous infarction, sodium ozagrel and lomerizine hydrochloride were administered. Idiopathic thrombocytopenic purpura was additionally diagnosed based on the decreased platelet count which was then treated with predonisolone. After these treatment, his migraine attack disappeared. In this patient, platelet destruction due to idiopathic thrombocytopinic purpura and subsequent release of serotonin seemed to have involved in the occurrence of migrainous infarction.

Topics: 1-Naphthylamine; Adult; Blood Platelets; Cerebral Infarction; Humans; Male; Methacrylates; Migraine Disorders; Prednisolone; Purpura, Thrombocytopenic, Idiopathic; Serotonin; Treatment Outcome

In this study, the clinical effects were compared between a thromboxane synthetase inhibitor (sodium ozagrel) and a thrombolytic agent (urokinase) in patients with acute cerebral infarction. The subjects consisted of 598 patients admitted on the day of the onset of the cerebral infarction in the territory of the internal carotid artery who showed a low density area on CT images within 5 days. Of these patients, 300 were treated with sodium ozagrel and classified as Group Oz, while the remaining 298 were treated with urokinase and classified as Group Ur. The results were as follows: 1. In group Oz, complete recovery of motor impairment was seen in 209 (69.7%) patients. Complete recovery within 3 weeks after onset was seen in 186 (62.0%) patients. In group Ur, complete recovery of motor impairment was seen in 175 (58.7%) patients. Complete recovery within 3 weeks after onset was seen in 120 (40.3%) patients. Therefore, a higher incidence of complete recovery of the motor impairment was noted in group Oz [p < 0.001: chi 2 test]. Similarly, complete recovery within 3 weeks after onset was more frequent in group Oz [p < 0.001: chi 2 test]. 2. In group Oz, complete recovery was made contribution statistically by Anosognosia (Ag) and unilateral neglect (UN) on admission [multivariate analysis: p < 0.01]. In group Ur, complete recovery was made contribution statistically by Ag (p < 0.01), UN (p < 0.01) and aphasia (p < 0.05). 3. Progressive stroke was observed in 29 (9.5%) patients in the group Oz and in 71 (23.0%) patients in group Ur. There was a higher incidence of progressive stroke in group Ur [p < 0.001: chi 2 test] 4. All patients with progressive stroke had initial evidence of deterioration of neurological deficits within 6 days after the onset in group Oz, and within 5 days after the onset in group Ur. The maximal period from the beginning to the end of the deterioration of neurological deficit was 7 days. 5. In group Oz, progressive stroke was only seen in 29 (29.9%) of the patients who were admitted with motor disturbances and unilateral neglect. In group Ur, progressive stroke was seen in 8 (4.3%) of the 187 patients with motor disturbances without higher cortical dysfunction, in 17 (47.2%) of the 36 patients with motor disturbances and higher cortical dysfunction without unilateral neglect and was seen in 46 (61.3%) of the patients with motor disturbances and unilateral neglect. 6. Hemorrhagic infarction was observed in 14 (4.6%) patients in group Oz

Topics: Adult; Aged; Cerebral Infarction; Fibrinolytic Agents; Humans; Methacrylates; Middle Aged; Thromboxane-A Synthase; Urokinase-Type Plasminogen Activator

The efficacy of post-ischemic treatment with AJ-3941 ((+/-)-(E)-1-(3-fluoro-6,11-dihydrodibenz[b,e]-oxepine-11-yl )-4-(3-phenyl-2- propenyl)-piperazine dimaleate, CAS 143110-70-7), a cerebrovascular selective Ca2+ channel antagonist, on brain infarction induced by focal ischemia-reperfusion in rats was evaluated. Focal ischemia was induced by transient occlusion of middle cerebral artery (MCA) with a 3-0 nylon monofilament for 90 min. One day after MCA occlusion (MCAo), brain infarct size was determined by measuring 2,3,5-triphenyltetrazonium chloride-negative stained area of the serial brain sections. The development of cerebral infarction was observed in both regions of cortex and subcortex, such as striatum, caudatum, putamen, hippocampus and corpus callosum. Post-ischemic treatment with AJ-3941 (1 or 3 mg/kg p.o., 10 min and 3 h after the occlusion) significantly reduced the infarct size and volume in the ipsilateral hemisphere in a dose-dependent manner, compared to the solvent control. The reducing effect was observed mainly in the cortical region, and a significant reduction of the subcortical infarct volume was found at the higher dose (3 mg/kg). Post-ischemic treatment with the thromboxane A2 synthetase inhibitor, sodium ozagrel (150 micrograms/kg/min i.v. infusion, between 1 h and 24 h after the MCAo) did not reduce the infarct volume in the hemisphere after ischemia-reperfusion. AJ-3941 had only minimum effect on the elevation of body temperature during ischemia-reperfusion. These results indicate that post-ischemic treatment with AJ-3941 may ameliorate the brain injury after the transient focal cerebral ischemia, and they suggest that AJ-3941 has beneficial effects for treatment of ischemic cerebral damage, such as stroke.

Topics: Animals; Body Temperature; Brain; Calcium Channel Blockers; Cerebral Cortex; Cerebral Infarction; Dibenzoxepins; Enzyme Inhibitors; Ischemic Attack, Transient; Male; Methacrylates; Piperazines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Thromboxane-A Synthase

The present study was designed to examine the effects of sodium ozagrel on hemostatic markers and cerebral blood flow in lacunar infarction. Ten cases of lacunar infarction in which sodium ozagrel was given (administered group), 10 cases of lacunar infarction in which sodium ozagrel was not given (nonadministered group), and 10 age-matched controls in which cerebrovascular diseases were absent but risk factors were similar to those of the patients (control group) were studied. Intravenous infusion of 80 mg of sodium ozagrel was done twice a day for 2 weeks. Platelet factor 4, beta-thromboglobulin, and fibrinopeptide A were significantly higher in the administered and nonadministered groups than in the control group at the time of admission. Platelet factor 4, beta-thromboglobulin, fibrinopeptide A, and thromboxane B2 were decreased significantly by the administration of sodium ozagrel. The blood flow in the cerebral cortex was significantly lower in the administered and nonadministered groups than in the control group. The blood flows around the infarcted area, in the cerebral cortex, and in the cerebral white matter were significantly increased by the administration of sodium ozagrel. Sodium ozagrel is considered to decrease platelet aggregation and increase cerebral blood flow by decreasing thromboxane A2, which has a platelet-aggregating and a vasoconstricting action. Sodium ozagrel is considered to be effective in the acute phase of lacunar infarction.

Topics: Aged; beta-Thromboglobulin; Cerebral Infarction; Cerebrovascular Circulation; Enzyme Inhibitors; Fibrinopeptide A; Hemostasis; Humans; Magnetic Resonance Angiography; Methacrylates; Middle Aged; Platelet Factor 4; Thromboxane-A Synthase

Effects of thromboxane A2 (TXA2) synthase inhibitors (CV-4151 and ozagrel) on cerebral thrombosis and cerebral damage were examined in a rat middle cerebral artery (MCA) thrombosis model and their potencies were compared with the conventional antithrombotic agents, aspirin and ticlopidine. CV-4151 significantly inhibited photochemically induced MCA thrombosis by oral (1 and 10 mg/kg) and intravenous (1 mg/kg) administration. Ozagrel (10 mg/kg, p.o.) also inhibited it. The potency of CV-4151 was about 10 times stronger than that of ozagrel, being comparable with the inhibition of blood TXA2 generation. Aspirin (100 mg/kg, p.o.) and ticlopidine (300 mg/kg, p.o.) showed an inhibitory tendency on MCA thrombosis. Twenty-four h after photochemical stimulation, cerebral edema and cerebral infarction were observed, and the lactate content in the brain increased. CV-4151 and ozagrel prevented this edema, and the antiedema effects of the drugs were correlated with the antithrombotic effect on thrombotic MCA occlusion. CV-4151 (10 mg/kg, p.o.), furthermore, significantly reduced the infarct size and inhibited the increase in lactate content. These results indicate that TXA2 synthase inhibitors inhibit cerebral damage by inhibition of MCA occlusion with thrombosis, probably resulting from the inhibition of TXA2 generation, and their effects are superior to those of aspirin and ticlopidine. TXA2 might play an important role in cerebral damage in the MCA thrombosis model. CV-4151 might be a useful drug for the treatment of cerebral thrombosis and for the prevention of cerebral infarction.

Topics: Animals; Aspirin; Brain Chemistry; Brain Edema; Cerebral Arteries; Cerebral Infarction; Drug Evaluation, Preclinical; Fatty Acids, Monounsaturated; Fibrinolytic Agents; Guinea Pigs; Intracranial Embolism and Thrombosis; Lactates; Lactic Acid; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Methacrylates; Photochemistry; Potassium; Pyridines; Rabbits; Rats; Rats, Sprague-Dawley; Rose Bengal; Sodium; Thromboxane A2; Ticlopidine

The effects of (E)-3-[p-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoic acid (OKY-046) on thromboxane A2 (TXA2) synthetase in vitro and on experimental animal models of sudden death and cerebral infarction were studied. IC50 values of OKY-046 for the TXA2 synthetase of human, rabbit, dog and guinea pig washed platelets were 0.004, 0.004, 0.26 and 2.4 microM, respectively. OKY-046 at concentrations up to 1 mM, however, did not inhibit prostacyclin (PGI2) synthetase from bovine aorta microsomes or cyclooxygenase and PGE2 isomerase from sheep seminal vesicle microsomes. Similarly, platelet 12-lipoxygenase was not affected by OKY-046. Evidence for a re-direction of arachidonate metabolism from thromboxane synthesis toward PGI2 synthesis was obtained using rat peritoneal cells. Namely, OKY-046 increased PGI2 production accompanied by an inhibition of TXA2 production at a concentration of more than 1 microM. OKY-046 at a dose of 0.1 mg/kg (i.v.) in dogs inhibited the aortic and mesenteric arterial contraction of rabbit induced by the addition of arachidonate to extracorporated blood of the dogs. OKY-046 at a dose of 0.3 mg/kg (i.v.) prevented the arachidonate-induced sudden death and also decreased the incidence of cerebral infarction induced by injection of arachidonate into the internal carotid artery in rabbits. Aspirin also decreased the incidence of cerebral infarction at a dose of 30 mg/kg (i.v.). These results suggest that OKY-046 may be valuable for the treatment of cerebrovascular and cardiovascular diseases associated with vasoconstriction and thrombosis due to TXA2.

Topics: Acrylates; Animals; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Cerebral Infarction; Cytochrome P-450 Enzyme System; Death, Sudden; Dogs; Epoprostenol; Female; Guinea Pigs; Intramolecular Oxidoreductases; Isomerases; Male; Methacrylates; Prostaglandin-E Synthases; Prostaglandin-Endoperoxide Synthases; Rabbits; Rats; Rats, Inbred Strains; Thromboxane-A Synthase; Vasodilator Agents