ozagrel and Brain-Ischemia

In patients with acute ischemic stroke (AIS), platelets are activated in the acute phase, releasing neurotoxic, and thrombogenic eicosanoids, which may reduce the brain blood flow and cause brain damage. Sodium ozagrel (ozagrel), a thromboxane A2 synthase inhibitor, is one of the most studied drugs which may reduce the risk of neurological impairment and reduce the volume of brain damage. We systematically reviewed all published randomized controlled trials (RCTs) comparing ozagrel with control among patients with AIS.. We searched seven databases, using the Cochrane Stroke Group search strategy and the terms of ozagrel and stroke. Two independent investigators evaluated trial quality using the Cochrane Collaboration's risk of bias tool and extracted the data from each study. Pooled analyses for the outcomes of combined death or disability and improvement of neurological impairment were calculated.. The effect of ozagrel on the reduction of death for AIS at the end of follow-up was relative risk (RR) = 0·67 (95% CI: 0·11 to 4·04, P = 0·67). The effect evaluated by Modified Edinburgh-Scandinavian Stroke Scale (MESSS) at the end of treatment was mean difference (MD) = -4·17 (95% CI, -4·95 to -3·40; P<0·00001). The most severe adverse events of ozagrel were digestive hemorrhage and hemorrhagic stroke; however, there was no significant difference between the two groups. The subgroup analysis of different dose showed that 80 and 160 mg ozagrel per day might both increase the improvement of the neurological impairment.. During scheduled treatment, ozagrel is effective for the improvement of neurological impairment for AIS patients. However, the evidence of ozagrel to reduce the long-term death or disability is limited and quality of these trials is insufficent hence, large-sample and high quality RCTs are warrented to confirm the efficacy of ozagrel for acute ischemic stroke.

Topics: Brain Ischemia; Dose-Response Relationship, Drug; Fibrinolytic Agents; Humans; Methacrylates; Randomized Controlled Trials as Topic; Stroke; Treatment Outcome

Cilostazol, an inhibitor of phosphodiesterase 3, has various pleiotropic effects besides its antiplatelet activity. This study examined the efficacy of cilostazol for the treatment of acute perforating artery infarction.. In this prospective, randomized, open-label, blinded-end point trial, 100 patients with cerebral infarction in the territory of the lenticulostriate arteries were enrolled within 48 h of onset. Patients were randomly treated with both cilostazol and ozagrel for 14 days (n = 50, cilostazol group) or ozagrel alone for 14 days (n = 50, control group). The primary end point was the proportion of favorable outcomes 30 days after randomization as defined by a modified Rankin Scale (mRS) score of 0-2. Secondary end points included the incidence of neurological deterioration (an increase of ≥ 2 on the National Institutes of Health Stroke Scale within 7 days).. Favorable outcomes (mRS scores 0-2) were similar in both groups (81.3 and 82.0% in the cilostazol and control groups, respectively). The incidence of neurological deterioration was lower in the cilostazol group than the control group (12.5 and 16.0%, respectively) with a 21.9% relative risk reduction, although the difference was not statistically significant.. Cilostazol did not prevent the neurological deterioration of perforating artery infarction.

Topics: Aged; Aged, 80 and over; Brain Ischemia; Cilostazol; Double-Blind Method; Drug Therapy, Combination; Female; Fibrinolytic Agents; Humans; Male; Methacrylates; Middle Aged; Stroke; Tetrazoles; Time Factors; Treatment Outcome

The preventive effect of the serine protease inhibitor FUT-175 (nafamostat mesilate), a potent inhibitor of the complement system, against vasospasm was evaluated in 34 high risk patients with thick and diffuse subarachnoid hemorrhage (SAH) demonstrated by computed tomography corresponding to Fisher group 3. All patients underwent surgery within 96 hours following SAH and received the thromboxane A2 synthetase inhibitor, OKY-046, as part of standard care. FUT-175 (40-160 mg/day) was administered during the initial 4 days following surgery. 455 patients treated without FUT-175 in the Nagasaki SAH Data Bank (non-FUT group) formed the control group. FUT-175 significantly decreased the incidence of symptomatic vasospasm in patients with severe neurological grade (Hunt and Hess grade 3, p < 0.02; Hunt and Hess grade 4, p < 0.02). The incidence of favorable outcome was 76.5% in the FUT group and 60.4% in the non-FUT group, but not statistically different. However, when patients of Hunt and Hess grade 5 were excluded, the FUT group had a significantly improved outcome (p < 0.05). This study suggests that FUT-175 has an additive effect to OKY-046 in preventing vasospasm in high risk patients with severe SAH.

Topics: Aged; Aneurysm, Ruptured; Benzamidines; Brain Damage, Chronic; Brain Ischemia; Drug Evaluation; Drug Synergism; Enzyme Inhibitors; Female; Glasgow Coma Scale; Guanidines; Humans; Intracranial Aneurysm; Ischemic Attack, Transient; Male; Methacrylates; Middle Aged; Postoperative Complications; Rupture, Spontaneous; Serine Proteinase Inhibitors; Severity of Illness Index; Subarachnoid Hemorrhage; Thromboxane-A Synthase; Treatment Outcome

A 92-year-old woman developed sudden consciousness disturbance, global aphasia and right hemiparesis. She had atrial fibrillation and cardioembolic stroke was diagnosed. Tissue plasminogen activator was administered, and endovascular treatment was initiated. The left middle cerebral artery was occluded and complete recanalisation was achieved after direct aspiration first-pass technique. However, MRI immediately after treatment showed reocclusion. Endovascular treatment was repeated and complete recanalisation was achieved. There was no evidence of cerebral artery dissection, but angiography soon after the second procedure revealed early reocclusion. Ozagrel, an antiplatelet agent, was administered intravenously and prevented reocclusion. Endothelial injury was speculated to have occurred during the first mechanical thrombectomy, leading to recurrent occlusion. Though the patient continued to have right hemiparesis, she recovered from her consciousness disturbance and aphasia after re-treatment.

Topics: Aged, 80 and over; Atrial Fibrillation; Brain Ischemia; Cerebral Angiography; Endovascular Procedures; Female; Fibrinolytic Agents; Humans; Infarction, Middle Cerebral Artery; Magnetic Resonance Angiography; Methacrylates; Middle Cerebral Artery; Recurrence; Reoperation; Thrombectomy; Treatment Outcome

Argatroban is a thrombin inhibitor agent for acute noncardioembolic ischemic stroke in Japan. We studied the prognosis in patients with acute stroke treated by argatroban in comparison with the control group with ozagrel in our hospital.. A total of 513 patients with acute noncardioembolic ischemic stroke were enrolled retrospectively from our hospital database. Of all patients with stroke, 353 were administered with argatroban. The other 160 control patients were administered with ozagrel. The patients were examined as to their stroke types, the neurological severity according to the National Institutes of Health Stroke Scale (NIHSS), and clinical outcomes on discharge were determined according to the modified Rankin Scale (mRS).. A total of 353 patients with acute noncardioembolic stroke, including 138 with lacunar infarction (LIs) and 215 with atherothrombotic infarction (ATI) showed functional recovery by argatroban, but the effectiveness of argatroban was not superior to ozagrel therapy defined by the control group. A total of 255 patients with ATI who were treated with both argatroban and ozagrel showed improvement by 1 point. We could not find any significant difference between argatroban and ozagrel in the 2 stroke subtypes, LI and ATI. We also found that combination therapy of argatroban and edaravone was not superior to argatroban monotherapy in clinical outcome.. Argatroban therapy was not superior to control with ozagrel therapy in acute noncardioembolic ischemic stroke, including LI and ATI, regardless of the use of edaravone.

Topics: Aged; Aged, 80 and over; Antithrombins; Arginine; Brain Ischemia; Female; Fibrinolytic Agents; Humans; Male; Methacrylates; Middle Aged; Pipecolic Acids; Prognosis; Retrospective Studies; Severity of Illness Index; Stroke; Sulfonamides

Ozagrel sodium (ozagrel), a thromboxane A2 synthesis inhibitor, is used for ischemic stroke patients in several countries, despite a lack of strict evidence of its benefits. We investigated whether ozagrel was beneficial for patients with atherothrombotic stroke or lacunar infarction.. This was a retrospective observational study using the Diagnosis Procedure Combination database in Japan. We identified patients with atherothrombotic stroke or lacunar infarction who were admitted to 781 hospitals from July 1, 2010 to March 31, 2012. Propensity score-matched analyses were performed separately for patients with atherothrombotic stroke and those with lacunar infarction, which balanced differences in baseline characteristics between patients who received ozagrel (ozagrel group) and those who did not (control group) in each stroke subtype. The modified Rankin Scale scores at discharge and occurrence of hemorrhagic complications after admission were compared between the ozagrel and control groups.. After the propensity score matching, 2726 pairs of patients with atherothrombotic stroke and 1612 pairs of patients with lacunar infarction were analyzed. Ordinal logistic regression analyses showed that ozagrel use was not significantly associated with modified Rankin Scale score at discharge in patients with atherothrombotic stroke (odds ratio: .99; 95% confidence interval: .88-1.11) or in those with lacunar infarction (odds ratio: 1.00; 95% confidence interval: .87-1.16). The occurrence of hemorrhagic complications did not differ significantly between the ozagrel and control groups.. The present study suggested that ozagrel was safe to use but did not improve functional outcomes in patients with atherothrombotic or lacunar infarction.

Topics: Adult; Aged; Aged, 80 and over; Brain Ischemia; Chi-Square Distribution; Disability Evaluation; Enzyme Inhibitors; Female; Hemorrhage; Humans; Logistic Models; Male; Matched-Pair Analysis; Methacrylates; Middle Aged; Patient Discharge; Propensity Score; Recovery of Function; Retrospective Studies; Risk Factors; Stroke; Stroke, Lacunar; Thromboxane-A Synthase; Treatment Outcome

Brain ischemia leads to severe disruption of the nervous system and recovery is often prolonged. Rehabilitative post-ischemia pharmacological treatment may therefore be important for behavioral recovery, especially for cognition and motor behavior. The present study investigated the effects of combined vinpocetine and ozagrel administration on the behavioral recovery of rats from global brain ischemia. The results suggest that the combined treatment leads to significantly better improvement compared to single drug administration. We conclude that the combined use of vinpocetine and ozagrel may provide beneficial effects to patients suffering from brain ischemia.

Topics: Animals; Brain Ischemia; CA1 Region, Hippocampal; Cell Count; Male; Maze Learning; Methacrylates; Neurons; Neuroprotective Agents; Neuropsychological Tests; Random Allocation; Rats; Rats, Sprague-Dawley; Treatment Outcome; Vinca Alkaloids

Platelet activation and subsequent aggregation play a key role in the pathogenesis of ischemic brain damage. Recent studies revealed that enhanced platelet activation is also observed after ischemia, suggesting that secondary thrombus formation might participate in the development of cerebral infarction. The binding of platelet glycoprotein GPIIb/IIIa (integrin alpha(IIb)beta3) to fibrinogen is the final common pathway in platelet aggregation. Therefore, GPIIb/IIIa antagonists might be useful in acute ischemic stroke as well as in the secondary prevention of ischemic stroke. In the present study, we evaluated the effect of three compounds, FK419 ((S)-2-acetylamino-3-[(R)-[1-[3-(piperidin-4-yl) propionyl] piperidin-3-ylcarbonyl] amino] propionic acid trihydrate), a novel nonpeptide GPIIb/IIIa antagonist, ozagrel, a selective thromboxane A(2) synthase inhibitor, and argatroban, a thrombin inhibitor, on middle cerebral artery (MCA) patency and ischemic brain damage using photochemically induced MCA thrombosis model in guinea pigs. FK419, ozagrel, or argatroban was administered 5 min after the termination of photoirradiation. FK419 dose-dependently improved MCA patency by decreasing the total occlusion time, time to continuous reperfusion, and the number of cyclic flow reductions, at doses that inhibited ADP-induced platelet aggregation ex vivo. In contrast, ozagrel only improved total occlusion time, and argatroban showed no improvement in MCA patency. FK419 also reduced ischemic brain damage in a dose-dependent fashion, whereas ozagrel and argatroban did not. Finally, FK419 ameliorated neurological deficits, whereas ozagrel and argatroban did not. These results indicate that FK419, a GPIIb/IIIa antagonist, ameliorates ischemic brain damage by improving MCA patency after occlusion and that FK419 is a promising candidate for the treatment of acute ischemic stroke.

Topics: Animals; Antithrombins; Arginine; Blood Coagulation; Blood Platelets; Brain Ischemia; Disease Models, Animal; Guinea Pigs; Infarction, Middle Cerebral Artery; Male; Methacrylates; Pipecolic Acids; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Reperfusion Injury; Sulfonamides; Thromboxane B2

The neuroprotective property and the effects on hemodynamics of hydroxy fasudil, an active metabolite of an antispastic drug, fasudil, were examined. In rats, hydroxy fasudil was found following intravenous infusion or intraperitoneal administration of fasudil, and the maximum plasma concentration of hydroxy fasudil was approximately 25 or 40% of the parent drug, respectively. The i.v. administration of hydroxy fasudil produced significant increases in regional cerebral blood flow in dogs. Hydroxy fasudil relaxed the KCl, PGF2alpha or U-46619-induced contraction in canine basilar or middle cerebral arterial strips, concentration-dependently. The neuroprotective property of hydroxy fasudil was examined on delayed neuronal death in gerbils. Hydroxy fasudil (3 mg/kg) significantly protected against the ischemia-induced neuronal loss. To further clarify the effect on neurological impairments, hydroxy fasudil was tested in a rat model of microembolization stroke. Intravenous administration of hydroxy fasudil improved neurological functions, significantly reduced the size of the infarct area and prevented the accumulation of neutrophils. The present findings suggest that hydroxy fasudil has an efficacy to improve the hemodynamic function and to inhibit neutrophil-mediated damage, and contributes to the potency and long duration of the cytoprotective properties of fasudil on ischemic brain damage, and also suggest a critical role for rho kinase in the pathogenesis of cerebral ischemic injury, and the potential utility of rho kinase inhibitor as a therapeutic agent in stroke.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Brain; Brain Ischemia; Cerebral Arteries; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Gerbillinae; Hemodynamics; In Vitro Techniques; Infusions, Intravenous; Injections, Intraperitoneal; Intracellular Signaling Peptides and Proteins; Male; Methacrylates; Muscle Contraction; Muscle, Smooth, Vascular; Neuroprotective Agents; Protein Serine-Threonine Kinases; Rats; Regional Blood Flow; Reperfusion Injury; rho-Associated Kinases

1. The neuroprotective properties of fasudil (HA1077), a novel protein kinase inhibitor, were evaluated in two animal models of cerebral ischaemia: transient bilateral carotid artery occlusion in Mongolian gerbils and cerebral microembolization in rats. 2. The cytoprotective effect of fasudil on delayed neuronal death in gerbils was compared with the effects of nimodipine, a calcium channel antagonist and ozagrel, a thromboxane A2 synthetase inhibitor. The average of the neuronal cell density in the ischaemic control group was 17.8 +/- 2.1 cells mm-1, whereas fasudil (30 mg kg-1) significantly diminished the loss of CA1 neurones with the average of the neuronal cell density of 101.0 +/- 22.0 cells mm-1; nimodipine (10 mg kg-1) and ozagrel (30 mg kg-1) did not significantly protect against the ischaemia-induced neuronal loss. 3. In the rat model, the effects of fasudil on the histological and neurological consequences of cerebral microembolization produced via the injection of microspheres were examined. Twenty-four hours after the injection of microspheres into the internal carotid artery, all animals in the control group showed typical symptoms of stroke. Neurological function was significantly improved in the fasudil-treated animals. In the controls, the infarcted area in a cortical slice selected to include the hippocampal area was 0.25 +/- 0.01 cm2 (mean +/- s.e.mean) (43.9 +/- 2.4% of cortical section of the half hemisphere); the difference was significant compared to the mean area of 32.7 +/- 2.8 and 21.5 +/- 4.8% observed in rats treated with fasudil (3, 10 mg kg-1), respectively. Fasudil (10 mg kg-1) significantly suppressed the increased water content in ischaemic brain tissues (saline-treated rats, 82.4 +/- 0.2% vs fasudil-treated rats, 81.0 +/- 0.4%). 4. These results suggest that: (i) various protein kinases are involved in the pathogenesis of ischaemic injury; and (ii) the inhibition of protein kinases may be efficacious in preventing neuronal death, thus improving neurological function in the brain damage associated with ischaemic stroke.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Body Water; Brain Chemistry; Brain Ischemia; Calcium Channel Blockers; Cell Death; Embolism; Enzyme Inhibitors; Gerbillinae; Male; Methacrylates; Neurons; Neuroprotective Agents; Nimodipine; Protein Kinase Inhibitors; Rats; Thromboxane-A Synthase

In order to clarify the role of platelets as a factor aggravating cerebral ischemia, an experimental model of ischemia was investigated using thrombocytopenic rats. In addition, the prostacyclin derivative (OP-41483) and the thromboxane A2 synthetase inhibitor (OKY-046), both of which inhibit platelet aggregation, were tested for possible beneficial effects on cerebral ischemia. Cerebral ischemia was produced in spontaneously hypertensive male rats using bilateral common carotid artery ligation (BLCL). Thrombocytopenia was produced with an antiplatelet antiserum which reduced the platelet count to less than 6 x 10(4)/microliters by 24 h. OP-41483 was administered four times hourly (500 ng/kg x 4, i.p.), beginning 1 h prior to BLCL. Similarly, OKY-046 was injected four times hourly (10 mg/kg x 4, i.p.). Brain metabolites such as ATP, lactate and pyruvate and water content were determined after 3 h of cerebral ischemia. Brain levels of ATP in the ischemic rats with thrombocytopenia were higher than those of the ischemic rats without thrombocytopenia. In addition, thrombocytopenia reduced the increase of lactate and water content in the ischemic brain. Animals treated with OP-41483 also maintained higher levels of ATP and lower levels of lactate and water compared to animals given a vehicle. OKY-046 significantly reduced brain water content, but had no effect on the ischemic alteration of brain metabolite levels. These results indicate that platelets play an important role in the progression of metabolic change during ischemia.

Topics: Adenosine Triphosphate; Animals; Blood Platelets; Body Water; Brain; Brain Ischemia; Epoprostenol; Immune Sera; Lactates; Male; Methacrylates; Platelet Aggregation Inhibitors; Platelet Count; Pyruvates; Rats; Rats, Inbred SHR; Reference Values; Thrombocytopenia; Thromboxane-A Synthase

The protective effect of thromboxane synthetase inhibitor, OKY-046, on brain ischemia was studied in spontaneously hypertensive rats. Cerebral ischemia was developed by bilateral carotid artery ligation (BCL) for 1 or 3 h and thereafter, circulation was restored for 15 min. OKY-046, 5 or 30 mg/kg, or saline as control was administered i.v. before BCL. Neither blood pressure nor blood gases were altered by OKY-046 or saline injection. During BCL, cerebral cortical blood flow was reduced to 25 and 15% of the resting value at 30 and 60 min, respectively, and these changes were not different among the groups. In rats with ischemia longer than 1 h, the blood flow was well preserved by OKY-046, 30 mg/kg, to 10-17% of the resting level, thus significantly higher than that (less than 5%) in non-treated rats. After 15 min recirculation, the supratentorial lactate level was lower and adenosine triphosphate (ATP) was higher in OKY-046-treated rats than in the saline-treated ischemic rats. Plasma thromboxane B2 was increased markedly in 1 h ischemic-reperfused rats without treatment and the increase was almost completely inhibited by OKY-046. In contrast, 6-keto-prostaglandin F1 alpha was increased 8.5-fold after ischemia and the increase was not affected by the treatment. OKY-046 seems to have an antiischemic effect on acutely induced cerebral ischemia. Selective inhibition of thromboxane A2 production and an inversely high level of prostaglandin I2 may be an important contribution to protection of the microcirculation during ischemia and preservation of ischemic cerebral metabolism.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Brain Chemistry; Brain Ischemia; Cerebrovascular Circulation; Epoprostenol; Female; Lactates; Methacrylates; Pyruvates; Radioimmunoassay; Rats; Rats, Inbred SHR; Thromboxane A2; Thromboxane-A Synthase