ozagrel and fasudil

After an interval of 6 years, the Japanese Guidelines for the Management of Stroke were revised in 2015 in accordance with recent advances in clinical knowledge. The chapter on subarachnoid hemorrhage includes new and revised recommendations for diagnosis, treatment selection, and management of vasospasm. The chapter on diagnosis recommends re-examination of vascular images at regular intervals in cases in which cerebral aneurysm was not detected on the first examination. The section dealing with treatment selection for cerebral aneurysmal emphasizes that the method for aneurysm obliteration should be selected based on consultation with both surgical and endovascular specialists. The role of triple-H therapy(i.e., induced hypertension, hypervolemia, and hemodilution) has changed from a preventive measure to a treatment option for symptomatic cerebral vasospasm.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Antifibrinolytic Agents; Endovascular Procedures; Humans; Infusions, Intra-Arterial; Japan; Methacrylates; Neurosurgical Procedures; Practice Guidelines as Topic; Severity of Illness Index; Subarachnoid Hemorrhage; Vascular Surgical Procedures

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

Sub-analysis of the fasudil post-marketing surveillance study compared the safety and efficacy of fasudil plus ozagrel to fasudil only. A total of 3690 patients received fasudil and 1138 received fasudil plus ozagrel between 1995 and 2000. The occurrence of adverse events, occurrence of low density areas associated with vasospasm on computed tomography, absence of symptomatic vasospasm, and poor clinical outcomes associated with vasospasm were compared between the fasudil and fasudil plus ozagrel groups. The pharmacokinetics of fasudil were assessed in 5 patients with subarachnoid hemorrhage. The drug interaction between fasudil and ozagrel was pharmacologically investigated in vitro and in vivo. The occurrence of adverse events and clinical outcomes were similar between the two groups. The occurrences of symptomatic vasospasm and low density areas were lower in the fasudil group than in the fasudil plus ozagrel group. The average trough value (8-hour value) of the fasudil active metabolite, hydroxyfasudil, was 50 nM. Fasudil showed no pharmacological interaction with ozagrel. The combination of fasudil plus ozagrel was well tolerated, but did not result in better efficacy than fasudil only.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Aged; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Male; Methacrylates; Middle Aged; Product Surveillance, Postmarketing; Protein Kinase Inhibitors; rho-Associated Kinases; Subarachnoid Hemorrhage; Thromboxane-A Synthase; Treatment Outcome; Vasospasm, Intracranial

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

The aim of this study was to investigate the mechanisms of the pathogenesis of hyperviscosity following cerebral ischemia. Focal ischemia was produced by embolic occlusion of the right middle cerebral artery (MCA) in rats for 1 hour, followed by recirculation. Twenty-four hours after MCA occlusion, fasudil, a protein kinase inhibitor, was administered intraperitoneally. Blood samples were taken from the abdominal aorta, and viscosity was measured using a cone-plate viscometer. The viscosity of whole blood in the ischemic attack group was significantly increased compared with the sham operated group 24 hours after MCA occlusion. Fasudil dose-dependently and significantly decreased the blood viscosity, and reduced to the normal range after administration of 10 mg/kg of fasudil (sham-operated rats, 5.17+/-0.05 cP; pre dose/ischemic rats, 6.05+/-0.08 cP; post dose/ischemic rats, 5.23+/-0.14 cP; 37.5 sec(-1)). Our findings suggest that cerebral ischemia induces a potent, systemic and long-lasting hyperviscosity, and that the inhibition of protein kinases, especially rho kinase, is efficacious in preventing this hyperviscosity.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Arterial Occlusive Diseases; Blood Viscosity; Calcium Channel Blockers; Dose-Response Relationship, Drug; Enzyme Inhibitors; Erythrocytes; Hematocrit; Hemodilution; Ischemic Attack, Transient; Male; Methacrylates; Middle Cerebral Artery; Nimodipine; Protein Kinase Inhibitors; Rats; Rats, Wistar; Thromboxane-A Synthase

Fasudil hydrochloride is a new type of intracellular calcium antagonist, different from the calcium entry blockers that are commonly employed for clinical use. Since September 1995, the combination of fasudil hydrochloride and ozagrel sodium, an inhibitor of thromboxane A2 synthesis, has been used to treat 60 patients at risk of cerebral vasospasm after aneurysmal subarachnoid hemorrhage. The effectiveness of this combination therapy was investigated by comparison with the outcome of 57 patients previously treated with only ozagrel sodium. The combination therapy was significantly more effective (p < 0.01) in reducing the incidence of low density areas on computed tomography scans, and reduced, but not significantly, the occurrence of symptomatic vasospasm. The combination therapy of fasudil hydrochloride and ozagrel sodium has superior effectiveness over only ozagrel sodium in treating patients at risk of vasospasm after aneurysmal subarachnoid hemorrhage.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Adult; Aged; Aneurysm, Ruptured; Calcium Channel Blockers; Drug Therapy, Combination; Female; Fibrinolytic Agents; Humans; Intracranial Aneurysm; Ischemic Attack, Transient; Male; Methacrylates; Middle Aged; Postoperative Complications; Retrospective Studies; Subarachnoid Hemorrhage; Treatment Outcome

To determine the pathogenetic mechanism underlying the maintenance of arterial narrowing during the chronic phase of cerebral vasospasm caused by subarachnoid hemorrhage (SAH), we examined the effect of ozagrel, a thromboxane A2 (TXA2) synthetase inhibitor, on chronic vasospasm in a canine two-hemorrhage model in comparison with that of fasudil, an inhibitor of protein kinases. The magnitude of the vasospasm was determined angiographically. On SAH day 7, a vasospasm was observed in every dog. Intraarterial or intravenous administration of ozagrel (3 mg/kg/30 min) did not reverse the vasospasm but tended to increase bleeding. In contrast, intraarterial administration of fasudil (3 mg/kg/30 min) significantly reversed the vasospasm. These findings suggest that: 1) TXA2 does not participate in the maintenance of chronic vasospasm after SAH; and 2) the protein kinases, particularly myosin-light chain kinase and protein kinase C, are involved in the pathogenesis of arterial narrowing during the chronic phase of cerebral vasospasm.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Cerebral Hemorrhage; Dogs; Enzyme Inhibitors; Female; Ischemic Attack, Transient; Male; Methacrylates; Protein Kinase Inhibitors; Thromboxane-A Synthase; Vasoconstriction

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