ozagrel and Subarachnoid-Hemorrhage

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

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

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

The efficacy and possible side effects of thromboxane A2 (TXA2) synthetase inhibitor in the treatment of cerebral vasospasm after subarachnoid hemorrhage (SAH) were assessed for 24 patients who presented with grades I to IV of the Hunt and Hess classification. All patients underwent aneurysmal clipping within 48 hours after SAH. Postoperatively, TXA2 synthetase inhibitor, Cataclot [sodium (E)-3-[p-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoate] was administered to 13 patients by continuous drip infusion at a dose of 1 microgram/kg/min for 8 to 14 days (group A). The remaining 11 patients did not receive this drug (group B). Of the 13 patients in group A, seven patients (54%) showed no symptomatic vasospasm after SAH. Four patients (31%) developed a transient deterioration of consciousness and/or motor disturbance. Three of these patients fully recovered, while one of them showed a mild neurological deficit on discharge. One patient (8%) developed permanent dysphasia and hemiparesis as a result of ischemic brain damage due to vasospasm. One patient (8%) died of the side effect. On the other hand, of the 11 patients in group B, only three (27%) showed no symptomatic vasospasm. One (9%) patient presented a transient neurological deficit but fully recovered upon discharge. Four patients (36%) showed permanent neurological deficits, although they all could lead an independent life after discharge. The three remaining patients developed a severe disturbance of consciousness caused by ischemia due to vasospasm, and two of them died within 1 month after the onset of SAH. In the group treated with Cataclot, two patients developed an epidural hematoma late during the administration of the drug. Of these two, one patient died of increased intracranial pressure that was accelerated by the complication. These results indicate that TXA2 synthetase inhibitor is effective in not only decreasing the occurrence of symptomatic vasospasm but also reducing the neurological deterioration due to vasospasm after SAH. However, this drug has a hazardous side effect in that it may promote a tendency to bleed, which caused death in one of our patients.

Topics: Adult; Aged; Female; Humans; Intracranial Aneurysm; Ischemic Attack, Transient; Male; Methacrylates; Middle Aged; Prognosis; Rupture, Spontaneous; Subarachnoid Hemorrhage; Thromboxane-A Synthase; Tomography, X-Ray Computed

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

Topics: Acrylates; Adult; Aged; Clinical Trials as Topic; Female; Humans; Ischemic Attack, Transient; Male; Methacrylates; Middle Aged; Subarachnoid Hemorrhage; Thromboxane-A Synthase

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

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

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

The effects of subarachnoid hemorrhage (SAH) on intracranial prostaglandins (PGs) were studied in canines. Subarachnoid hemorrhage was produced by the "two hemorrhage" method. Basilar artery caliber and regional cerebral blood flow (rCBF) in the occipital cortex were reduced by 42% and 43% during delayed vasospasm, respectively. Once delayed vasospasm had developed, intravenous infusion of OKY-046, a selective inhibitor of thromboxane (TX) A2 synthetase, induced no significant change in angiographic vasospasm but caused a significant increase in rCBF. In delayed vasospasm, cortical levels of PGF2 alpha were significantly decreased, whereas plasma levels of PGF2 alpha and TXB2 in the transverse sinus were significantly increased. The intravenous infusion of OKY-046 in delayed vasospasm induced a significant increase in cortical PGF2 alpha and PGE in the occipital cortex, and caused a significant increase in plasma 6-keto-PGF1 alpha and a significant decrease in plasma TXB2 in the transverse sinus. In delayed vasospasm, decreased cortical levels of PGF2 alpha may reflect a decrease in rCBF and increased plasma PGF2 alpha and TXB2 levels may reflect enhancement of intravascular coagulation. These PGs have very strong and various biological activities. The results suggest that SAH induces complicated changes of intracranial PGs and OKY-046 can improve these pathological changes.

Topics: Animals; Basilar Artery; Brain; Cerebrovascular Circulation; Dinoprost; Dogs; Infusions, Intravenous; Ischemic Attack, Transient; Methacrylates; Prostaglandins E; Subarachnoid Hemorrhage; Thromboxane-A Synthase

In order to examine the functional changes in the vascular smooth muscle, the effects of a thromboxane A2 synthetase inhibitor (OKY-046) and a calcium channel blocker (diltiazem) on vessels following subarachnoid hemorrhage, and the contractile activity of cerebral vessels with various vasoactive agents, were investigated by studying isometric tension recordings in rings of cat basilar artery. The maximum contractile activities of the vessels in response to noradrenalin and adrenaline during the course of subarachnoid hemorrhage were significantly less than those in the control group. On the other hand, the maximum contractile activity of the vessels in response to prostaglandin F2 alpha on the seventh day following subarachnoid hemorrhage was significantly augmented compared with that in the control group. A significant decline in the relaxation of responsiveness to diltiazem during the course of subarachnoid hemorrhage was observed compared with that of diltiazem in the control group. This responsiveness to vasoactive agents was not influenced by the application of OKY-046. The present study reveals functional changes in vascular smooth muscle exposed to subarachnoid hemorrhage in response to vasoactive agents and a calcium entry blocker. Thromboxane A2 may not be a significantly influential factor in the present results. It is suggested that cerebral vasospasm may well be related to functional changes of the arterial wall, which appear to be associated with derangement of the mechanisms of smooth muscle constriction and dilatation based on organic changes.

Topics: Animals; Basilar Artery; Cats; Diltiazem; Dinoprost; Disease Models, Animal; Epinephrine; Methacrylates; Muscle Contraction; Muscle, Smooth, Vascular; Norepinephrine; Serotonin; Subarachnoid Hemorrhage; Thromboxane-A Synthase

Topics: Acrylates; Animals; Dogs; Ischemic Attack, Transient; Methacrylates; Subarachnoid Hemorrhage; Thromboxane-A Synthase

The prevention of cerebral vasospasm with OKY-046, an imidazole derivative and a thromboxane synthetase inhibitor, was studied co-operatively at ten neurosurgical services. Intravenous administrations of 2, 5 or 10 mu/kg/minute of OKY-046 were given continuously from the earliest possible day to the 14th SAH-day to 82 patients with ruptured cerebral aneurysm. Sixty-eight patients (83%) showed moderate to high high-density (SAH) in their initial CTs. Angiographic vasospasms were seen in 58 patients, representing 71% of all cases or 81% of the 72 cases for which angiograms were available: the vasospasms of 45 patients (55 or 63%) were moderate to severe. Symptomatic vasospasm occurred, however, only in 27 patients (33%): in 18 of those cases, moreover, the symptoms were mild or transient. The conditions of the patients at one month after the SAH were classified into 9 grades from 0 (normal) to 8 (deceased). Fifty-two patients (63%) were classified as 0 or 1, and 64 (78%) as better than 3 (possible daily life unaided). The administration of OKY-046 was proven to decrease TXB2 in the blood. This paper emphasizes the effectiveness of the drug for symptomatic vasospasm, and supports our previous contention that cerebral microthrombosis may play an important role in the pathogenesis of cerebral vasospasm.

Topics: Acrylates; Adult; Aged; Drug Eruptions; Female; Hemorrhage; Humans; Intracranial Aneurysm; Ischemic Attack, Transient; Male; Meclofenamic Acid; Methacrylates; Middle Aged; Recurrence; Subarachnoid Hemorrhage; Thromboxane-A Synthase