ozagrel and Rupture--Spontaneous

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 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

The influence of the TXA2-synthetase inhibitor OKY-046 (Xanbon) on haematological findings for the coagulation-fibrinolysis system and platelet aggregation was investigated in patients with subarachnoid bleeding during or after the administration. Changes in alpha 2-PI activity and the levels of fibrinogen, t-PA and PAI antigen were observed. Especially, PAI activity and PAI antigen were found to be significantly increased as compared with levels before the administration. On the other hand, the platelet aggregation induced by various agents and the activity of AT-III were not greatly altered after the administration of OKY-046.

Topics: Adenosine Diphosphate; Adult; Aged; Aged, 80 and over; Blood Coagulation; Blood Platelets; Collagen; Female; Fibrinogen; Fibrinolysis; Humans; Intracranial Aneurysm; Male; Methacrylates; Middle Aged; Plasminogen Inactivators; Platelet Activating Factor; Rupture, Spontaneous; Thromboxane-A Synthase; Tissue Plasminogen Activator