Shuichi Takaki

Significance of Elevated Thrombin-Antithrombin III Complex and Plasmin-α2-Plasmin Inhibitor Complex in the Acute Stage of Nontraumatic Subarachnoid Hemorrhage

Thrombin-antithrombin III complex (TAT) and plasmin-alpha 2-plasmin inhibitor complex (PIC) were examined in the acute stage in 51 patients with nontraumatic subarachnoid hemorrhage. TAT and PIC values were correlated with severity at the time of onset and with outcome. In the patients whose TAT levels were 25 ng/ml or more and PIC levels were 3.0 micrograms/ml or more (n = 16), only 25% had a good or fair outcome. In the patients with TAT levels less than 25 ng/ml or PIC levels less than 3.0 micrograms/ml (n = 35), on the other hand, 82.9% had a good or fair outcome. There were no significant differences in TAT and PIC levels between patients who experienced arterial spasm and those who did not. These results indicate that TAT and PIC values may reflect the severity of the brain damage induced by subarachnoid hemorrhage. It is speculated that marked coagulation and fibrinolytic disorders occur in the acute stage of subarachnoid hemorrhage.

Ventriculolumbar Perfusion of 3-[(4-Amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea Hydrochloride

We report on the toxicity, intrathecal pharmacokinetics, and therapeutic effect of the ventriculolumbar perfusion of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitros our ea hydrochloride (ACNU) against the subarachnoid dissemination of primary central nervous system tumors. Fifteen patients received ventriculolumbar perfusion of ACNU. One was treated with ventriculolumbar perfusion of ACNU alone, and the others underwent concomitant systemic chemotherapy; three of these patients received irradiation as well. ACNU was administered at an initial dose of 0.5 and was increased to 1.5 to 10.0 mg in six patients. Because of a lack of Level 2 or greater toxicity, the subsequent seven patients received 8.7 to 10.0 mg of ACNU dissolved in artificial cerebrospinal fluid (CSF) at a concentration of 0.1 mg/ml, from the start of the treatment. During ACNU administration, the lumbar CSF was drained at approximately the same rate as that of the infusion. Twelve patients received from 3 to 42 courses (average, 14 courses). The cumulative dose of ACNU ranged from 5 to 330.4 mg (average, 82.9 mg). One patient had a convulsion; two patients experienced transient headache, nausea, and vomiting; two others reported transient headache, nausea, vomiting, and fecal incontinence; and one experienced transient nausea, vomiting, and fecal incontinence. No side effects were noted in the other nine patients. When 9.0 to 9.5 mg of ACNU, dissolved in 90 to 95 ml of artificial CSF, was administered for 37 to 52 min, the maximum concentration of ACNU in the lumbar CSF was 9.86 to 12.79 micrograms/ml and the area under the drug concentration-time curve was 260.8 to 502.5 micrograms.min/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Distribution of mouse interferon-β in normal and brain tumour-bearing mice

SummaryThe distribution of125I-labelled recombinant mouse interferon-β (rMuIFN-β) in normal and glioma (203 glioma) bearing mice was studied by radioassay and macro-autoradiography at 15 and 30 min after a single intravenous injection. The level of rMuIFN-β in the spleen was about 20-fold higher than in serum. Concentrations higher than the serum level was detected in the lung, liver and kidney. The concentration of rMuIFN-β in the brain was 8% of the serum level and the concentration in the glioma 30 min after administration was about 10-fold higher than in normal mouse brain. Macro-autoradiographic study demonstrated a wide distribution range and selective uptake in glioma tissue. Furthermore, we found that mouse gliomas were sensitive to mouse IFN-β. Our findings demonstrate that in the mouse glioma model, intravenously administered interferon reaches the tumour.

Neurotoxicity and pharmacokinetics of ventriculolumbar perfusion of methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-gluco-pyranoside (MCNU) in dogs

SummaryVentriculolumbar perfusion of methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU), a water soluble nitrosourea with log P-0.71, may be efficacious in the treatment of subarachnoid dissemination of malignant glioma. We used 2 dogs to study the neurotoxicity and pharmacokinetics of MCNU. MCNU (1 mg), dissolved in 10 ml of artificial CSF, was administered via the right lateral ventricle during a period of 18 to 42 min and the CSF was drained by lumbar puncture. The perfusion was repeated once a week for 10 consecutive weeks. No neurological and systemic symptoms were noted after perfusion. Histological examination of the brain and spinal cord showed local denudation of the ependyma and local subependymal spongy degeneration and gliosis in the lateral ventricle into which MCNU was administered in one dog and local denudation of the ependyma in the other. When administration was over a period of 21 to 38 min, the MCNU concentration in the lumbar CSF peaked at 11.11 to 50.67 Μg/ml, in 28 to 78 min. The area under the drug concentration-time curve (AUC) was 1152 Μg×min/ml on average, significantly larger than that of ACNU. The elimination phase followed linear kinetics and the half-time was 41.1 min on average, significantly longer than that of ACNU. These findings suggest that ventriculolumbar perfusion of MCNU may be effective in the treatment of subarachnoid dissemination of malignant glioma notwithstanding some local histological changes.

Intrathecal Perfusion Therapy with Nitrosoureas Against Subarachnoid Dissemination of Glioma: Experimental and Clinical Studies

To test the feasibility of intrathecal perfusion of nitrosoureas in the treatment of subarachnoid dissemination of malignant glioma, the neurotoxicity and pharmacokinetics of ACNU and MCNU were studied in dogs. ACNU or MCNU 1–2 mg/10–20 ml of solution was administered via right lateral ventricle for 15 to 71 min and CSF was drained by lumbar puncture. No neurological symptom was noted after perfusion once a week for 10 weeks. Histological abnormality was minimum after ACNU and remarkable after MCNU perfusion. When ACNU or MCNU 1 mg/10 ml was perfused for 21 to 38 min, the AUC and the half-time were 460 ug × min/ml and 17.4 min on average in ACNU and 1152 ug × min/ml and 41.1 min on average in MCNU. Based on these experimental studies 4 patients with subarachnoid dissemination of malignant glioma were treated by intrathecal perfusion of ACNU. Improvement in symptom and/or CSF cytology was obtained in all cases. These findings suggested the usefulness of intrathecal perfusion of ACNU in the treatment of patients with subarachnoid dissemination of malignant glioma.

Antiproliferative Effect of Trapidil on a PDGF-Producing Glioma Cell Line In Vivo

Cell proliferation is regulated by growth factors which stimulate mitogenicity through binding to specific receptors on target cells. The platelet-derived growth factor (PDGF) is produced by many kinds of cells.

Lymphoproliferative lesion of the hypoglossal nerve: Case report

A rare case of a lymphoproliferative lesion in the hypoglossal nerve is reported. The patient, a 52-year-old woman, had symptoms identical with those of hypoglossal neurinoma. Computed tomography and magnetic resonance imaging revealed a lesion at the left cerebellomedullary angle. The tumor was removed, and histopathological studies revealed that the tumor consisted predominantly of lymphocytes.