Masaki Shibota

Effects of idebenone on neurological deficits, local cerebral blood flow, and energy metabolism in rats with experimental cerebral ischemia

Improvement of energy metabolism in ischemic cerebral tissue benefits the therapy of occlusive cerebrovascular disorders. In the present study, the effects of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (idebenone) on neurological signs, such as ischemic seizures, lactate and ATP contents of the cerebral cortex, and local cerebral blood flow, were assessed in stroke-prone spontaneously hypertensive rats (SHRSP) with experimentally induced cerebral ischemia. Experimental cerebral ischemia was caused by bilateral carotid artery occlusion (BCAO) in male SHRSP (8-10 weeks old). Pretreatment with idebenone (10-100 mg/kg, p.o.) for 3 or 10 days delayed the onset of ischemic seizure (acute stroke) and prolonged survival time in SHRSP roughly in a dose-dependent manner. When the compound (100 mg/kg, i.p.) was given once 30 min after BCAO, it exerted similar ameliorating effects on the neurological deficits. When idebenone (100 mg/kg for 3 days) was given orally, it did not significantly inhibit the decrease in regional cerebral blood flow induced by BCAO. However, the same treatment markedly inhibited increases in the lactate content and lactate/pyruvate ratio and the decrease in ATP content of the cerebral cortex. The compound did not affect cerebral blood flow in normal rats. These results suggest that idebenone ameliorates the neurological deficits related to cerebral ischemia, and that this effect is mediated by improving cerebral energy metabolism.

Effects of idebenone on lipid peroxidation and hemolysis in erythrocytes of stroke-prone spontaneously hypertensive rats

Stroke-prone spontaneously hypertensive rats (SHRSP) were kept on a 1% NaCl solution as drinking water to shorten the onset-time of a stroke. The level of lipoperoxide (LPO) in the erythrocytes of SHRSP loaded with salt for 22 days was significantly higher than that of the controls. Idebenone treatment (30 mg/kg per day, p.o.) markedly decreased the LPO to the level of the controls. Hemolysis in SHRSP was accelerated by the salt-loading. Idebenone significantly inhibited the hemolysis in a dose-dependent manner. These results suggest that idebenone inhibits lipid peroxidation in erythrocytes and stabilizes the erythrocyte membrane.

Cerebrovascular permeability in stroke-prone spontaneously hypertensive rats

Abstract Cerebrovascular permeability in the stroke-prone strain of spontaneously hypertensive (SHR) rats drinking a 1% NaCl solution was examined by injection of Evans blue, or 125I-labeled human serum albumin (125I-HSA), before and immediately after the onset of stroke. Leakage of Evans blue was locally found in the brain or spinal cord from rats with stroke signs, but not in those from rats without the signs. Examination of serial sections of the blue areas revealed association of dye leakage with pathological changes such as medial thickening and fibrinoid degeneration of arterioles, petechial hemorrhage, and edema. The increased cerebrovascular permeability to 125I-HSA was observed only in the blue spot areas but not in other parts of brain even in the rats with stroke signs. These findings indicate that increased cerebrovascular permeability is limited to the focal area with small vascular lesions which are closely related to the onset of stroke.

SYSTEMS IMPLEMENTED BY SPONSORS TO ASSURE CONDUCT OF CLINICAL TRIALS IN COMPLIANCE WITH JAPANESE GCP

The systems implemented by a sponsor for conducting clinical trials in accordance with Japanese good clinical practice (GCP) are presented from the planning stage to the new drug application (NDA) stage. Special attention is given to the sponsors internal organization for review of clinical trial plans, selection of medical institutions/investigators, monitoring, and review of case report forms and final reports, as well as auditing. Major problems in quality assurance are discussed from the standpoint of the sponsor. Some of the differences in the Japanese GCP and draft International Conference on Harmonization (ICH) GCP are also discussed.