Takayuki Ozaki

Behavioral and Electroencephalographic Studies of Beagles with an Eck's Fistula: Suitability as a Model of Hepatic Encephalopathy

Behavioral manifestations, electroencephalograms (EEGs) and visually evoked potentials (VEPs) were studied in beagles with Ecks fistula (portacaval shunt [PCS]), an established model of hyperammonemia, to determine whether they developed CNS disorders characteristic of hepatic encephalopathy. After PCS, behavioral changes occurred in the form of listlessness, sluggishness (altered gait, snapping and transient catatonia-like symptoms) and apparent blindness, which appeared in that order and progressed to coma and death in some animals. The EEGs from the frontal cortex showed a gradual decrease in voltage and frequency. Development of snapping and catatonia-like symptoms coincided with the occurrence of high voltage fast waves in the EEGs from the occipital cortex. In comatose Ecks fistula dogs. flattening of the EEGs was recorded from the frontal cortex and a lowered voltage was noted in the EEGs from the occipital cortex. After PCS, the latencies and amplitudes of the components of VEP were increased. The snapping and catatonia-like symptoms were markedly ameliorated by carbamazepine and the coma by flumazenil and thyrotropin-releasing hormone. These findings indicate that Ecks fistula dogs provide a useful model of hepatic encephalopathy.

Hypolipidemic effect of NS-1 and other related drugs in rhesus monkeys

NS-1, 4-[2-(4-isopropylbenzamido)ethoxy]benzoic acid, is a novel chemical compound which has been found to be a potent hypolipidemic agent in rhesus monkeys. Significant reductions in serum cholesterol and phospholipids were observed in normolipidemic monkeys following oral doses of 30-300 mg/kg/day. A dose of 300 mg/kg/day for 28 days lowered serum cholesterol and phospholipid levels by 49% and 41%, respectively. NS-1 was more potent than clofibrate, clinofibrate, simfibrate, bezafibrate, gemfibrozil, nicomol and probucol in hypolipidemic activity in the same model. Lipoprotein analysis showed that NS-1 reduced low density lipoprotein much more than high density lipoprotein. The results suggest that NS-1 may have hypolipidemic activity in hyperlipidemic patients.

Effect of THD-341, a new hypocholesterolemic agent, on experimental atherosclerosis in rabbits

The influence of THD-341, N-(2,6-dimethylphenyl)-delta8-dihydroabietamide, upon the formation and regression of atherosclerosis and on serum and liver lipid levels has been studied. When rabbits were fed a 1% cholesterol diet for 7 weeks, THD-341 added at a dietary level of 0.01% during the last 4 weeks almost completely prevented the formation of atherosclerotic lesions and the elevation of serum and liver cholesterol levels. When the drug was fed for 10 weeks, either in the normal or cholesterol diet, to rabbits with pre-established atherosclerosis induced by cholesterol feeding for 11 weeks, it did not affect the extent or severity of the lesions but inhibited the progression of lipid deposition in the aorta in a group fed the cholesterol diet during the final 10-weeks period. The reduction of serum and liver cholesterol levels was greater in the drug-treated groups than in the normal rabbit chow-fed group.

Hypocholesterolemic action of a novel Δ8-dihydroabietamide derivative, THD-341, in rats

The hypocholesterolemic properties of THD-341, N-(2,6-dimethylphenyl)-delta8-dihydroabietamide, were studied in rats. THD-341 reduced serum cholesterol levels in cholesterol-cholate-fed rats at a concentration of less than 0.001% in the diet or an oral dose of less than 3 mg/kg, once a day. When compared in terms of the 50% inhibitory dose for serum cholesterol elevation (ID 50%, % in diet), THD-341 (0.0008%) was comparable to D-thyroxine (0.0005%), more potent than estradiol (0.003%), and far more potent than clofibrate (0.2%), beta-sitosterol (0.8%), cholestyramine (2%), or nicotinic acid (3%). A daily intravenous injection of THD-341 was also effective (ID 50%: 7 mg/kg). THD-341 reduced serum and liver cholesterol in rats made hypercholesterolemic by 0.3% dietary thiouracil or 0.25% dietary cholate. Liver cholesteriol was more profoundly affected than the serum cholesterol. In normal rats, cholesterol was reduced in liver but not in serum. Its mechanism of action is unknown but the results suggest that THD-341 inhibits cholesterol absorption or re-absorption.

実験的肝性昏睡ラットモデルにおける血中および脳内アンモニア濃度ならびに昏睡に対するラクチトール(NS-4)の作用

Encephalopathy caused by hepatic cirrhosis is often associated with portasystemic shunt and hepatic parenchymal injury. Together, these are known as a combined-type symptom. Two experimental hepatic comatose models with combined-type symptom were developed in rats. Both of these models involve the administration of ammonium acetate (500 mg/kg) into the cecum in portacaval shunted (PCS) rats. In addition, hepatic injury was induced in one model by carbontetrachloride (CCl4) and in the other by dimethylnitrosamine (DMNA). These model rats showed a higher increase in the concentration of ammonia in the blood and a higher incidence of coma as determined by the loss of the righting reflex than did rats subjected to a shunt only (PCS operation + ammonia loading) or hepatic parenchymal injury only (CCl4 treatment + ammonia loading). The effect of lactitol, administered orally for 7.5 days, on the experimental hepatic coma was compared with that of lactulose. Lactitol significantly inhibited the increase in blood and brain ammonia concentration at doses of 3 and 6 g/kg/day and also reduced the incidence of coma. The effects of lactitol were similar to those of lactulose, a therapeutic agent for hepatic encephalopathy. Therefore, lactitol should be useful in the clinical treatment of hyperammonemia or hepatic encephalopathy.

実験的肝性昏睡ラット脳波に対するラクチトール(NS-4)の改善作用について

Electroencephalographic (EEG) studies were conducted to demonstrate the ameliorating effects of lactitol and its reference drug lactulose on the disturbance of consciousness caused by severe hepatic encephalopathy in rats permanently implanted with cortical electrodes. A novel experimental animal model of combined-type human hepatic encephalopathy was prepared by portacaval shunting followed by a single treatment with dimethylnitrosamine (30 mg/kg, i.p.). Lactitol or lactulose was orally administered twice a day for seven days and once on the morning of the eighth day. Ammonium acetate (500 mg/kg) was injected into the cecum 4 hr after the final administration of the drug. In control animals not treated with either drug, but in which hepatic encephalopathy had been induced, ammonium acetate induced a comatose state defined by a loss of the righting reflex accompanied by slowing or flattening of the cortical EEG. In control animals, significant increases in delta (1-3 Hz)-activity and significant decreases in beta (13-25 Hz)-activity during coma were detected by means of EEG power spectral analysis. Lactitol at doses of 3 g/kg/day or higher or lactulose at 6 g/kg/day significantly suppressed these EEG changes. Both drugs also suppressed in a dose-dependent manner the loss of the righting reflex. Lactitol may therefore be useful for ameliorating the disturbance of consciousness in patients with hepatic encephalopathy.