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The influence of diazepam treatment following prolonged ethanol administration was toxicologically examined in rhesus monkeys and rats. In the monkey, ethanol was intragastrically administered through a chronically implanted catheter by programmed infusions at doses of 1.5 g/kg 4 times daily every 6 hours over a period of 5 or 10 weeks and followed by intragastric administration of diazepam 4 mg/kg twice a day for 5 weeks. In the rat, ethanol was administered by gavage at doses of 8 g/kg once a day or 4 g/kg twice a day for 5 weeks after which diazepam 300 mg/kg was intragastrically administered once daily for 5 weeks. In the monkey, ethanol produced such toxic changes as hypertriglyceridaemia, fatty metamorphosis of the hepatocytes associated with megamitochondria, proliferation of smooth endoplasmic reticulum and vacuolation in the hepatocytes, and gastritis. Diazepam did not aggravate but mostly alleviated these changes. In the rat, on the contrary, the serum GPT level slightly elevated due to the ethanol administration, and remained at the elevated level with the diazepam treatment in contrast with the complete recovery with non-treatment for 5 weeks after the ethanol administration. However, such changes as increase of fat droplets in the hepatocytes and the triglyceride concentration in the liver which had been developed by ethanol administration recovered during the diazepam treatment period. In spite of the recovery, the elevation of the serum GPT level being remained by diazepam may indicate possible influence of diazepam on the liver function when the drug is administered after prolonged administration of ethanol.

Toxicological studies on the influence of diazepam following prolonged administration of ethanol in the rhesus monkey and rat.