Combination treatment of hepatic encephalopathy due to thioacetamide-induced fulminant hepatic failure in the rat with benzodiazepine and opioid receptor antagonists

Background/Aims: Treatment of hepatic encephalopathy with drugs acting on t he target organ of this syndrome, the brain, is unsatisfactory. Combination treatment with different neurotransmitter receptor antagonists may be a ra tional option to optimize treatment. Methods: The effects of various doses of the benzodiazepine receptor antago nist Ro 15-3505 and the opioid receptor antagonist naloxone, alone or in co mbination, were tested on hepatic encephalopathy in rats with thioacetamide -induced hepatic failure in an open-field activity meter. Comparison of sin gle and combination treatment was also done using a neurological test batte ry. In addition, we compared survival of treatment-responder rats with trea tment non-responders. Results: Naloxone dose dependently increased ambulatory activity and improv ed neurological score. Ro 15-3505 also improved ambulatory activity and neu rological score; however, the improvement was less evident at higher doses. Combination treatment was not superior to single treatment. Survival was i ncreased in treatment-responder rats. Conclusions: The failure of combination treatment with Ro 15-3505 and nalox one to further improve hepatic encephalopathy may suggest that the two neur otransmitter systems are interrelated or that hepatic encephalopathy may no t be further improved by drugs acting on the brain.