Combination treatment of hepatic encephalopathy due to thioacetamide-induced fulminant hepatic failure in the rat with benzodiazepine and opioid receptor antagonists.
OBJECTIVE
Treatment of hepatic encephalopathy with drugs acting on the target organ of this syndrome, the brain, is unsatisfactory. Combination treatment with different neurotransmitter receptor antagonists may be a rational option to optimize treatment.


METHODS
The effects of various doses of the benzodiazepine receptor antagonist Ro 15-3505 and the opioid receptor antagonist naloxone, alone or in combination, were tested on hepatic encephalopathy in rats with thioacetamide-induced hepatic failure in an open-field activity meter. Comparison of single and combination treatment was also done using a neurological test battery. In addition, we compared survival of treatment-responder rats with treatment non-responders.


RESULTS
Naloxone dose dependently increased ambulatory activity and improved neurological score. Ro 15-3505 also improved ambulatory activity and neurological score; however, the improvement was less evident at higher doses. Combination treatment was not superior to single treatment. Survival was increased in treatment-responder rats.


CONCLUSIONS
The failure of combination treatment with Ro 15-3505 and naloxone to further improve hepatic encephalopathy may suggest that the two neurotransmitter systems are interrelated or that hepatic encephalopathy may not be further improved by drugs acting on the brain.
Celik
T
T
Department of Medical Pharmacology, Gülhane Military Medical Academy, Ankara, Turkey.
Uzbay
T
T
Cinar
K
K
Bozkaya
H
H
Uzunalimoglu
O
O
Yurdaydin
C
C
D000818:Animals; D001569:Benzodiazepines / Q000627:therapeutic use*; D001570:Benzodiazepinones / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006501:Hepatic Encephalopathy / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D009043:Motor Activity; D009270:Naloxone / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016019:Survival Analysis; D013853:Thioacetamide
D001570:Benzodiazepinones; D009292:Narcotic Antagonists; D013853:Thioacetamide; D001569:Benzodiazepines; D009270:Naloxone; C040725:Ro 15-3505