Combination Therapy of Isoniazid and Hepamerz (L-ornithine, L-aspartate) -Effects on Liver and Kidney Functions of Rabbits

Abstract

Background:  Isoniazid (INH), first line drug for antitubercular treatment, induces hepatic necrosis in some of human beings in normal doses and in experimental animals in toxic doses. Reactive toxic metabolites of INH are released which disrupt hepatocellular membrane and cause necrosis. So there is a need to find some hepatoprotective and antioxidant agent. Hepamerz is prescribed for liver disease acute hepatitis i.e. viral, non-viral, drug induced, chronic hepatitis, fatty liver with hyperammonaemia, hepatic encephalopathy.

Objective:  Purpose of this research was an attempt to observe protective effects of hepamerz on liver and kidney against isoniazid induced toxicity in rabbits.

Methods:  Study was conducted on oryctolagus cuniculus rabbits (1-1.5 kg) of either sex for the period of 11 days. Rabbits were divided in five groups at random with 6 animals in each group. In group I normal liver and renal function tests were recorded without any drug. In group II effects of hepamerz (1.5cc/kg/i.p.) were observed.  In Group III isoniazid (50 mg/kg/ day i.p.) was administered. In group IV (a+b) combined effects of isoniazid (50mg/kg /day i.p) and hepamerz (1.5 cc/kg) intraperitoneally and orally were observed respectively. Liver function tests (bilirubin, ALT and AST) and renal function tests (BUN and creatinine) were performed. Rabbits were sacrificed on 12^th day for observing histopathological changes in liver and kidney.

Results:  In biochemical analysis, hepamerz (group II) showed hepatoprotective and nephroprotective effects. Liver and kidney architecture remained almost intact in group II. In group III, bilirubin level increased (P < 0.05). Histological picture of liver revealed ballooning degeneration, portal inflammation and necrosis of hepatocytes which are signs of acute inflam-mation. 50% necrosis was observed in kidney. In group IV (a+b) there was decrease (P<0.05) in ALT level, liver archi-tecture manifested increased inflammatory changes as well as apoptosis, rise (P < 0.05) in BUN and creatinine levels show-ing nephrotoxicity. In this group rabbits also manifested central neurological effects (tonic clonic convulsions), peripheral neurological effects (paraplegia). There was no mortality in group I and II while in group III, IVa and IVb there was 33%, 83% and 66% mortality respectively. It can be concluded that INH induced biochemical and histopathological changes are not antagonized by concurrent administration of hepamerz for 11days. Additionally nephrotoxic and neurotoxic effects were observed by this combination therapy.

Key Words:  Hepatotoxicity, Nephrotoxicity, INH-induced hepatotoxicity, Hepamerz, Liver Function Tests, Renal Function Tests.