ABSTRACT
Paracetamol, in toxic doses, is associated with extensive liver damage. This represents one of the common causes of morbidity and mortality in drug poisoning cases. This study was undertaken to investigate the possible potentiation of the hepatoprotective action of N-acetylcysteine (NAC) by cimetidine (CMD), an inhibitor of hepatic microsomal oxidative enzymes. The effects of NAC, cimetidine and the two in combination, administered 2 h post-paracetamol dose, on mortality, plasma glutamic oxaloacetic (GOT) and glutamic pyruvic (GPT) transaminase activities and hepatic reduced glutathione (GSH) levels were investigated in mice 24 h after treatment with a single oral dose of paracetamol (400 mg/kg). Both NAC and cimetidine caused a partial improvement of survival rate, plasma GOT and GPT activities. In addition, they prevented the depletion of hepatic GSH contents. However, concomitant administration of NAC and cimetidine produced a 100% survival rate and a marked reduction in plasma GOT and GPT activities to within the normal range, while significantly raising hepatic GSH concentrations to values close to those measured in saline-treated control animals. It is therefore concluded that cimetidine and N-acetylcysteine may have an additive hepatoprotective action in the treatment of paracetamol overdose.
Subject(s)
Acetaminophen/toxicity , Acetylcysteine/pharmacology , Analgesics, Non-Narcotic/toxicity , Cimetidine/pharmacology , Free Radical Scavengers/pharmacology , Histamine H2 Antagonists/pharmacology , Liver/drug effects , Acetaminophen/administration & dosage , Acetylcysteine/administration & dosage , Acetylcysteine/therapeutic use , Administration, Oral , Alanine Transaminase/blood , Analgesics, Non-Narcotic/administration & dosage , Animals , Aspartate Aminotransferases/blood , Cimetidine/administration & dosage , Cimetidine/therapeutic use , Free Radical Scavengers/administration & dosage , Free Radical Scavengers/therapeutic use , Glutathione/metabolism , Histamine H2 Antagonists/administration & dosage , Histamine H2 Antagonists/therapeutic use , Liver/enzymology , Liver/pathology , Liver Diseases/mortality , Liver Diseases/pathology , Liver Diseases/prevention & control , Male , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Necrosis , Survival RateABSTRACT
1. The isolated choroid plexus of the rabbit takes up 5-methyltetrahydrofolate from the incubation medium. 2. Other folate analogues (pteroylglutamic acid, methotrexate, 5-formyltetrahydrofolate = folinic acid) inhibited the uptake of 5-methyltetrahydrofolate. 3. The uptake of 5-methyltetrahydrofolate was inhibited by low temperature, anaerobic conditions and dinitrophenol. 4. The anticonvulsant drugs, diphenylhydantoin and phenobarbital, had no effect on 5-methyltetrahydrofolate uptake. 5. The inhibitory effect of pteroylglutamic acid on the uptake of 5-methyltetrahydrofolate by the choroid plexus may explain the effect of long-term folic acid therapy in aggravating vitamin B12 neuropathy in pernicious anaemia.
