ADVERSE REACTIONS TO COTRIMOXAZOLE IN HIV-INFECTION - A REAPPRAISAL OF THE GLUTATHIONE-HYDROXYLAMINE HYPOTHESIS

It is postulated that the unstable hydroxylamine metabolite of sulpham ethoxazole is responsible for the adverse reactions to co-trimoxazole and in HIV infection systemic glutathione deficiency leads to a reduce d capacity to counteract the hydroxylamine toxicity. This hypothesis h as been investigated by studying the metabolism of sulphamethoxazole a nd assessing glutathione status in HIV infection in order to explore t he modification of treatment. It is concluded that the toxicity of pla sma sulphamethoxazole hydroxylamine is counteracted by normal glutathi one concentrations as is the case in HIV-seropositive patients, but th at increased oxidation within certain cells in HIV infected individual s may possibly give rise to increased concentrations of reactive inter mediates of sulphamethoxazole. Sulphametrole and sulphamethoxazole hav e similar hair-lives but are metabolized differently: in vivo no oxidi sed metabolites of sulphametrole could be detected, In a retrospective study the rate of adverse reactions to trimethoprim-sulphametrole app eared to be in the lower range of those reported for trimethoprim-sulp hamethoxazole indicating that the combination of trimethoprim-sulphame trole may be more favourable. The ratio of trimethoprim: sulphonamide is 1:5, but in-vitro studies with Toxoplasma gondii indicate that beca use of the synergic effect of both agents the dose of sulphonamide is possibly unnecessarily high.