Cerebral vacuolation induced in rats by the administration of LUP-3FDC, an anti-tuberculosis cocktail

A study was conducted to determine the subacute oral toxicity of LUP-3FDC (a cocktail composed of rifampicin, isoniazid and pyrazinamide) and LUP-Q1 (gatifloxicin sesquihydrate) as well as the potential effects of their combination when administered as repeated sublethal oral (gavage) doses for a period of 90 days in seven (7) groups of Wistar rats. Three (3) additional groups were allowed to live for 28 days after the end of treatment to evaluate the potential reversibility of any toxic effects observed. Mortality was observed at all dose levels. General body weakness and hind limb paralysis (attributable to peripheral neuropathy) were observed in animals administered 1400 mg/kg/day LUP-3FDC, 800 mg/kg/day LUP 3-FDC+300 mg/kg/day LUP Q1 and 1400 mg/kg/day LUP-3FDC+300 mg/kg/day LUP-Q1. The administration of LUP-3FDC at doses of 1100 or 1400 mg/kg/day or a combination of 1400 mg/kg/day LUP-3FDC and 300 mg/kg/day LUP-Q1 induced an increased incidence of vacuolation in the brain compared to control animals. This effect, which was observed predominantly in the cerebellar roof nuclei, was attributed to the isoniazid component of the compound. Vacuoles were located primarily in the myelinated areas close to cerebellar roof nuclei, but were also seen in the olfactory tubercle, thalamus, cerebral cortex, septum and basal ganglia. Females were more susceptible to this change; vacuoles were still evident in males and females 28 days after the cessation of compound administration. The rat cerebellum is prone to develop vacuolation with age; isoniazid may “accelerate” or “enhance” this tendency in young rats.