Renal and general tolerability of repeated doses of nimesulide in normal subjects

Abstract

The renal and general tolerability of nimesulide was studied in 16 healthy men, randomised to 4 groups of 4 subjects. The groups all underwent 2 treatment periods of 7 days each, separated by a washout period of 14 days. The second treatment period was always at a higher dosage level than the first. There were 4 dosage regimens: placebo, and nimesulide 200, 300 and 400mg, all given twice daily by mouth according to a double-blind design. The tolerability of nimesulide was assessed by regular clinical examination, nondirected questions about adverse events, haematological and biochemical screening, and daily urine testing. Plasma and urinary concentrations of Tamm-Horsfall glycoprotein (THG), urinary retinol-binding protein (RBP) and beta-N-acetyl glucosaminidase (NAG) on days 1, 3, 7, and 10 of each period were used as selective indicators of nephrotoxicity. The highest dose of nimesulide (800mg daily) was associated with abdominal pain and indigestion in 5 of 8 recipients. The 400 and 600mg daily dosages were well tolerated. There were no clinically significant alterations in the haematological or biochemical screening tests during the study, and daily urinalysis remained normal throughout. The renal toxicity tests showed no evidence of nephrotoxicity associated with the administration of nimesulide in 14 subjects. The other 2 subjects each had modest increases in either urinary THG or NAG concentrations during treatment with nimesulide 800mg daily, but the results of their other tests remained normal. The study, therefore, showed only equivocal evidence of minor renal toxicity with nimesulide 800mg daily. Nimesulide 400 and 600mg daily were well tolerated in all respects, even though these dosages are higher than those recommended for clinical use.