Benurestat, a urease inhibitor for the therapy of infected ureolysis.

A single oral administration of the urease inhibitor benurestat (2-(p-chlorobenz-amido)acetohydroxamic acid) to the human at 15 or 25 mg per kg produced, for 4 hr, mean urinary levels of inhibitory activity that were 700 to 1900 times that equivalent concentration of benurestat required to inhibit Proteus mirabilis urease by 90 per cent. In the rat these same dosage levels produced urinary inhibitory activity equivalent to 16 to 140 fold that required for 90 per cent urease inhibition. Benurestat administration, 25, 50, or 100 mg per kg, caused a decrease in the urinary excretion of ammonia from rats with experimental P. mirabilis genitourinary tract infection. The formation of struvite calculi was inhibited under these conditions. Nitrofurantoin, sulfamethoxazole, and ampicillin also slowed the formation of struvite calculi in infected rats and together with benurestat a potentiation of the inhibition of calculi formation was secured. Some combination therapies composed of benurestat plus an antibacterial agent, sulfamethoxazole or ampicillin, were effective in promoting the net dissolution of formed calculi. The number of viable bacteria present in the bladders of infected rats was significantly less after the administration of benurestat plus nitrofurantoin, sulfamethoxazole, or ampicillin than the respective numbers that were obtained from control infected rats or from rats administered either component of the combination separately.