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.