A randomized double-blind study of acetohydroxamic acid in struvite nephrolithiasis.
Williams J J,Rodman J S,Peterson C M
The New England journal of medicine
We studied the effects of the bacterial urease inhibitor acetohydroxamic acid on the growth of struvite stones in the urinary tract. Eighteen patients who received acetohydroxamic acid (15 mg per kilogram of body weight per day, in divided oral doses) for a mean of 15.8 months were compared in a randomized double-blind study with 19 patients who received placebo for a mean of 19.6 months. Seven patients given placebo reached a pre-determined end point: a 100 per cent increase in the two-dimensional surface area of their stones. No patient who received acetohydroxamic acid had a doubling of stone size (P less than 0.01). Nine patients receiving the drug and one patient receiving placebo required a decrease in dosage or cessation of treatment because of adverse effects (P less than 0.01). Episodes of tremulousness (n = 5, P less than 0.05), which reversed with a decrease in drug dose, and phlebothrombosis (n = 3, P not significant) were limited to the group given acetohydroxamic acid. We conclude that acetohydroxamic acid effectively inhibits the growth of struvite stones in the short term in patients infected with urea-splitting bacteria, but the prevalence of adverse reactions appears to be high and the toxicity and effectiveness of long-term therapy for struvite nephrolithiasis remain to be defined.
New drug therapy for kidney stones: a review of cellulose sodium phosphate, acetohydroxamic acid, and potassium citrate.
Lake K D,Brown D C
Drug intelligence & clinical pharmacy
Kidney stones have an overall incidence of two to three percent in western countries. In many patients, the disease process is difficult to control and recurrence rates are high: 20 to 50 percent over the subsequent ten years. The pathogenesis and standard methods of treatment for the five major types of stones (i.e., calcium oxalate, struvite, calcium phosphate, uric acid, and cystine) are reviewed. Three new drugs are reviewed in the context of their roles in the selective treatment of kidney stones. Cellulose sodium phosphate (Calcibind) is a nonabsorbable ion-exchange resin with a limited indication for the treatment of calcium stones associated with absorptive hypercalciuria Type I. Acetohydroxamic acid (Lithostat) is an urease-inhibitor that is indicated as adjunctive therapy in patients with chronic urea-splitting urinary tract infections and struvite stones. Potassium citrate (Urocit) is an investigational agent that has clinical efficacy in patients with calcium oxalate and calcium phosphate stones who are hypocitraturic. In addition, potassium citrate is an alkalinizing agent that can be used in patients with uric acid stones.
Interaction between acetohydroxamic acid and 12 antibiotics against 14 gram-negative pathogenic bacteria.
Musher D M,Saenz C,Griffith D P
Antimicrobial agents and chemotherapy
Acetohydroxamic acid (AHA) is a potent inhibitor of urease which prevents alkalinization of urine and stone formation in rats in the presence of infection caused by urease-producing bacteria. Because an antibacterial effect of AHA, and synergy between kanamycin and AHA have also been described, we studied the interaction between AHA and 12 antibiotics against 14 gram-negative bacteria. Synergy, sometimes to a striking degree, was found in 17% of interactions; however, antagonism was detected in 5%. Infecting organisms would need to be studied individually before the antibacterial effect of AHA and an antibiotic could be predicted.
Benurestat, a urease inhibitor for the therapy of infected ureolysis.
Andersen J A
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.
Urease. The primary cause of infection-induced urinary stones.
Griffith D P,Musher D M,Itin C
Previous reports have suggested that urease-producing bacteria play a prominent role in the formation of infection-induced urinary stones. We have carried out crystalization experiments in vitro which show that bacterial urease alkalinizes urine, thereby causing: (i) supersaturation with respect to struvite and calcium phosphate; and (ii) formation of struvite and apatite crystals. Growth of Proteus in urea-free urine or in urine which contained a urease inhibitor did not cause alkalinization, supersaturation, or crystallization of struvite and apatite. Growth of Klebsiella, Escherichia coli, or Pseudomonas was not associated with significant alkalinization, supersaturation, or crystallization. Struvite and apatite crystals dissolved in Proteus-infected urine in which undersaturation was maintained by urease inhibition. Similar results in all experiments were obtained using human urine and a synthetic urine which was devoid of matrix, pyrophosphate, or other undefined solutes. Urease-induced supersaturation appears to be the primary cause of infection-induced urinary stones.
Acetohydroxamic acid: clinical studies of a urease inhibitor in patients with staghorn renal calculi.
Griffith D P,Gibson J R,Clinton C W,Musher D M
The Journal of urology
The hydrolysis of urea by the bacterial enzyme urease pathologically increase urinary ammonia, bicarbonate, carconate and alkalinity. These factors contribute to the formation of urinary stones and to the virulence of bacteria. Acetohydroxamic acid, a potent inhibitor of urease, has been administered to 23 patients with staghorn renal calculi and urea-splitting urinary infection. Urinary ammonia and alkalinity has been reduced in every patient. A dose of 1.0 gm. acetohydroxamic acid daily has been well tolerated and effective for 2 to 12 months, even in patients with impaired renal function.
Prevention of infected urinary stones in rats by urease inhibitor: a new hydroxamic acid derivative.
Takeuchi H,Kobashi K,Yoshida O
We tested the inhibitory power and urinary excretion of several derivatives of hippurohydroxamic acid, including some newly synthesized compounds. m-Methoxyhippurohydroxamic acid (UCD II) strongly inhibited urease activity and high urinary excretion after oral administration to rats. UCD II inhibited the alkalinization of infected urine in vitro and in vivo and prevented bladder stone formation when it was orally administered to rats with urinary tract infection caused by Proteus mirabilis. The clinical application of UCD II to the prevention of pathologic sequelae of urinary infection with urease-producing bacteria awaits evaluation of the safety of the compound.
Urease inhibitor therapy in infected renal stones.
Martelli A,Buli P,Cortecchia V
The strict dependence of struvite and carbonate apatite renal stones on the urease-producing germs confirm the need to combine bacterial urease inhibitor drugs with antibiotic treatment. Of the two antiurease drugs used the better results were obtained with acetohydroxamic acid, both for its minimum side effects and its more powerful urease-inhibitor capacity. Thus stone recurrence was avoided even in patients with urinary infection not responding to specific antibiotic treatment.
Pharmacokinetics of acetohydroxamic acid in patients with staghorn renal calculi.
Putcha L,Griffith D P,Feldman S
European journal of clinical pharmacology
Acetohydroxamic acid (AHA), a bacterial urease inhibitor, has been recently approved by the United States Food and Drug Administration as a potential drug for the successful treatment of patients with infection induced staghorn renal calculi. The present study was designed to evaluate the disposition of 14C-AHA following oral administration to patients. The results of the study, while in a limited number of patients, indicate that upon oral administration, AHA is very rapidly absorbed from the gastrointestinal tract. Evaluation of urinary excretion data suggests that patients with compromised renal function have low recoveries of AHA in the urine. These data are supported by a strong linear correlation between creatinine clearance and AHA elimination. Acetamide and CO2 are identified as the two major metabolites of AHA in man. CO2 is eliminated in the breath and accounts for 20-45% of the administered dose, while acetamide is eliminated in the urine and accounts for only 9-14% of the administered dose. The remaining dose is eliminated as intact AHA in the urine (19-48%). Saliva concentrations of total radioactivity depict a strong positive correlation with their respective plasma concentrations. Parameter estimates from 14CO2 concentrations in breath as a function of time data closely correspond to the pharmacokinetic parameters of AHA in patients indicating that CO2 may be a primary metabolite derived directly from AHA rather than a secondary metabolite formed by the metabolism of an intermediate product. Upon multiple dose administration of AHA, there is the potential for significant accumulation of acetamide due to its relatively long half-life.
Effects of a novel urease inhibitor, N-(diaminophosphinyl)isopentenoylamide on the infection stone in rats.
Satoh M,Munakata K,Takeuchi H,Yoshida O,Takebe S,Kobashi K
Chemical & pharmaceutical bulletin
We evaluated the effect of a novel potent urease inhibitor, N-(diaminophosphinyl)isopentenoylamide (IPA), on the development of an infection bladder stone using our urolithiasis model in rats. IPA was excreted into urine after oral administration to rats, and the cumulative urinary recovery rate of unchanged IPA reached about 29.6% within 24 h (50 mg/kg). The oral administration of IPA (6.25 mg/kg, b.i.d., 5 d) significantly inhibited the development of the infection bladder stone. The present result suggests that IPA is a very promising compound in the prevention of formation and recurrence of an infection stone owing to a high efficacy and a low toxicity of IPA in animals.
Evaluation of effects of novel urease inhibitor, N-(pivaloyl)glycinohydroxamic acid on the formation of an infection bladder stone using a newly designed urolithiasis model in rats.
Satoh M,Munakata K,Takeuchi H,Yoshida O,Takebe S,Kobashi K
Chemical & pharmaceutical bulletin
By using our new infection stone model of a rat, we evaluated the effect of a novel urease inhibitor, N-(pivaloyl)glycinohydroxamic acid (P-GHA), on the formation of an infection bladder stone. The oral dosing of P-GHA significantly inhibited the elevation of the urinary ammonia level of rats having the urinary tract infection with Proteus mirabilis. A short term regimen (7 d, 730 +/- 38 mg/kg) with P-GHA significantly inhibited the development of the infection bladder stone. Furthermore, a long term combination regimen (11 d) of P-GHA and aminobenzylpenicillin markedly inhibited the development of the infection bladder stone, and also caused a very slight renal impairment to the rats tested in contrast with the method of Vermeulen et al. Our infection stone model in rats, therefore, seems to be useful for the evaluation of therapeutic agents in long term examinations.
Medical management of common urinary calculi.
Pietrow Paul K,Karellas Michael E
American family physician
Nephrolithiasis is a common condition affecting nearly 5 percent of U.S. men and women during their lifetimes. Recurrent calculi can be prevented in most patients by the use of a simplified evaluation, reasonable dietary and fluid recommendations, and directed pharmacologic intervention. Serum studies and 24-hour urine collections are the mainstays of metabolic investigation and usually are warranted in patients with recurrent calculi. Although some stones are the result of inherited conditions, most result from a complex interaction between diet, fluid habits, and genetic predisposition. Calcium-sparing diuretics such as thiazides often are used to treat hypercalciuria. Citrate medications increase levels of this naturally occurring stone inhibitor. Allopurinol can be helpful in patients with hyperuricosuria, and urease inhibitors can help break the cycle of infectious calculi. Aggressive fluid intake and moderated intake of salt, calcium, and meat are recommended for most patients.