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Abstract: Urease is an attractive drug target for designing anti-infective agents against pathogens such as Helicobacter pylori, Proteus mirabilis, and Ureaplasma urealyticum. In the past century, hundreds of medicinal chemists focused their efforts on explorations of urease inhibitors. Despite the FDA’s approval of acetohydroxamic acid as a urease inhibitor for the treatment of struvite nephro-lithiasis and the widespread use of N-(n-butyl)thiophosphoric triamide as a soil urease inhibitor as nitrogen fertilizer synergists in agriculture, urease inhibitors with high potency and safety are urgently needed. Exploration of novel urease inhibitors has therefore become a hot research topic recently. Herein, inhibitors identified worldwide from 2016 to 2021 have been reviewed. They structurally belong to more than 20 classes of compounds such as urea/thioure analogues, hydroxamic acids, sul-fonamides, metal complexes, and triazoles. Some inhibitors showed excellent potency with IC50 val-ues lower than 10 nM, having 10000-fold higher potency than the positive control thiourea.

Objective: To evaluate the bacteriological features in non-struvite nephrolithiasis and in its associated urinary tract infection, and to establish the relationship between the two pathologies. Methods: The non-struvite calculi from 132 patients were aseptically extracted by percutaneous nephrolithotomy (PNL). The midstream urine and calculi were bacteriologically and biochemically processed. Results: Most calculi (78%) were located to renal pelvis, associated with hydronephrosis, the biochemical composition confirming the lack of struvite and revealing the predominance of calcium oxalate. The females presented significantly more colonized calculi (50%) than males (21.9%), with higher bacteriological diversity. There is a significant relation between the presence of colonized calculi and urinary tract infections, 24.2% of calculi and 25.8% of the urine samples presenting positive cultures. In 70.4% of cases, we found the same antibiotic resistance pattern between the pathogens isolated from calculi and urine, thus considering them identical strains. The Enterobacteriaceae represented the most predominant bacteria both from calculi (62.5%) and urine (63.6%), approximatively 30% being resistant to cephalosporins and over 50% resistant to fluoroquinolones, ampicillin and tetracycline. There were 3.8% of cases in which the calculi were colonized but the urine was sterile, the bacteria being sensitive to cephalosporins that are used as prophylaxis. Conclusions: In all the cases, the same bacterial species was found both in calculi and urine, and 70.4% of them were phenotypically identical. The resistance to the second generation cephalosporins is lower than in the case of other antibiotics, which makes them the most suitable for prophylaxis in PNL.

A new chemolytic therapy with amino acid preparation was tried for use on struvite renal stones in two dogs, which were admitted to Azabu University Veterinary Teaching Hospital. No other special diet, for the purpose of dissolving the stones, was fed during the treatment. Dissolution of the stones began at week 1, and no stone was detected on radiography at week 4 in both cases. The amino acid preparation thereafter has been administered every 2-3 days to prevent formation of the stones. After 6 months from treatment, complete dissolution was confirmed, and no relapse has been observed. Therefore, it is concluded that chemolytic therapy with amino acid preparation might be useful for the treatment of nephrolithiasis with struvite renal stones in dogs.

Objectives. Struvite calculus formation requires an alkaline urinary pH. An acidic urinary pH will dissolve struvite calculi and prevent recurrent struvite stone formation. Long-term urinary acidification has been unsuccessful. We sought to determine whether a gastric patch (with viable parietal cells) anastomosed to the renal pelvis could create an acidic urinary milieu. Methods. A vascularized stomach patch (from the greater curvature) was anastomosed to the left renal pelvis in 15 female pigs. The right kidney was used as a control. The first 6 pigs were used to refine the surgical technique. The remaining 9 pigs were subjected to a formal gastropyeloplasty and followed up for 4 weeks. Urine was collected before and after stimulation with pentagastrin. Urine pH was measured from both kidneys in response to gastrin stimulation and oral intake. The kidneys, ureters, and bladders were examined for gross changes and histologic review. Results. The 9 test animals had more acidic urine in the control kidney than in the gastropyeloplasty kidney. Pentagastrin had no significant impact on urinary pH. Hydroureteronephrosis and a concentrating defect were noted in the treated kidney. Histologic review revealed smooth muscle hyperplasia of the left ureter and viable parietal cells in the stomach patch. Conclusions. An animal model was developed to transfer a gastric patch to the renal pelvis. Hydronephrosis and ureteral dilation were associated with this gastric patch. We were unable to acidify the urine despite viable parietal cells in the transposed stomach segment. Further refinements of this concept may be successful in acidifying urine in the hope of preventing recurrent struvite nephrolithiasis.

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.

Reduced glomerular filtration rate (GFR) and hypercalciuria in primary struvite nephrolithiasis. Struvite nephrolithiasis is caused by infection with bacteria that possess the enzyme urease, and convert urea to ammonia that raises urine pH and crystallizes with magnesium and tri valent phosphate ion. Of the 75 of our 1431 stone patients with struvite stones 52 were women. Struvite stones occurred almost exclusively in women; a minority of women and most men had mixed stones of struvite and calcium oxalate. Increased serum creatinine levels and reduced creatinine clearance were common in patients with struvite stones, not in those with mixed stones; both were rare in calcium stone disease. Men and women with mixed struvite, calcium oxalate stones were hypercalciuric, but women with struvite stones were not. Patients with mixed stones usually had initial symptoms of stone passage, and were less likely to need surgery, including nephrectomy, or to form contralateral stones. Patients with struvite stones usually presented with infection or no symptom, not passage. We conclude that struvite stones occur in two forms. The struvite stone is a disease of women, presumably occurring de novo from infection. The mixed stones occur in both sexes, presumably from secondary infection in hypercalciuric patients who begin with calcium–oxalate stone disease.