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PLoS One ; 13(8): e0198881, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30157195


OBJECTIVE: To identify in vitro inhibitors of xanthine crystallization that have potential for inhibiting the formation of xanthine crystals in urine and preventing the development of the renal calculi in patients with xanthinuria. METHODS: The formation of xanthine crystals in synthetic urine and the effects of 10 potential crystallization inhibitors were assessed using a kinetic turbidimetric system with a photometer. The maximum concentration tested for each compound was: 20 mg/L for 3-methylxanthine (3-MX); 40 mg/L for 7-methylxanthine (7-MX), 1-methylxanthine (1-MX), theobromine (TB), theophylline, paraxanthine, and caffeine; 45 mg/L for 1-methyluric acid; 80 mg/L for 1,3-dimethyluric acid; and 200 mg/L for hypoxanthine. Scanning electron microscopy was used to examine the morphology of the crystals formed when inhibitory effects were observed. RESULTS: Only 7-MX, 3-MX, and 1-MX significantly inhibited xanthine crystallization at the tested concentrations. Mixtures of inhibitors had an additive effect rather than a synergistic effect on crystallization. CONCLUSION: Two of the inhibitors identified here-7-MX and 3-MX-are major metabolites of TB. In particular, after TB consumption, 20% is excreted in the urine as TB, 21.5% as 3-MX, and 36% as 7-MX. Thus, consumption of theobromine could protect patients with xanthinuria from the development of renal xanthine calculi. Clinical trials are necessary to demonstrate these effects in vivo.

Precipitação Química/efeitos dos fármacos , Cálculos Renais/química , Cálculos Renais/prevenção & controle , Urolitíase , Xantina/química , Xantinas/farmacologia , Aldeído Oxidase/deficiência , Aldeído Oxidase/urina , Cristalização , Regulação para Baixo/efeitos dos fármacos , Humanos , Técnicas In Vitro , Erros Inatos do Metabolismo/prevenção & controle , Erros Inatos do Metabolismo/urina , Erros Inatos do Metabolismo da Purina-Pirimidina/prevenção & controle , Erros Inatos do Metabolismo da Purina-Pirimidina/urina , Urolitíase/prevenção & controle , Urolitíase/urina , Xantina/antagonistas & inibidores , Xantina/urina , Xantina Desidrogenase/deficiência , Xantina Desidrogenase/urina
Artigo em Inglês | MEDLINE | ID: mdl-29723117


Hereditary xanthinuria (type I) is caused by an inherited deficiency of the xanthine oxidorectase (XDH/XO), and is characterized by very low concentration of uric acid in blood and urine and high concentration of urinary xanthine, leading to urolithiasis. Type II results from a combined deficiency of XDH/XO and aldehyde oxidase. Patients present with hematuria, renal colic, urolithiasis or even acute renal failure. Clinical symptoms are the same for both types. In a third type, clinically distinct, sulfite oxidase activity is missing as well as XDH/XO and aldehyde oxidase. The prevalence is not known, but about 150 cases have been described so far. Hypouricemia is sometimes overlooked, that´s why we have set up the diagnostic flowchart. This consists of a) evaluation of uric acid concentrations in serum and urine with exclusion of primary renal hypouricemia, b) estimation of urinary xanthine, c) allopurinol loading test, which enables to distinguish type I and II; and finally assay of xanthine oxidoreductase activity in plasma with molecular genetic analysis. Following this diagnostic procedure we were able to find first patients with hereditary xanthinuria in our Czech population. We have detected nine cases, which is one of the largest group worldwide. Four patients were asymptomatic. All had profound hypouricemia, which was the first sign and led to referral to our department. Urinary concentrations of xanthine were in the range of 170-598 mmol/mol creatinine (normal < 30 mmol/mol creatinine). Hereditary xanthinuria is still unrecognized disorder and subjects with unexplained hypouricemia need detailed purine metabolic investigation.

Aldeído Oxidase/deficiência , Erros Inatos do Metabolismo/epidemiologia , Erros Inatos do Metabolismo da Purina-Pirimidina/epidemiologia , Purinas/metabolismo , Xantina Desidrogenase/deficiência , Xantina Desidrogenase/metabolismo , Adulto , Aldeído Oxidase/sangue , Aldeído Oxidase/urina , Alopurinol/metabolismo , Criança , Pré-Escolar , República Tcheca/epidemiologia , Diagnóstico Diferencial , Humanos , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/urina , Erros Inatos do Metabolismo da Purina-Pirimidina/sangue , Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico , Erros Inatos do Metabolismo da Purina-Pirimidina/urina , Erros Inatos do Transporte Tubular Renal/sangue , Erros Inatos do Transporte Tubular Renal/epidemiologia , Erros Inatos do Transporte Tubular Renal/urina , Ácido Úrico/sangue , Ácido Úrico/urina , Cálculos Urinários/sangue , Cálculos Urinários/epidemiologia , Cálculos Urinários/urina , Xantina/sangue , Xantina/urina , Xantina Desidrogenase/sangue , Xantina Desidrogenase/urina