RESUMEN
Cystinuria is an inherited autosomal recessive disease of the kidneys of recurring nature that contributes to frequent urinary tract infections due to bacterial growth and biofilm formation surrounding the stone microenvironment. In the past, commonly used strategies for managing cystinuria involved the use of (a) cystine crystal growth inhibitors such as l-cystine dimethyl ester and lipoic acid, and (b) thiol-based small molecules such as N-(2-mercaptopropionyl) glycine, commonly known as tiopronin, that reduce the formation of cystine crystals by reacting with excess cystine and generating more soluble disulfide compounds. However, there is a dearth of simplistic chemical approaches that have focused on the dual treatment of cystinuria and the associated microbial infections. This work strategically exploited a single chemical approach to develop a nitric oxide (NO)-releasing therapeutic compound, S-nitroso-2-mercaptopropionyl glycine (tiopronin-NO), for the dual management of cystine stone formation and the related bacterial infections. The results successfully demonstrated that (a) the antibacterial activity of NO rendered tiopronin-NO effective against the stone microenvironment inhabitants, Escherichia coli and Pseudomonas aeruginosa, and (b) tiopronin-NO retained the ability to undergo disulfide exchange with cystine while being reported to be safe against canine kidney and mouse fibroblast cells. Thus, the synthesis of such a facile molecule aimed at the dual management of cystinuria and related infections is unprecedented in the literature.
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Infecciones Bacterianas , Cistinuria , Ratones , Animales , Perros , Cistinuria/tratamiento farmacológico , Tiopronina/farmacología , Tiopronina/uso terapéutico , Cistina/farmacología , Disulfuros , Escherichia coli , Óxido NítricoRESUMEN
The current pharmacotherapy of neuropathic pain is inadequate as neuropathic pain involves varied clinical manifestations with multifactorial etiology, modulated by a cascade of physical and molecular events leading to different clinical presentations of pain. There is an accumulating evidence of the involvement of oxidative stress in neuropathy, and antioxidants have shown promise in mitigating neuropathic pain syndromes. To explore the evidence supporting this beneficial proclivity of antioxidants, this study investigated the antinociceptive effectiveness of N-(2-mercaptopropionyl)glycine or tiopronin, a well-recognized aminothiol antioxidant, in a refined chronic constriction injury (CCI) rat model of neuropathic pain. Tiopronin (10, 30, and 90 mg/kg, i.p.) and pregabalin (30 mg/kg, i.p.) were administered daily after CCI surgery. The neuropathic paradigms of mechanical/cold allodynia and mechanical/heat hyperalgesia were assessed on days 3, 7, 14, and 21 post-nerve ligation. At the end of study, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels were estimated in the sciatic nerve, dorsal root ganglion, and spinal cord for assessing the extent of oxidative stress. The expression of neuropathic nociception was attenuated by tiopronin which was observed as a significant attenuation of CCI-induced allodynia and hyperalgesia. Tiopronin reversed the neuronal oxidative stress by significantly reducing MDA, and increasing SOD, CAT, and GSH levels. Pregabalin also showed similar beneficial propensity on CCI-induced neuropathic aberrations. These findings suggest prospective neuropathic pain attenuating efficacy of tiopronin and further corroborated the notion that antioxidants are effective in mitigating the development and expression of neuropathic pain and underlying neuronal oxidative stress.
Asunto(s)
Antioxidantes/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Tiopronina/uso terapéutico , Animales , Antioxidantes/farmacología , Catalasa/metabolismo , Frío , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Glutatión/metabolismo , Calor , Hiperalgesia/metabolismo , Masculino , Malondialdehído/metabolismo , Neuralgia/metabolismo , Ratas Sprague-Dawley , Nervio Ciático/efectos de los fármacos , Nervio Ciático/lesiones , Nervio Ciático/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Superóxido Dismutasa/metabolismo , Tiopronina/farmacología , TactoRESUMEN
INTRODUCTION: To systematically review the effect of additional drug therapy as metaphylaxis in patients with cystinuria. EVIDENCE ACQUISITION: A literature search of three databases (MEDLINE, Embase and the Cochrane Library) was performed according to the PRISMA-guidelines enclosing articles published up to May 2019. A total of 1117 articles were screened. Thirty-four publications met the inclusion criteria for this review. EVIDENCE SYNTHESIS: Male-female ratio in the studied cohorts was 49.9% - 50.1%. The majority of studies showed a positive effect in reducing stone events and/or urinary cystine excretion. D-Penicillamine showed success in 13/14 (92%) studies, whereas Tiopronin-treatment showed a reduction in all (8/8; 100%) studies. All studies on Captopril (4/4) showed a decrease, however not all significant. The same is true for studies on Thiols in combination with Captopril (2/2). Furthermore, Tiopronin showed less side effects compared to D-penicillamine, respectively 30% and 37%. Captopril showed the least adverse events, with one event in nine patients. CONCLUSIONS: The evidence on benefit of additional drug therapy in patients with cystinuria is scarce. All studied medications showed an effect on stone event and urinary cystine excretion, when used in addition to hyperhydration, alkalization and a diet low on methionine. Based on this systematic review, no drug can be preferred over another. An important aspect in the choice of drug is the risk of side effects. Therefore, the choice of additional drug should be personalized for every patient where the risk of side effects should be taken into consideration.
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Cistinuria/tratamiento farmacológico , Quimioterapia Combinada , Captopril/uso terapéutico , Cistina/uso terapéutico , Medicina Basada en la Evidencia , Femenino , Humanos , Masculino , Penicilamina/uso terapéutico , Tiopronina/uso terapéuticoRESUMEN
Cystinuria comprises less than 1% of kidney stones and is associated with impaired health-related quality of life (HRQOL). Limited evidence is available regarding HRQOL of patients with cystinuria treated with tiopronin (Thiola®). The objective of this study was to assess the HRQOL of patients with or without tiopronin treatment. For this cross-sectional survey, patients on tiopronin treatment were recruited through the "Thiola® Total Care Hub," a specialty pharmacy used to dispense tiopronin, and compared with patients not taking tiopronin (non-tiopronin group) who were identified from the Cystinuria Contact Registry at New York University School of Medicine. Consented patients responded to a survey that included questions about their experiences with kidney stones, the Wisconsin stone quality of life (WISQOL) (disease-specific) questionnaire, and the short form-36 version 2 (SF-36v2) (generic) HRQOL questionnaire. Statistical analyses included independent-sample t tests, one-way analysis of variance (ANOVA), and correlations. The survey was completed by 312 patients: 267 in the tiopronin group (144 male, 123 female; mean 49 years) and 45 in the non-tiopronin group (10 male, 35 female; mean 48 years). Both groups utilized pain medications similarly (24% overall). Patients on tiopronin had a significantly better HRQOL than patients not on tiopronin for all WISQOL domains (p < 0.001) and all but the physical functioning SF-36v2 domain (p < 0.001), where both groups approached the US normative mean, when controlling for the last stone event. Compared with patients in the non-tiopronin group, patients taking tiopronin reported better HRQOL on both the WISQOL and SF-36v2.
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Cistinuria/tratamiento farmacológico , Calidad de Vida , Tiopronina/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Cistinuria/complicaciones , Femenino , Humanos , Cálculos Renales/complicaciones , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Oxidative stress contributes significantly to HCC pathogenesis. In this study, we investigated the possible chemoprotective effect of the thiol group-containing compound, tiopronin, against HCC induced chemically by diethylnitrosamine (DENA) in rats. In addition, we elucidated the possible underlying molecular mechanism. Adult male Wistar rats were divided into: Control group, DENA-treated group and tiopronin + DENA-treated group. Liver function tests (ALT, AST, ALP, albumin, total and direct bilirubin) as well as alpha fetoprotein (AFP) concentration were measured in the sera of samples. Oxidative stress biomarkers such as malondialdehyde, nitric oxide, catalase and glutathione peroxidase were measured in the liver tissue homogenates. Determination of the phosphorylated apoptosis signal-regulating kinase 1 (phospho-ASK1), phospho-P38 and phospho-P53 proteins by western blotting, caspase 3 by immunofluorescence in addition to histopathological examination of the liver tissues were performed. Our results showed that tiopronin prevented the DENA-induced elevation of the liver function enzymes and AFP. It also preserved the activities of antioxidant enzymes as well as providing protection from the appearance of HCC histopathological features. Interestingly, tiopronin significantly decreased the expression level of phospho-ASK1, phospho-P38 and phospho-P53, caspase 3 in the liver tissues. These novel findings suggested that tiopronin is an antioxidant drug with a chemoprotective effect against DENA-induced HCC through maintaining the normal activity of ASK1/ P38 MAPK/ P53 signalling pathway.
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Carcinoma Hepatocelular/metabolismo , Dietilnitrosamina/toxicidad , Neoplasias Hepáticas Experimentales/metabolismo , MAP Quinasa Quinasa Quinasa 5/metabolismo , Tiopronina/uso terapéutico , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Alquilantes/toxicidad , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/prevención & control , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/prevención & control , MAP Quinasa Quinasa Quinasa 5/antagonistas & inhibidores , Masculino , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Tiopronina/farmacología , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
OBJECTIVE: To evaluate medical treatments, in terms of adverse events (AEs) and therapeutic goals, in a large series of patients with cystinuria. PATIENTS AND METHODS: Data from 442 patients with cystinuria were recorded retrospectively. Crystalluria was studied in 89 patients. A mixed-effects logistic regression model was used to estimate how urine pH, specific gravity and cysteine-binding thiols (CBT) correlate with risk of cystine crystalluria. RESULTS: Alkalizing agents and CBT agents were given to 88.8% (n = 381) and 55.3% (n = 238) of patients, respectively. Gastrointestinal AEs were reported in 12.3%, 10.4% and 2.6% of patients treated with potassium bicarbonate, potassium citrate and sodium bicarbonate, respectively (P = 0.008). The percentages of patients who experienced at least one AE with tiopronin (24.6%) and with D-penicillamine (29.5%) were similar (P = 0.45). Increasing urine pH and decreasing urine specific gravity significantly reduced the risk of cystine crystalluria, whereas D-penicillamine and tiopronin treatments did not reduce this risk (odds ratio [OR] 1 for pH ≤6.5; OR 0.52 [95% confidence interval {95% CI} 0.28-0.95] for 7.0
Asunto(s)
Cistinuria , Adolescente , Adulto , Anciano , Niño , Preescolar , Cistinuria/tratamiento farmacológico , Cistinuria/prevención & control , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Francia , Humanos , Concentración de Iones de Hidrógeno , Lactante , Masculino , Persona de Mediana Edad , Penicilamina/efectos adversos , Penicilamina/uso terapéutico , Estudios Retrospectivos , Bicarbonato de Sodio/efectos adversos , Bicarbonato de Sodio/uso terapéutico , Tiopronina/efectos adversos , Tiopronina/uso terapéutico , Resultado del Tratamiento , Urinálisis , Adulto JovenRESUMEN
PURPOSE OF REVIEW: The incidence of pediatric nephrolithiasis is on the rise, with a significant related morbidity and a concomitant relevant increase in healthcare costs. The purpose of this review is to portray the current epidemiology and cause of renal stones in children, to provide a framework for appropriate clinical evaluation on an individual basis, and a guidance regarding treatment and prevention for the significant risk of lifelong recurrence and deriving complications. RECENT FINDINGS: The early identification of modifiable risk factors and other abnormalities is essential, to prevent related morbidity, the onset of chronic kidney disease, and the associated increased risk of developing other diseases. The implementation of risk reduction strategies, including dietary modifications and targeted pharmacological therapies, will significantly influence stone recurrences and preserve renal function. SUMMARY: Future research is desirable, with the aim to strengthen personalized conservative management of pediatric nephrolithiasis as first-line treatment.
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Dieta , Ambiente , Nefrolitiasis/epidemiología , Alopurinol/uso terapéutico , Quelantes/uso terapéutico , Niño , Tratamiento Conservador , Dietoterapia , Diuréticos/uso terapéutico , Diuréticos Conservadores de Potasio/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Humanos , Nefrolitiasis/prevención & control , Nefrolitiasis/terapia , Penicilamina/uso terapéutico , Citrato de Potasio/uso terapéutico , Factores de Riesgo , Inhibidores de los Simportadores del Cloruro de Sodio/uso terapéutico , Tiopronina/uso terapéuticoRESUMEN
BACKGROUND: Ischemia-reperfusion (I/R) injury of the heart as a consequence of myocardial infarction or cardiac surgery represents a serious clinical problem. One of the most prominent mechanisms of I/R injury is the development of oxidative stress in the heart. In this regard, I/R has been shown to enhance the production of reactive oxygen/nitrogen species in the heart which lead to the imbalance between the pro-oxidants and antioxidant capacities of the endogenous radical-scavenging systems. OBJECTIVES: Increasing the antioxidant capacity of the heart by the administration of exogenous antioxidants is considered beneficial for the heart exposed to I/R. N-acetylcysteine (NAC) and Nmercaptopropionylglycine (MPG) are two sulphur containing amino acid substances, which belong to the broad category of exogenous antioxidants that have been tested for their protective potential in cardiac I/R injury. OBSERVATIONS: Pretreatment of hearts with both NAC and MPG has demonstrated that these agents attenuate the I/R-induced alterations in sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils in addition to improving cardiac function. While experimental studies have revealed promising data suggesting beneficial effects of NAC and MPG in cardiac I/R injury, the results of clinical trials are not conclusive because both positive and no effects of these substances have been reported on the post-ischemic recovery of heart following cardiac surgery or myocardial infarction. CONCLUSION: It is concluded that both NAC and MPG exert beneficial effects in preventing the I/Rinduced injury; however, further studies are needed to establish their effectiveness in reversing the I/R-induced abnormalities in the heart.
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Acetilcisteína/farmacología , Acetilcisteína/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Corazón/efectos de los fármacos , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Tiopronina/uso terapéutico , Acetilcisteína/química , Animales , Antioxidantes/química , Corazón/fisiopatología , Humanos , Daño por Reperfusión Miocárdica/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Tiopronina/químicaRESUMEN
The diagnosis and treatment of patients with rare inherited metabolic disorders associated with recurrent and often obstructive kidney stones are important to the prevention of chronic kidney disease or end stage renal disease. Two case studies in this article describe the diagnosis and management of cystinuria, the most common rare kidney stone disorder.
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Cistinuria/diagnóstico , Íleon/trasplante , Cálculos Renales/cirugía , Uréter/cirugía , Adolescente , Adulto , Cistinuria/complicaciones , Cistinuria/terapia , Dietoterapia , Diuréticos/uso terapéutico , Femenino , Fluidoterapia , Humanos , Cálculos Renales/etiología , Masculino , Cumplimiento de la Medicación , Citrato de Potasio/uso terapéutico , Procedimientos de Cirugía Plástica , Insuficiencia Renal Crónica/etiología , Bicarbonato de Sodio , Tiopronina/uso terapéutico , Tomografía Computarizada por Rayos X , UreteroscopíaRESUMEN
Bacopa monnieri (BM, family Scrophulariaceae) is used in several traditional systems of medicine for the management of epilepsy, depression, neuropathic pain, sleep disorders and memory deficits. The present study investigated the potential of BM methanol (BM-MetFr) and BM n-butanol fractions (BM-ButFr) to reduce chemotherapy-induced emesis in Suncus murinus (house musk shrew). Cisplatin (30 mg/kg, i.p.) reliably induced retching and/or vomiting over a 2 day period. BM-MetFr (10-40 mg/kg, s.c.) and BM-ButFr (5-20 mg/kg, s.c.) antagonized the retching and/or vomiting response by â¼59.4% (p < 0.05) and 78.9% (p < 0.05), respectively, while the 5-HT3 receptor antagonist, palonosetron (0.5 mg/kg, s.c.), reduced the response by â¼71% (p < 0.05). The free radical scavenger/antioxidant, N-(2-mercaptopropionyl)-glycine (30-300 mg/kg, s.c.) reduced the retching and/or vomiting response occurring on day one non-significantly by 44% (p > 0.05). In conclusion, the n-butanol fractions of BM have anti-emetic activity comparable with palonosetron and MPG. BM may be useful alone or in combination with other anti-emetic drugs for the treatment of chemotherapy-induced emesis in man.
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Antieméticos/farmacología , Antineoplásicos/efectos adversos , Bacopa/química , Cisplatino/efectos adversos , Extractos Vegetales/farmacología , Vómitos/inducido químicamente , Vómitos/tratamiento farmacológico , Animales , Isoquinolinas/farmacología , Isoquinolinas/uso terapéutico , Masculino , Palonosetrón , Quinuclidinas/farmacología , Quinuclidinas/uso terapéutico , Antagonistas de la Serotonina/farmacología , Antagonistas de la Serotonina/uso terapéutico , Musarañas , Tiopronina/farmacología , Tiopronina/uso terapéutico , Vómitos/prevención & controlRESUMEN
BACKGROUND: Synthetic and natural antioxidants including Bacopa monnieri (L.) Pennell (Scrophulariaceae) which also possess anti-dopaminergic properties, have been proposed to be useful for emetogenic chemotherapy. In this study, synthetic [N-(2-mercaptopropionyl) glycine (MPG), vitamin C (Vit-C)] and natural [grape seed proanthocyanidin (GP), B. monnieri n-butanolic fraction (BM-ButFr)] antioxidants and their combinations were evaluated against cisplatin-induced emesis in pigeons during a 24 h observation period. METHODS: Emesis was induced using cisplatin (7.0 mg/kg, i.v). MPG (10, 20, 30 mg/kg), Vit-C (100, 200, 300 mg/kg), GP (50, 100, 150 mg/kg) and BM-ButFr (5, 10, 20 mg/kg) and their combinations were administered i.m., 15 min before cisplatin administration. The number of vomiting bouts, retching, emetic latency and % weight loss were recorded to assess antiemetic potential. Antioxidant activity was evaluated by the DPPH free radical scavenging assay (FRSA). RESULTS: Significant attenuation of vomiting bouts, retching, % weight loss along with an increase in latency was produced by all the antioxidants and their combinations compared to cisplatin alone and this is the first report of this activity of GP in pigeons. Low EC50 values in the FRSA for MPG (67.66 µg/mL), Vit-C (69.42 µg/mL), GP (6.498 µg/mL) and BM-ButFr (55.61 µg/mL) compared to BHT standard (98.17 µg/mL) demonstrated their radical scavenging capacity. Correlation between the antioxidant activity and antiemetic efficacy disclosed a high degree of correlation for the tested antioxidants. CONCLUSION: The selected synthetic and natural antioxidants and their combinations were able to attenuate cisplatin-induced vomiting, which correlated with their potent in vitro antioxidant activity.
Asunto(s)
Antioxidantes/uso terapéutico , Cisplatino/toxicidad , Extractos Vegetales/uso terapéutico , Vómitos/inducido químicamente , Vómitos/tratamiento farmacológico , Animales , Antieméticos/aislamiento & purificación , Antieméticos/uso terapéutico , Antineoplásicos/toxicidad , Antioxidantes/aislamiento & purificación , Ácido Ascórbico/aislamiento & purificación , Ácido Ascórbico/uso terapéutico , Bacopa , Columbidae , Femenino , Extracto de Semillas de Uva/aislamiento & purificación , Extracto de Semillas de Uva/uso terapéutico , Masculino , Extractos Vegetales/aislamiento & purificación , Proantocianidinas/aislamiento & purificación , Proantocianidinas/uso terapéutico , Tiopronina/aislamiento & purificación , Tiopronina/uso terapéuticoRESUMEN
Cystinuria is an inherited disorder characterized by defective renal reabsorption of cystine and dibasic amino acids leading to nephrolithiasis. This study was conducted to analyze the genotypes and phenotypes of pediatric patients with cystinuria. Eight children from Seoul National University Hospital and Asan Medical Center presenting with cystinuria from January 2003 to June 2016 were retrospectively analyzed. Mutational studies were performed by direct sequencing. Two of the 8 were male and 6 were female. The median ages at onset and diagnosis were 1.5 (range, 0.3-13.6) and 2.6 (range, 0.7-16.7) years, respectively. The median followed up was 7.7 (range, 3.4-14.0) years. Mutational analyses were performed in 7 patients and revealed biallelic SLC3A1 mutations (AA genotype) in 4 patients, a single heterozygous SLC3A1 mutation (A- genotype) in 1 patient, biallelic SLC7A9 mutations (BB genotype) in 1 patient, and a single heterozygous SLC7A9 mutation (B- genotype) in 1 patient. Two of the mutations were novel. No genotype-phenotype correlations were observed, except for earlier onset age in patients with non-AA genotypes than in patients with the AA genotype. All patients suffered from recurrent attacks of symptomatic nephrolithiasis, which lead to urologic interventions. At the last follow-up, 3 patients had a mild-to-moderate degree of renal dysfunction. This is the first study of genotypic and phenotypic analyses of patients with cystinuria in Korea.
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Cistinuria/patología , Estudios de Asociación Genética , Adolescente , Sistemas de Transporte de Aminoácidos Básicos/genética , Sistemas de Transporte de Aminoácidos Neutros/genética , Pueblo Asiatico/genética , Niño , Preescolar , Cistinuria/tratamiento farmacológico , Cistinuria/genética , ADN/química , ADN/genética , ADN/metabolismo , Análisis Mutacional de ADN , Femenino , Genotipo , Heterocigoto , Humanos , Lactante , Masculino , Nefrolitiasis/etiología , Polimorfismo Genético , República de Corea , Estudios Retrospectivos , Bicarbonato de Sodio/uso terapéutico , Tiopronina/uso terapéuticoRESUMEN
Hepatotoxicity induced by sorafenib and antiviral therapy is a limitation for its continuation treatment for patients with advanced hepatitis B virus-related hepatocellular carcinoma (HCC). This prospective study determined the efficacy of tiopronin in hepatotoxicity prevention of HBV-related HCC treatment. Eighty-two patients (median age, 50 years; 71 % male) of advanced HCC treated with sorafenib and antiviral therapy were included, of whom 40 were given the supplementation of tiopronin. The primary endpoint was liver function which was checked before the treatment and every week during the therapy. Besides, course discontinuations, dose reductions, HBV DNA levels and treatment efficacy were evaluated. Patient characteristics and liver function were comparable (p > 0.05). The proportion of abnormal liver function was significantly lower in tiopronin group than in control group including alanine transaminase (ALT, p = 0.035), aspartate aminotransferase (AST, p = 0.041), total bilirubin (TBIL, p = 0.021) and albumin (ALB, p = 0.001). Rates of course discontinuations (p = 0.024) and dose reductions (p = 0.046) were significantly lower in tiopronin groups, and disease control rate (p = 0.036) was higher. No difference was found in HBV DNA level. Multivariate regression analysis showed that sorafenib (OR 7.837; 95 % CI 3.845-15.333; p = 0.004), antiviral therapy (OR 3.871; 95 % CI 1.572-9.569; p = 0.044) and hepatoprotective drug (OR 3.007; 95 % CI 1.321-6.308; p = 0.046) played important roles in clinical outcome. Tiopronin tends to prevent the HCC patients from the treatment-induced hepatotoxicity, enhance patients' tolerance to sorafenib and antiviral therapy and even improve the cancer treatment efficacy.
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Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Hígado/efectos de los fármacos , Tiopronina/uso terapéutico , Antineoplásicos/efectos adversos , Antivirales/efectos adversos , Carcinoma Hepatocelular/virología , Quimioterapia Combinada , Femenino , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Hígado/lesiones , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Niacinamida/efectos adversos , Niacinamida/análogos & derivados , Compuestos de Fenilurea/efectos adversos , SorafenibRESUMEN
AIMS AND BACKGROUND: Chemotherapy-related hepatotoxicity is a limitation for the continuation of chemotherapy in patients with advanced colorectal cancer (CRC). This prospective study determined the efficacy of tiopronin infusion in chemotherapy-induced hepatoxicity. METHODS AND STUDY DESIGN: One hundred and fifty patients having advanced CRC treated with first-line palliative chemotherapy were included, of whom 86 were treated with mFOLFOX7 plus supplementation of tiopronin and 64 were treated with the same regimen without tiopronin. Aspartate aminotransferase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), total bilirubin (TBIL), gamma-glutamyl transferase (γ-GT), alkaline phosphatase (ALP), and albumin (ALB) were recorded before treatment and during every therapy cycle. In addition, course discontinuations, dose reductions, and chemotherapy efficacy were evaluated. RESULTS: The age and gender of the two groups were comparable (P >0.05). The proportions of abnormal mean ALT (P = 0.042), AST (P = 0.045), TBIL (P = 0.044) and ALB (P = 0.043) were significantly lower in the tiopronin group than the control group. Course discontinuations (P = 0.002), dose reductions (P = 0.005) and efficacy (P = 0.012) were significantly different between the two groups. Multivariate logistic regression analysis showed that the hepatoprotective drug played an important role in clinical outcome (OR = 6.837; 95% CI, 1.845 to 25.333; P = 0.004). CONCLUSIONS: Tiopronin tends to decrease the incidence of chemotherapy-induced hepatoxicity, enhance patients' tolerance to mFOLFOX7 treatment, and even benefit the efficacy of chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Neoplasias Colorrectales/tratamiento farmacológico , Sustancias Protectoras/uso terapéutico , Tiopronina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Aspartato Aminotransferasas/sangre , Bilirrubina/sangre , Médula Ósea/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Incidencia , L-Lactato Deshidrogenasa/sangre , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Estudios Prospectivos , Albúmina Sérica/metabolismo , Resultado del Tratamiento , gamma-Glutamiltransferasa/sangreRESUMEN
Over the past 10 years, major progress has been made in the knowledge of urinary lithogenesis, including the potential pathogenetic role of Randall's plaques and renal tubular crystal retention. Urine supersaturation is the driving force of this process and can be induced by some risk factors, including low urine volume, high urinary excretion of calcium oxalate and uric acid and low urinary excretion of citrate. Primary hypercalciuria can be due to intestinal overabsorption renal leak and bone reabsorption of calcium. Prophilaxis is mainly conducted with thiazides and low calcium diet which is indicated only in the intestinal form. Primary hyperoxaluria is treated with pyridoxine and may require in the severe forms simultaneous renal and liver transplantation. Enteric hyperoxaluria is secondary to fatty acids malabsorption and requires diet, oral calcium and cholestiramine. Hyperuricosuria is caused by diet endogenous overproduction, mainly due to enzymatic defects or high renal excretion of uric acid. Urine alkalinization with K or K and Mg citrate can prevent stone formation even in idiopathic uric acid nephrolithiasis, in which a defect of urine acidification is supposed to be the main abnormality, and in hypocitraturic patients. Cystinuria is a rare inherited defect with an intense clinical impact. It can be classified in three forms and urinary stone formation is the role. Increased solubility and conversion of cystine in a more soluble form are the main goals of the prophylaxis which includes K citrate and thiol agents administration. Tiopronin is preferred to D-penicillamine due to its lower side effects.
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Cistinuria/prevención & control , Hipercalciuria/prevención & control , Hiperoxaluria/prevención & control , Riñón/metabolismo , Nefrolitiasis/metabolismo , Nefrolitiasis/terapia , Catárticos/uso terapéutico , Ácido Cítrico/uso terapéutico , Cistinuria/complicaciones , Quimioterapia Combinada , Humanos , Hipercalciuria/complicaciones , Hiperoxaluria/complicaciones , Nefrolitiasis/dietoterapia , Nefrolitiasis/tratamiento farmacológico , Nefrolitiasis/etiología , Nefrolitiasis/prevención & control , Compuestos Organometálicos/uso terapéutico , Piridoxina/uso terapéutico , Factores de Riesgo , Distribución por Sexo , Tiazidas/uso terapéutico , Tiopronina/uso terapéutico , Resultado del Tratamiento , Complejo Vitamínico B/uso terapéuticoRESUMEN
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a clinicopathologic syndrome of which the main feature is diffuse macrovesicular hepatic steatosis caused by deposition of excessive free fatty acid and triglyceride in liver parenchyma. AIM: To observe the efficacy of Tiopronin in treatment of severe nonalcoholic fatty liver disease (NAFLD). PATIENTS AND METHODS: 30 patients with severe NAFLD were treated with Tiopronin for 3 months. 30 healthy people were selected as control. The body mass index (BMI) and plasma levels of endotoxin (ET), leptin, IL-6 and IL-8 were measured before and after treatment. RESULTS: The serum levels of ET, leptin, IL-6 and IL-8 in severe NAFLD group were significantly higher than those in control group (p < 0.05). After treatment with Tiopronin, these indexes were significantly lower than before (p < 0.05). CONCLUSIONS: The intestinal endotoxemia (IETM) occurs in patients with severe NAFLD. Leptin, IL-6 and IL-8 play important roles in pathogenesis of NAFLD. Tiopronin can reduce the levels of ET, leptin, IL-6 and IL-8 for treatment of NAFLD.
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Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Tiopronina/uso terapéutico , Adulto , Índice de Masa Corporal , Endotoxinas/sangre , Femenino , Humanos , Interleucina-6/sangre , Interleucina-8/sangre , Leptina/sangre , Masculino , Enfermedad del Hígado Graso no Alcohólico/sangre , Triglicéridos/sangreRESUMEN
We investigated anti-colitic effects of N-(2-mercaptopropionyl)-glycine (NMPG), a diffusible antioxidant, in TNBS-induced rat colitis model and a potential molecular mechanism underlying the pharmacologic effect of the antioxidant. NMPG alleviated colonic injury and effectively lowered myeloperoxidase activity. Moreover, NMPG substantially attenuated expression of pro-inflammatory mediators in the inflamed colon. NMPG induced hypoxia-inducible factor-1α (HIF-1α) in human colon carcinoma cells, leading to elevated secretion of vascular endothelial growth factor (VEGF), a target gene product of HIF-1 involved in ulcer healing of gastrointestinal mucosa. NMPG induction of HIF-1α occurred by inhibiting HIF prolyl hydroxylase-2 (HPH-2), an enzyme that plays a major role in negatively regulating HIF-1α protein stability. In in vitro Von Hippel-Lindau protein binding assay, the inhibitory effect of NMPG on HPH-2 was attenuated by escalating dose of ascorbate but not 2-ketoglutarate, cofactors of the enzyme. Consistent with this, cell-permeable ascorbate significantly attenuated NMPG induction of HIF-1α in cells. Our data suggest that NMPG is an anti-colitic antioxidant that exerts its pharmacologic effects at least partly through activation of an ulcer healing pathway, HIF-1-VEGF.
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Antioxidantes/uso terapéutico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Colitis/tratamiento farmacológico , Colitis/enzimología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Prolil Hidroxilasas/metabolismo , Tiopronina/uso terapéutico , Animales , Antioxidantes/farmacología , Ácido Ascórbico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Colitis/patología , Difusión , Activación Enzimática/efectos de los fármacos , Células HCT116 , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Tiopronina/farmacología , Ácido Trinitrobencenosulfónico , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
UNLABELLED: Bilateral obstructive nephrolithiasis is a rare cause of acute kidney injury (AKI) in early childhood. As soon as the identification of AKI secondary to ureteral stone is made, it will necessitate an emergency treatment. PATIENTS: We report three infants with AKI caused by bilateral obstructive ureteral cystine stones. They were diagnosed with acute post-renal injury due to obstructive bilateral ureteral stones based on ultrasound scan findings. Immediately, bilateral ureteral stents were inserted for urinary drainage. Once renal function recovered to normal, each patient underwent ureteroscopy and percutaneous nephrolithotomy at the same session. Cystinuria was diagnosed by stone analysis and increased urinary excretion of cystine. Patients were advised to maintain a high fluid intake and were treated with potassium citrate in addition to tiopronin. CONCLUSIONS: With these three cases we would like to emphasize the importance of urolithiasis in the differential diagnosis of acute renal failure in young children, since urolithiasis may only cause nonspecific symptoms in this population. An early diagnosis with prompt treatment and a close follow-up are the key for achieving the best long-term outcome in cystinuria.
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Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/etiología , Cistinuria/complicaciones , Cistinuria/diagnóstico , Lesión Renal Aguda/terapia , Anuria/diagnóstico , Anuria/etiología , Anuria/terapia , Preescolar , Cistinuria/terapia , Diagnóstico Diferencial , Diuréticos/uso terapéutico , Femenino , Fluidoterapia , Humanos , Lactante , Citrato de Potasio/uso terapéutico , Tiopronina/uso terapéuticoRESUMEN
AIM: To study the protective effects of tiopronin against high fat diet-induced non-alcoholic steatohepatitis in rats. METHODS: Male Sprague-Dawley rats were given a high-fat diet for 10 weeks. The rats were administered tiopronin (20 mg/kg) or a positive control drug ursodeoxycholic acid (UDCA, 15 mg/kg) via gavage daily from week 5 to week 10. After the rats were sacrificed, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), free fatty acids (FFA), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C), and liver homogenate FFA, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) were measured using commercial analysis kits. The expression levels of CYP2E1 mRNA and protein were determined using RT-PCR and immunoblot assays, respectively. RESULTS: Tiopronin significantly lowered both the serum ALT and AST levels, while only the serum ALT level was lowered by UDCA. Tiopronin significantly decreased the serum and liver levels of TG, TC and FFA as well as the serum LDL-C level, and increased the serum HDL-C level, while UDCA decreased the serum and liver TC levels as well as the serum LDL-C level, but did not change the serum levels of TG, FFA and HDL-C. Tiopronin apparently ameliorated the hepatocyte degeneration and the infiltration of inflammatory cells in the livers, but UDCA did not affect the pathological features of the livers. Both tiopronin and UDCA ameliorated the mitochondrial abnormality in the livers. The benefits of tiopronin were associated with increased SOD and GSH-Px activities, and with decreased MDA activity and CYP2E1 expression in the livers. CONCLUSION: Tiopronin exerts protective effects against non-alcoholic steatohepatitis in rats, which may be associated with its antioxidant properties and regulation of lipid metabolism.
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Antioxidantes/uso terapéutico , Dieta Alta en Grasa/efectos adversos , Hígado Graso/metabolismo , Hígado Graso/prevención & control , Hígado/efectos de los fármacos , Tiopronina/uso terapéutico , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Colesterol/sangre , Citocromo P-450 CYP2E1/metabolismo , Ácidos Grasos no Esterificados/sangre , Hígado Graso/sangre , Hígado Graso/patología , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratas , Ratas Sprague-Dawley , Triglicéridos/sangre , Ácido Ursodesoxicólico/uso terapéuticoRESUMEN
UNLABELLED: A significant study from the USA compares cystine stone formers and routine stone formers; the former group had a higher requirement for therapeutic procedures, but this was less if they took chelating agents, although remaining higher than in the latter group. Other interesting findings are also presented. OBJECTIVE: First, to compare two types of stone formers (SF), those with cystinuria and those without, for effects of treatments for stones, as cystinuria leads to recurrent stones that are difficult to fragment with shock-wave lithotripsy, and there is disagreement about the efficacy of current treatments. Second, to compare these two groups with respect to blood pressure (BP) and renal function, as cystine stones may be associated with more morbidity than are routine stones. PATIENTS AND METHODS: Fifty-two cystinuric patients (cystine SF) entering our programme since 1970 were compared with 3215 SF without cystinuria (routine SF), of whom 114 had a single functioning kidney (routine SF + nephrectomy). All patients had three 24-h urine and blood samples taken to determine the risk of stones before their first clinic visit; these studies were repeated after therapy was initiated, and at regular intervals to monitor therapy. Cystine was measured in the urine samples of the cystine SF. All stone-related procedures were recorded, and BP measured at clinic visits. Creatinine clearances (CCr) were calculated from each set of serum and urine values. Cystine supersaturation (SS) was directly measured in 16 urine samples collected before treatment and 13 afterward. RESULTS: Patients were treated with increased fluid intake, potassium alkali and chelating agents such as alpha-mercapto-propionyl-glycine, as needed. The mean (sd) CCr, corrected for age and gender, was significantly lower at entry in cystine SF than in routine SF, at 91 (6) vs 160 (1) L/day, respectively (P < 0.001), and remained so at the last CCr. Neither systolic nor diastolic BP, similarly corrected, differed between the groups, but cystine SF had significantly more procedures, corrected for time at risk, before treatment than did routine SF, at 4.0 (0.4) vs 1.86 (0.06), respectively (P < 0.001); time-adjusted procedures decreased significantly in both groups during treatment, but remained higher in cystine SF, at 0.88 (0.14) vs 0.23 (0.02), respectively, (P < 0.001). Urine volume and pH were significantly higher in cystine SF than in routine SF, both before and during treatment. Cystine SS decreased during treatment, consistent with the increase in urine volume and decline in procedure rates during treatment. CONCLUSION: Cystine SF have significantly higher procedure rates than routine SF, but procedure rates decline during therapy, although they remain higher than in routine SF. The lower CCr in cystinurics suggests that treatment to prevent stone recurrence and the need for procedures is particularly important, and emphasizes the need for a close follow-up. Use of cystine SS measurements may allow closer monitoring of the effect of treatment on the risk of stone recurrence.