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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.

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.

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.

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.

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., (© 2019 John Wiley & Sons Australia, Ltd.)

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 8.0, P <0.001)., Conclusion: Adverse events were frequent with D-penicillamine and tiopronin. Alkaline hyperdiuresis was well tolerated and reduced cystine crystalluria. Urine specific gravity ≤1.005 and urine pH >7.5, while warning about calcium-phosphate crystallization, should be the goals of medical therapy., (© 2019 The Authors BJU International © 2019 BJU International Published by John Wiley & Sons Ltd.)

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.

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

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 ∼59.4% (p < 0.05) and 78.9% (p < 0.05), respectively, while the 5-HT 3 receptor antagonist, palonosetron (0.5 mg/kg, s.c.), reduced the response by ∼71% (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., (Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

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.

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., Competing Interests: The authors have no potential conflicts of interest to disclose.

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 EC 50 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.

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.

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.

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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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.

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.

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., (Copyright © 2012 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

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.

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.

Purpose: To determine the effect of cystine-binding thiol drugs (CBTD) on urinary cystine capacity in patients with cystinuria., Patients and Methods: Seven cystinuric patients performed two sets of urine collections while on and off CBTD while controlling for all other variables: diet and fluid and alkali intake. They monitored and recorded their diet for 3 days and performed urine collections on days 2 and 3. They then stopped the CBTD for 7 days. On days 8, 9, and 10, they replicated their diets of days 1 through 3 and performed two more urine collections on days 9 and 10. Two patients took D-penicillamine, four took tiopronin, and one took tiopronin and captopril. The cystine capacity was determined, and the values obtained when the patient was on and off the CBTD were compared to determine whether CBTDs affect urinary cystine capacity. To measure the cystine capacity, we used a solid-phase assay in which cystine crystals are added to the urine and incubated for 48 hours. The crystals are spun down and resolubilized in high-pH buffer, and the amount of cystine in the crystals is calculated. The solid phase will take up cystine from urine (negative cystine capacity) that is supersaturated and give up cystine to an undersaturated urine (positive cystine capacity)., Results: All seven patients had significant improvement in urinary cystine capacity on CBTDs. The mean cystine capacity off CBTD was -130.6 +/- 280.8, while the value during CBTD use was 43.1 +/- 131.2 (P < 0.05). On CBTDs, two patients still had negative values, but both had important improvements. The mean urinary volumes were similar on and off CBTD, indicating adequate and similar fluid intake. Urine pH values and urinary excretion of sodium and urea also were comparable, indicating consistency of citrate intake and diet., Conclusions: Our results demonstrate that CBTDs lower the urinary supersaturation of cystine, as shown by a less-negative or more-positive cystine capacity. Cystine capacity can be measured directly, even in the presence of CBTDs. The value of this measurement lies in the potential to monitor the response to the drug, prescribe the minimum effective dose, and potentially decrease the adverse effects often associated with CBTDs.

Background: Delayed ischemic preconditioning promotes cardioprotection via genomic reprogramming. We hypothesize that molecular regulation of mitochondrial energetics is integral to this cardioprotective program., Methods and Results: Preconditioning was induced by use of 3 episodes of 3-minute coronary artery occlusion separated by 5 minutes of reperfusion. Twenty-four hours later, infarct size was reduced by 58% after preconditioning compared with sham-operated controls (P<0.001). Cardiac mitochondria were isolated from sham and preconditioned rat hearts. Mitochondrial respiration and ATP production were similar between the groups; however, preconditioned mitochondria exhibit modest hyperpolarization of the inner mitochondrial membrane potential (> or =22% versus control, P<0.001). After 35-minute anoxia and reoxygenation, preconditioned mitochondria demonstrated a 191+/-12% improvement in ADP-sensitive respiration (P=0.002) with preservation of electron-transfer-chain (ETC) activity versus controls. This augmented mitochondrial recovery was eradicated when preconditioning was abolished by the antioxidant 2-mercaptopropionyl glycine (2-MPG). These biochemical modulations appear to be regulated at the genomic level in that the expression of genes encoding rate-controlling complexes in the ETC was significantly upregulated in preconditioned myocardium, with a concordant induction of steady-state protein levels of cytochrome oxidase, cytochrome c, and adenine nucleotide translocase-1. 2-MPG abolished preconditioning induction of these transcripts. Moreover, transcripts of nuclear regulatory peptides known to orchestrate mitochondrial biogenesis, nuclear respiratory factor-1 and peroxisome-proliferator-activated receptor gamma coactivator 1alpha, were significantly induced in preconditioned myocardium., Conclusions: Delayed preconditioned mitochondria display increased tolerance against anoxia-reoxygenation in association with modifications in mitochondrial bioenergetics, with concordant genomic induction of a mitochondrial energetic gene regulatory program. This program appears to be mediated by reactive oxygen species signaling.

Advances in molecular genetics have brought a deeper understanding of cystinuria. This autosomal recessive disease, which is caused by a defective tubular reabsorption of cystine and the three dibasic amino acids arginine, lysine and ornithine, results in a lifelong risk of renal stone formation because of the low solubility of cystine in urine. Mutations detected within the two genes known to be associated with cystinuria, SLC3A1 (related to type I) and SLC7A9 (related to non-type I), cannot, however, in all cases explain the disease. Inasmuch as a high urinary concentration of cystine is the basis of stone formation in these patients, our aim was to measure urinary total cystine, arginine, lysine and ornithine, in patients currently lacking a full genetic explanation for their disease. Thirty-three patients with cystinuria who were on long-term treatment with tiopronin or D-penicillamine were divided into two groups. Group 1 comprised eight patients who carried mutation in one of the SLC3A1 alleles and two patients who completely lacked mutations both in the SLC3A1 and the SLC7A9 genes, that is genetic findings discordant with the increased urinary excretion of cystine and the dibasic amino acids in these patients. Group 2 comprised 23 patients homozygous for mutations within SLC3A1, that is genetic findings in accordance with the excretion pattern of classic type I cystinuria. When the two groups were compared, Group 1 had a significantly higher total urinary excretion of cystine ( p<0.01) as well as of arginine, lysine and ornithine ( p<0.05) than Group 2. Also, when the two patients without mutations were excluded from the calculations, there still was a significant difference in the urinary excretion of total cystine ( p<0.05). This suggests that the two patients without any detected mutations in the two known cystine transport genes also contributed to the difference. These unexpected findings indicate that an additional gene or genes participate in the urinary cystine reabsorption in the cystinuric patients who currently are without a full genetic explanation for their disease.

Objective: To observe the harmful effects of oxygen free radicals and the protective roles of Tiopronin in severely scalded rats after delayed fluid resuscitation., Methods: Rats inflicted with 30% III degree scald on the back were employed as the model. They were divided into delayed resuscitation (D) and Tiopronin treatment (T) groups. The changes in superoxide dismutase (SOD) and malonyldialdehyde (MDA) in plasma and subeschar fluid were determined at 24 to 48 postburn hours (PBHs) by means of electron spin resonance (ESR) technique and other routine methods. And the pathomorphological changes in the heart, liver, kidneys and small intestine, and changes in the blood biochemical indices were simultaneously determined. Normal rats were taken as control group (N)., Results: The plasma SOD level was was lower than that in N group, while the MDA content in plasma and subeschar fluid in D group was much higher than that in N group. Changes in all the blood biochemical and internal organ pathomorphology were more obvious in the D group. on the other hand, the rat plasma SOD level in T group increased obviously (P < 0.01) while the MDA contents was decreased in T group (P < 0.05) when compared with those rats of D group. In addition, the internal organ pathomorphology and blood biochemical indices were improved evidently in T group., Conclusion: Oxidative stress injury was evoked in severely scalded rats after delayed fluid resuscitation, and it could be protected to some extent by Tiopronin.

Cystinuria, an autosomal-recessive disorder, is the cause of 1 - 2 % of all kidney stones observed in adults and about 10 % of those observed in infants. Despite increasing understanding of underlying pathomechanisms, patients still form recurrent stones and have to undergo repeated interventions with increasing risk of renal insufficiency. Dietary and medical metaphylaxis may lower the frequency of recurrent stones but are often not practiced. Regular follow-up examinations and optimal therapy significantly enlarge stone-free intervals. This review offers an overview of the underlying pathogenetic mechanisms as well as guidance for diagnosis, monitoring, metaphylaxis and therapy of cystinuria following the recommendations of the Deutsche Gesellschaft für Urologie (DGU) and the European Association of Urology (EAU).

Thirty two patients with cystinuria were enrolled in this long-term study and 16 patients were treated with tiopronin for 24 weeks. Tiopronin reduced daily urinary cystine excretion from 901.48 mg (before treatment) to 488.60 mg (on the average of 12th week and 24th week after tiopronin administration) successfully. Tiopronin therapy was tolerated well, but side effects were observed in 13 events in 6 patients. Thus tiopronin was expected to be effective in preventing cystine stone formation and tolerated well.

Objective: To observe sulfhydryl compound variation in the injury of pancreatic cells and the effects of external sulfhydryl compounds on cytoprotection., Methods: Male Wistar mice were divided randomly into three groups: groups A and B served as animal models (retrograde duct infusion with 5% sodium taurocholate), in group A, 45 animals were treated with normal saline therapy, in group B, 45 animals were treated with Tiopronin therapy; and group C, 15 animals, were designated as normal control. Animals were killed at 2, 4, 6, 12 and 24 h, and pancreatic tissue was analyzed for total sulfhydryl (TSH), nonprotein sulfhydryl (NPSH) and malondialdehyde (MDA). Histopathology, serum amylase (Sam) and C reactive protein (CRP) were assessed as well., Results: Levels of Sam and CRP increased in both group A and group B, with corresponding pathological changes of acute nerotic pancreatitis (ANP). Levels of TSH, NPSH and protein sulfhydryl (PSH) in group A decreased markedly during pancreatitis (P < 0.01), but MDA increased significantly (P < 0.01). The depletion of NPSH in group B was markedly ameliorated at 4 h or 6 h, when Tiopronin was prophylactically administered (P < 0.05), after which the level of MDA showed very little increase when compared to group A (P < 0.01). Histopathological damage was attenuated to a certain extent, in regards to serum amylase and CRP., Conclusions: All sulfhydryl compounds decreased significantly during ANP; external sulfhydryl compound could protect the pancreatic cells most likely as a type of scavengers of oxygen free radicals, which are critically involved in the pathophysiology of ANP. Sulfhydryl plays an important role in the action of pancreatic cytoprotection.

The genotoxic potential of potassium dichromate (K(2)Cr(2)O(7)) was evaluated in vivo in mice using different mutagenic end points. Chromosomal aberrations in bone-marrow and spermatocytes as well as sperm abnormalities in the tested mice were determined. The doses used were 3, 6, 12 mg K(2)Cr(2)O(7)kg(-1) body weight which correspond to 1/16, 1/8, 1/4 the experimental LD(50), respectively. The protective roles of i.p. injection with thiola (a synthetic sulfhydryl compound) at 20 mg kg(-1) body weight and feeding treatment with soybean seeds (30% of the diet) were also studied. For chromosomal aberration analysis, subacute treatment for a period of 3 weeks were performed. All the tested doses of K(2)Cr(2)O(7) induced a statistically significant increase in the percentage of chromosomal aberrations in both somatic and germ cells with dose and time relationships. The percentage of the induced chromosomal aberrations was significantly minimized in all groups of mice i.p. treated with thiola or fed soybean seeds during the period of treatment. Potassium dichromate also induced a significant increase (P<0.01) in the percentage of abnormal sperms at the doses 6 and 12 mg kg(-1) body weight. Such percentage reached 7.52+/-0.45, 5.50+/-0.53 and 4.28+/-0.45 in mice treated with the highest tested dose of K(2)Cr(2)O(7), K(2)Cr(2)O(7) and thiola; K(2)Cr(2)O(7) and soybean, respectively compared with 2.14+/-0.33 for the control. In conclusion, the results demonstrate the genotoxic effect of potassium dichromate in mice. The results also confirm the protective role of thiola and soybean seeds against the genotoxicity of potassium dichromate.

Injury during reperfusion can partially offset the benefit of relief of ischemia in myocardial infarctions rapidly treated with thrombolytic drugs or angioplasty. We assessed whether bucillamine (N-[2-mercapto-2-methylpropionyl]-L-cysteine) is potentially useful to treat myocardial reperfusion injury. Bucillamine is a potent sulfhydryl donor not previously tested as a treatment of reperfusion injury. Cardiac myocytes were exposed to hydrogen peroxide or a xanthine/xanthine oxidase system resulting in injury-induced release of lactate dehydrogenase. Bucillamine (125-500 microM) prevented lactate dehydrogenase release in a concentration-dependent manner. Bucillamine, which has two donatable thiol groups, was twice as protective as N-2-mercaptopropionyl glycine, which contains a single donatable thiol group. Dogs were then exposed to 90 min of coronary artery occlusion and 48 h of reperfusion before sacrifice. Beginning at the onset of reperfusion, bucillamine, 11 or 22 mg/kg per hour, or vehicle (saline) was administered intravenously for 3 h. There was a dose-related response to bucillamine for infarct size, normalized for size of the region at risk and adjusted for collateral blood flow to the ischemic region. Infarct size was reduced by 41% in the group treated with bucillamine 22 mg/kg per hour, compared with the vehicle group. Bucillamine, probably through an antioxidant mechanism, reduced infarct size when administered during reperfusion.

Based on previous observations of the diurnal variation of urinary cystine excretion, the use of separate day and night urine collections was proposed. To improve the medical treatment of patients with cystinuria, this strategy was performed to guide the fluid intake and the administration of SH compounds (tiopronin, D-penicillamine, and MESNA).Twenty-six patients (19 treated with SH compounds and seven with alkalinization and hydration only) were followed during two 3.5-year periods. During Period 1, 24-h urine was collected and during Period 2, separate day and night urine was collected. There were 56 episodes of high urinary cystine supersaturation (> 1,200 micromol/l) during Period 2, 47% of which would have evaded detection with 24-h urine analysis. In comparison with Period 1, the urinary cystine concentration was lower (P < 0.05), and the urinary volume was higher (P < 0.05) during Period 2. Patients treated with tiopronin had reduced cystine excretion (P < 0.05) and at the end of Period 2, an increased dose of tiopronin, reflecting a more aggressive treatment. Furthermore, a reduced number of stone episodes and need of active stone removal (P < 0.05) was noted in the whole group of patients. Analyses of separate day and night urine samples can be used advantageously to reveal episodes of high supersaturation with cystine not detected in 24-h urine samples. Such a procedure might be useful for optimizing the treatment of patients with cystinuria.

For many years, urine alkalinization has been one of the cornerstones in the treatment of homozygous cystinuria. Because of the relationship found between the excretion of urinary sodium and cystine, potassium citrate has emerged as the preferred sodium-free alkalizing agent. To evaluate the usefulness of potassium citrate for urine alkalization in cystinuric patients, sodium bicarbonate and potassium citrate were compared in 14 patients (10 on tiopronin treatment and four without treatment with sulfhydryl compounds). The study started with 1 week without the use of any alkalizing agents (Period 0) followed by 2 weeks with sodium bicarbonate (Period 1) and 2 weeks with potassium citrate (Period 2). Urinary pH, volume, excretion of sodium, potassium, citrate and free cystine, as well as the plasma potassium concentration, were recorded. Potassium citrate was shown to be effective as an alkalizing agent and, in this respect, not significantly different from sodium bicarbonate. Even though a normal diet was used, a significant increase in urinary sodium excretion was observed with sodium bicarbonate (Period 1). Urinary potassium and citrate excretion increased with potassium citrate (Period 2). A significant correlation was found between urinary sodium and cystine in the tio-pronin-treated patients. No significant differences in cystine excretion were recorded in Periods 0, 1 and 2. Plasma potassium was significantly higher during Period 2, but only one patient developed a mild hyperkalemia (5.0 mmol/l). The use of potassium citrate for urine alkalization in homozygous cystinuria is effective and can be recommended in the absence of severe renal impairment.

The purpose of this study was to summarize 14 years of clinical experience with medical treatment of 88 cystinuric dogs. Of special interest was evaluation of recurrence rate of cystine uroliths and adverse effects during long-term tiopronin treatment. Twenty-six different breeds were recognized, and the most common breeds were Dachshunds, Tibetan Spaniels, and Basset Hounds. In 76 of 88 treated dogs (86%), re-formation of cystine uroliths was prevented. Recurrence rate of cystine uroliths changed from 7 months before to 18 months during tiopronin treatment. On 28 occasions, bladder stones were found, and in about 60% of the dogs, the uroliths dissolved. Quantitative measurement of the urinary excretion of cystine showed a significantly (P < .03) higher excretion of cystine in dogs with recurrent urolith formation than in dogs with only 1 urolith episode. Another finding was a significant (P = .02) decrease in urinary cystine excretion in older (>5 years) than in younger (<5 years) dogs. Adverse effects were found in 11 dogs, and the most severe signs were aggressiveness and myopathy. All signs disappeared when tiopronin treatment was stopped. In conclusion, this study emphasizes the importance of an individual strategy for lifelong treatment of cystinuria. In addition to increasing water intake, chemical modification of the cysteine molecule into a more soluble form by means of tiopronin is useful. In dogs with re-formed cystine uroliths, dissolution may be induced by increasing the tiopronin dosage to 40 mg/kg body weight per day. In dogs with a low urolith recurrence rate and low urinary cystine excretion, the tiopronin dosage may be decreased or treatment discontinued.

Purpose: We describe baseline metabolic abnormalities and evaluate mercaptopropionylglycine plus potassium citrate treatment for urinary abnormalities and to prevent new stone formation in children with cystine stones., Materials and Methods: Daily urinary excretions of calcium, oxalate, citrate, magnesium, urate and phosphorus were determined in 18 children with cystine stone and 24 healthy children. The cystine stone cases were treated with 10 to 15 mg./kg. alpha-mercaptopropionylglycine and 1 mEq./kg. potassium citrate daily for a median 15 months. The potassium citrate dose was adjusted to render urinary pH 6.5 to 7.5., Results: There was no significant difference in baseline metabolic profile between the cystine stone and control groups except for citrate. The cystine stone group excreted less citrate than the control group (p = 0.044). After treatment median plus or minus standard deviation urinary cystine 245 +/- 233 to 140 +/- 106 mmol./mol. creatinine decreased from (p = 0.015), and urinary citrate increased from 255 +/- 219 to 729 +/- 494 mg./1.73 m.2 (p = 0.003). No serious adverse reaction was noted. Of the 15 patients with followup data 5 (33%) had 8 recurrent calculi (recurrence rate 0.64 per patient year)., Conclusions: Our results suggest that further investigation of low citrate excretion is needed in cystinuric children. Potassium citrate therapy is effective in increasing urinary pH and urinary citrate. However, high recurrence rate and persistent cystinuria in our patients emphasize the inadequacy of our treatment schedule in the prevention of recurrent cystine calculi.

We determined the efficacy of alpha-mercaptopropionyl-glycine administered in a low dosage continuously or every other day for prophylaxis of cystine calculosis. Two homozygous cystinuric patients with previous calculosis and renal unilateral hypoplasia and been given preventive treatment with alpha-mercaptopropionyl-glycine continuously administered in a low dosage (1.5-4 mg Kg-1 day-1 for 14 1/2 years and 10(-4) mg Kg-1 day-1 for 9 years respectively). Neither calculosis, nor side effects were observed. Subsequently, the patients were given 4 mg Kg-1 of the drug every second day for 1 and 1-2 years respectively without calculosis or side effect being observed. A low dosage of alpha-mercaptopropionyl-glycine(1.5-4 mg Kg-1 day-1) supplied continuously or, for a short time, 4 mg Kg-1 day-1 supplied every other day can be effective in the prophylaxis of cystine nephrolithiasis in some homozygous patients with renal unilateral hypoplasia, with lower risk of side effects.

Objective: To observe the clearance effect of Tiopronin on oxygen free radicals in chronic hepatitis B patients., Methods: The ranthine oxidase assay was used to detect superoxide dismutase (SOD) in 80 chronic hepatitis B patients, the ALT, TBil, TP and AIG ratio of the patients were also tested. The 80 chronic hepatitis B patients were divided into two groups, the control group was treated with routine liver protective and jaundice regressing drugs while the treated group was additionally administered with Tiopromin besides the routine treatment., Results: In two groups of patients with similar ages and sexes, there showed no differences in levels of SOD, ALT, TBil, TP and ALB before treatment, as the SOD in treated group and control group were 106.57 (40.68 NU/ml and 105.18(44.59 NU/ml respectively, while the normal value for SOD in 16 normal persons was 165.9(23.36 NU/ml. After treatment, there were significant differences (P< 0.01) in SOD, ALT, TBil and ALB levels which showed SOD 187.93(35.24 NU/ml, ALT 38.41(22.22 U/L, TBil 23.15(12.46 micromol/L, ALB 43.28 (4.21 g/L in the treated group and SOD 157.96(47.29 NU/ml, ALT 68.52(34.19 U/L, TBil 30.38(21.80 micromol/L and ALB 40.36(5.19 g/L in the control group., Conclusions: There showed a good therapeutic effect of Tiopronin on the clearance of oxygen free radicals in chronic hepatitis B patients and also it can improve the liver function.

Cystinuria, an inherited disease, is clinically diagnosed by detecting cystine in urine. A colorimetric method using sodium cyanide and sodium nitroprusside is a simple qualitative test used to detect cystinuria. Several colorimetric methods have been proposed for quantitative analysis of cystine; however, we found that none of them were satisfactory because the results were not reproducible. The causes of non-reproducible results were: (1) insufficient reduction time for conversion of cystine to cysteine, and (2) the interference of creatinine. In this report, we present a method to quantitate cystine in urine. We also found that ascorbic acid and ferric chloride, but not zinc chloride, interfered with the color reaction. Using this method, 15 normal urine samples (10 males and 5 females) and 12 cystine stone forming patients' (5 males and 7 females) urine were analyzed. The method was compared to commercially available urine controls. Only captopril showed a dose dependent response and color intensity at 521 nm. Thiola and D-penicillamine showed little effect on cystine determination.

Background: D-penicillamine-induced muscle disorders are well-known, tiopronine-induced disorders are less often reported., Case Report: A 62-year-old patient, given tiopronine for rheumatoid arthritis, developed severe polymyositis with characteristic clinical and pathology features. The course was favorable after tiopronine withdrawal and substitution with methotrexate., Discussion: Clinicians should be aware of the side-effects of tiopronine, particularly muscle disorders, and implement careful surveillance to achieve early diagnosis and appropriate therapy.

We have previously reported that the thiol compound tiopronin protects rat kidneys in vitro against the toxic activity of cisplatin. The influence of tiopronin and sodium thiosulfate (STS) on the cytotoxicity of cisplatin has been investigated on P388 leukemic cells in vitro after 3 days. The combination has also been investigated in vivo in BDF1 mice bearing a P388 s.c. tumor. In contrast to STS, tiopronin did not significantly reduce the cytotoxic activity of cisplatin in vitro and nor did it affect the uptake of platinum (cisplatin-derived), binding to DNA or the percentage of interstrand cross-links (%ISCL) formation. The co-administration of cisplatin (4 mg/kg) and tiopronin (150 and 300 mg/kg) to BDF1 female mice bearing a s.c. P388 tumor produced a significant reduction in tumor growth similar to that of a single 6 mg/kg dose of cisplatin. Interestingly, pre-incubation in vitro of either tiopronin or STS for 2 h with the species formed from cisplatin by hydrolysis demonstrated their ability in inhibiting the cytotoxicity of these reactive platinum products. These results indicate that tiopronin does not reduce the cytotoxicity of cisplatin in vitro, as STS does. This may be, at least partly, because of a different effect of the two thiol compounds on the cellular uptake and binding of platinum to DNA. Notably, tiopronin substantially reduced tumor growth in mice treated with a non-toxic dose of cisplatin (p < or = 0.0277), suggesting some positive influence of this thiol compound on the antitumor properties of cisplatin. The ability of tiopronin to protect in vitro against the cytotoxicity of the aquation products of cisplatin may be related to its nephroprotective effect.

Early reperfusion of acute myocardial infarctions halts cell death due to ischemia but causes further injury, probably by oxidant mechanisms. We identified the window of opportunity during which antioxidants must be present in therapeutic concentrations to prevent reperfusion injury during 90 min of ischemia and 48 h of reperfusion in 57 dogs. We examined the effect on myocardial infarct size of intravenous infusion of N-2-mercaptopropionyl glycine (MPG), a diffusible antioxidant with a plasma half-time of 7 min, by using a series of protocols with a range of timing. Whereas infusions of MPG for > or =3 h reduced infarct size by approximately 50%, infusions for 1 h only (the first, second or third hours of reperfusion) caused only small reductions. A statistical analysis that focused on identifying components of group membership responsible for differences revealed that duration of treatment was a major determinant of infarct size. If begun any time within the first hour of reperfusion, infusions of > or =3 h markedly diminished infarct size. Because reperfusion injury proceeds for the first 3 h of reperfusion, but decreases thereafter, adequate protection is needed for > or =3 of the first 4 h of reperfusion, but more prolonged protection is not necessary.

In a case of typical cystinuria type I with left kidney hypoplasia and bilateral calculosis, calculi were dissolved by means of alpha-mercapto-propionyl-glycine and prophylaxis of the calculosis was performed by the same drug continuously administered in two divided doses (10-4 mg.kg-1.day-1) for 9 years, without urolithiasis. Then, the alpha-mercaptopropionyl-glycine every other day in one dose, 4 mg.kg-1.day-1, for two years was administered without calculosis. The arbitrary discontinuation of the drug by the patient was followed after 6 months from a right ureteral calculosis with transitory renal insufficiency. In our case the administration of a low dose of alpha-mercapto-propionyl-glycine every other day was useful in cystine calculosis prophylaxis.

Background: Cystinuria is an autosomal recessive disorder, and primary manifestation is the repeated formation of cystine calculi. Little information is available regarding clinical course of pediatric cystinuria having followed into adulthood. We report our experience with the management and the clinical course on cystinuria in children, who have been followed up for relatively long time., Materials and Methods: We retrospectively reviewed the records of all pediatric patients with cystinuria in whom urolithiasis was treated from 1970 to 1996., Results: A total of 15 pediatric patients with cystine calculi (9 boys, 6 girls) were treated in our hospital. Average age at diagnosis was 3 years 4 months old. Mean follow-up was 104 months. Stone location was upper urinary tract in 11 cases, bladder in 3 cases and both upper urinary tract and bladder in 1 case. Medical treatments including hydration, urine alkalization and dissolution therapy were performed in all patients. In three cases whose urinary cystine level ranged from 138 to 326 mg/gCr, cystine calculi were disappeared by medical therapy alone. In one of 3 cases vesicoureteral reflux was identified. Side effects were noticed in 30.0% of patients with tiopronin and in 85.7% of those with D-penicillamine, especially in 1 case with tiopronin nephrotic syndrome being noticed. Surgical procedures were performed in 13 patients (lithotomy: 17 calculi, endourology: 7 calculi and ESWL: 7 calculi). The stone free rate was 100% with lithotomy, 80 to 100% with endourology and 43% with ESWL at an average of 5.9 procedures. No complications were recognized after the surgical treatments. The stone events of 15 patients ranged from 0 to 1.5 (average 0.55). In all six patients followed up over the age of 20 years, stone recurrences were observed exclusively between 17 and 20 years of age., Conclusion: Dissolution therapy is more effective for cystinuric patients in whom urinary cystine excretion is less than 330 mg/gCr. For those cases with low urinary cystine level it is necessary to evaluate structural abnormalities of the urinary tract to avoid stone recurrence. ESWL and endourology should be tried for pediatric cystinuria except for neonates and infants, considering its safety. The patients and their parents must have adequate knowledge about the disease itself and its management. Prevention of cystine calculi recurrences depends on patient compliance to the therapeutic regimens necessitating close follow up according to the clinical conditions, especially for those in pubertic or postpubertic age.

The radioprotective effects of two flavonoids, orientin (Ot) and vicenin (Vc), obtained from the leaves of Ocimum sanctum, and the synthetic compounds WR-2721 and MPG (2-mercaptopropionyl glycine) have been compared by examining chromosome aberration in cells of bone marrow in irradiated mice. Healthy adult Swiss mice were injected intraperitoneally (i.p.) with 50 micrograms kg-1 body weight of Ot or Vc; 20 mg kg-1 of MPG; 150 mg kg-1 of WR-2721 or double distilled water (DDW). They were exposed to whole body irradiation of 2.0 Gy gamma radiation 30 min later. After 24 h, chromosomal aberrations were studied in the bone marrow of the femur by routine metaphase preparation after colchicine treatment. Radiation (2 Gy) increased the number of aberrant cells from less than 1% in controls to almost 20%. Pre-treatment with all the protective compounds resulted in a significant reduction in the percentage of aberrant metaphases as well as in the different types of aberration scored. Vc produced the maximum reduction in percent aberrant cells while MPG was the least effective; Ot and WR-2721 showed an almost similar effect. However, WR-2721 was the most effective against reduction of complex an almost similar effect. However, WR-2721 was the most effective against reduction of complex aberrations, followed by Vc. Neither flavonoids had any systemic toxicity, even at 200 mg kg-1 body weight. Considering the low dose needed for protection and the high margin between the effective and toxic doses, the ocimum flavonoids may be promising for human radiation protection.

Recurrence of growth of urinary stone is frequently observed during the clinical course of cystinuria patients. The aim of the present study is to examine the long-term outcome of cystinuria in Japan and clarify the effects of medical treatment on urinary stone. Thirty-one patients with cystinuria who had been followed up longer than 6 months were included. The follow-up period was 6-264 months with a mean of 89.5 months. Stone event was defined as appearance of new stone or radiological evidence of stone growth. All patients were managed with forced hydration and urine alkalization. Twenty-eight patients were treated with administration of thiol such as D-penicillamine or alpha-mercaptopropionylglycine. Stone events per year ranged from 0 to 1.09 with a median of 0.09. Stone events per patient-year was 0.19 for all patients. The average urinary cystine concentration during treatment in the favorable outcome group (stone events per year < 0.3) was lower that that in the unfavorable outcome group (stone events per year >/=0.3); 221.2 +/- 75.2 vs. 303.3 +/- 93.5 mg/l, although the difference was not statistically significant. Prognosis of urinary stone in Japanese patients with cystinuria was relatively good with large variation. The medical treatment to reduce urinary cystine concentration would be useful for the management of cystinuria.

Objective: To evaluate the clinical and etiological characteristics of childhood urolithiasis in Turkey., Methods: Ninety-two children with urolithiasis were studied retrospectively according to clinical patterns and etiological factors between January 1990 and January 1995., Results: The age range of the patients was from 2 months to 14 years (mean age 6.9 years), and there was a male/female ratio of 1.6. The onset of the disease was earlier in boys than in girls. The most striking features were the initial admission of 14 (15.2%) children after the development of chronic renal failure and that most of them (64.3%) had infection stones. The stones were localized in the upper urinary system in 68.5% of the patients; bladder stones were rare (10.9%). The recurrence rate at presentation was 15.2% in all patients. As etiological factors, an anatomical defect was found in 30.4% of the patients, infections in 31.5%, and metabolic disorders in 26.1%; 11 (12.0%) of them were classified as idiopathic. The earliest presentation was seen with metabolic and infection stones and the highest recurrence rate (37.5%) in patients with metabolic stones., Conclusion: Childhood urolithiasis is a serious problem in Turkey. In order to prevent the development of end-stage renal failure and to improve the patients' quality of life, more efforts should be made with respect to early diagnosis and management of renal stones and urinary tract infections.

Purpose: We determined the efficacy of a contemporary medical regimen for treatment of cystinuria., Materials and Methods: A total of 16 patients with cystinuria was followed for 7 to 141 months (mean 78.1). Standard therapy included hydration and alkalization. D-penicillamine or alpha-mercaptoproprionylglycine was added for failure of hydration and alkalization to prevent new stones or stone growth, or to cause dissolution. Captopril was added for failure of or intolerance to D-penicillamine or alpha-mercaptopropionylglycine. Radiography was performed every 6 to 12 months, at which time stone events were documented., Results: During hydration and alkalization 46 stone events occurred in 8 of 9 patients (1.6 events per patient-year). With addition of thiol derivatives 7 of 9 patients experienced 24 stone events, all 6 treated with hydration, alkalization and captopril experienced 10 events, and 4 of 5 treated with alkalization, thiols and captopril experienced 8 events (0.52, 0.71 and 0.54 events per patient-year, respectively). During a total treatment time of 104.1 patient-years 88 stone events occurred in 14 of 16 patients (0.84 events per patient-year)., Conclusions: D-penicillamine and alpha-mercaptopropionylglycine are effective in decreasing the rate of stone formation in patients in whom hydration and alkalization failed. While captopril may also be beneficial in this setting, it does not appear to be as effective as D-penicillamine or alpha-mercaptopropionylglycine, and it does not clearly add clinical benefit to those thiols. Our study demonstrates that patients with cystinuria are at high risk for recurrence when treated with any contemporary medical program. This natural history must be considered when evaluating the long-term efficacy of newer or alternative modes of medical and urological treatment.