Studies of the inhibitory activities of tiopronin and mercaptosuccinic acid on glutathione peroxidase and their cytotoxic and antioxidant properties.

Glutathione peroxidase (GPx), an important antioxidative enzmye, can be inhibited by various thiols, including of tiopronin and mercaptosuccinic acid (MSA). Recently, there has been discussion regarding the combination of tiopronin in anticancer therapy to overcome acquired resistance to anticancer drugs. However, thiols are also known to act as antioxidants, which can be contraindicated in cancer chemotherapy. This article focuses on the inhibitory effects of tiopronin and MSA on bovine and human glutathione peroxidase activities, and their effects on the redox status of cancer cells. IC50 values for the inhibition for the bovine erythrocyte enzyme were 356 and 24.7 µM for tiopronin and MSA, respectively, with the corresponding Ki values of 343 µM and 14.6 µM, respectively at pH 7.4 and 25 °C. MSA inhibited human GPx activity in human cancer cell lysates at its IC50 while tiopronin did not. Both compounds were cytotoxic to human cancer cell lines GUMBUS and HL-60, with IC50 values between 42.7 and 149.4 µM. Neither had an effect on cell cycle. Only MSA induced apoptosis in HL-60 cells but not in GUMBUS cells, while tiopronin resulted in no apoptosis in either cell line. Combination studies of the MSA with hydrogen peroxide in living cells enhanced the production of reactive oxygen species in GUMBUS cells while tiopronin acted as antioxidant in HL-60 cells. MSA and tiopronin antagonized the cytotoxic effect of cisplatin, doxorubicin and methotrexate in combination studies. Our findings indicate that the antioxidant properties of both thiols prevail over their GPx inhibitory activity in human cancer cell lines.

Protective effects of tiopronin against oxidative stress in severely burned patients.

OBJECTIVE: Tiopronin is an antioxidant. This study investigated the protective effect of tiopronin on oxidative stress in patients with severe burns. METHOD: Patients aged between 16 and 65 years old with >30% body surface area burns admitted to our burn unit from July 2011 to September 2016 were randomly divided into 3 groups: group A treated with tiopronin (15 mg/kg. 24 hrs), group B with vitamin C (792 mg/kg. 24 hrs), the other group with standard treatment (group C). All 3 groups also received standard treatment. Blood superoxide dismutase (SOD), malondialdehyde (MDA), and the biochemical indexes of liver, kidney, and heart were determined before treatment and 24 and 48 hrs after treatment. Samples from 8 normal healthy adult volunteers were also measured. The resuscitation fluid volume requirement for the first 24 hrs was calculated for 3 groups. RESULTS: The serum levels of MDA and the biochemical indexes in severely burned patients were higher than those in healthy volunteers (P<0.01). The serum SOD level of burn patients was lower (P<0.01). After treatment, the levels of SOD increased, the levels of MDA decreased, and the biochemical indexes of heart, liver, and kidney improved; these changes were more obvious in group A and group B compared to group C (P<0.05), and these changes were more obvious in group A compared to group B (P<0.05) at 48 hrs after treatment. There is less resuscitation fluid volume requirement to maintain adequate stable hemodynamic and urine output in the first 24 hrs in group A and group B compared to group C (P<0.05). CONCLUSION: Treatment with tiopronin could exert protective effects against burn-induced oxidative tissue damage and multiple-organ dysfunction, and also could reduce the volume of required fluid resuscitation in severely burned patients.

Effect of increasing doses of cystine-binding thiol drugs on cystine capacity in patients with cystinuria.

Appropriate dosing of cystine-binding thiol drugs in the management of cystinuria has been based on clinical stone activity. When new stones form, the dose is increased. Currently, there is no method of measuring urinary drug levels to guide the titration of therapy. Increasing cystine capacity, a measure of cystine solubility, has been promoted as a method of judging the effects of therapy. In this study, we gave increasing doses of tiopronin or D-penicillamine, depending on the patients' own prescriptions, to ten patients with cystinuria and measured cystine excretion and cystine capacity. The doses were 0, 1, 2, 3 g per day, given in two divided doses, and administered in a random order. Going from 0 to 1 g/day led to an increase in cystine capacity from - 39.1 to 130.4 mg/L (P < 0.009) and decreased 24 h cystine excretion from 1003.9 to 834.8 mg/day (P = 0.039). Increasing the doses from 1 to 2 to 3 g/day had no consistent or significant effect to further increase cystine capacity or decrease cystine excretion. Whether doses higher than 1 g/day have additional clinical benefit is not clear from this study. Limiting doses might be associated with fewer adverse effects without sacrificing the benefit of higher doses if higher doses do not offer clinical importance. However, trials with stone activity as an outcome would be desirable.

Influence of Tiopronin on the Metabolism of Alcohol in Healthy Subjects.

Drug safety- and drug-alcohol interaction studies have mainly been conducted for frequently prescribed drugs with high financial interests. Orphan drugs such as tiopronin (ORPHA25073) are often neglected in terms of clinical research. Tiopronin is a drug that is mainly used for the treatment of cystinuria. In this study, the interaction of tiopronin regarding the metabolism of alcohol (primary objective), and the safety of tiopronin in combination with alcohol was tested in healthy volunteers.In this randomised, double-blind, cross-over study, 13 healthy subjects received 500 mg tiopronin or an identical looking placebo 1 h before the intake of 0.8 g of alcohol per kg of bodyweight. Blood alcohol concentrations were measured over the course of 12 h after consumption. The experiment was repeated 7 days later with the previous placebo group receiving the active drug and vice-versa. Changes in blood alcohol AUC and elimination rate k were analysed using a 2-tailed t-test. Further acetaldehyde concentrations were measured. Additionally, the concentration ability of the subjects was tested and any adverse effects were recorded.There was no significant change in blood alcohol or acetaldehyde concentration. Significant differences in concentration tests refer presumably to learning effects. No serious adverse event occurred. All adverse events were reversible and there was no significant difference in occurrence between drug and placebo group.It was demonstrated that tiopronin does not affect the metabolism of alcohol. Intake of tiopronin in combination with alcohol has no safety implications on healthy subjects.

Glutathione-mediated drug release from Tiopronin-conjugated gold nanoparticles for acute liver injury therapy.

Tiopronin-conjugated gold nanoparticles (TPN@GNPs), with glutathione (GSH)-responsive drug release property, were developed for acute liver injury therapy. The TPN@GNPs were prepared using a one-pot synthesis method and characterized by UV-vis and transmission electronic microscopy methods. The TPN@GNPs displayed typical surface plasmon resonance of nanogold with a narrow size distribution (ca. 2 nm). The in vitro drug release profiles of the conjugates indicated that TPN@GNPs were able to release TPN in a sustained fashion for 4 h at a simulated intracellular level of GSH. pH values or ionic strengths of the release media had no obvious influence on TPN release from the surface of nanoparticles. The pharmacokinetic studies in rats showed that the TPN@GNPs had longer MRT (7.71 h) than TPN (3.96 h), indicating sustained release pattern of TPN@GNPs in vivo. The sustained release of TPN at the relative high GSH concentration could ameliorate the instability of TPN and enable the drug release in the target cells. Although the IC50 value of TPN@GNPs with TPN/AuCl4(-) of 3:1 (mol/mol) showed slight increase in comparison with that of the free TPN in HepG2 cells (1.26±1.07 vs. 1.73±1.16 mg/mL), the TPN@GNPs displayed better effects over TPN in the treatment of acute liver injury in vivo. In a liver injury mice model induced by CCl4, the histological analysis showed both the TPN@GNPs and free TPN group could repair the liver injury. In addition, the biochemical parameters showed TPN@GNPs could reduced the aminotransferase to a lower level compared with TPN, which might be due to the sustained drug release and passive liver targeting properties of TPN@GNPs. It demonstrated that gold nanoparticle-based drug delivery system allowed smart functions and superior properties by taking advantages of the unique small size effects and surface chemical properties.

Investigating the effect of antioxidant treatment on the protective effect of preconditioning in anesthetized rabbits.

Reactive oxygen and nitrogen species are critical in preconditioning (PC). We sought to determine the effect of N-2-mercaptopropionyl glycine (MPG) on infarct size and on the oxidative status. Rabbits were exposed to 30-minute regional ischemia of the heart, which was followed by 3-hour reperfusion: (1) a control group without further intervention, (2) a PC1 group that was subjected to one cycle of PC, (3) a PC4 group that was subjected to 4 cycles of PC, (4) an MPG group that was treated with MPG for 60 minutes, starting 10 minutes before reperfusion, (5) MPG-PC1, and (6) the MPG-PC4 groups that were treated with the same dose of MPG and with 1 or 4 cycles of PC, respectively. Blood samples were drawn and collected for metabonomic analysis. In another series of experiments, 6 groups respective to the described ones were subjected to 30-minute regional ischemia of the heart and 20 minutes of reperfusion, after which pieces of heart tissue were quickly excised for malondialdehyde, nitrotyrosine, and glutathione content assessment. All PC and MPG groups developed smaller infarct size compared with control (16.5% ± 3.9%, 13.7% ± 3.1%, 18.6% ± 5.0%, 9.7% ± 2.0%, 15.0% ± 2.8% vs. 48.05% ± 7.2%; P < 0.05). MPG did not prevent lipid peroxidation and nitrotyrosine formation but enhanced the glutathione content. PC and MPG induced similar nuclear magnetic resonance changes. Long MPG infusion reduces the infarct size without abolishing the effect of PC, providing novel insights into the activity of MPG in PC.

Nephrotic syndrome occurring during tiopronin treatment for cystinuria.

Cystinuria is an autosomal recessive disorder characterized with abnormal tubular reabsorption of cystine and dibasic amino acids leading to cystine urolithiasis. The classical form is caused by mutations in the SLC3A1 gene (OMIM 220100). The cornerstone of the treatment is high hydration and alkalization of the urine to achieve urine pH between 7.0 and 7.5, at which point, cystine solubility in the urine is optimal. These measures very often fail, and thus addition of sulfhydryl agents like penicillamine and tiopronin (mercaptopropionyl glycine) is recommended. Herein, we report a 3-year-old boy with cystinuria resulting in recurrent nephrolithiasis requiring surgery and extracorporeal shock wave lithotripsy. Nine months after introduction of tiopronin, the boy manifested generalized edema, oliguria, and biochemical indices of nephrotic syndrome. Tiopronin was withdrawn, and the boy was given only supportive treatment. Within 10 days, he entered into clinical and biochemical remission. Pediatricians should be aware of this adverse effect of tiopronin, and therefore, testing of the urine with strips or sulfosalicylic acid at least once weekly at home may be very helpful for early detection of proteinuria.

A phase I clinical trial of tiopronin, a putative neuroprotective agent, in aneurysmal subarachnoid hemorrhage.

BACKGROUND: The neurotoxic aldehyde 3-aminopropanal (3-AP) contributes to brain injury following cerebral ischemia. Tiopronin (N-2-mercaptopropionyl-glycine[N-2-MPG]) is a US Food and Drug Administration (FDA)-approved drug for the treatment of cystinuria and a putative neuroprotective agent that has been shown to bind and neutralize 3-AP and reduce infarct volumes. OBJECTIVE: The objective of this trial was to establish the safety of tiopronin administration in patients with aneurysmal subarachnoid hemorrhage (aSAH) in preparation for further trials of its efficacy as a neuroprotective agent in this disease process. METHODS: This Phase I dose-escalation trial enrolled three-patient cohorts using a conventional "3+3" study design. Tiopronin dose began at 1 g/d until aSAH Day 14. Each subsequent cohort received a dose of tiopronin based on predetermined guidelines. A maximum dose of 3 g/d was selected, because this is the maximum FDA-approved dose for long-term cystinuria treatment. Subjects were monitored for known side effects of tiopronin. RESULTS: Nine patients were enrolled, the minimum number required based on the study design. None of these patients experienced serious side effects attributable to tiopronin, and no adverse events were noted that could not be attributed to the pathophysiology of aSAH. CONCLUSION: The administration of 3 g/d of tiopronin following aSAH for up to 14 days appears to be safe and without the side effects associated with long-term use. Plans for a randomized, placebo-controlled Phase II trial of tiopronin for neuroprotection following aSAH are underway.

Cystinuria in children and young adults: success of monitoring free-cystine urine levels.

Medical treatment of cystinuria is often disappointing. Patients undergo frequent surgery, which is often followed by early relapse. The aim of our study was to evaluate the efficacy of medical treatment of cystinuria, to prevent formation or to reduce the numbers and dimensions of renal stones. Twenty cystinuric patients were treated with a combined approach, including cystine-binding drugs. Free and bound urine cystine levels were measured every 4 months. Drug dosage was adjusted to maintain free urine cystine level below 100 micromol/mmol creatinine. Eighteen patients completed the study; detection of new stones was reduced from 0.28 per year to 0.03 per year, and, in six patients, the numbers and dimensions of pre-existing renal stones were reduced. Surgery was required in one subject, and no relapse was observed 12 months afterwards. The dosage required to achieve target levels was closely correlated with patient body weight: older children required a lower dose. Medical management of cystinuria is feasible. The treatment must be personalised in children, as the amount of drug required is strictly dependent on body size.

Rapid ventricular pacing induces delayed cardioprotection against myocardial stunning.

Tachycardia with rapid ventricular pacing induces delayed preconditioning against arrhythmias secondary to coronary artery occlusion (CAO) and reperfusion (CAR) but its effects on myocardial stunning remains unknown. Accordingly, we investigated whether delayed preconditioning with ventricular pacing develops against myocardial stunning and whether this phenomenon is triggered by reactive oxygen species. Eight chronically instrumented conscious dogs underwent three experimental sequences in a random order a week apart: (a) 10-min CAO (coronary occluder) followed by CAR, i.e. "Control" sequence; (b) pacing (right ventricular electrodes, 240 beats/min during 40 min) performed 24 h before the 10-min CAO, i.e. "PC" sequence; and (c) N-(2-mercaptopropionyl)-glycine (MPG, 100 mg/kg per h) administered concomitantly to pacing and 10-min CAO performed 24 h later, i.e. "PC+MPG" sequence. During "Control", left ventricular (LV) wall thickening (%, sonomicrometry) was dramatically reduced during CAO (-96 +/- 5% from 2.9 +/- 0.4 mm) and remained depressed during CAR demonstrating myocardial stunning. During "PC", LV wall thickening was not altered by pacing per se and was similarly decreased during CAO vs. "Control". However, during CAR, LV wall thickening was improved vs. "Control" (e.g. -24 +/- 5% and -8 +/- 4% from corresponding baseline for "PC" and "Control", respectively at 2 h-CAR; P<0.05), demonstrating delayed preconditioning. Administration of MPG during pacing (n=5) abolished the beneficial effects of pacing. Myocardial lactate extraction and transmural distribution of regional myocardial blood flow (fluorescent microspheres) were not modified, by pacing. In conclusion, tachycardia with rapid ventricular pacing induces delayed cardioprotection against myocardial stunning. The production of reactive oxygen species independently from ischemia appears to be a major trigger for this phenomenon.

Protective effects of alpha-tocopherol and tiopronin against cisplatin-induced ototoxicity.

OBJECTIVE: To investigate the possible protective effects of alpha-tocopherol and tiopronin against cisplatin-induced cochlear damage. Cisplatin ototoxicity and nephrotoxicity seem to result from the inhibition of cochlear antioxidant defences, causing an increase in the amount of reactive oxygen species. Antioxidants, such as alpha-tocopherol and tiopronin, are able to suppress lipid peroxidation, thus attenuating tissue damage. MATERIAL AND METHODS: Hartley albino guinea pigs were used. The animals were treated for 7 consecutive days with either (I) cisplatin alone, (II) cisplatin+alpha-tocopherol acetate, (III) cisplatin+tiopronin, (IV) cisplatin+alpha-tocopherol acetate+tiopronin, (V) alpha-tocopherol acetate alone or (VI) tiopronin alone. Changes in cochlear function were characterized by means of compound action potential threshold shifts. After the functional testing, tympanic bullae were removed and processed for morphological examination of the sensorineural epithelium. Renal function was evaluated by measuring serum blood urea nitrogen and creatinine levels. RESULTS: Cisplatin induced progressive high-frequency hearing loss of 40-50 dB SPL. Alpha-tocopherol and tiopronin co-therapy significantly slowed the progression of hearing loss. Treatment with alpha-tocopherol acetate or tiopronin alone was less effective. Morphological observations showed an important loss of outer hair cells and degeneration of the organ of Corti in the basal and middle turns. Injection of both alpha-tocopherol and tiopronin reduced cochlear outer hair cell loss more than treatment with a single drug. Beneficial effects of alpha-tocopherol and tiopronin on cisplatin-induced nephrotoxicity were observed. CONCLUSION: This study supports the hypothesis that alpha-tocopherol and tiopronin interfere with cisplatin-induced damage, and suggests that concurrent treatment with the two drugs can be useful in protecting against hearing loss.

Delayed ischemic preconditioning activates nuclear-encoded electron-transfer-chain gene expression in parallel with enhanced postanoxic mitochondrial respiratory recovery.

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.

The protective role of tiopronin in cisplatin ototoxicity in Wistar rats.

The purpose of this study was to evaluate cisplatin-induced ototoxicity and the protective effects of tiopronin. Twenty-four adult Wistar rats served as subjects and were divided into three groups. Eight rats receiving only saline (group A) were used as controls. Eight rats received cisplatin (2 mg/kg) injections (group B) and eight rats received cisplatin and tiopronin (300 mg/kg) (group C) for 8 consecutive days. Both ears of all animals were tested by DPOAE before treatment and on the 4th and 9th days. Seventy-two hours after the final recording session, all animals were killed, and the left cochleas were prepared for electron microscopy and analysed. DPOAE responses were significantly reduced in group B compared to controls (p<0.05). When tiopronin was added, DPOAE responses were significantly increased compared to those obtained with the administration of cisplatin alone (p<0.05). The cochleogram showed that tiopronin had a significant protective effect in the basal half and in the lower half of the middle turn. We conclude that tiopronin, a drug effective in protecting against cisplatin nephrotoxicity, is also effective in protecting against cisplatin ototoxicity.

[Cystinuria - Cystine Stones: Recommendations for Diagnosis, Therapy and Follow-up]. / Zystinurie - Zystinsteinleiden: Aktuelle Empfehlungen zur Diagnostik, Therapie und Nachsorge.

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).

[Long-term study of tiopronin in patients with cystinuria].

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.

Cystinuria in the dog: clinical studies during 14 years of medical treatment.

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.

Prophylaxia of cystine calculosis by alpha-mercaptopropionyl-glycine administered continuously or every other day.

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.

Cystine analyses of separate day and night urine as a basis for the management of patients with homozygous cystinuria.

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.

Failure of N-2-mercaptopropionyl glycine to reduce myocardial infarction after 3 days of reperfusion in rabbits.

Recent studies have reported that prolonged infusion of N-2-mercaptopropionyl glycine (MPG), a diffusible antioxidant, could limit infarct size in dogs. However, there are no comparable studies testing this agent in other species. We examined the efficacy of MPG in a rabbit model of infarction. Rabbit hearts were subjected to a 30-min coronary artery occlusion. Infarct size expressed as a percentage of risk zone was determined by either triphenyltetrazolium chloride (TTC) staining after 3h of reperfusion (study 1) or by histology after 72 h of reperfusion (study 2). In study 1, 37 +/- 2.6% of the risk zone infarcted in the control group. Intravenous MPG at a rate of 100 mg/kg/h starting 15 min after the onset of ischemia and continuing until 1 h after reperfusion had no effect on infarct size (35.4 +/- 3.4% infarction). However, infusion of MPG until the end of reperfusion significantly reduced infarct size as measured with TTC to 17.2 +/- 2.5% (p < 0.01 vs. control group). In study 2, 48.6 +/- 4.0% of the risk zone infarcted in the control group. In the treatment group MPG was started as above and was continued for 4 h of reperfusion followed by an intramuscular injection at the termination of the intravenous infusion. No protection was seen after 72 h of reperfusion (43.8 +/- 2.1% infarction). These findings reveal that MPG at a dose and schedule that appeared to protect the dog heart could not effect sustained protection in the rabbit heart. TTC staining revealed that MPG appeared to have preserved viability for up to 3 h of reperfusion suggesting that failure may have been due to early withdrawal of the drug. Alternatively, early TTC staining may yield spurious results under conditions in which protection is dependent upon antioxidant or free radical scavenger treatment as has previously been suggested. It is concluded that MPG as administered in the previous canine studies does not limit infarct size in all species, thus raising a concern about MPG's potential efficacy in man.

[Tiopronin-induced nephrotic syndrome with minimal glomerular lesions]. / Syndrome néphrotique à lésions glomérulaires minimes secondaire à la prise de tiopronine.

BACKGROUND: In the very large majority of cases, nephrotic syndrome with minimal glomerular lesions is an idiopathic condition. Drugs can favor the glomerulopathy. The effect of non-steroidal antiinflammatory drugs is well known, but other drugs, particularly tiopronin may be incriminated. CASE REPORT: A 73-year-old patient developed severe nephrotic syndrome with minimal glomerular lesions 6 weeks after tiopronin therapy was initiated. Complete and spontaneous remission of the nephrotic syndrome was achieved 5 weeks after drug withdrawal. No recurrent lipoidic nephrosis has been observed at 3 years follow-up. CONCLUSION: Tiopronin-induced nephrotic syndrome with minimal glomerular lesions is usually severe and develops rapidly. Remission occurs rapidly after drug withdrawal. Weekly urine checks with dip-strips should be proposed in patients treated with tiopronin.