Adverse events associated with currently used medical treatments for cystinuria and treatment goals: results from a series of 442 patients in France.

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.

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.

Tiopronin-induced membranous nephropathy: a case report.

BACKGROUND: Tiopronin, a glycine derivative extensively used to treat cystinuria and hepatic cell injury, can give rise to rare complications such as proteinuria and nephrotic syndrome. However, the pathological characteristics of this secondary nephropathy are poorly understood. Here, we report a case of tiopronin-induced nephrotic syndrome. CASE PRESENTATION: A 65-year-old Chinese man with a history of myasthenia gravis admitted tiopronin for hepatoprotection therapy. After 3 months later, he presented with rapid weight gain, massive peripheral edema, and proteinuria in the nephrotic range. Laboratory findings included serum albumin (20 g/L), total protein (38 g/L), and total cholesterol (11.78 mmol/L). A 24-hour urine protein collection contained 8620 mg. Percutaneous renal biopsy revealed a uniformly thickened glomerular and rigid basement membrane with immunoglobulin G (IgG) and complement C3 deposited along the glomerular capillary wall. Withdrawal of tiopronin-induced proteinuria complete remission and clinical resolution of nephrotic syndrome. CONCLUSIONS: Potential risk of kidney injury exists with long-term tiopronin treatment. Membranous nephropathy was a common renal pathologic feature. Proteinuria in the nephrotic range may spontaneously remit after tiopronin withdrawal. Periodic urine analysis and patient follow-up are recommended with tiopronin therapy.

Efectos adversos de las tiopurinas en pacientes con enfermedad inflamatoria intestinal / Adverse events of thiopurine immunomodulators in patients with inflammatory bowel disease

Antecedentes Las tiopurinas son los inmunosupresores más utilizados para el tratamiento de la enfermedad inflamatoria intestinal.ObjetivosEvaluar la incidencia de eventos adversos (EA) en pacientes con enfermedad inflamatoria intestinal tratados con azatioprina (AZA) o con 6-mercaptopurina (MP) en nuestro hospital, las características de dichos efectos, la distribución de los factores socio-demográficos y los posibles factores predisponentes.MétodosSe incluyeron 377 pacientes con enfermedad inflamatoria intestinal que fueron diagnosticados hasta 2008 y que recibieron AZA o MP durante el curso de su enfermedad. Se recogieron retrospectivamente datos demográficos, clínicos y de laboratorio sobre su enfermedad e información detallada sobre cualquier EA.ResultadosCincuenta y un pacientes tuvieron algún tipo de EA con AZA o MP (13,5%), y el 11% suspendieron el tratamiento por toxicidad. Se observó una asociación estadísticamente significativa con la enfermedad de Crohn (p=0,008). Hubo mielotoxicidad en 18 pacientes (4,8%) con un tiempo medio de aparición de las anomalías en los análisis de laboratorio de 16 meses. Nueve pacientes presentaron toxicidad hepática secundaria a estos fármacos (2,4%), uno de ellos desarrolló hiperplasia nodular regenerativa e hipertensión portal. Diez pacientes sufrieron pancreatitis aguda (2,7%) con un tiempo medio de aparición de 27 días y una asociación estadísticamente significativa con la enfermedad de Crohn (p=0,03) y tabaquismo (p=0,01). Quince pacientes presentaron intolerancia gastrointestinal (4%), pero cinco pudieron continuar con la medicación administrada en dosis fraccionadas o tras cambiar a MP.ConclusionesLas tiopurinas presentan un porcentaje significativo de EA (13,5%), que si bien suelen ser leves, nos obligan a hacer un seguimiento de todos los casos y, en algunos incluso a suspender el tratamiento(AU)

Background Thiopurine immunomodulators are the most commonly used immunosuppressants in inflammatory bowel disease.AimsTo evaluate the incidence of adverse events (AE) in patients with inflammatory bowel disease treated with azathioprine (AZA) or 6-mercaptopurine (MP) in our hospital, the features of these effects, the distribution of socio-demographic factors, and the possible predisposing factors.MethodsWe included 377 patients with inflammatory bowel disease who were diagnosed through 2008 and who received AZA or MP during the course of their disease. We collected retrospective demographic, clinical, and laboratory data about their disease and detailed information on any AE.ResultsFifty-one patients had some form of AE with AZA or MP (13.5%) and 11% discontinued therapy because of toxicity. Statistically significant association with Crohn's disease was found (P=.008). Myelotoxicity occurred in 18 patients (4.8%) with a mean time of laboratory abnormalities appearing after 16 months. Nine patients had hepatotoxicity secondary to these drugs (2.4%); one of them developed nodular regenerative hyperplasia and portal hypertension. Ten patients had acute pancreatitis (2.7%) with a mean time occurrence of 27 days and a statistically significant association with Crohn's disease (P=.03) and smoking (P=.01). Fifteen patients had gastrointestinal intolerance (4%) but 5 were able to continue with medication given in divided doses or switching to MP.ConclusionsThiopurine immunomodulators have a significant percentage of AE (13.5%), which, although usually mild, forced us to follow up all cases and sometimes even suspend treatment(AU)

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.

Collagen cross-linking with Au nanoparticles.

Tiopronin (N-(2-mercaptopropionyl)glycine)-protected gold nanoparticles (TPAu) were cross-linked to collagen via EDC (1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide) coupling. On average, each TPAu forms eight amide bonds with collagen lysine moieties. The resulting gels were studied with environmental SEM, TEM, micro-DSC, and TNBS assay. The porous structure of collagen was significantly altered by cross-linking, resulting in the reduction of the pore size from ca. 140 to <1 microm depending on the concentration of nanoparticles. The collagenase biodegradation assay showed improved stability of cross-linked material. The cell viability assay, CellTiter96, indicates that the gold nanoparticles are not toxic at the concentrations used in gel synthesis. This new material has potential for the delivery of small molecule drugs as well as Au nanoparticles for photothermal therapies, imaging, and cell targeting.

[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.

Yellow nail syndrome associated with thiol compound therapy for rheumatoid arthritis. Two case reports.

Yellow nail syndrome is characterized by ungual dystrophy, lower limb lymphedema, and pleural effusions or bronchiectasis. Rheumatoid arthritis is the autoimmune disorder most often associated with yellow nail syndrome. We report two new cases of yellow nail syndrome in patents receiving thiol compound therapy for rheumatoid arthritis. Eight similar cases have been reported since 1979, suggesting a possible causative effect of this class of drugs.

The antioxidant N-2-mercaptopropionyl glycine attenuates left ventricular hypertrophy in in vivo murine pressure-overload model.

OBJECTIVES: In order to identify the role of reactive oxygen species (ROS) in cardiac hypertrophy, we examined the effect of N-2-mercaptopropionyl glycine (MPG) on cardiac hypertrophy. BACKGROUND: Recent in vitro studies have suggested that ROS play an important role as a second messenger in cardiac hypertrophy. It was therefore thought to be of particular value to examine the relevance of studies using in vitro models for cardiac hypertrophy in an in vivo setting. METHODS: The transverse thoracic aorta in mice was constricted, and MPG (100 mg/kg) was infused intraperitoneally twice daily. The animals were assessed seven days after the operation for hemodynamic functions, oxidative stress and antioxidative enzyme activities. RESULTS: Banding of the transverse aorta in mice resulted in an increase in the ratio of heart weight to tibia length and the appearance of an endogenous atrial natriuretic factor messenger ribonucleic acid (mRNA) seven days postoperatively. Administration of MPG significantly attenuated the hypertrophic responses induced by pressure overload. Cardiac hypertrophy was accompanied by increases in heme oxygenase-1 mRNA expression and lipid peroxidation, which was eliminated by the treatment with MPG. Pressure overload led to increases in antioxidant enzyme activities, such as superoxide dismutase and glutathione peroxidase, but not catalase, activity. CONCLUSIONS: Our results indicated that oxidative stress was increased in our model and that it plays an important role in the development of cardiac hypertrophy.

[Nephrotic syndrome and anasarca status, secondary to treatment with tiopronin in a case of cystinuria]. / Síndrome nefrótico y estado de anasarca, secundario al tratamiento con tiopronina en un caso de cistinuria.

OBJECTIVE: To describe a case of cystinuria treated with tiopronin that produced the nephrotic syndrome. METHODS/RESULTS: A case of nephrotic syndrome with ascites and heart failure in a patient who had received tiopronin for the treatment of cystinuria is presented. Cystinuria as a rare cause of kidney stones is analyzed. The clinical features, diagnosis and the side effects of treatment with tiopronin are discussed. The patient recovered after withdrawal of the drug. CONCLUSIONS: It must be emphasized that patients treated with tiopronin should be screened for proteinuria.

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.

HLA-A33/B44/DR6 is highly related to intrahepatic cholestasis induced by tiopronin.

In order to elucidate the immunogenetic predisposition of tiopronin (mercaptopropionylglycine)-induced intrahepatic cholestasis, human leukocyte antigen (HLA) was analyzed in patients with tiopronin-induced liver injury. HLA-A, -B, -C, and -DR loci of 14 patients (10 males and 4 females) with tiopronin-induced liver injury were compared with those of control subjects. The mean duration of tiopronin administration was 26 days and that of jaundice was 4.5 months. The elevation of biliary enzymes lasted from 2 months to up to 10 years. Most of the cases manifested intrahepatic cholestasis on liver biopsy. Lymphocyte transformation test with tiopronin was positive in 6 of 8 (75%) tested cases. Thirteen patients (92.9%) had HLA-A33, 10 (71.4%) had B44, and 9 (64.3%) patients had DR6. These are statistically higher in the patients with tiopronin-induced cholestasis than in the general population. Ten of those with tiopronin-induced liver dysfunction (71.4%) had A33/B44 and 8 (57.1%) had A33/B44/DR6 in their haplotype. In conclusion, long-lasting tiopronin-induced intrahepatic-cholestasis is highly linked to specific HLA-A33, -B44 and -DR6.

[Polymyositis induced by tiopronine]. / Polymyosite induite par la tiopronine.

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.

[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.