Tiopronin (Thiola)

Tiopronin (Thiola) is an inhibitor of cystine precipitation and excretion and used for the treatment of cystinuria [1].

Cystinuria is an inherited autosomal recessive disease that is characterized by the formation of cystine stones in the ureter, kidneys and bladder.

In seven cystinuric patients, tiopronin decreased the urinary supersaturation of cystine. The mean cystine capacity without tiopronin was 130.6 + 280.8, while the value during tiopronin use was 43.1 + 131.2 [1]. In 13 patients with cystinuria, the excretion of free cystine increased by 0.75 mg for each mM increase in urinary sodium, which suggested tubular reabsorption of cystine is in a sodium-dependent way [2]. In thirty-one patients with homozygous cystinuria, tiopronin reduced the urinary free cystine excretion by 0.15 mg in a dose-dependant way. Low doses of tiopronin increased urinary excretion of total cystine as well as the mixed disulfide [3]. In 13 patients with cystinuria, tiopronin decreased urinary cystine excretion from 901.48 mg to 488.60 mg [4].

References:
[1].  Dolin DJ, Asplin JR, Flagel L, et al. Effect of cystine-binding thiol drugs on urinary cystine capacity in patients with cystinuria. J Endourol, 2005, 19(3): 429-432.
[2].  Lindell A, Denneberg T, Edholm E, et al. The effect of sodium intake on cystinuria with and without tiopronin treatment. Nephron, 1995, 71(4): 407-415.
[3].  Lindell A, Denneberg T, Jeppsson JO. Urinary excretion of free cystine and the tiopronin-cysteine-mixed disulfide during long term tiopronin treatment of cystinuria. Nephron, 1995, 71(3): 328-342.
[4].  Koide T, Yoshioka T, Miyake O, et al. Long-term study of tiopronin in patients with cystinuria. Hinyokika Kiyo, 2003, 49(2): 115-120.

Influence of Tiopronin on the Metabolism of Alcohol in Healthy Subjects.[Pubmed:28142160]

Drug Res (Stuttg). 2017 Apr;67(4):204-210.

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.

Action of Bacopa monnieri to antagonize cisplatin-induced emesis in Suncus murinus (house musk shrew).[Pubmed:28363413]

J Pharmacol Sci. 2017 Apr;133(4):232-239.

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 approximately 59.4% (p < 0.05) and 78.9% (p < 0.05), respectively, while the 5-HT3 receptor antagonist, palonosetron (0.5 mg/kg, s.c.), reduced the response by approximately 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.

Genotype and Phenotype Analysis in Pediatric Patients with Cystinuria.[Pubmed:28049243]

J Korean Med Sci. 2017 Feb;32(2):310-314.

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.

Retrograde intrarenal surgery in the management of pediatric cystine stones.[Pubmed:28262541]

J Pediatr Urol. 2017 Oct;13(5):487.e1-487.e5.

OBJECTIVE: To investigate the efficacy and safety of retrograde intrarenal surgery (RIRS) in the treatment of pediatric cystine stones. STUDY DESIGN: Data of the pediatric patients who underwent RIRS for kidney stones were retrospectively evaluated. A total of 14 children with cystine stones managed with RIRS were identified. In addition to the patient demographics and stone characteristics, all retrospectively obtained operative data were evaluated and discussed in detail, with an emphasis on the success and complication rates. RESULTS: Mean age of the 14 cases was 10.9 +/- 2.2 years (range: 7-15). Mean stone size was 13.6 +/- 2.4 mm (range: 10-18) (Summary table). Of these stones, four were located in the renal pelvis, three were in the lower, three were in the middle and the remaining four were located in upper calyx. Ureteral access sheath was used in 12 (85.7%) patients. The double-J ureteral stent was placed pre-operatively in one case and was inserted postoperatively in 12 cases. Mean operation time was 38.2 +/- 7.2 min (range: 30-50). Complications were observed in two cases: mild ureteral laceration in the first and fever on the second postoperative day in the second patient. All of the patients were stone free on sonographic evaluation at the 4-week follow-up evaluation. Although potassium citrate treatment was initiated in 11 patients, tiopronin treatment was initiated in four patients for recurrence prophylaxis during long-term follow-up. During a mean follow-up period of 25.7 +/- 5.2 months, stone recurrence was noted in one patient. DISCUSSION: Treatment of patients with cystine stones is challenging, due to high risk of rapid recurrence in the presence of residual fragments. Besides allowing complete stone clearance in all cases in the current series, RIRS is a highly reproducible method that can be safely performed, even in recurrences. The major limitations of the current study were low number of patients and short follow-up period. CONCLUSION: The results clearly indicated that RIRS is a safe treatment modality in the management of pediatric cystine stones.

[Cystinuria caused by a SLC7A9 missense mutation in Siamese-crossbred littermates in Germany].[Pubmed:28585658]

Tierarztl Prax Ausg K Kleintiere Heimtiere. 2017 Aug 11;45(4):265-272.

Cystinuria is caused by defective proximal renal tubular reabsorption of the amino acids cystine, ornithine, lysine, and arginine (COLA). The low solubility of cystine in mildly acidic urine may lead to the formation of urinary cystine crystals and uroliths. Much progress has been made recently in the diagnosis and understanding of cystinuria in companion animals. In cats, cystinuria affects equally both genders independent of neutering status and, despite being rare, already more cystinuria-causing mutations have been detected in cats compared to dogs. In this study a litter of Siamese-crossbred cats in Germany was assessed clinically for cystinuria and screened for mutations known to cause cystinuria in cats. An adult male castrated cat was presented with cystine crystalluria and calculi-related urinary obstruction and treated with perineal urethrostomy, cystotomy, and medical management. This cat and a neutered male littermate without evidence of urinary tract disease were found to be positive for cystine by urinary nitroprusside test, to have increased urinary COLA values and to be homozygous for the p.Val294Glu mutation in the SLC7A9 gene coding for b(0,+)AT subunit of the b(0,+) renal COLA transporter. Another littermate was non-cystinuric and did not carry this mutation. The same SLC7A9 mutation was previously found in a Maine coon, a Sphinx and a medium-haired cat in North America suggesting a common ancestor and likely first widespread SLC7A9 mutation causing cystinuria in cats. Genetic screening for this mutation may offer a simple and precise mean to diagnose other cats for cystinuria and offer specific management.

Tiopronin is a prescription thiol drug used to control the rate of cystine precipitation and excretion in the disease cystinuria.

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