Cysteamine

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Ranjan Dohil - One of the best experts on this subject based on the ideXlab platform.

  • enteric coated Cysteamine for the treatment of paediatric non alcoholic fatty liver disease
    Alimentary Pharmacology & Therapeutics, 2011
    Co-Authors: Ranjan Dohil, Betty L Cabrera, Susanne Schmeltzer, T Wang, Janis Durelle, K B Duke, Jeffrey B Schwimmer, J E Lavine
    Abstract:

    Aliment Pharmacol Ther 2011; 33: 1036–1044 Summary Background  Non-alcoholic fatty liver disease (NAFLD) is a common cause of liver disease in children. Hepatic fat accumulation and oxidative stress contribute to its pathogenesis. Cysteamine bitartrate readily traverses cellular membranes and is a potent antioxidant. Aim  To evaluate the safety and efficacy of enteric-coated (EC) Cysteamine in children with NAFLD. Method  Children, aged ≥10 y, meeting screening criteria with biopsy-proven NAFLD and serum ALT ≥60 IU/L, received twice-daily EC-Cysteamine for 24 weeks. Monthly ALT, AST, body mass index (BMI) and gastrointestinal symptom scores were measured. Subjects with >50% reduction or normalisation of ALT achieved the primary endpoint. Results  Of the 13 children enrolled (mean age 14.0 years), 11 completed EC-Cysteamine therapy (mean dose 15.2 mg/kg/day) and were included in the final analysis. For these 11 subjects, the mean ALT levels at baseline and 24 weeks were 120.2 and 55 IU/L respectively (P = 0.002), and the AST levels were 60 and 36 IU/L respectively (P = 0.007). The primary endpoint was reached in 7 and normalisation (≤40 IU/L) of ALT in 5. After 24 week therapy, mean adiponectin levels increased (P = 0.009) and CK-18 fragment levels decreased (P = 0.013), insulin levels remained unchanged (P = 0.99). Mean leptin levels were decreased in responders (P = 0.044). Mean BMI was 34.5 at baseline and 34.2 kg/m2 after treatment (P = 0.35). Mean symptom scores at baseline (1.1) and at 24 weeks (0.7) were similar. No major adverse events were reported. Conclusions  Enteric-coated Cysteamine reduces ALT and AST levels in children with NAFLD without reduction in body mass index. Further studies will evaluate optimal Cysteamine therapeutic dose and effect on liver histology in NAFLD (Clinicaltrials.gov protocol ID: 07-1699).

  • pharmacokinetics of enteric coated Cysteamine bitartrate in healthy adults a pilot study
    British Journal of Clinical Pharmacology, 2010
    Co-Authors: Jon A Gangoiti, Meredith Fidler, Bruce Barshop, Jerry A Schneider, Betty L Cabrera, Ranjan Dohil
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Cysteamine bitartrate is taken lifelong, every 6 h and for the treatment of cystinosis. Recent studies using Cysteamine for for other diseases such as neurodegenerative disorders adopt the same dosing regimen for Cysteamine. Regular Cysteamine bitartrate (Cystagon) may cause upper gastrointestinal symptoms in some patients. WHAT THIS STUDY ADDS • This is the only study that provides pharmacokinetic data for Cysteamine delivered in an enteric-release preparation in normal subjects. EC-Cysteamine is very well tolerated and does not cause increased gastrin concentrations, even at relatively high doses. • EC-Cysteamine at the higher dose results in better drug uptake as measured by Cmax and AUC and is more likely to be effective. AIMS Cysteamine bitartrate (Cystagon®) is the approved treatment for cystinosis. Poor compliance and patient outcome may occur because the drug needs to be taken every 6 h and in some patients causes gastrointestinal symptoms due to hypergastrinaemia. A formulation of Cysteamine requiring twice daily ingestion would improve the quality of life for these patients. This study compares the pharmacokinetics and gastrin production following Cysteamine bitartrate non-enteric-coated and Cysteamine bitartrate enteric-coated in normal healthy subjects. METHODS Enteric-coated Cysteamine was prepared. Following single doses of Cysteamine bitartrate non-enteric-coated 450 mg and Cysteamine bitartrate enteric-coated 450 mg and 900 mg, serial plasma Cysteamine and gastrin concentrations were measured. Two subjects also received Cysteamine bitartrate non-enteric-coated 900 mg. Gastrointestinal (GI) symptoms were recorded. RESULTS Six healthy adults (mean age 20.7 years, range 18–24 years; mean weight 59.3 kg) received drug. All post-dose gastrin concentrations were within the normal range (<100 pg ml–1). The tmax following Cysteamine bitartrate non-enteric-coated (mean and SD is 75 ± 19 min) was shorter than Cysteamine bitartrate enteric-coated (220 ± 74 min) (P= 0.001), but only the Cmax and AUC estimates following 900 mg Cysteamine bitartrate enteric-coated were significantly greater than any of the other preparations or doses (P < 0.05). One patient had GI symptoms following both 900 mg Cysteamine bitartrate non-enteric-coated and Cysteamine bitartrate enteric-coated. CONCLUSION Although patient numbers were low, single high doses of Cysteamine bitartrate enteric-coated were better tolerated than similar doses of Cysteamine bitartrate non-enteric-coated in the healthy subjects and all had normal gastrin concentrations. The delayed tmax following Cysteamine bitartrate enteric-coated suggested that the Cysteamine was released enterically.

  • long term treatment of cystinosis in children with twice daily Cysteamine
    The Journal of Pediatrics, 2010
    Co-Authors: Ranjan Dohil, Meredith Fidler, Jerry A Schneider, Jon A Gangoiti, Betty L Cabrera, Bruce Barshop
    Abstract:

    Objective Cystinosis causes renal and other organ failure. Treatment with 6-hourly Cysteamine bitartrate (Cystagon, Mylan, Morgantown, West Virginia) reduces intracellular cystine and the rate of organ deterioration. A recent study showed that an enteric-release Cysteamine required less frequent daily dosing. This report describes the long-term use of enteric-coated (EC) Cysteamine bitartrate (Cystagon) in children with cystinosis. Study design After a pharmacokinetic and pharmacodynamic study of EC-Cysteamine in children with cystinosis, 5 patients remained on twice-daily treatment. White blood cell cystine levels were measured 12 hours after ingestion every 4 to 8 weeks. These levels were then compared with the patient's previous 6-h post-dose levels taken while on regular Cysteamine bitartrate before entering the study. Blood chemistry was also measured. Results Five children with cystinosis (mean age, 9 years; range, 8 to 17 years) who previously took Cysteamine bitartrate (mean dose, 47 mg/kg body wt), received EC-Cysteamine for 10 to 27 months (mean dose, 25 mg/kg body wt) and had mean white blood cell cystine levels of 0.77 and 0.71 nmol half-cystine/mg protein, respectively. During the study period, patients maintained adequate growth and there was no significant deterioration in renal or thyroid function. Two children were required to restart acid suppression after 6 months on EC-Cysteamine therapy. Conclusions Long-term, twice-daily EC-Cysteamine, given at approximately 60% of the previous daily dose of Cysteamine bitartrate, was effective at maintaining white blood cell cystine levels within a satisfactory range. There was no significant deterioration in renal or thyroid function.

  • twice daily Cysteamine bitartrate therapy for children with cystinosis
    The Journal of Pediatrics, 2010
    Co-Authors: Ranjan Dohil, Meredith Fidler, Jerry A Schneider, Jon A Gangoiti, Frederick J Kaskel, Bruce Barshop
    Abstract:

    Objective Cystinosis causes renal and other organ failure. Regular 6-hourly Cysteamine bitartrate (Cystagon; Mylan, Morgantown, West Virginia) reduces intracellular cystine and the rate of organ deterioration. A formulation of Cysteamine requiring less frequent dosing may improve compliance and possibly patient outcome. Methods Enteric-release Cysteamine was prepared. For a period of 1 month, patients received their regular Cysteamine dose every 6 hours (stage I). The patients then underwent pharmacokinetic and pharmacodynamic studies following washout periods using single-doses of Cysteamine and enteric-release Cysteamine (stage II). Finally, the patients commenced regular enteric-release Cysteamine therapy (stage III). Weekly trough white blood cell (WBC) cystine levels were recorded. Results Seven children with cystinosis (mean age, 11.8 years; range, 8-17 years) who received Cysteamine and enteric-release Cysteamine (mean dose, 45 and 28.8 mg/kg body weight/day, respectively) had mean WBC cystine levels of 0.7 ± 0.3 and 0.41 ± 0.22 nmol half-cystine/mg protein in study stages I and III, respectively. Study stage II showed that the mean time (Tmax) to reach the maximum plasma Cysteamine level (Cmax) was longer for enteric-release Cysteamine than for Cysteamine (176 minutes vs 60 minutes; P = .001), but the mean Cmax at the same dose was similar. Mean serum gastrin levels were similar after ingestion of Cysteamine and enteric-release Cysteamine. Conclusions Twelve-hour enteric-release Cysteamine, given at approximately 60% of the previous daily dose of Cysteamine, was effective in maintaining trough WBC cystine levels within a satisfactory range.

  • understanding intestinal Cysteamine bitartrate absorption
    The Journal of Pediatrics, 2006
    Co-Authors: Ranjan Dohil, Meredith Fidler, Bruce Barshop, Reena Deutsch, Jon A Gangoiti, Michael B Martin, Jerry A Schneider
    Abstract:

    Objectives To test the hypothesis that a controlled-release preparation of Cysteamine, with fewer daily administrations, would improve the quality of life for patients with cystinosis. Study design A specifically designed nasoenteric tube was used to administer Cysteamine directly into the stomach, small intestine (SI) and colon and serial plasma Cysteamine, serum gastrin and leukocyte cystine levels were measured. Results Eight control subjects (mean age 23.2 years) and 6 subjects with cystinosis (mean age 15.2 years) were studied. Cysteamine absorption (maximum concentration and area under the curve of the concentration-time gradient) was greater from the SI than stomach or cecum (P Conclusions The absorption of Cysteamine and the effect of this agent on leukocyte cystine depletion are more profound after SI administration. Enteric-coated Cysteamine, targeted for SI release, may require fewer daily dosages. Not all patients with cystinosis require acid-suppression therapy.

Jerry A Schneider - One of the best experts on this subject based on the ideXlab platform.

  • copper deficiency in patients with cystinosis with Cysteamine toxicity
    The Journal of Pediatrics, 2013
    Co-Authors: Jerry A Schneider, Martine T P Besouw, Mirian C H Janssen, Marcella Greco, Francesco Emma, Elisabeth A M Cornelissen, Koen Desmet, Flemming Skovby, Francois Nobili
    Abstract:

    Objectives To assess whether copper deficiency plays a role in the recently described Cysteamine toxicity in patients with cystinosis, and to examine whether polymorphisms in copper transporters, lysyl oxidase, and/or type Iprocollagen genes could be responsible forthe occurrence of Cysteamine toxicity in a small subset of patients with cystinosis. Study design Thirty-six patients with cystinosis were included: 22 with Fanconi syndrome (including 7 with Cysteamine toxicity), 12 after renal transplantation, 1 receiving hemodialysis, and 1 with ocular cystinosis. Serum copper and ceruloplasmin levels and urinary copper/creatinine ratio were measured. Genes ATP7A and CTR1 (encodingcoppertransporters),LOX(encoding lysyl oxidase), andCOL1A1andCOL1A2(encodingtype I procollagen) were analyzedinpatientswith(n=6)andwithout(n=5)toxicity.Fibroblast (pro)collagen synthesiswas compared in patients with (n = 3) and those without (n = 2) Cysteamine toxicity. Results All 22 patients with Fanconi syndrome had increased urinary copper excretion. Serum copper and ceruloplasmin levels were decreased in 9 patients, including all 7 patients with Cysteamine toxicity. No specific sequence variations were associated with toxicity. All fibroblasts exhibited normal (pro)collagen synthesis. Conclusion Patients with cystinosis with Cysteamine toxicity demonstrate copper deficiency. This can cause decreased activity of lysyl oxidase, the enzyme that generates the aldehydes required for collagen cross-linking. Thus, copper supplementation might prevent Cysteamine toxicity. (J Pediatr 2013;163:754-60).

  • Cysteamine toxicity in patients with cystinosis
    The Journal of Pediatrics, 2011
    Co-Authors: Martine T P Besouw, Marcella Greco, Francesco Emma, Francois Nobili, William A Gahl, Richard Bowker, Jeanpaul Dutertre, Marc R Lilien, John Mckiernan, Jerry A Schneider
    Abstract:

    OBJECTIVE: To report new adverse effects of Cysteamine. STUDY DESIGN: Detailed clinical information was obtained from the patients' physicians. RESULTS: New adverse events were reported in 8 of 550 patients with cystinosis treated with Cysteamine in Europe during the last 5 years. Detailed clinical information was not available for 2 of these patients, 1 of whom died from cerebral ischemia. The 6 evaluable patients developed vascular elbow lesions (6/6), neurologic symptoms (1/6), bone and muscle pain (2/6), and/or skin striae (2/6). Analysis of biopsy specimens from the elbow lesions demonstrated angioendotheliomatosis with irregular collagen fibers. In 3 of the 6 patients, the daily Cysteamine dose exceeded the recommended maximum of 1.95 g/m(2)/day. Dose reduction led to improvement of signs and symptoms in all 6 patients, suggesting a causal relationship with Cysteamine administration. CONCLUSION: Cysteamine administration can be complicated by the development of skin, vascular, neurologic, muscular, and bone lesions. These lesions improve after Cysteamine dose reduction. Doses >1.95 g/m(2)/day should be prescribed with great caution, but underdosing is not advocated.

  • pharmacokinetics of enteric coated Cysteamine bitartrate in healthy adults a pilot study
    British Journal of Clinical Pharmacology, 2010
    Co-Authors: Jon A Gangoiti, Meredith Fidler, Bruce Barshop, Jerry A Schneider, Betty L Cabrera, Ranjan Dohil
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Cysteamine bitartrate is taken lifelong, every 6 h and for the treatment of cystinosis. Recent studies using Cysteamine for for other diseases such as neurodegenerative disorders adopt the same dosing regimen for Cysteamine. Regular Cysteamine bitartrate (Cystagon) may cause upper gastrointestinal symptoms in some patients. WHAT THIS STUDY ADDS • This is the only study that provides pharmacokinetic data for Cysteamine delivered in an enteric-release preparation in normal subjects. EC-Cysteamine is very well tolerated and does not cause increased gastrin concentrations, even at relatively high doses. • EC-Cysteamine at the higher dose results in better drug uptake as measured by Cmax and AUC and is more likely to be effective. AIMS Cysteamine bitartrate (Cystagon®) is the approved treatment for cystinosis. Poor compliance and patient outcome may occur because the drug needs to be taken every 6 h and in some patients causes gastrointestinal symptoms due to hypergastrinaemia. A formulation of Cysteamine requiring twice daily ingestion would improve the quality of life for these patients. This study compares the pharmacokinetics and gastrin production following Cysteamine bitartrate non-enteric-coated and Cysteamine bitartrate enteric-coated in normal healthy subjects. METHODS Enteric-coated Cysteamine was prepared. Following single doses of Cysteamine bitartrate non-enteric-coated 450 mg and Cysteamine bitartrate enteric-coated 450 mg and 900 mg, serial plasma Cysteamine and gastrin concentrations were measured. Two subjects also received Cysteamine bitartrate non-enteric-coated 900 mg. Gastrointestinal (GI) symptoms were recorded. RESULTS Six healthy adults (mean age 20.7 years, range 18–24 years; mean weight 59.3 kg) received drug. All post-dose gastrin concentrations were within the normal range (<100 pg ml–1). The tmax following Cysteamine bitartrate non-enteric-coated (mean and SD is 75 ± 19 min) was shorter than Cysteamine bitartrate enteric-coated (220 ± 74 min) (P= 0.001), but only the Cmax and AUC estimates following 900 mg Cysteamine bitartrate enteric-coated were significantly greater than any of the other preparations or doses (P < 0.05). One patient had GI symptoms following both 900 mg Cysteamine bitartrate non-enteric-coated and Cysteamine bitartrate enteric-coated. CONCLUSION Although patient numbers were low, single high doses of Cysteamine bitartrate enteric-coated were better tolerated than similar doses of Cysteamine bitartrate non-enteric-coated in the healthy subjects and all had normal gastrin concentrations. The delayed tmax following Cysteamine bitartrate enteric-coated suggested that the Cysteamine was released enterically.

  • long term treatment of cystinosis in children with twice daily Cysteamine
    The Journal of Pediatrics, 2010
    Co-Authors: Ranjan Dohil, Meredith Fidler, Jerry A Schneider, Jon A Gangoiti, Betty L Cabrera, Bruce Barshop
    Abstract:

    Objective Cystinosis causes renal and other organ failure. Treatment with 6-hourly Cysteamine bitartrate (Cystagon, Mylan, Morgantown, West Virginia) reduces intracellular cystine and the rate of organ deterioration. A recent study showed that an enteric-release Cysteamine required less frequent daily dosing. This report describes the long-term use of enteric-coated (EC) Cysteamine bitartrate (Cystagon) in children with cystinosis. Study design After a pharmacokinetic and pharmacodynamic study of EC-Cysteamine in children with cystinosis, 5 patients remained on twice-daily treatment. White blood cell cystine levels were measured 12 hours after ingestion every 4 to 8 weeks. These levels were then compared with the patient's previous 6-h post-dose levels taken while on regular Cysteamine bitartrate before entering the study. Blood chemistry was also measured. Results Five children with cystinosis (mean age, 9 years; range, 8 to 17 years) who previously took Cysteamine bitartrate (mean dose, 47 mg/kg body wt), received EC-Cysteamine for 10 to 27 months (mean dose, 25 mg/kg body wt) and had mean white blood cell cystine levels of 0.77 and 0.71 nmol half-cystine/mg protein, respectively. During the study period, patients maintained adequate growth and there was no significant deterioration in renal or thyroid function. Two children were required to restart acid suppression after 6 months on EC-Cysteamine therapy. Conclusions Long-term, twice-daily EC-Cysteamine, given at approximately 60% of the previous daily dose of Cysteamine bitartrate, was effective at maintaining white blood cell cystine levels within a satisfactory range. There was no significant deterioration in renal or thyroid function.

  • twice daily Cysteamine bitartrate therapy for children with cystinosis
    The Journal of Pediatrics, 2010
    Co-Authors: Ranjan Dohil, Meredith Fidler, Jerry A Schneider, Jon A Gangoiti, Frederick J Kaskel, Bruce Barshop
    Abstract:

    Objective Cystinosis causes renal and other organ failure. Regular 6-hourly Cysteamine bitartrate (Cystagon; Mylan, Morgantown, West Virginia) reduces intracellular cystine and the rate of organ deterioration. A formulation of Cysteamine requiring less frequent dosing may improve compliance and possibly patient outcome. Methods Enteric-release Cysteamine was prepared. For a period of 1 month, patients received their regular Cysteamine dose every 6 hours (stage I). The patients then underwent pharmacokinetic and pharmacodynamic studies following washout periods using single-doses of Cysteamine and enteric-release Cysteamine (stage II). Finally, the patients commenced regular enteric-release Cysteamine therapy (stage III). Weekly trough white blood cell (WBC) cystine levels were recorded. Results Seven children with cystinosis (mean age, 11.8 years; range, 8-17 years) who received Cysteamine and enteric-release Cysteamine (mean dose, 45 and 28.8 mg/kg body weight/day, respectively) had mean WBC cystine levels of 0.7 ± 0.3 and 0.41 ± 0.22 nmol half-cystine/mg protein in study stages I and III, respectively. Study stage II showed that the mean time (Tmax) to reach the maximum plasma Cysteamine level (Cmax) was longer for enteric-release Cysteamine than for Cysteamine (176 minutes vs 60 minutes; P = .001), but the mean Cmax at the same dose was similar. Mean serum gastrin levels were similar after ingestion of Cysteamine and enteric-release Cysteamine. Conclusions Twelve-hour enteric-release Cysteamine, given at approximately 60% of the previous daily dose of Cysteamine, was effective in maintaining trough WBC cystine levels within a satisfactory range.

Elena Levtchenko - One of the best experts on this subject based on the ideXlab platform.

  • ophthalmic outcome in a belgian cohort of cystinosis patients treated with a compounded preparation of Cysteamine eye drops retrospective analysis
    Ophthalmology and therapy, 2019
    Co-Authors: Freya Peeters, Elena Levtchenko, Catherine Cassiman, Karel Van Keer, Koenraad Veys, Ingele Casteels
    Abstract:

    Introduction Treatment of the anterior segment problems in cystinosis is challenging as oral Cysteamine is ineffective in the treatment of corneal problems because of its avascular structure. Although Cysteamine eye drops have been formulated to counter this issue, the stability of Cysteamine in these off-licensed formulations and treatment compliance are major problems. The aim of this retrospective study was to determine the efficacy of a compounded preparation of aqueous 0.5% Cysteamine eye drops in the management of corneal complications of cystinosis.

  • Cysteamine an old drug with new potential
    Drug Discovery Today, 2013
    Co-Authors: Martine T P Besouw, Elena Levtchenko, Rosalinde Masereeuw, Lambert P Van Den Heuvel
    Abstract:

    Cysteamine is an amino thiol with the chemical formula HSCH2CH2NH2. Endogenously, Cysteamine is derived from coenzyme A degradation, although its plasma concentrations are low. Most experience with Cysteamine as a drug originates from the field of the orphan disease cystinosis, in which Cysteamine is prescribed to decrease intralysosomal cystine accumulation. However, over the years, the drug has been used for several other applications both in vitro and in vivo. In this article, we review the different applications of Cysteamine, ending with an overview of ongoing clinical trials for new indications, such as neurodegenerative disorders and nonalcoholic fatty liver disease (NAFLD). The recent development of an enteric-coated Cysteamine formulation makes Cysteamine more patient friendly and will extend its applicability for both old and new indications.

  • Cysteamine restores glutathione redox status in cultured cystinotic proximal tubular epithelial cells
    Biochimica et Biophysica Acta, 2011
    Co-Authors: Martijn J Wilmer, Lambertus P Van Den Heuvel, Rosalinde Masereeuw, Leo A J Kluijtmans, Thea J A M Van Der Velden, Peter H G M Willems, Peter G Scheffer, L A H Monnens, Elena Levtchenko
    Abstract:

    Recent evidence implies that impaired metabolism of glutathione has a role in the pathogenesis of nephropathic cystinosis. This recessive inherited disorder is characterized by lysosomal cystine accumulation and results in renal Fanconi syndrome progressing to end stage renal disease in the majority of patients. The most common treatment involves intracellular cystine depletion by Cysteamine, delaying the development of end stage renal disease by a yet elusive mechanism. However, cystine depletion does not arrest the disease nor cures Fanconi syndrome in patients, indicating involvement of other yet unknown pathologic pathways. Using a newly developed proximal tubular epithelial cell model from cystinotic patients, we investigate the effect of cystine accumulation and Cysteamine on both glutathione and ATP metabolism. In addition to the expected increase in cystine and defective sodium-dependent phosphate reabsorption, we observed less negative glutathione redox status and decreased intracellular ATP levels. No differences between control and cystinosis cell lines were observed with respect to protein turnover, albumin uptake, cytosolic and mitochondrial ATP production, total glutathione levels, protein oxidation and lipid peroxidation. Cysteamine treatment increased total glutathione in both control and cystinotic cells and normalized cystine levels and glutathione redox status in cystinotic cells. However, Cysteamine did not improve decreased sodium-dependent phosphate uptake. Our data implicate that Cysteamine increases total glutathione and restores glutathione redox status in cystinosis, which is a positive side-effect of this agent next to cystine depletion. This beneficial effect points to a potential role of Cysteamine as anti-oxidant for other renal disorders associated with enhanced oxidative stress.

  • the origin of halitosis in cystinotic patients due to Cysteamine treatment
    Molecular Genetics and Metabolism, 2007
    Co-Authors: Martine Besouw, Henk J Blom, A Tangerman, Adriana De Graafhess, Elena Levtchenko
    Abstract:

    INTRODUCTION: Cystinosis is a rare autosomal recessive disorder characterized by the intralysosomal accumulation of cystine. Cysteamine removes cystine from the lysosome and slows down the progression of the disease. One of its side effects is the induction of halitosis, which can interfere with patients' willingness to comply with Cysteamine treatment. OBJECTIVE: To identify breath sulphur compounds causing halitosis induced by Cysteamine therapy in patients with cystinosis. STUDY DESIGN: After the ingestion of 15mg/kg Cysteamine whole blood (n=4), urine (n=4) and breath (n=8) volatile sulphur compounds levels were measured every 60min over a 360min period by gas chromatography and the Cysteamine plasma concentrations (n=4) were measured by high-performance liquid chromatography. RESULTS: The expired air of cystinotic patients contained elevated concentrations of methanethiol (MT, median maximum value 0.5 (range 0-11)nmol/L) and, in particular, dimethylsulphide (DMS, median maximum value 15 (range 2-83)nmol/L). DMS concentrations higher than 0.65nmol/L are known to cause halitosis. Maximal plasma values of Cysteamine (median 46 (range 30-52)micromol/L) preceded those of MT and DMS, confirming that Cysteamine is converted to MT and DMS. Less than 3% of the amount of Cysteamine ingested was excreted as MT and DMS via expired air and 0.002% via urine. CONCLUSION: Halitosis induced by Cysteamine intake is caused by DMS and to a lesser extent by MT, excreted via the expired air. Further studies should focus on the possibilities of reducing the formation of these volatile sulphur compounds or masking their odour, which would improve the rates of compliance with Cysteamine treatment.

  • strict Cysteamine dose regimen is required to prevent nocturnal cystine accumulation in cystinosis
    Pediatric Nephrology, 2006
    Co-Authors: Elena Levtchenko, Leo A H Monnens, Lambertus P Van Den Heuvel, Martijn J Wilmer, Carin M Van Dael, Addy C De Graafhess, Henk J Blom
    Abstract:

    Cystinosis is an autosomal recessive disorder, caused by mutations in the lysosomal cystine carrier cystinosin, encoded by the CTNS gene. The disease generally manifests with Fanconi syndrome during the first year of life and progresses towards end stage renal disease before the age of 10 years. Cysteamine depletes intralysosomal cystine content, postpones the deterioration of renal function and the occurrence of extra-renal organ damage. Based on the pharmacokinetic data, patients with cystinosis are advised to use Cysteamine every 6 h. The aim of this study was (1) to evaluate the Cysteamine dose regimen in Dutch patients with cystinosis and (2) to determine morning polymorphonuclear (PMN) leukocyte cystine content 6 h vs 9 h after the last evening Cysteamine dose. Only 5/22 of Dutch cystinosis patients ingested Cysteamine every 6 h. Morning (8 a.m.) PMN cystine content in 11 examined patients was elevated 9 h after 12.5-15 mg/kg evening Cysteamine dose compared to the value 6 h after the ingestion of the same dose (0.73+/-0.81 nmol vs 0.44+/-0.52 nmol cystine/mg protein, p =0.02). In conclusion, only the minority of Dutch cystinosis patients follows the recommended strict Cysteamine dose regimen. We provide evidence that Cysteamine has to be administered every 6 h, including the night, as it has much better effect for maintaining low PMN cystine levels.

Bruce Barshop - One of the best experts on this subject based on the ideXlab platform.

  • Cysteamine modulates oxidative stress and blocks myofibroblast activity in ckd
    Journal of The American Society of Nephrology, 2014
    Co-Authors: Daryl M Okamura, Bruce Barshop, Jon A Gangoiti, Nadia M Bahrami, Shuyu Ren, Katie Pasichnyk, Juliana M Williams, Jesus M Lopezguisa, Ikuyo Yamaguchi, Jeremy S Duffield
    Abstract:

    Therapytoslowtherelentlessexpansionofinterstitialextracellularmatrixthatleads to renal functional decline in patients with CKD is currently lacking. Because chronic kidney injury increases tissue oxidative stress, we evaluated the antifibrotic efficacy of Cysteamine bitartrate, an antioxidant therapy for patients with nephropathic cystinosis, in a mouse model of unilateral ureteral obstruction. Fresh Cysteamine (600 mg/kg) was added to drinking water daily beginning on the day of surgery, and outcomes were assessed on days 7, 14, and 21 after surgery. Plasma Cysteamine levels showed diurnal variation, with peak levels similar to those observed in patients with cystinosis. In Cysteamine-treated mice, fibrosis severity decreased significantly at 14 and 21 days after unilateral ureteral obstruction, and renal oxidized protein levels decreased at each time point, suggesting reduced oxidative stress. Consistent with these results, treatment of cultured macrophages with Cysteamine reduced cellular generation of reactive oxygen species. Furthermore, treatment with Cysteamine reduced a-smooth muscle actin–positive interstitial myofibroblast proliferation and mRNA levels of extracellular matrix proteins in mice and attenuated myofibroblast differentiation and proliferation in vitro ,b ut did not augment TGF-b signaling. In a study of renal ischemia reperfusion, Cysteamine therapy initiated 10 days after injury and continued for 14 days decreased renal fibrosis by 40%. Taken together, these data suggest previously unrecognized antifibrotic actions of Cysteamine via TGF-b–independent mechanisms that include oxidative stress reduction and attenuation of the myofibroblast response to kidney injury and support further investigation into the potential benefit of Cysteamine therapy in the treatment of CKD.

  • pharmacokinetics of enteric coated Cysteamine bitartrate in healthy adults a pilot study
    British Journal of Clinical Pharmacology, 2010
    Co-Authors: Jon A Gangoiti, Meredith Fidler, Bruce Barshop, Jerry A Schneider, Betty L Cabrera, Ranjan Dohil
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Cysteamine bitartrate is taken lifelong, every 6 h and for the treatment of cystinosis. Recent studies using Cysteamine for for other diseases such as neurodegenerative disorders adopt the same dosing regimen for Cysteamine. Regular Cysteamine bitartrate (Cystagon) may cause upper gastrointestinal symptoms in some patients. WHAT THIS STUDY ADDS • This is the only study that provides pharmacokinetic data for Cysteamine delivered in an enteric-release preparation in normal subjects. EC-Cysteamine is very well tolerated and does not cause increased gastrin concentrations, even at relatively high doses. • EC-Cysteamine at the higher dose results in better drug uptake as measured by Cmax and AUC and is more likely to be effective. AIMS Cysteamine bitartrate (Cystagon®) is the approved treatment for cystinosis. Poor compliance and patient outcome may occur because the drug needs to be taken every 6 h and in some patients causes gastrointestinal symptoms due to hypergastrinaemia. A formulation of Cysteamine requiring twice daily ingestion would improve the quality of life for these patients. This study compares the pharmacokinetics and gastrin production following Cysteamine bitartrate non-enteric-coated and Cysteamine bitartrate enteric-coated in normal healthy subjects. METHODS Enteric-coated Cysteamine was prepared. Following single doses of Cysteamine bitartrate non-enteric-coated 450 mg and Cysteamine bitartrate enteric-coated 450 mg and 900 mg, serial plasma Cysteamine and gastrin concentrations were measured. Two subjects also received Cysteamine bitartrate non-enteric-coated 900 mg. Gastrointestinal (GI) symptoms were recorded. RESULTS Six healthy adults (mean age 20.7 years, range 18–24 years; mean weight 59.3 kg) received drug. All post-dose gastrin concentrations were within the normal range (<100 pg ml–1). The tmax following Cysteamine bitartrate non-enteric-coated (mean and SD is 75 ± 19 min) was shorter than Cysteamine bitartrate enteric-coated (220 ± 74 min) (P= 0.001), but only the Cmax and AUC estimates following 900 mg Cysteamine bitartrate enteric-coated were significantly greater than any of the other preparations or doses (P < 0.05). One patient had GI symptoms following both 900 mg Cysteamine bitartrate non-enteric-coated and Cysteamine bitartrate enteric-coated. CONCLUSION Although patient numbers were low, single high doses of Cysteamine bitartrate enteric-coated were better tolerated than similar doses of Cysteamine bitartrate non-enteric-coated in the healthy subjects and all had normal gastrin concentrations. The delayed tmax following Cysteamine bitartrate enteric-coated suggested that the Cysteamine was released enterically.

  • long term treatment of cystinosis in children with twice daily Cysteamine
    The Journal of Pediatrics, 2010
    Co-Authors: Ranjan Dohil, Meredith Fidler, Jerry A Schneider, Jon A Gangoiti, Betty L Cabrera, Bruce Barshop
    Abstract:

    Objective Cystinosis causes renal and other organ failure. Treatment with 6-hourly Cysteamine bitartrate (Cystagon, Mylan, Morgantown, West Virginia) reduces intracellular cystine and the rate of organ deterioration. A recent study showed that an enteric-release Cysteamine required less frequent daily dosing. This report describes the long-term use of enteric-coated (EC) Cysteamine bitartrate (Cystagon) in children with cystinosis. Study design After a pharmacokinetic and pharmacodynamic study of EC-Cysteamine in children with cystinosis, 5 patients remained on twice-daily treatment. White blood cell cystine levels were measured 12 hours after ingestion every 4 to 8 weeks. These levels were then compared with the patient's previous 6-h post-dose levels taken while on regular Cysteamine bitartrate before entering the study. Blood chemistry was also measured. Results Five children with cystinosis (mean age, 9 years; range, 8 to 17 years) who previously took Cysteamine bitartrate (mean dose, 47 mg/kg body wt), received EC-Cysteamine for 10 to 27 months (mean dose, 25 mg/kg body wt) and had mean white blood cell cystine levels of 0.77 and 0.71 nmol half-cystine/mg protein, respectively. During the study period, patients maintained adequate growth and there was no significant deterioration in renal or thyroid function. Two children were required to restart acid suppression after 6 months on EC-Cysteamine therapy. Conclusions Long-term, twice-daily EC-Cysteamine, given at approximately 60% of the previous daily dose of Cysteamine bitartrate, was effective at maintaining white blood cell cystine levels within a satisfactory range. There was no significant deterioration in renal or thyroid function.

  • twice daily Cysteamine bitartrate therapy for children with cystinosis
    The Journal of Pediatrics, 2010
    Co-Authors: Ranjan Dohil, Meredith Fidler, Jerry A Schneider, Jon A Gangoiti, Frederick J Kaskel, Bruce Barshop
    Abstract:

    Objective Cystinosis causes renal and other organ failure. Regular 6-hourly Cysteamine bitartrate (Cystagon; Mylan, Morgantown, West Virginia) reduces intracellular cystine and the rate of organ deterioration. A formulation of Cysteamine requiring less frequent dosing may improve compliance and possibly patient outcome. Methods Enteric-release Cysteamine was prepared. For a period of 1 month, patients received their regular Cysteamine dose every 6 hours (stage I). The patients then underwent pharmacokinetic and pharmacodynamic studies following washout periods using single-doses of Cysteamine and enteric-release Cysteamine (stage II). Finally, the patients commenced regular enteric-release Cysteamine therapy (stage III). Weekly trough white blood cell (WBC) cystine levels were recorded. Results Seven children with cystinosis (mean age, 11.8 years; range, 8-17 years) who received Cysteamine and enteric-release Cysteamine (mean dose, 45 and 28.8 mg/kg body weight/day, respectively) had mean WBC cystine levels of 0.7 ± 0.3 and 0.41 ± 0.22 nmol half-cystine/mg protein in study stages I and III, respectively. Study stage II showed that the mean time (Tmax) to reach the maximum plasma Cysteamine level (Cmax) was longer for enteric-release Cysteamine than for Cysteamine (176 minutes vs 60 minutes; P = .001), but the mean Cmax at the same dose was similar. Mean serum gastrin levels were similar after ingestion of Cysteamine and enteric-release Cysteamine. Conclusions Twelve-hour enteric-release Cysteamine, given at approximately 60% of the previous daily dose of Cysteamine, was effective in maintaining trough WBC cystine levels within a satisfactory range.

  • understanding intestinal Cysteamine bitartrate absorption
    The Journal of Pediatrics, 2006
    Co-Authors: Ranjan Dohil, Meredith Fidler, Bruce Barshop, Reena Deutsch, Jon A Gangoiti, Michael B Martin, Jerry A Schneider
    Abstract:

    Objectives To test the hypothesis that a controlled-release preparation of Cysteamine, with fewer daily administrations, would improve the quality of life for patients with cystinosis. Study design A specifically designed nasoenteric tube was used to administer Cysteamine directly into the stomach, small intestine (SI) and colon and serial plasma Cysteamine, serum gastrin and leukocyte cystine levels were measured. Results Eight control subjects (mean age 23.2 years) and 6 subjects with cystinosis (mean age 15.2 years) were studied. Cysteamine absorption (maximum concentration and area under the curve of the concentration-time gradient) was greater from the SI than stomach or cecum (P Conclusions The absorption of Cysteamine and the effect of this agent on leukocyte cystine depletion are more profound after SI administration. Enteric-coated Cysteamine, targeted for SI release, may require fewer daily dosages. Not all patients with cystinosis require acid-suppression therapy.

Jon A Gangoiti - One of the best experts on this subject based on the ideXlab platform.

  • Cysteamine modulates oxidative stress and blocks myofibroblast activity in ckd
    Journal of The American Society of Nephrology, 2014
    Co-Authors: Daryl M Okamura, Bruce Barshop, Jon A Gangoiti, Nadia M Bahrami, Shuyu Ren, Katie Pasichnyk, Juliana M Williams, Jesus M Lopezguisa, Ikuyo Yamaguchi, Jeremy S Duffield
    Abstract:

    Therapytoslowtherelentlessexpansionofinterstitialextracellularmatrixthatleads to renal functional decline in patients with CKD is currently lacking. Because chronic kidney injury increases tissue oxidative stress, we evaluated the antifibrotic efficacy of Cysteamine bitartrate, an antioxidant therapy for patients with nephropathic cystinosis, in a mouse model of unilateral ureteral obstruction. Fresh Cysteamine (600 mg/kg) was added to drinking water daily beginning on the day of surgery, and outcomes were assessed on days 7, 14, and 21 after surgery. Plasma Cysteamine levels showed diurnal variation, with peak levels similar to those observed in patients with cystinosis. In Cysteamine-treated mice, fibrosis severity decreased significantly at 14 and 21 days after unilateral ureteral obstruction, and renal oxidized protein levels decreased at each time point, suggesting reduced oxidative stress. Consistent with these results, treatment of cultured macrophages with Cysteamine reduced cellular generation of reactive oxygen species. Furthermore, treatment with Cysteamine reduced a-smooth muscle actin–positive interstitial myofibroblast proliferation and mRNA levels of extracellular matrix proteins in mice and attenuated myofibroblast differentiation and proliferation in vitro ,b ut did not augment TGF-b signaling. In a study of renal ischemia reperfusion, Cysteamine therapy initiated 10 days after injury and continued for 14 days decreased renal fibrosis by 40%. Taken together, these data suggest previously unrecognized antifibrotic actions of Cysteamine via TGF-b–independent mechanisms that include oxidative stress reduction and attenuation of the myofibroblast response to kidney injury and support further investigation into the potential benefit of Cysteamine therapy in the treatment of CKD.

  • pharmacokinetics of enteric coated Cysteamine bitartrate in healthy adults a pilot study
    British Journal of Clinical Pharmacology, 2010
    Co-Authors: Jon A Gangoiti, Meredith Fidler, Bruce Barshop, Jerry A Schneider, Betty L Cabrera, Ranjan Dohil
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Cysteamine bitartrate is taken lifelong, every 6 h and for the treatment of cystinosis. Recent studies using Cysteamine for for other diseases such as neurodegenerative disorders adopt the same dosing regimen for Cysteamine. Regular Cysteamine bitartrate (Cystagon) may cause upper gastrointestinal symptoms in some patients. WHAT THIS STUDY ADDS • This is the only study that provides pharmacokinetic data for Cysteamine delivered in an enteric-release preparation in normal subjects. EC-Cysteamine is very well tolerated and does not cause increased gastrin concentrations, even at relatively high doses. • EC-Cysteamine at the higher dose results in better drug uptake as measured by Cmax and AUC and is more likely to be effective. AIMS Cysteamine bitartrate (Cystagon®) is the approved treatment for cystinosis. Poor compliance and patient outcome may occur because the drug needs to be taken every 6 h and in some patients causes gastrointestinal symptoms due to hypergastrinaemia. A formulation of Cysteamine requiring twice daily ingestion would improve the quality of life for these patients. This study compares the pharmacokinetics and gastrin production following Cysteamine bitartrate non-enteric-coated and Cysteamine bitartrate enteric-coated in normal healthy subjects. METHODS Enteric-coated Cysteamine was prepared. Following single doses of Cysteamine bitartrate non-enteric-coated 450 mg and Cysteamine bitartrate enteric-coated 450 mg and 900 mg, serial plasma Cysteamine and gastrin concentrations were measured. Two subjects also received Cysteamine bitartrate non-enteric-coated 900 mg. Gastrointestinal (GI) symptoms were recorded. RESULTS Six healthy adults (mean age 20.7 years, range 18–24 years; mean weight 59.3 kg) received drug. All post-dose gastrin concentrations were within the normal range (<100 pg ml–1). The tmax following Cysteamine bitartrate non-enteric-coated (mean and SD is 75 ± 19 min) was shorter than Cysteamine bitartrate enteric-coated (220 ± 74 min) (P= 0.001), but only the Cmax and AUC estimates following 900 mg Cysteamine bitartrate enteric-coated were significantly greater than any of the other preparations or doses (P < 0.05). One patient had GI symptoms following both 900 mg Cysteamine bitartrate non-enteric-coated and Cysteamine bitartrate enteric-coated. CONCLUSION Although patient numbers were low, single high doses of Cysteamine bitartrate enteric-coated were better tolerated than similar doses of Cysteamine bitartrate non-enteric-coated in the healthy subjects and all had normal gastrin concentrations. The delayed tmax following Cysteamine bitartrate enteric-coated suggested that the Cysteamine was released enterically.

  • long term treatment of cystinosis in children with twice daily Cysteamine
    The Journal of Pediatrics, 2010
    Co-Authors: Ranjan Dohil, Meredith Fidler, Jerry A Schneider, Jon A Gangoiti, Betty L Cabrera, Bruce Barshop
    Abstract:

    Objective Cystinosis causes renal and other organ failure. Treatment with 6-hourly Cysteamine bitartrate (Cystagon, Mylan, Morgantown, West Virginia) reduces intracellular cystine and the rate of organ deterioration. A recent study showed that an enteric-release Cysteamine required less frequent daily dosing. This report describes the long-term use of enteric-coated (EC) Cysteamine bitartrate (Cystagon) in children with cystinosis. Study design After a pharmacokinetic and pharmacodynamic study of EC-Cysteamine in children with cystinosis, 5 patients remained on twice-daily treatment. White blood cell cystine levels were measured 12 hours after ingestion every 4 to 8 weeks. These levels were then compared with the patient's previous 6-h post-dose levels taken while on regular Cysteamine bitartrate before entering the study. Blood chemistry was also measured. Results Five children with cystinosis (mean age, 9 years; range, 8 to 17 years) who previously took Cysteamine bitartrate (mean dose, 47 mg/kg body wt), received EC-Cysteamine for 10 to 27 months (mean dose, 25 mg/kg body wt) and had mean white blood cell cystine levels of 0.77 and 0.71 nmol half-cystine/mg protein, respectively. During the study period, patients maintained adequate growth and there was no significant deterioration in renal or thyroid function. Two children were required to restart acid suppression after 6 months on EC-Cysteamine therapy. Conclusions Long-term, twice-daily EC-Cysteamine, given at approximately 60% of the previous daily dose of Cysteamine bitartrate, was effective at maintaining white blood cell cystine levels within a satisfactory range. There was no significant deterioration in renal or thyroid function.

  • twice daily Cysteamine bitartrate therapy for children with cystinosis
    The Journal of Pediatrics, 2010
    Co-Authors: Ranjan Dohil, Meredith Fidler, Jerry A Schneider, Jon A Gangoiti, Frederick J Kaskel, Bruce Barshop
    Abstract:

    Objective Cystinosis causes renal and other organ failure. Regular 6-hourly Cysteamine bitartrate (Cystagon; Mylan, Morgantown, West Virginia) reduces intracellular cystine and the rate of organ deterioration. A formulation of Cysteamine requiring less frequent dosing may improve compliance and possibly patient outcome. Methods Enteric-release Cysteamine was prepared. For a period of 1 month, patients received their regular Cysteamine dose every 6 hours (stage I). The patients then underwent pharmacokinetic and pharmacodynamic studies following washout periods using single-doses of Cysteamine and enteric-release Cysteamine (stage II). Finally, the patients commenced regular enteric-release Cysteamine therapy (stage III). Weekly trough white blood cell (WBC) cystine levels were recorded. Results Seven children with cystinosis (mean age, 11.8 years; range, 8-17 years) who received Cysteamine and enteric-release Cysteamine (mean dose, 45 and 28.8 mg/kg body weight/day, respectively) had mean WBC cystine levels of 0.7 ± 0.3 and 0.41 ± 0.22 nmol half-cystine/mg protein in study stages I and III, respectively. Study stage II showed that the mean time (Tmax) to reach the maximum plasma Cysteamine level (Cmax) was longer for enteric-release Cysteamine than for Cysteamine (176 minutes vs 60 minutes; P = .001), but the mean Cmax at the same dose was similar. Mean serum gastrin levels were similar after ingestion of Cysteamine and enteric-release Cysteamine. Conclusions Twelve-hour enteric-release Cysteamine, given at approximately 60% of the previous daily dose of Cysteamine, was effective in maintaining trough WBC cystine levels within a satisfactory range.

  • understanding intestinal Cysteamine bitartrate absorption
    The Journal of Pediatrics, 2006
    Co-Authors: Ranjan Dohil, Meredith Fidler, Bruce Barshop, Reena Deutsch, Jon A Gangoiti, Michael B Martin, Jerry A Schneider
    Abstract:

    Objectives To test the hypothesis that a controlled-release preparation of Cysteamine, with fewer daily administrations, would improve the quality of life for patients with cystinosis. Study design A specifically designed nasoenteric tube was used to administer Cysteamine directly into the stomach, small intestine (SI) and colon and serial plasma Cysteamine, serum gastrin and leukocyte cystine levels were measured. Results Eight control subjects (mean age 23.2 years) and 6 subjects with cystinosis (mean age 15.2 years) were studied. Cysteamine absorption (maximum concentration and area under the curve of the concentration-time gradient) was greater from the SI than stomach or cecum (P Conclusions The absorption of Cysteamine and the effect of this agent on leukocyte cystine depletion are more profound after SI administration. Enteric-coated Cysteamine, targeted for SI release, may require fewer daily dosages. Not all patients with cystinosis require acid-suppression therapy.

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