Effects of various levels of coated cysteamine hydrochloride in the diet on feed intake, digestibility, ruminal fermentation, and blood metabolites in growing Charolais crossbred cattle.

This study investigated the impact of different levels of coated cysteamine hydrochloride (CSH) supplementation on ruminal fermentation, nutrient digestibility, and blood metabolites in Charolais cross bulls. Twelve bulls were allotted to three feeding treatments in a replicated 3 × 3 Latin square design: 0% CSH (control), 0.5% CSH, and 1.0% CSH in concentrate. Animals were fed concentrate at 1.5% of body weight. Dry matter intake (DMI) and DMI as a percentage of body weight showed no significant differences among treatments (p > 0.10). Nutrient digestibility was consistent across treatments, except for a slight decrease in NDF digestibility with 1% CSH (p = 0.07). Ruminal pH, ammonia nitrogen, volatile fatty acid (VFA) proportions, and total VFA concentration were similar among treatments (p > 0.05). Total bacteria, fungal zoospores, and protozoa populations in the rumen did not vary significantly (p > 0.05). Blood glucose and triglyceride concentrations remained stable (p > 0.05), while blood urea nitrogen (BUN) levels were higher in CSH-supplemented groups (p < 0.05). In conclusion, incorporating CSH levels ranging from 0.5% to 1.0% into the diet did not adversely affect feed intake, ruminal fermentation, or microbial populations. Additionally, 1.0% CSH improved BUN concentration in growing Charolais cross bulls.

Efficacy, Safety, Satisfaction, Adherence to Treatment With Nano-Formulated Cysteamine Tranexamic Acid Cream to Treat Melasma.

BACKGROUND: Melasma is a chronic pigmentary disorder. In this study, an innovative cream combining cysteamine and tranexamic acid (TXA) was assessed. OBJECTIVE: To evaluate the safety, efficacy, and patient satisfaction of a novel nano-formulated cysteamine and TXA combination cream in treating subjects with epidermal melasma. METHODS:   Fifty (50) randomized subjects participated and received cysteamine and TXA combination cream. The cream was applied for 30 minutes daily for a 3-month duration. Treatment effectiveness, safety, patient satisfaction, and adherence were evaluated. RESULTS: A continuous improvement in melasma was observed, with modified Melasma Area and Severity Index (mMASI) scores improving by 40%, 57%, and 63% at 30, 60, and 90 days, respectively. The primary endpoint of a decrease in mMASI scores was met, with 91% of participants experiencing melasma improvement. Patient Satisfaction and Patient Adherence scores indicated satisfaction. Convenience exhibited the strongest correlation with patient adherence.  Conclusion: Nano-formulated cysteamine and TXA combination cream showed significant efficacy in decreasing mMASI score while demonstrating a strong safety profile and patient satisfaction.  J Drugs Dermatol. 2024;23(7):529-537.     doi:10.36849/JDD.7765R1.

Cysteamine Nanoemulsion Delivery by Inhalation to Attenuate Adverse Effects of Exposure to Cigarette Smoke: A Metabolomics Study in Wistar Rats.

There is a pressing need for novel pharmacological interventions and drug delivery innovations to attenuate the cigarette smoke-associated oxidative stress and lung disease. We report here on the attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) and metabolomics of Wistar rats exposed to cigarette smoke for 28 days. The animals were treated for 15 days with plain cysteamine given orally or cysteamine as nanoemulsion given orally or via inhalation. The study design also included two control groups as follows: rats exposed to cigarette smoke but did not receive a treatment (diseased control group) and rats neither exposed to cigarette smoke nor a treatment (normal control group). The targeted metabolomics using Parallel Reaction Monitoring showed that in the diseased control group, ornithine, nicotinamide, xanthine, hypoxanthine, and caprolactam were increased compared with the normal control group. In addition, (±)8(9)-DiHET, which was initially downregulated in the diseased control group, exhibited a reversal of this trend with cysteamine nanoemulsion given via inhalation. The cysteamine nanoemulsion delivered by inhalation highlighted the importance of the route of drug administration for targeting the lungs. To the best of our knowledge, this is the first work to use ATR-FTIR and metabolomics in Wistar rat lung tissues, suggesting how cysteamine nanoemulsion can potentially reduce cigarette smoke-induced oxidative damage. The metabolites reported herein have potential implications for discovery of novel theranostics and, thus, to cultivate diagnostic and therapeutic innovation for early prevention and treatment of cigarette smoke-associated lung diseases.

Morphological changes and their associations with clinical parameters in children with nephropathic cystinosis and chronic kidney disease prior to kidney replacement therapy over 25 years.

BACKGROUND: Infantile nephropathic cystinosis (INC) is a rare lysosomal storage disorder, mostly and often firstly affecting the kidneys, together with impaired disharmonious growth and rickets, eventually resulting in progressive chronic kidney disease (CKD). With the introduction of cysteamine therapy, most pediatric patients reach adulthood with no need for kidney replacement therapy. Still, detailed changes in INC patients' clinical and morphological presentation over the past decades have not yet been thoroughly investigated. METHODS: Two groups with a respective total of 64 children with INC and 302 children with CKD, both treated conservatively and aged 2 to 18 years, were prospectively observed in the time span from 1998 to 2022 with 1186 combined annual clinical and morphological examinations clustered into two measurement periods (1998 to 2015 and ≥ 2016). RESULTS: In INC patients, thoracic proportion indices remained markedly increased, whereas body fat stores remained decreased over the past 25 years (+ 1 vs. below ± 0 z-score, respectively). Their CKD peers presented with overall improved growth, general harmonization of body proportions, and improved body fat stores, while INC patients only presented with an isolated significant increase in leg length over time (∆0.36 z-score). eGFR adjusted for age did not significantly change over the past 25 years in both groups. Alkaline phosphatase (ALP) showed a significant decrease in CKD patients over time, while remaining above normal levels in INC patients. CONCLUSIONS: Disproportionate thoracic shape and impaired body fat stores remain the most characteristic morphological traits in INC patients over the past 25 years, while causal mechanisms remain unclear.

Fibrosing colonopathy associated with cysteamine bitartrate delayed-release capsules in cystinosis patients.

BACKGROUND: The objective of this report is to identify and characterize cases of fibrosing colonopathy, a rare and underrecognized adverse event, associated with cysteamine delayed-release (DR) in patients with nephropathic cystinosis. METHODS: We searched the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the medical literature for postmarketing reports of fibrosing colonopathy associated with cysteamine through August 2, 2023. RESULTS: We identified four cases of fibrosing colonopathy reported with the use of cysteamine DR. The time to onset ranged from 12 to 31 months. In one case, the patient required surgery to have a resection of a section of the strictured colon and a diverting ileostomy. Fibrosing colonopathy was diagnosed by histopathology in two of the cases. CONCLUSIONS: Our case series identified the risk of fibrosing colonopathy in patients taking cysteamine DR and prompted regulatory action by the FDA. As outlined in changes to the U.S. prescribing information for cysteamine DR, healthcare professionals should be aware of the potential risk of fibrosing colonopathy with cysteamine DR, especially as symptoms can be non-specific leading to misdiagnosis or delayed diagnosis. If the diagnosis of fibrosing colonopathy is confirmed, consideration should be given to permanently discontinuing cysteamine DR and switching to cysteamine immediate-release treatment.

Gastrointestinal challenges in nephropathic cystinosis: clinical perspectives.

Gastrointestinal (GI) sequelae, such as vomiting, hyperacidity, dysphagia, dysmotility, and diarrhea, are nearly universal among patients with nephropathic cystinosis. These complications result from disease processes (e.g., kidney disease, cystine crystal accumulation in the GI tract) and side effects of treatments (e.g., cysteamine, immunosuppressive therapy). GI involvement can negatively impact patient well-being and jeopardize disease outcomes by compromising drug absorption and patient adherence to the strict treatment regimen required to manage cystinosis. Given improved life expectancy due to advances in kidney transplantation and the transformative impact of cystine-depleting therapy, nephrologists are increasingly focused on addressing extra-renal complications and quality of life in patients with cystinosis. However, there is a lack of clinical data and guidance to inform GI-related monitoring, interventions, and referrals by nephrologists. Various publications have examined the prevalence and pathophysiology of selected GI complications in cystinosis, but none have summarized the full picture or provided guidance based on the literature and expert experience. We aim to comprehensively review GI sequelae associated with cystinosis and its treatments and to discuss approaches for monitoring and managing these complications, including the involvement of gastroenterology and other disciplines.

Combination of 5% cysteamine and 4% nicotinamide in melasma: Efficacy, tolerability, and safety.

BACKGROUND: Melasma is a chronic dermatosis that impacts the patient's quality of life and can present considerable challenges in terms of effective treatment. OBJECTIVE: To evaluate the effectiveness, tolerability, and safety of 5% cysteamine combined with 4% nicotinamide in female subjects with melasma. METHODS: This single-center, single-arm, prospective, open-label study evaluated patients with melasma using a combination cream of 5% cysteamine and 4% nicotinamide in a progressive regimen (60 min in the first month, 120 min in the second month, and 180 min in the third month). RESULTS: Overall, 35 treated subjects exhibited reduced modified Melasma Area and Severity Index (mMASI) (p < 0.001) and decreased MelasQoL scores (p < 0.001), accompanied by improved brightness, luminosity, homogeneity, and spot intensity (p < 0.001). Photographic and colorimetric analysis revealed smaller spots and improved homogeneity. LIMITATIONS: Adherence to progressive daily treatment could not be evaluated long-term. CONCLUSION: A combination cream comprising 5% cysteamine and 4% nicotinamide was effective, tolerable, and safe for treating melasma.

Estudo piloto sobre a eficácia e segurança do uso da cisteamina 5% como terapia de contato por toda noite no tratamento do melasma facial / Efficacy and safety of the 5% cysteamine cream left in overnight for facial melasma: a pilot study

Não se aplica, trata-se de uma carta

Not applicable, this is a letter.

A novel sustained-release cysteamine bitartrate formulation for the treatment of cystinosis: Pharmacokinetics and safety in healthy male volunteers.

The strict intake regimen of cysteamine bitartrate formulations, associated with side effects, is a concern for the treatment compliance in cystinosis therapy. Therefore, there is a need for a cysteamine formulation with an improved pharmacokinetic profile. This study investigated the pharmacokinetics, safety and tolerability of a new sustained-release cysteamine dosage form, PO-001, in healthy volunteers. This was a randomized, investigator-blinded, three-way cross-over study to compare single doses (600 mg) of PO-001 with Cystagon® (immediate-release) and Procysbi® (delayed-release). Collected blood samples were analyzed for plasma cysteamine concentrations and pharmacokinetic parameters were estimated by noncompartmental analysis. In addition, plasma cysteamine concentrations were analyzed using a population pharmacokinetic approach using NONMEM® . Pharmacokinetics showed clear sustained-release characteristics of PO-001 over time with a lower Cmax and longer Tmax compared to Cystagon® and Procysbi® . All treatment-emergent adverse events were of mild severity, with the exception of two subjects who reported moderate severity gastrointestinal problems including vomiting and diarrhea, which were related to Cystagon® intake. Population PK simulations showed a favourable PK profile based on Cmax and Ctrough concentrations at steady state. In conclusion, a single dose of 600 mg PO-001 was well tolerated with no findings of clinical concern. This new cysteamine bitartrate formulation showed pharmacokinetics of a sustained-release formulation, which may be beneficial for the treatment of cystinosis patients. This study supports advancing this type of sustained-release formulation into a subsequent study to confirm reduced dosing frequency with efficient control of white blood cells (WBCs) cystine levels. Netherlands Trial Registry (NTR) (NL67638.056.18).

The Anti-oxidative Effects of Encapsulated Cysteamine During Mice In Vitro Matured Oocyte/Morula-Compact Stage Embryo Culture Model: a Comparison of High-Efficiency Nanocarriers for Hydrophilic Drug Delivery-a Pilot Study.

Although it is well-recognized that antioxidant nano-encapsulation has many benefits such as minimizing side effects (e.g., high-dose toxicity), the most attention was paid to the hydrophobic antioxidant not hydrophilic. In this regard, we sought to compare two hydrophilic model nanocarriers to deliver the optimal dose of cystamine (Cys) into the in vitro matured oocyte and the first cleavage stages until morula-compact stage embryonic cells. The formation of Cys-loaded solid self-emulsifying lipid (Cys + SLN) and Cys-loaded chitosan shell (Cys-CS-NC) were confirmed by FT-IR and UV-Vis spectrophotometry, dynamic light scattering (DLS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) technologies. In two experiments, the oocytes/presumptive zygotes were cultured under various concentrations of Cys-SLN and Cys-CS-NC. The results of nuclear staining (aceto-orcein and Hoechst 33342), H2DCFDA fluorescent staining, chemiluminescence test, and quantitative reverse transcription-PCR (qRT-PCR) technique as in vitro toxicity studies demonstrated that adding the lowest dose of Cys-encapsulated in both nanocarriers [Cys-SLN (5 µM) and Cys-CS-NC (10 µM)] to maturation or culture medium could accumulate a strong anti-oxidative effect in oocyte/embryo by controlled release and enhanced intracellular penetration of Cys. In comparison, Cys-SLN (5 µM) is more effective than Cys-CS-NC (10 µM) groups to improve the expression of antioxidant genes (SOD, CAT, GPx) or anti-apoptotic (BCL-2) gene and decreased apoptosis (BAX and caspase-3) or intra-/extracellular ROS levels. In a nutshell, both nanocarriers (CS-NC or SLN) can deliver the lowest dose of Cys into the oocyte/embryo, thus encouraging a better expansion of antioxidant genes and enhancing the development of in vitro oocyte/embryo.

Efficacy and Safety of Topical Cysteamine in Corneal Cystinosis: A Systematic Review and Meta-Analysis.

PURPOSE: To evaluate safety and efficacy of topical cysteamine ophthalmic solution for corneal cystinosis. METHODS: Seven databases were searched (PubMed, OVID, EMBASE, Web of Science, Cochrane Central, Google Scholar, and ClinicalTrials.gov) for relevant studies, using appropriate keywords. Comparative observational studies and randomized controlled trials comparing cysteamine with control or other formulations for treatment of corneal or ophthalmic cystinosis were included. Outcome measurements were improvement or response to therapy, change in corneal cystine crystal score (CCCS), in vivo confocal microscopy score (IVCM), cystine crystal depth, contrast sensitivity (CS), photophobia score, and safety. DESIGN: Systematic review and meta-analysis. RESULTS: Seven studies were included. Compared to placebo and control, the cysteamine arm was better in terms of improvements and responses to therapy (2 studies showed a risk ratio [RR] of 16; 95% confidence interval [CI]: 2.30-111.37) and crystal density score (1 study showed a mean difference [MD] of -0.80; 95% CI: -1.56 to -0.04). No significant differences were observed in terms of improvement in CS (1 study showed an RR of 7.00; 95% CI: 0.47-103.27). Compared to cystamine, cysteamine showed benefits in terms of crystal density score (MD -0.94; 95% CI: -1.64 to -0.24). Compared to a newer formulation, the standard formulation (cysteamine [Cystaran]; 0.55% cysteamine hydrochloride + benzalkonium chloride 0.01%) performed better in terms of decreasing CCCS. Another newer, viscous formulation, Cystadrops, performed better than the standard formulation in terms of change in CCCS, IVCM score, corneal crystal depth, and photophobia score; however, local adverse effects and blurring were higher in the group receiving Cystadrops. CONCLUSIONS: Conventional cysteamine (0.1% to 0.3%) performed better than placebo (control) in terms of response to therapy. In terms of decreasing corneal cystine density, cysteamine (0.55%) was better than cystamine (0.55%), and the viscous Cystadrops (0.55%) was better than the standard formulation (0.1%).

Clinical evaluation of efficacy and tolerability of cysteamine 5% cream in comparison with tranexamic acid mesotherapy in subjects with melasma: a single-blind, randomized clinical trial study.

This study was aimed at evaluating the efficacy of Tranexamic Acid (TA) mesotherapy versus cysteamine 5% cream in the treatment of melasma. This single-blind, randomized clinical trial was conducted among 54 subjects between 2018 and 2019. Cysteamine 5% cream group was instructed to apply the cream on the melasma lesions 30 min before bed for 4 consecutive months. Conversely, 0.05 mL (4 mg/mL) TA mesotherapy was performed by a physician every 4 weeks until 2 months. The severity of melasma was evaluated using both Dermacatch® device and the modified Melasma Area Severity Index (mMASI). The most remarkable improvement rate was observed in the TA group at the third visit based on mMASI and Dermacatch® values at 47% and 15% in turn. The mMASI scores were substantially improved in both groups at the second visit (cysteamine vs TA 8.48 ± 2.34 and 7.03 ± 3.19; P = 0.359) and third visit (cysteamine vs TA 6.32 ± 2.11 and 5.52 ± 2.55; P = 0.952) as compared to baseline (cysteamine vs TA: 11.68 ± 2.70 and 10.43 ± 2.69). Dermacatch® values were significantly declined at the second and third visits (cysteamine vs TA 42.54 ± 12.84 and 38.75 ± 9.80, P = 0.365; 40.74 ± 12.61 and 36.17 ± 10.3, P = 0.123, respectively) compared with baseline (cysteamine vs TA 45.76 ± 13.41 and 42.41 ± 10.48), although the improvement rates between two groups were not significantly different. Findings suggest that none of the cysteamine and TA mesotherapy treatments measured by both mMASI and Dermacatch® methods have substantial advantages over the other; however, complications are less in the cysteamine than the TA mesotherapy group.

Alanine Aminotransferase and Gamma-Glutamyl Transpeptidase Predict Histologic Improvement in Pediatric Nonalcoholic Steatohepatitis.

BACKGROUND AND AIMS: Predictive, noninvasive tools are needed to monitor key features of nonalcoholic fatty liver disease (NAFLD) in children that relate to improvement in liver histology. The purpose of this study was to evaluate the relationship between liver chemistries and liver histology using data from the CyNCh (Cysteamine Bitartrate Delayed-Release for the Treatment of NAFLD in Children) clinical trial. APPROACH AND RESULTS: This study included 146 children. Improvement in liver histology, defined as decrease in nonalcoholic fatty liver disease (NAFLD) Activity Score ≥2 points without worsening of fibrosis, occurred in 43 participants (30%). There were 46 participants with borderline zone 1 nonalcoholic steatohepatitis (NASH) at baseline, with resolution in 28% (12 of 46). Multivariate models were constructed using baseline and change in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) at 52 weeks, for improvement in (1) liver histology primary outcome, (2) borderline zone 1 NASH, and (3) fibrosis. For improvement in histology, the model (P < 0.0001) retained baseline and change in GGT (area under the receiver operating characteristic [AUROC], 0.79; 95% confidence interval [CI], 0.71-0.87). For borderline zone 1 NASH, the model (P = 0.0004) retained baseline and change in ALT (AUROC, 0.80; 95% CI, 0.67-0.93). For fibrosis, the model (P < 0.001) retained baseline and change in ALT (AUROC, 0.80; 95% CI, 0.67-0.93). Additional clinical parameters were added to the models using Akaike's information criterion selection, and significantly boosted performance: improvement in histology with AUROC of 0.89 (95% CI, 0.82-0.95), borderline zone 1 NASH with AUROC of 0.91 (95% CI, 0.83-0.99), and fibrosis with AUROC of 0.89 (95% CI, 0.82-0.94). Models were validated using data from the TONIC (Treatment of Nonalcoholic Fatty Liver Disease in Children) trial. CONCLUSIONS: In children with NAFLD, dynamic changes in serum ALT and GGT are associated with change in liver histology and appear to be powerful indicators of histological response.

Long-term follow-up of cystinosis patients treated with 0.55% cysteamine hydrochloride.

BACKGROUND/AIMS: Cystinosis is a rare, autosomal recessive disorder causing defective transport of cystine out of lysosomes. Cystadrops (0.55% cysteamine hydrochloride in viscous solution) has been used on a named-patient basis to treat the accumulation of cystine crystals in the cornea in patients with cystinosis. METHODS: Retrospective analysis of the Temporary Authorisation for Use cohort of 130 patients who received Cystadrops between 2013 and 2017 in France. RESULTS: Patients received an average dosage of 3.3 (±0.94) instillations per eye per day. Over the duration of follow-up, of up to 45 months, patients maintained visual acuity scores of 0.0, which approximated normal. Corneal cystine crystal scores tended to decrease over time, stabilising after around 27 months between 1.22 and 1.87. Photophobia decreased within 3 months, stabilising on scores of around 1.5 and 1.7. 47 non-serious adverse reactions were reported, which were generally transient irritation, stinging or blurred vision. Four serious adverse events were reported, including keratitis and corneal ulcer, but these may have been caused by the underlying disease. CONCLUSION: This large safety cohort confirms the efficacy, safety and tolerability of Cystadrops in real-world clinical practice.

Oral cysteamine as an adjunct treatment in cystic fibrosis pulmonary exacerbations: An exploratory randomized clinical trial.

BACKGROUND: Emerging data suggests a possible role for cysteamine as an adjunct treatment for pulmonary exacerbations of cystic fibrosis (CF) that continue to be a major clinical challenge. There are no studies investigating the use of cysteamine in pulmonary exacerbations of CF. This exploratory randomized clinical trial was conducted to answer the question: In future pivotal trials of cysteamine as an adjunct treatment in pulmonary exacerbations of CF, which candidate cysteamine dosing regimens should be tested and which are the most appropriate, clinically meaningful outcome measures to employ as endpoints? METHODS AND FINDINGS: Multicentre double-blind randomized clinical trial. Adults experiencing a pulmonary exacerbation of CF being treated with standard care that included aminoglycoside therapy were randomized equally to a concomitant 14-day course of placebo, or one of 5 dosing regimens of cysteamine. Outcomes were recorded on days 0, 7, 14 and 21 and included sputum bacterial load and the patient reported outcome measures (PROMs): Chronic Respiratory Infection Symptom Score (CRISS), the Cystic Fibrosis Questionnaire-Revised (CFQ-R); FEV1, blood leukocyte count, and inflammatory markers. Eighty nine participants in fifteen US and EU centres were randomized, 78 completed the 14-day treatment period. Cysteamine had no significant effect on sputum bacterial load, however technical difficulties limited interpretation. The most consistent findings were for cysteamine 450mg twice daily that had effects additional to that observed with placebo, with improved symptoms, CRISS additional 9.85 points (95% CI 0.02, 19.7) p = 0.05, reduced blood leukocyte count by 2.46x109 /l (95% CI 0.11, 4.80), p = 0.041 and reduced CRP by geometric mean 2.57 nmol/l (95% CI 0.15, 0.99), p = 0.049. CONCLUSION: In this exploratory study cysteamine appeared to be safe and well-tolerated. Future pivotal trials investigating the utility of cysteamine in pulmonary exacerbations of CF need to include the cysteamine 450mg doses and CRISS and blood leukocyte count as outcome measures. CLINICAL TRIAL REGISTRATION: NCT03000348; www.clinicaltrials.gov.

I-152, a supplier of N-acetyl-cysteine and cysteamine, inhibits immunoglobulin secretion and plasma cell maturation in LP-BM5 murine leukemia retrovirus-infected mice by affecting the unfolded protein response.

Excessive production of immunoglobulins (Ig) causes endoplasmic reticulum (ER) stress and triggers the unfolded protein response (UPR). Hypergammaglobulinemia and lymphadenopathy are hallmarks of murine AIDS that develops in mice infected with the LP-BM5 murine leukemia retrovirus complex. In these mice, Th2 polarization and aberrant humoral response have been previously correlated to altered intracellular redox homeostasis. Our goal was to understand the role of the cell's redox state in Ig secretion and plasma cell (PC) maturation. To this aim, LP-BM5-infected mice were treated with I-152, an N-acetyl-cysteine and cysteamine supplier. Intraperitoneal I-152 administration (30 µmol/mouse three times a week for 9 weeks) decreased plasma IgG and increased IgG/Syndecan 1 ratio in the lymph nodes where IgG were in part accumulated within the ER. PC containing cytoplasmic inclusions filled with IgG were present in all animals, with fewer mature PC in those treated with I-152. Infection induced up-regulation of signaling molecules involved in the UPR, i.e. CHAC1, BiP, sXBP-1 and PDI, that were generally unaffected by I-152 treatment except for PDI and sXBP-1, which have a key role in protein folding and PC maturation, respectively. Our data suggest that one of the mechanisms through which I-152 can limit hypergammaglobulinemia in LP-BM5-infected mice is by influencing IgG folding/assembly as well as secretion and affecting PC maturation.

Collaboration between academics, small pharmaceutical company and patient organizations in the development of a new formulation of cysteamine in nephropathic cystinosis: A successful story.

Rare diseases usually concern small and disseminated population. Implementing clinical research with the right design, outcomes measures and the recruitment of patients are challenges. Collaborations, training and multidisciplinary approach are often required. In this article, we provide an overview of a successful collaboration in nephropathic cystinosis (NC), focusing on what was the key of success, the interactions between academics, the pharmaceutical company and patients organizations. NC is considered as a very rare disease. In 2010, a new formulation of cysteamine, the only available treatment to improve renal outcome of the disease, was proposed by a small American company. Studies were implemented in France under the coordination of an expert of the disease and the clinical investigation center of Lyon. The collaboration resulted in a good recruitment and retention of the patients in the study and most of all in the availability of the new formulation in France. Patients could have facilitated the research by being involved in the early stages of the studies. Involving patients and public early in the process is particularly important in rare diseases as the patient is a great source of knowledge and has his own expectations. Priorities of research, design, conduct and reporting of clinical trials can be defined in collaboration with adults but also with young patients or public, the first concerned in rare diseases. This concept is still to be developed and improved especially with paediatric patients.

Inhalable nano into micro dry powders for ivacaftor delivery: The role of mannitol and cysteamine as mucus-active agents.

In this paper the innovative approach of nano into micro dry powders (NiM) was applied to incorporate into mannitol or mannitol/cysteamine micromatrices ivacaftor-loaded nanoparticles for pulmonary delivery in CF. Nanoparticles composed by a mixture of two polyhydrohydroxyethtylaspartamide copolymers containing loaded with ivacaftor at 15.5% w/w were produced. The nanoparticles were incorporated into microparticles to obtain NiM that were fully characterized in terms of size, morphology, interactions with artificial Cf mucus (CF-AM) as well as for aerodynamic behaviour. Finally the activity of ivacaftor-containing NiM was evaluated by in vitro preliminary experiments. NiM at matrix composed by a mixture of mannitol:cysteamine showed greater ability to reduce CF-AM viscosity whereas that based on just mannitol showed better aerodynamic properties with a FPF of about 25%. All produced NiM showed very good cytocompatibility and the released ivacaftor was able to restore the chroride transport in vitro.

Effects of EPA on bovine oocytes matured in vitro with antioxidants: Impact on the lipid content of oocytes and early embryo development.

The eicosapentaenoic acid (EPA) is an n-3 polyunsaturated fatty acid (PUFA) present in the lipid composition of bovine oocytes. Little is known about the importance of EPA in bovine oocyte maturation and embryo development in vitro. Although previous work suggest that n-3 PUFAs may inhibit oocyte maturation, the available data are inconsistent. In this study, we evaluated the effect of EPA (1, 10, 100 nM) during in vitro maturation (IVM) of bovine oocytes, alone and in combination with vitamin E (VE) or cysteamine (CYS). EPA treatment in IVM decreased oocyte lipid content and affected lipid droplets pattern (P < 0.05). EPA 100 nM reduced oocytes maturation rate (P < 0.05), without affecting cumulus expansion. At the concentrations tested, EPA did not modify embryo development. However, the addition of antioxidants during IVM reduced the levels of reactive oxygen species in the culture system by increasing intracellular glutathione content (P < 0.05). Besides, the combination of EPA with VE or CYS reduced the percentages of MI oocytes after 24 h of IVM (P < 0.05). EPA reduced oocyte lipid content without any detrimental for embryo development.