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2.
PLoS One ; 14(12): e0223954, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31800572

RESUMO

BACKGROUND: Cystinosis is a rare disorder caused by recessive mutations of the CTNS gene. Current therapy decreases cystine accumulation, thus slowing organ deterioration without reversing renal Fanconi syndrome or preventing eventual need for a kidney transplant.15-20% of cystinosis patients harbour at least one nonsense mutation in CTNS, leading to premature end of translation of the transcript. Aminoglycosides have been shown to permit translational read-through but have high toxicity level, especially in the kidney and inner ear. ELX-02, a modified aminoglycoside, retains it read-through ability without the toxicity. METHODS AND FINDINGS: We ascertained the toxicity of ELX-02 in cells and in mice as well as the effect of ELX-02 on translational read-through of nonsense mutations in cystinotic mice and human cells. ELX-02 was not toxic in vitro or in vivo, and permitted read-through of nonsense mutations in cystinotic mice and human cells. CONCLUSIONS: ELX-02 has translational read-through activity and produces a functional CTNS protein, as evidenced by reduced cystine accumulation. This reduction is comparable to cysteamine treatment. ELX-02 accumulates in the kidney but neither cytotoxicity nor nephrotoxicity was observed.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/fisiologia , Aminoglicosídeos/farmacologia , Cistina/metabolismo , Cistinose/tratamento farmacológico , Lisossomos/metabolismo , Mutação , Animais , Transporte Biológico , Cistinose/metabolismo , Cistinose/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Biossíntese de Proteínas
3.
J Pediatr Endocrinol Metab ; 32(10): 1187-1191, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31600138

RESUMO

Background Short stature is a common presentation in paediatric practice. Rickets can lead to poor growth and finding the underlying cause of rickets can, at times, be challenging. Case presentation The child was initially referred due to parental concerns of delayed walking, bowed legs, waddling gait and faltering growth. She was noted to have features of rickets. Bone profile and renal functions were reported to be within the normal range, however, on later review it was noted that adult values for inorganic phosphate had been given for reference ranges. Following a series of investigations, the underlying diagnosis for all her problems was made. Discussion This case demonstrates the complex diagnostic journey of a child whose presentation was not typical of the rare disorder. Unusually, the patient had no symptoms of polyuria or polydipsia and urine osmolality was normal.


Assuntos
Cisteamina/administração & dosagem , Cistinose/diagnóstico , Nanismo/diagnóstico , Raquitismo/diagnóstico , Pré-Escolar , Eliminadores de Cistina/administração & dosagem , Cistinose/complicações , Cistinose/tratamento farmacológico , Diagnóstico Diferencial , Nanismo/complicações , Feminino , Humanos , Prognóstico , Raquitismo/complicações
4.
J Pediatr Endocrinol Metab ; 32(4): 375-382, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30849045

RESUMO

Background Cystinosis is a rare autosomal-recessive disorder caused by a defective transport of cystine across the lysosomal membrane. Previous studies have mapped cystinosis to the CTNS gene which is located on chromosome 17p13, and various CTNS mutations have been identified to correlate them with this disease. Methods We analyzed six patients from five unrelated families who were diagnosed with cystinosis in our hospital. We described the diagnostic procedures for all the patients and proposed alternative therapies for cystinosis patients instead of using cysteamine, an orphan drug which was commercially unavailable in China. Moreover, genetic analysis of all patients' samples was carried out to identify novel CTNS gene mutations. Results and conclusions The patients in this study were followed up from 1 to more than 10 years to monitor their growth and development, which indicated that the alternative therapies we used were helpful to ameliorate the complications of the cystinosis patients without cysteamine. Furthermore, by sequencing the patients' genome, we identified novel mutations in the CTNS gene including: c.477C > G (p.S159R), c.274C > T (p.Q92X) and c.680A > T (p.E227V); these mutations were only observed in cystinosis patients and had never been reported in any other populations, suggesting they might be specific to Chinese cystinosis patients.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/genética , Cistinose/diagnóstico , Genética Populacional , Mutação , Adolescente , Criança , Pré-Escolar , China/epidemiologia , Cistinose/tratamento farmacológico , Cistinose/epidemiologia , Cistinose/genética , Feminino , Seguimentos , Hormônio do Crescimento Humano/administração & dosagem , Humanos , Lactente , Masculino , Linhagem , Prognóstico
5.
Mol Genet Metab ; 126(4): 413-415, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30685240

RESUMO

INTRODUCTION: Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene. Patients with nephropathic cystinosis suffer not only from renal disease but have also other systemic complications like myopathy and swallowing dysfunction. Dysphagia for solid food is mentioned in patients with cystinosis, but in clinical practice swallowing investigations are only performed when the patient has complaints. The aim of this study was to explore the swallowing function in patients with cystinosis by use of the Test of Mastication and Swallowing Solids (TOMASS), and to compare their performance with patients with myotonic dystrophy type 1 - a neuromuscular disease in which dysphagia for solid food is a known problem. METHODS: Twenty adult patients with cystinosis (11 men and 9 women, range 19-51 years) and 10 patients with myotonic dystrophy type 1 (5 men and 5 women, range 20-60 years) were included. All cystinosis patients were treated with cysteamine. Data of the two groups were compared with normative data using independent-samples t-tests. In case the variables were not normally distributed, the non-parametric Mann-Whitney U test was used. RESULTS: There was a significant difference in the number of bites, masticatory cycles, swallows and total time between the normal values and cystinosis patients. The results of the cystinosis patients were comparable to those of the patients with myotonic dystrophy. DISCUSSION AND CONCLUSION: Adult patients with cystinosis have significant dysphagia for solid food. Clinicians treating these patients should be aware of this fact. The TOMASS can be performed easily in clinical practice to investigate whether patients with cystinosis have swallowing dysfunction. The swallowing dysfunction can now be diagnosed by use of a non-invasive, very simple, non-harmful test. It can be discussed whether this should be added to the regular care scheme of cystinosis patients in order to regularly follow-up swallowing function.


Assuntos
Cistinose/complicações , Transtornos de Deglutição/etiologia , Deglutição , Nefropatias/complicações , Adulto , Cisteamina/uso terapêutico , Cistinose/tratamento farmacológico , Feminino , Humanos , Masculino , Mastigação , Pessoa de Meia-Idade , Distrofia Miotônica/complicações , Adulto Jovem
6.
Curr Eye Res ; 44(5): 497-504, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30624086

RESUMO

PURPOSE: To examine if current development on using contact lenses for drug delivery of cysteamine to treat ocular symptoms of cystinosis can be tinted to mitigate photophobia common in patients by reducing transmittance Methods: Commercial contact lenses were placed in a carbon black solution to examine loading after lens synthesis. Silicone hydrogel contact lenses were also synthesized with carbon black added prior to UV curing. Transmittance was measured using UV-vis spectrophotometry over the range of 190-1190 nm and compared to unmodified contact lenses. Lens parameters of refractive index, ion permeability, and Young's modulus were measured using a refractometer, release of sodium chloride, and the cantilever method. Cysteamine release was measured by loading lenses into 5% cysteamine solution and then monitoring the release of the drug using UV-vis spectrophotometry. Vitamin E diffusion barriers were also added to lenses via ethanol solution, and the release of cysteamine from these modified lenses was also examined. RESULTS: No leeching of carbon black was detected during experiments. Loading of pre-made contact lenses led to uneven distribution of carbon black throughout lens. Adding 0.3% carbon black to lens monomer solution prior to UV-curing led to even distribution and a transmittance reduction of approximately 50%. Ion permeability was reduced from 6.19 ± 0.90 x 10-3 to 1.28 ± 0.06 x 10-3 mm2 min-1, and Young's modulus was decreased from 1.58 ± 0.08 to 1.29 ± 0.06 MPa. Cysteamine releases from carbon black lenses with and without vitamin E were comparable to controls, although the loading solution of vitamin E/ethanol had to be tripled to achieve a similar mass loading to control. CONCLUSIONS: Carbon black increases the softness of contact lenses, but a loading of 0.3% maintains lens parameters required for wear. The release of cysteamine is also possible with carbon black lenses, albeit requiring a higher loading concentration of vitamin E to achieve similar release times.


Assuntos
Lentes de Contato Hidrofílicas , Doenças da Córnea/metabolismo , Eliminadores de Cistina/farmacocinética , Cistinose/metabolismo , Sistemas de Liberação de Medicamentos , Fotofobia/prevenção & controle , Fuligem/química , Animais , Anti-Hipertensivos/farmacocinética , Doenças da Córnea/tratamento farmacológico , Cisteamina/farmacocinética , Cisteamina/uso terapêutico , Eliminadores de Cistina/uso terapêutico , Cistinose/tratamento farmacológico , Módulo de Elasticidade , Microscopia Eletrônica de Varredura , Coelhos , Refratometria , Espectrofotometria Ultravioleta , Timolol/farmacocinética , Vitamina E/administração & dosagem , Vitaminas/administração & dosagem
7.
J Bras Nefrol ; 41(1): 131-141, 2019.
Artigo em Inglês, Português | MEDLINE | ID: mdl-30465592

RESUMO

Care for patients with chronic and rare diseases is complex, especially considering the lack of knowledge about the disease, which makes early and precise diagnosis difficult, as well as the need for specific tests, sometimes of high complexity and cost. Added to these factors are difficulties in obtaining adequate treatment when available, in raising patient and family awareness about the disease and treatment compliance. Nephropathic cystinosis is among these diseases. After more than 20 years as a care center for these patients, the authors propose a follow-up protocol, which has been used with improvement in the quality of care and consists of a multidisciplinary approach, including care provided by a physician, nurse, psychologist, nutritionist and social worker. In this paper, each field objectively exposes how to address points that involve the stages of diagnosis and its communication with the patient and their relatives or guardians, covering the particularities of the disease and the treatment, the impact on the lives of patients and families, the approach to psychological and social issues and guidelines on medications and diets. This protocol could be adapted to the follow-up of patients with other rare diseases, including those with renal involvement. This proposal is expected to reach the largest number of professionals involved in the follow-up of these patients, strengthening the bases for the creation of a national protocol, observing the particularities of each case.


Assuntos
Cistinose/diagnóstico , Cistinose/tratamento farmacológico , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/tratamento farmacológico , Doenças Raras/diagnóstico , Doenças Raras/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Protocolos Clínicos , Cistinose/complicações , Cistinose/psicologia , Diálise , Síndrome de Fanconi/complicações , Síndrome de Fanconi/psicologia , Feminino , Humanos , Lactente , Recém-Nascido , Falência Renal Crônica/etiologia , Transplante de Rim , Masculino , Equipe de Assistência ao Paciente , Gravidez , Doenças Raras/complicações , Doenças Raras/psicologia , Diálise Renal , Resultado do Tratamento , Adulto Jovem
8.
Pediatr Nephrol ; 34(4): 571-578, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29260317

RESUMO

Cystinosis is a rare autosomal-recessive lysosomal storage disease with high morbidity and mortality. It is caused by mutations in the CTNS gene that encodes the cystine transporter, cystinosin, which leads to lysosomal cystine accumulation. Patients with infantile nephropathic cystinosis, the most common and most severe clinical form of cystinosis, commonly present with renal Fanconi syndrome by 6-12 months of age, and without specific treatment, almost all will develop end-stage renal disease (ESRD) by 10-12 years of age. Early corneal cystine crystal deposition is a hallmark of the disease. Cystinosis also presents with gastrointestinal symptoms (e.g., vomiting, decreased appetite, and feeding difficulties) and severe growth retardation and may affect several other organs over time, including the eye, thyroid gland, gonads, pancreas, muscles, bone marrow, liver, nervous system, lungs, and bones. Cystine-depleting therapy with cysteamine orally is the only specific targeted therapy available for managing cystinosis and needs to be combined with cysteamine eye drops for corneal disease involvement. In patients with early treatment initiation and good compliance to therapy, long-term cysteamine treatment delays progression to ESRD, significantly improves growth, decreases the frequency and severity of extrarenal complications, and is associated with extended life expectancy. Therefore, early diagnosis of cystinosis and adequate life-long treatment with cysteamine are essential for preventing end-organ damage and improving the overall prognosis in these patients.


Assuntos
Cisteamina/administração & dosagem , Eliminadores de Cistina/administração & dosagem , Cistinose/tratamento farmacológico , Sistemas de Transporte de Aminoácidos Neutros/genética , Cisteamina/efeitos adversos , Eliminadores de Cistina/efeitos adversos , Cistinose/complicações , Cistinose/diagnóstico , Cistinose/genética , Progressão da Doença , Esquema de Medicação , Predisposição Genética para Doença , Humanos , Mutação , Fatores de Tempo , Resultado do Tratamento
9.
Indian J Ophthalmol ; 67(1): 153-155, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30574930

RESUMO

A 36-year-old female presented initially with photophobia and visual deterioration. After examination and laboratory tests, patient was diagnosed with cystinosis. Cysteamine drops 4 × 1 drops/day was given as treatment for 1 year. During follow-up, in vivo confocal microscopy (IVCM) and anterior segment optical coherence tomography (AS-OCT) was performed. Photophobia was relieved and IVCM obtained the decrease in size and density of corneal crystals 1 year after. Depth of corneal crystals did not change but crystal density score reduced with cysteamine treatment.


Assuntos
Segmento Anterior do Olho/diagnóstico por imagem , Córnea/patologia , Doenças da Córnea/diagnóstico , Cisteamina/administração & dosagem , Cistinose/tratamento farmacológico , Microscopia Confocal/métodos , Tomografia de Coerência Óptica/métodos , Adulto , Doenças da Córnea/tratamento farmacológico , Cristalização , Eliminadores de Cistina/administração & dosagem , Cistinose/diagnóstico , Feminino , Seguimentos , Humanos , Soluções Oftálmicas , Acuidade Visual
10.
Pediatr Nephrol ; 34(5): 873-881, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30413946

RESUMO

BACKGROUND: Cystinosis is an ultrarare disorder caused by mutations of the cystinosin (CTNS) gene, encoding a cystine-selective efflux channel in the lysosomes of all cells of the body. Oral therapy with cysteamine reduces intralysosomal cystine accumulation and slows organ deterioration but cannot reverse renal Fanconi syndrome nor prevent the eventual need for renal transplantation. A definitive therapeutic remains elusive. About 15% of cystinosis patients worldwide carry one or more nonsense mutations that halt translation of the CTNS protein. Aminoglycosides such as geneticin (G418) can bind to the mammalian ribosome, relax translational fidelity, and permit readthrough of premature termination codons to produce full-length protein. METHODS: To ascertain whether aminoglycosides permit readthrough of the most common CTNS nonsense mutation, W138X, we studied the effect of G418 on patient fibroblasts. RESULTS: G418 treatment induced translational readthrough of CTNSW138X constructs transfected into HEK293 cells and expression of full-length endogenous CTNS protein in homozygous W138X fibroblasts. CONCLUSIONS: Reduction in intracellular cystine indicates that the CTNS protein produced is functional as a cystine transporter. Interestingly, similar effects were seen even in W138X compound heterozygotes. These studies establish proof-of-principle for the potential of aminoglycosides to treat cystinosis and possibly other monogenic diseases caused by nonsense mutations.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/genética , Cistinose/tratamento farmacológico , Fibroblastos/efeitos dos fármacos , Gentamicinas/farmacologia , Terminação Traducional da Cadeia Peptídica/efeitos dos fármacos , Códon sem Sentido , Cistina/metabolismo , Cistinose/genética , Fibroblastos/metabolismo , Vetores Genéticos/genética , Gentamicinas/uso terapêutico , Células HEK293 , Humanos , Terminação Traducional da Cadeia Peptídica/genética , Plasmídeos/genética , RNA Mensageiro/análise , Proteínas Recombinantes/genética , Transfecção
11.
Drug Des Devel Ther ; 12: 2795-2804, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30233142

RESUMO

Background: Cysteamine bitartrate delayed-release (DR) capsule (Procysbi®) is approved for treatment of nephropathic cystinosis in the USA, Canada, and the EU. The capsules contain cysteamine bitartrate beads that are enteric coated with acid-resistant Eudragit L 30 D-55, preventing drug release in the acidic stomach environment while allowing dissolution of the beads in the more alkaline environment of the small intestine. Patients who have difficulty swallowing capsules can open capsules, sprinkle beads onto 4 ounces of a suitable food or liquid, gently mix, and consume the entire content within 30 minutes. Foods found to be suitable for administration, and described in the Procysbi US labeling, include fruit juices (except grapefruit juice), applesauce, and berry jelly; there are minor variations in the foods and liquids recommended by regulatory authorities in other countries. This study aimed to assess the stability of enteric-coated beads exposed to additional foods at different conditions to expand the list of suitable foods for drug administration. Methods: For each test condition, beads from eight opened 75 mg cysteamine bitartrate DR capsules were gently mixed with test food and maintained at a prespecified temperature and duration; remaining undissolved beads were then recovered from the food. The recovered beads were split into two portions: one assayed for remaining drug content and the other subjected to dissolution testing to assess the effect on the drug-release profile. Results: The results show that bead integrity was maintained when mixed with foods at pH values <5.5 at all time points when refrigerated (2°C-8°C) and at room (20°C-22°C) and lukewarm (37°C-41°C) temperatures. Bead integrity was not maintained when mixed with foods at pH values of ≥5.5 at room temperature. Conclusion: The results from this in vitro dissolution study help in identifying additional foods that may be used for the administration of cysteamine bitartrate DR beads from opened capsules using the sprinkle method.


Assuntos
Cisteamina/uso terapêutico , Cistinose/tratamento farmacológico , Cápsulas/administração & dosagem , Cápsulas/uso terapêutico , Cisteamina/administração & dosagem , Alimentos , Sucos de Frutas e Vegetais , Humanos , Concentração de Íons de Hidrogênio , Temperatura
13.
Rev Med Chil ; 146(1): 111-115, 2018 Jan.
Artigo em Espanhol | MEDLINE | ID: mdl-29806685

RESUMO

Nephropatic cystinosis (NC) is a rare disease associated with pathogenic variants in the CTNS gene, with a common variant that consists of a 57kb-deletion involving CTNS. Patients with NC that are treated with cysteamine improve their life quality and expectancy. We report a 12-month-old girl with a poor growth rate since the 4th month of life. She was admitted to the Hospital with acute kidney injury, severe dehydration and metabolic acidosis. She was treated with volume restorative and bicarbonate. Proximal tubulopathy and Fanconi's syndrome was diagnosed. Medical treatment improved renal function that was stabilized in stage 4 chronic kidney disease (CKD). Since infantile NC was suspected, CTNS genetic analysis was considered. Genomic DNA was isolated from peripheral blood to perform PCR for exons 3-12 in CTNS gene and for the specific 57kb-deletion PCR. Afterwards, variant segregation analysis was performed in the familiar trio. The genetic analysis showed that the patient was homozygous for the common 57kb-deletion encompassing CTNS that had been inherited from her asymptomatic heterozygous parents. The molecular confirmation allowed genetic counselling for parents and facilitated the access to cysteamine. Oral treatment with cysteamine resulted in improvement of renal function to CKD stage 3. After 16 months of treatment the patient shows metabolic stability and mild recovery of height. Ophthalmologic follow-up detected ocular cystine crystals 12 months after diagnosis, starting cysteamine drops.


Assuntos
Cistinose/diagnóstico , Cistinose/genética , Cisteamina/uso terapêutico , Eliminadores de Cistina/uso terapêutico , Cistinose/tratamento farmacológico , Feminino , Humanos , Lactente , Reação em Cadeia da Polimerase , Diagnóstico Pré-Natal
14.
Internist (Berl) ; 59(8): 861-867, 2018 08.
Artigo em Alemão | MEDLINE | ID: mdl-29671012

RESUMO

This article presents a case of cystinosis in a young man. Diagnosis of the disease and the problem of transition to adult care are described. Cystinosis is a rare lysosomal storage disease with first manifestation in early childhood presenting as renal Fanconi syndrome. Without treatment, the disease leads to severe health impairment. Due to the rarity of the disease, a correct diagnosis is often delayed. Without treatment, cystinosis often leads to end-stage renal failure, blindness, hypothyroidism, diabetes mellitus, and rickets. Cystine-depleting therapy with cysteamine significantly improves mortality and quality of life.


Assuntos
Cisteamina/uso terapêutico , Eliminadores de Cistina/uso terapêutico , Cistina/sangue , Cistina/metabolismo , Cistinose/diagnóstico , Cistinose/tratamento farmacológico , Síndrome de Fanconi/tratamento farmacológico , Adulto , Criança , Pré-Escolar , Cisteamina/administração & dosagem , Eliminadores de Cistina/administração & dosagem , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/etiologia , Humanos , Rim/patologia , Lisossomos/metabolismo , Masculino , Qualidade de Vida
15.
Adv Ther ; 35(2): 199-209, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29411268

RESUMO

INTRODUCTION: Cystinosis is a rare, metabolic, autosomal recessive, genetic lysosomal storage disorder characterized by an accumulation of cystine in various organs and tissues. Cysteamine bitartrate (CB) is a cystine-depleting aminothiol agent approved in the United States and Europe in immediate-release and delayed-release (DR) formulations for the treatment of nephropathic cystinosis in children and adults. It is recommended that CBDR be administered with fruit juice (except grapefruit juice) for maximum absorption. Omeprazole is a proton pump inhibitor that inhibits gastric acid secretion and, theoretically, may cause the premature release of cysteamine by increasing intragastric pH, thereby affecting the PK of CBDR. METHODS: This open-label, three-period, randomized study in healthy adult subjects was designed primarily to compare the pharmacokinetics of CBDR capsules after a single oral dose administered with orange juice, water, or multiple oral doses of omeprazole with water at steady state. A total of 32 subjects were randomly assigned to receive study agents in one of two treatment sequences. RESULTS: All subjects completed the study and baseline characteristics of the overall population and the two treatment sequence populations were similar. Peak mean plasma cysteamine concentrations following co-administration of CBDR capsules with orange juice (1892 ng/mL) were higher compared with co-administration with water (1663 ng/mL) or omeprazole 20 mg and water (1712 ng/mL). Mean time to peak plasma concentration was shorter with omeprazole co-administration (2.5 h) compared with orange juice (3.5 h) or water (3.0 h). Statistical comparisons between treatment groups indicated that exposure as assessed by AUC0-t, AUC0-∞, and Cmax were all within the 80-125% bioequivalence ranges for all comparisons. All treatments were generally well tolerated. CONCLUSION: Overall, the pharmacokinetics of cysteamine bitartrate DR capsules are not significantly impacted by co-administration with orange juice, water only, or omeprazole (with water). FUNDING: Horizon Pharma, Inc.


Assuntos
Cisteamina/farmacocinética , Eliminadores de Cistina/farmacocinética , Cistinose/tratamento farmacológico , Sucos de Frutas e Vegetais , Omeprazol/farmacologia , Inibidores da Bomba de Prótons/farmacologia , Administração Oral , Adolescente , Adulto , Citrus sinensis , Cisteamina/administração & dosagem , Eliminadores de Cistina/administração & dosagem , Preparações de Ação Retardada , Interações Medicamentosas , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Água , Adulto Jovem
16.
Pediatr Nephrol ; 33(7): 1165-1172, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29435659

RESUMO

BACKGROUND: Bone impairment appears to be a novel complication of nephropathic cystinosis despite cysteamine therapy. Its exact underlying pathophysiology is nevertheless unclear. The objective of this study was to evaluate bone status among patients included in the French Crystobs study. METHODS: In addition to clinical data, bone status was evaluated using biomarkers (ALP, PTH, 25-D, 1-25D, FGF23), DXA (spine and total body), and high-resolution peripheral quantitative computed tomography (HR-pQCT) at the tibia and radius. Results were compared to age- and gender-matched healthy controls (1:2 basis) from the local reference cohorts. RESULTS: At a median age of 22.5 (10.2-34.6) years, 10 patients with nephropathic cystinosis were included (2 receiving conservative therapies, 2 undergoing hemodialysis, 6 with a past of renal transplantation); 7 out of 10 patients complained of a bone symptom (past of fracture, bone deformations, and/or bone pain). Biochemicals and spine DXA did not show any significant abnormalities. Using HR-pQCT, significant decreases in cortical parameters (e.g., cortical thickness 850 (520-1100) versus 1225 (480-1680) µm; p < 0.05) and total volumetric bone mineral density (290 (233-360) versus 323 (232-406) mg/cm3; p < 0.05) were observed in cystinotic patients in comparison to controls at the tibia. There were no differences for trabecular parameters. Similar results were observed at the radius. CONCLUSIONS: In this pilot study, bone impairment (rather cortical than trabecular) is a significant clinical problem in nephropathic cystinosis; 70% of patients displayed significant bone symptoms, during teenage or young adulthood. This new complication should be known by physicians because of its potential dramatic impact on quality of life.


Assuntos
Densidade Óssea , Doenças Ósseas/diagnóstico , Osso Cortical/fisiopatologia , Cistinose/complicações , Absorciometria de Fóton , Adolescente , Adulto , Fatores Etários , Biomarcadores/análise , Doenças Ósseas/epidemiologia , Doenças Ósseas/etiologia , Doenças Ósseas/fisiopatologia , Criança , Osso Cortical/diagnóstico por imagem , Cisteamina , Cistinose/tratamento farmacológico , Feminino , Humanos , Masculino , Projetos Piloto , Prevalência , Estudos Prospectivos , Qualidade de Vida , Rádio (Anatomia)/diagnóstico por imagem , Rádio (Anatomia)/fisiopatologia , Índice de Gravidade de Doença , Tíbia/diagnóstico por imagem , Tíbia/fisiopatologia , Tomografia Computadorizada por Raios X , Adulto Jovem
17.
Int J Pharm ; 544(2): 380-391, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29217475

RESUMO

Cystinosis is an orphan disease caused by a genetic mutation that leads to deposition of cystine crystals in many organs including cornea. Ophthalmic manifestation of the disease can be treated with hourly instillation of cysteamine eye drops. The hourly eye drop instillation is tedious to the patients leading to poor compliance and additionally, significant degradation of the drug occurs within one week of opening the bottle, which further complicates this delivery approach. This paper focuses on designing a contact lens to treat the disease with improved efficacy compared to eye drops, and also exploring safety of the drug eluding contact lens in an animal model. Our goal is to design a lens that is safe and that can deliver a daily therapeutic dose of cysteamine to the cornea while retaining drug stability. We show that cysteamine diffuses out rapidly from all lenses due to its small size. Vitamin E incorporation increases the release duration of both ACUVUE®OASYS® and ACUVUE® TruEyeTM but the effect is more pronounced in TruEyeTM likely due to the low solubility of vitamin E in the lens matrix and higher aspect ratio of the barriers. The barriers are not effective in hydrogel lenses, which along with the high aspect ratio in silicone hydrogels suggests that barriers could be forming at the interface of the silicone and hydrogel phases. The presence of vitamin E has an additional beneficial effect of reduction in the oxidation rates, likely due to a transport barrier between the oxygen diffusing through the silicone channels and drug located in the hydrogel phase. Based on this study, both Acuvue®OASYS® and ACUVUE® TruEyeTM can be loaded with vitamin E to design a cysteamine eluting contact lenses for effective therapy of cystinosis. The lenses must be worn for about 4-5 hr. each day, which is less than the typical duration of daily-wear. The vitamin E and cysteamine loaded lenses did not exhibit any toxicity in a rabbit model over a period of 7-days.


Assuntos
Lentes de Contato Hidrofílicas/efeitos adversos , Cisteamina/farmacologia , Eliminadores de Cistina/farmacologia , Cistinose/tratamento farmacológico , Sistemas de Liberação de Medicamentos/efeitos adversos , Vitamina E/farmacologia , Animais , Córnea/efeitos dos fármacos , Córnea/patologia , Cisteamina/uso terapêutico , Eliminadores de Cistina/uso terapêutico , Difusão , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Feminino , Masculino , Modelos Animais , Modelos Biológicos , Oxirredução/efeitos dos fármacos , Coelhos , Fatores de Tempo , Vitamina E/uso terapêutico
18.
Farm. hosp ; 41(6): 678-687, nov.-dic. 2017. ilus, graf
Artigo em Espanhol | IBECS | ID: ibc-169375

RESUMO

La cistinosis ocular es una enfermedad rara que se caracteriza por el depósito de cristales de cistina a nivel corneal, los cuales dificultan la visión de los pacientes. La cisteamina oral se administra en forma de cisteamina, pero esta no alcanza la córnea debido a la falta de vascularización corneal, por lo que es necesaria la aplicación tópica ocular. El objetivo del presente trabajo es determinar la estabilidad de un hidrogel oftálmico de cisteamina, potencialmente formulable en servicios de farmacia hospitalaria, conservado este bajo diferentes condiciones de almacenamiento durante un periodo de 30 días. Los parámetros físicos y químicos evaluados han sido la osmolalidad, el pH y la concentración de cisteamina, siendo esta última valorada mediante un método de cromatografía líquida de ultra alta presión, empleando un detector de masas en tándem (UPLC-MS/MS). Los ensayos descriptivos se han basado en la medición de la transparencia y los ensayos microbiológicos en la realización de pruebas de esterilidad. Los resultados obtenidos permiten concluir que el hidrogel de cisteamina es estable durante un periodo de 30 días, recomendándose que su conservación sea en nevera (AU)


Ocular cystinosis is a rare disease characterised by the deposit of cystine crystals on the corneal surface, which hinder patients' eyesight. Oral cysteamine is given as cysteamine; however, it does not reach the cornea due to the lack of corneal vascularization making necessary its administration by the topical ocular route. The aim of the present study is to determine the stability of an ophthalmic hydrogel of cysteamine, which can be potentially prepared at hospital pharmacy departments, under different preservation conditions during a follow-up of 30 days. Different physical and chemical parameters were evaluated: osmolality, pH and cysteamine concentration, which has been measured by a method of ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS). Descriptive assays were also performed, such as transparency measurement and microbiological assays in order to verify its sterility. The obtained results allow us to conclude that the cysteamine hydrogel is stable during 30 days, being recommendable its preservation in refrigerated conditions (AU)


Assuntos
Humanos , Hidrogéis/uso terapêutico , Cistinose/tratamento farmacológico , Doenças da Córnea/tratamento farmacológico , Ácido Hialurônico/uso terapêutico , Espectrometria de Massas/métodos , Ácido Ditionitrobenzoico/uso terapêutico , Análise Estatística
19.
Farm Hosp ; 41(6): 678-687, 2017 Nov 01.
Artigo em Espanhol | MEDLINE | ID: mdl-29112493

RESUMO

Ocular cystinosis is a rare disease characterised by the deposit of cystine crystals on the corneal surface, which hinder patients' eyesight. Oral cysteamine is given as cysteamine; however, it does not reach the cornea due to the lack of corneal vascularization making necessary its  administration by the topical ocular route. The aim of the present study is to  determine the stability of an ophthalmic hydrogel of cysteamine, which can be  potentially prepared at hospital pharmacy departments, under different preservation conditions during a follow-up of 30 days. Different physical  and chemical parameters were evaluated: osmolality, pH and  cysteamine concentration, which has been measured by a method of ultra  performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS).  Descriptive assays were also performed, such as transparency measurement and  microbiological assays in order to verify its sterility. The obtained results  allow us to conclude that the cysteamine hydrogel is stable during 30 days,  being recommendable its preservation in refrigerated conditions.


Assuntos
Cisteamina/administração & dosagem , Cisteamina/uso terapêutico , Cistinose/tratamento farmacológico , Oftalmopatias/tratamento farmacológico , Hidrogel de Polietilenoglicol-Dimetacrilato/administração & dosagem , Hidrogel de Polietilenoglicol-Dimetacrilato/uso terapêutico , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/uso terapêutico , Administração Tópica , Química Farmacêutica , Humanos
20.
BMC Nephrol ; 18(1): 300, 2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-28950840

RESUMO

BACKGROUND: Cystinosis is a rare autosomal recessive lysosomal disorder characterized by the accumulation of cystine in lysosomes. Cystinosis is much rarer in Asian than Caucasian populations. There are only 14 patients have with cystinosis alive in Japan. Most cystinosis is the nephropathic infantile form, as indicated by its apparent and severe clinical manifestations, including renal and ocular symptoms. Patients with the nephropathic juvenile form account for 5% of those with cystinosis. Their diagnosis is frequently delayed and difficult because of slower progression to end-stage renal disease and fewer cystine crystals in the cornea. Molecular analysis and a cysteine-binding protein assay should be performed when patients with proximal tubulopathy of an unknown origin are encountered. CASE PRESENTATION: A 12-year-old boy had been suffering from Fanconi syndrome since he was 3 years old. He was only recently diagnosed despite repeated ophthalmological examinations. Corneal cystine crystals were found when he was 12 years old, and he was diagnosed with cystinosis by high free cystine content in granulocytes (6.36 nmol half-cystine/mg protein, normal: <0.15). Analysis of the CTNS gene showed two novel heterozygous single nucleotide substitutions of c.329G > C and c.329 + 2 T > C. Both were splicing site variants causing exon 6 skipping proven by transcript analysis, although the functional prediction site showed c.329G > C, p.(Gly110Ala) as a benign missense substitution. The patient's estimated glomerular filtration rate was 66.8 mL/min/1.73 m2. He was immediately treated with cysteamine after diagnosis. CONCLUSIONS: Even if no ophthalmological abnormalities are present, nephropathic juvenile cystinosis should be suspected in children with Fanconi syndrome. Transcript analysis was useful to detect pathogenic splicing variants in this patient.


Assuntos
Cistinose/diagnóstico , Cistinose/genética , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/genética , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/genética , Criança , Cisteamina/uso terapêutico , Cistinose/tratamento farmacológico , Síndrome de Fanconi/tratamento farmacológico , Humanos , Masculino , Síndrome Nefrótica/tratamento farmacológico , Microscopia com Lâmpada de Fenda/métodos
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