RESUMEN
BACKGROUND: New therapies for the treatment of mucopolysaccharidoses that target the brain, including intrathecal enzyme replacement, are being explored. Quantitative analysis of the glycosaminoglycans (GAGs) that accumulate in these disorders is required to assess the disease burden and monitor the effect of therapy in affected patients. Because current methods lack the required limit of quantification and specificity to analyze GAGs in small volumes of cerebrospinal fluid (CSF), we developed a method based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). METHODS: Samples of CSF (25 µL) were evaporated to dryness and subjected to methanolysis. The GAGs were degraded to uronic acid-N-acetylhexosamine dimers and mixed with internal standards derived from deuteriomethanolysis of GAG standards. Specific dimers derived from heparan, dermatan and chondroitin sulfates (HS, DS and CS) were separated by UPLC and analyzed by electrospray ionization MS/MS using selected reaction monitoring for each targeted GAG product and its corresponding internal standard. RESULTS: CSF from control pediatric subjects (n = 22) contained <0.38 mg/L HS, 0.26 mg/L DS, and 2.8 mg/L CS, whereas CSF from patients with Hurler syndrome (n = 7) contained concentrations of DS and HS that were at least 6-fold greater than the upper control limits. These concentrations were reduced by 17.5% to 82.5% after allogeneic transplantation and treatment with intrathecal and intravenous enzyme replacement therapy. CONCLUSIONS: The method described here has potential value in monitoring patients with mucopolysaccharidoses receiving treatment targeted to the brain.
Asunto(s)
Sulfatos de Condroitina/líquido cefalorraquídeo , Dermatán Sulfato/líquido cefalorraquídeo , Heparitina Sulfato/líquido cefalorraquídeo , Mucopolisacaridosis I/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Calibración , Niño , Sulfatos de Condroitina/normas , Cromatografía Líquida de Alta Presión , Dermatán Sulfato/normas , Deuterio , Dimerización , Terapia de Reemplazo Enzimático , Trasplante de Células Madre Hematopoyéticas , Heparitina Sulfato/normas , Hexosaminas/líquido cefalorraquídeo , Humanos , Técnicas de Dilución del Indicador , Inyecciones Intravenosas , Inyecciones Espinales , Mucopolisacaridosis I/terapia , Estándares de Referencia , Valores de Referencia , Espectrometría de Masas en Tándem , Ácidos Urónicos/líquido cefalorraquídeoRESUMEN
PURPOSE: To characterize the nature of a heparin contaminant's clinical effects in cases reported to the Adverse Event Reporting System (AERS). The FDA received reports of heparin-associated adverse events (AEs) starting in late 2007-early 2008 during a national investigation of allergic-type events. The investigation identified Baxter Healthcare-brand heparin product due to its strongest association with the events. Later, oversulfated chondroitin sulfate (OSCS), a heparin-like contaminant, was discovered. METHODS: This study was a case series of heparin reports in AERS received 1 January 2008 to 31 March 2008. Variables considered were frequency of treatment settings, AEs, mortality; as well as heparin dose and OSCS contamination. RESULTS: Five hundred seventy-four AERS cases (unduplicated reports) were identified and included. Of 94 cases with a fatal outcome, 68 reported at least one AE term from the list used to identify an allergic-type event. Nearly 75% of AEs in cases of IV administration (n = 170/233) reportedly occurred within 10 minutes, whereas over half of subcutaneous administration cases (n = 13/23) resulted in times-to-event of greater than 24 hours. Although cases with a time-to-event of less than 10 minutes appeared to correlate with higher levels of OSCS contamination, no clear differences were noted between high- and low-to-absent OSCS concentration lots with respect to AEs observed. CONCLUSIONS: Intravenous administration and a higher OSCS concentration appeared to correlate with a more rapid onset of event. The FDA continues to monitor AEs associated with heparin use and has taken appropriate regulatory action to ensure a safe heparin drug supply.
Asunto(s)
Anticoagulantes/efectos adversos , Sulfatos de Condroitina/efectos adversos , Hipersensibilidad a las Drogas/etiología , Heparina/efectos adversos , Adolescente , Adulto , Sistemas de Registro de Reacción Adversa a Medicamentos , Anciano , Anciano de 80 o más Años , Anticoagulantes/química , Anticoagulantes/normas , Niño , Preescolar , Sulfatos de Condroitina/química , Sulfatos de Condroitina/normas , Contaminación de Medicamentos , Femenino , Heparina/química , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Estados Unidos , United States Food and Drug Administration , Adulto JovenRESUMEN
Exogenous administration of chondroitin sulfate (CS) is widely practiced for the treatment of osteoarthritis, although the efficacy of this treatment has not been completely established by clinical studies. A reason for the inconsistency of the results may be the quality of the CS preparations, which are commercially available as dietary supplements. In this article, we describe the development of a new method of capillary electrophoresis (CE) for the quantification of CS concentrations, screening for other glycosaminoglycan or DNA impurities and determination of hyaluronan impurities in CS raw materials, tablets, hard capsules, and liquid formulations. Analysis is performed within 12 min in bare fused silica capillaries using reversed polarity and an operating phosphate buffer of low pH. The method has high sensitivity (lower limit of quantitation [LLOQ] values of 30.0 microg/ml for CS and 5.0 microg/ml for hyaluronan), high precision, and accuracy. Analysis of 11 commercially available products showed the presence of hyaluronan impurities in most of them (up to 1.5%). CE analysis of the samples after treatment with chondroitinase ABC and ACII, which depolymerize the chains to unsaturated disaccharides, with a previously described method (Karamanos et al., J. Chromatogr. A 696 (1995) 295-305) confirmed the results of hyaluronan determination and showed that the structural characteristics (i.e., disaccharide composition) of CS are very different, showing the different species or tissue origin and possibly affecting the therapeutic outcome.
Asunto(s)
Química Farmacéutica/normas , Sulfatos de Condroitina/normas , Electroforesis Capilar/métodos , Ácido Hialurónico/análisis , Animales , Cápsulas/análisis , Cartílago/química , Condroitina ABC Liasa/metabolismo , Condroitín Liasas/metabolismo , Sulfatos de Condroitina/aislamiento & purificación , Sulfatos de Condroitina/metabolismo , Disacáridos/análisis , Ácido Hialurónico/aislamiento & purificación , Control de Calidad , Reproducibilidad de los Resultados , Tiburones , Comprimidos/análisisAsunto(s)
Sulfatos de Condroitina/uso terapéutico , Osteoartritis de la Cadera/tratamiento farmacológico , Osteoartritis de la Rodilla/tratamiento farmacológico , Dolor/tratamiento farmacológico , Sulfatos de Condroitina/normas , Ensayos Clínicos como Asunto/normas , Humanos , Metaanálisis como Asunto , Osteoartritis de la Cadera/fisiopatología , Osteoartritis de la Rodilla/fisiopatologíaAsunto(s)
Sulfatos de Condroitina/uso terapéutico , Glucosamina/uso terapéutico , Osteoartritis/veterinaria , Animales , Cartílago Articular/efectos de los fármacos , Cartílago Articular/fisiología , Sulfatos de Condroitina/farmacocinética , Sulfatos de Condroitina/farmacología , Sulfatos de Condroitina/normas , Ensayos Clínicos como Asunto , Quimioterapia Combinada , Glucosamina/farmacocinética , Glucosamina/farmacología , Glucosamina/normas , Enfermedades de los Caballos/tratamiento farmacológico , Enfermedades de los Caballos/prevención & control , Caballos , Humanos , Osteoartritis/tratamiento farmacológico , Osteoartritis/prevención & control , Resultado del TratamientoRESUMEN
Heparin-induced thrombocytopenia (HIT) is a hypercoagulable syndrome strongly associated with thrombosis that is usually treated with drugs that inhibit factor Xa (danaparoid) or thrombin (lepirudin). In the present study the outcome of HIT-patients treated with danaparoid or lepirudin was compared using the single or combined endpoints of new thromboembolic complications (new TECs), amputations and/or death, and major bleeding. HIT-patients treated with lepirudin were enrolled in two prospective trials and patients, who were identified in the same two laboratories during the same time period, who were not enrolled into these studies but treated with danaparoid, were assessed retrospectively according to a standardized questionnaire. 126 danaparoid (60.3% female) and 175 lepirudin treated patients (58.3% female) fulfilled the same inclusion and exclusion criteria. In a time-to-event-analysis the cumulative risk of combined endpoint was higher in HIT-patients without thromboembolic complication at baseline treated with danaparoid (usually in prophylactic dose 750 anti-factor Xa units b.i.d. or t.i.d.s.c.) as compared to lepirudin (aPTT adjusted) (P = 0.020). Whereas HIT-patients with TEC at baseline who were usually treated with therapeutic dose had a similar outcome in both treatment groups (P = 0.913). Major bleeding occurred in 2.5% (95% CI 0.5-7.0%) of danaparoid treated patients as compared to 10.4% (95% CI 6.3-15.9%) of lepirudin treated patients until day 42 (P = 0.009). This indicates that the efficacies of therapeutic doses of danaparoid or lepirudin in preventing death, amputation or new TEC in HIT-patients do not differ largely, but the risk of bleeding seems to be higher in lepirudin treated patients. The prophylactic dose of danaparoid approved in the European Union for HIT without TEC at baseline seems suboptimal. A prospective comparative trial is required to verify these preliminary conclusions.
Asunto(s)
Anticoagulantes/normas , Sulfatos de Condroitina/normas , Dermatán Sulfato/normas , Heparina/efectos adversos , Heparitina Sulfato/normas , Hirudinas/análogos & derivados , Hirudinas/normas , Proteínas Recombinantes/normas , Trombocitopenia/tratamiento farmacológico , Factores de Edad , Anciano , Amputación Quirúrgica/estadística & datos numéricos , Anticoagulantes/administración & dosificación , Sulfatos de Condroitina/administración & dosificación , Dermatán Sulfato/administración & dosificación , Combinación de Medicamentos , Evaluación de Medicamentos , Femenino , Hemorragia/etiología , Heparitina Sulfato/administración & dosificación , Hirudinas/administración & dosificación , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/administración & dosificación , Estudios Retrospectivos , Encuestas y Cuestionarios , Trombocitopenia/inducido químicamente , Trombocitopenia/complicaciones , Trombocitopenia/mortalidad , Tromboembolia/etiología , Resultado del TratamientoRESUMEN
Heparin-induced thrombocytopenia (HIT) has become more prevalent in today's cardiac setting and has resulted in the need for alternative anticoagulant therapies. Danaparoid sodium, one alternative to heparin, has been used in six cardiopulmonary bypass procedures in this hospital. This clinical experience has resulted in the progressive refinement of a protocol for the 'safe' clinical use of danaparoid sodium. Although there were six positive outcomes with the use of danaparoid sodium, alternatives must be explored in order to find the optimal anticoagulant for the treatment of HIT.