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OBJECTIVES: Clinical use of microarray-based techniques for the analysis of many developmental disorders has emerged during the last decade. Thus, chromosomal microarray has been positioned as a first-tier test. This study reports the first experience in a Chilean cohort. METHODS: Chilean patients with developmental disabilities and congenital anomalies were studied with a high-density microarray (CytoScan(tm) HD Array, Affymetrix, Inc., Santa Clara, CA, USA). Patients had previous cytogenetic studies with either a normal result or a poorly characterized anomaly. RESULTS: This study tested 40 patients selected by two or more criteria, including: major congenital anomalies, facial dysmorphism, developmental delay, and intellectual disability. Copy number variants (CNVs) were found in 72.5% of patients, while a pathogenic CNV was found in 25% of patients and a CNV of uncertain clinical significance was found in 2.5% of patients. CONCLUSION: Chromosomal microarray analysis is a useful and powerful tool for diagnosis of developmental diseases, by allowing accurate diagnosis, improving the diagnosis rate, and discovering new etiologies. The higher cost is a limitation for widespread use in this setting. .

OBJETIVO: O uso clínico de técnicas baseadas em microarrays para a análise de transtornos de desenvolvimento tem surgido durante a última década. Assim, o microarray cromossômico tem sido posicionado como um teste de primeiro nível clínico. Relatamos a primeira experiência em uma coorte chilena. MÉTODOS: Pacientes chilenos com atraso de desenvolvimento e anomalias congênitas foram estudados com um microarray de alta densidade (CytoScan(tm) HD Array, Affymetrix, Inc., Santa Clara, CA, EUA). Pacientes tiveram estudos citogenéticos anteriores, ou um resultado normal ou de uma anomalia não bem caracterizada. RESULTADOS: Foram analisados 40 pacientes selecionados por dois ou mais critérios, incluindo: anomalias congênitas maiores, dismorfismo facial, atraso de desenvolvimento e deficiência intelectual. Uma variante do número de cópia (CNV) foi encontrada em 72,5% dos pacientes, enquanto que uma CNV patogênica foi encontrada em 25% dos pacientes e uma CNV de significado clínico incerto foi encontrada em 2,5% dos pacientes. CONCLUSÕES: A análise cromossômica microarray é uma ferramenta útil e poderosa em transtornos de desenvolvimento, permite um diagnóstico preciso, melhora a taxa de diagnóstico e descobre novas etiologias. O custo mais elevado é uma limitação para um uso difundido em nossa realidade. .

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OBJECTIVES: Clinical use of microarray-based techniques for the analysis of many developmental disorders has emerged during the last decade. Thus, chromosomal microarray has been positioned as a first-tier test. This study reports the first experience in a Chilean cohort. METHODS: Chilean patients with developmental disabilities and congenital anomalies were studied with a high-density microarray (CytoScan™ HD Array, Affymetrix, Inc., Santa Clara, CA, USA). Patients had previous cytogenetic studies with either a normal result or a poorly characterized anomaly. RESULTS: This study tested 40 patients selected by two or more criteria, including: major congenital anomalies, facial dysmorphism, developmental delay, and intellectual disability. Copy number variants (CNVs) were found in 72.5% of patients, while a pathogenic CNV was found in 25% of patients and a CNV of uncertain clinical significance was found in 2.5% of patients. CONCLUSION: Chromosomal microarray analysis is a useful and powerful tool for diagnosis of developmental diseases, by allowing accurate diagnosis, improving the diagnosis rate, and discovering new etiologies. The higher cost is a limitation for widespread use in this setting.

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INTRODUCCION: El tratamiento de la tuberculosis requiere de la administración conjunta de rifampicina (RIF) e isoniacida (ISO). RIF se descompone en medio ácido al producto 3-FRSV, que en presencia de ISO forma IH. La liberación secuencial de RIF en estómago e ISO en intestino podría llevar a un incremento en la estabilidad de RIF. En una etapa previa RIF e ISO se asociaron a los polielectrolitos carboximetilcelulosa (CMC) y ácido algínico (AA), respectivamente, para obtener los materiales portadores CMC-RIF y AA-ISO que permiten la liberación inmediata de RIF y sostenida ISO. Los mismos pueden ser comprimidos para formar matrices hidrofílicas polielectrolico-fármaco (MHPF).OBJETIVO: Evaluar el impacto de la liberación secuencial de RIF e ISO en la estabilidad de RIF en condiciones simulando el contenido gástrico.METODOS: Los estudios de liberación desde las MHPF MCM-RIF + AA-ISO se realizaron en fluido gástrico simulado, utilizando referencia soluciones de RIF o RIF + ISO y la matric CMC-RIF en las mismas condiciones. La evaluación se realizó durante 2 hs, a 37ºC utilizando el aparato 2. La cuantificación se realizó mediante un método de HPLC indicativo de estabilidad, que permitió identificar ambos fármacos y sus productos de degradación.RESULTADOS: La MHPF CMC-RIF presenta muy rápida velocidad de disolución. La combinación de las MHPF CMC-RIF y AA-ISO permite la liberación selectiva e inmediata de RIF en medio ácido, con mínimos niveles concominantes de ISO, permitiendo una reducción en la formación de IH. Este producto de descomposición ha sido asociado con incremento en los eventos hepatotóxicos asociados a la combinación de RIF e ISO. Sin embargo, CMC acelera la degradación de RIF a 3-FRSV.CONCLUSIONES: La liberación secuencial de RIF e ISO permite reducir la formación de IH y es una estrategia adecuada para el desarrollo de comprimidos bi-capa. La optimización de la estabilidad requiere la adecuación de la capa de liberación inmediata de RIF.

INTRODUCTION: Tuberculosis treatment requires the administration of a combination of rifampicin (RIF) and isoniazid (ISO). In acidic media RIF decomposes to 3-FRSV, which in the presence of ISO forms IH. The sequential release of RIF in the stomach and ISO in the intestine could lead to an increase in RIF stability. In a previous work RIF and ISO were associated to the polyelectrolytes carboxymethylcellulose (CMC) and alginic acid (AA) to obtain carrier material CMC-RIF and AA-ISO that allow immediate release of RIF sustained of ISO. These materials can be compressed to form swellable drug polyelectrolyte matrices (SDPM).OBJECTIVE: To evaluate the impact of the sequential release of RIF and ISO in the stability of RIF in conditions simulating gastric contents.METHODS: Release studies were carried out from SDPM CMC-RIF + AA-ISO in simulated gastric fluid using as references RIF or RIF + ISO solutions under the same conditions. Samples were taken for 2 hs at 37ºC, using apparatus 2. The presence of both drugs and degradation products was analyzed by a stability indicating HPLC techinique.RESULTS: The SDPM CMC-RIF presented very fast release rate. The combination of SDPM CMC-RIF and AA-ISO permits selective and immediate release of RIF in acidic media, with minumum levels of ISO, with noticeable reduction of IH formation. This product has been associated with an increased frequency in hepatotoxic events associated with RIF and ISO combination. However, CMC accelerated degradation of RIF to 3-FRSV.CONCLUSIONS: Sequential release of RIF and ISO allowed a reduction in the formation of IH and seemed to be a suitable strategy for the development of bilayer tablets. Stability optimization should include adapting the immediate release layer of RIF.

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INTRODUCCION: El tratamiento de la tuberculosis requiere de la administración conjunta de rifampicina (RIF) e isoniacida (ISO). RIF se descompone en medio ácido al producto 3-FRSV, que en presencia de ISO forma IH. La liberación secuencial de RIF en estómago e ISO en intestino podría llevar a un incremento en la estabilidad de RIF. En una etapa previa RIF e ISO se asociaron a los polielectrolitos carboximetilcelulosa (CMC) y ácido algínico (AA), respectivamente, para obtener los materiales portadores CMC-RIF y AA-ISO que permiten la liberación inmediata de RIF y sostenida ISO. Los mismos pueden ser comprimidos para formar matrices hidrofílicas polielectrolico-fármaco (MHPF).OBJETIVO: Evaluar el impacto de la liberación secuencial de RIF e ISO en la estabilidad de RIF en condiciones simulando el contenido gástrico.METODOS: Los estudios de liberación desde las MHPF MCM-RIF + AA-ISO se realizaron en fluido gástrico simulado, utilizando referencia soluciones de RIF o RIF + ISO y la matric CMC-RIF en las mismas condiciones. La evaluación se realizó durante 2 hs, a 37ºC utilizando el aparato 2. La cuantificación se realizó mediante un método de HPLC indicativo de estabilidad, que permitió identificar ambos fármacos y sus productos de degradación.RESULTADOS: La MHPF CMC-RIF presenta muy rápida velocidad de disolución. La combinación de las MHPF CMC-RIF y AA-ISO permite la liberación selectiva e inmediata de RIF en medio ácido, con mínimos niveles concominantes de ISO, permitiendo una reducción en la formación de IH. Este producto de descomposición ha sido asociado con incremento en los eventos hepatotóxicos asociados a la combinación de RIF e ISO. Sin embargo, CMC acelera la degradación de RIF a 3-FRSV.CONCLUSIONES: La liberación secuencial de RIF e ISO permite reducir la formación de IH y es una estrategia adecuada para el desarrollo de comprimidos bi-capa. La optimización de la estabilidad requiere la adecuación de la capa de liberación inmediata de RIF.

INTRODUCTION: Tuberculosis treatment requires the administration of a combination of rifampicin (RIF) and isoniazid (ISO). In acidic media RIF decomposes to 3-FRSV, which in the presence of ISO forms IH. The sequential release of RIF in the stomach and ISO in the intestine could lead to an increase in RIF stability. In a previous work RIF and ISO were associated to the polyelectrolytes carboxymethylcellulose (CMC) and alginic acid (AA) to obtain carrier material CMC-RIF and AA-ISO that allow immediate release of RIF sustained of ISO. These materials can be compressed to form swellable drug polyelectrolyte matrices (SDPM).OBJECTIVE: To evaluate the impact of the sequential release of RIF and ISO in the stability of RIF in conditions simulating gastric contents.METHODS: Release studies were carried out from SDPM CMC-RIF + AA-ISO in simulated gastric fluid using as references RIF or RIF + ISO solutions under the same conditions. Samples were taken for 2 hs at 37ºC, using apparatus 2. The presence of both drugs and degradation products was analyzed by a stability indicating HPLC techinique.RESULTS: The SDPM CMC-RIF presented very fast release rate. The combination of SDPM CMC-RIF and AA-ISO permits selective and immediate release of RIF in acidic media, with minumum levels of ISO, with noticeable reduction of IH formation. This product has been associated with an increased frequency in hepatotoxic events associated with RIF and ISO combination. However, CMC accelerated degradation of RIF to 3-FRSV.CONCLUSIONS: Sequential release of RIF and ISO allowed a reduction in the formation of IH and seemed to be a suitable strategy for the development of bilayer tablets. Stability optimization should include adapting the immediate release layer of RIF.

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