Caracterización de recién nacidos reanimados durante el año 2011 en el Hospital Clínico Regional de Concepción / Characterization of neonatal resuscitation during 2011 at Regional Clinical Hospital of Concepcion

INTRODUCCIÓN: La asfixia es responsable del 19 por ciento de las muertes neonatales que ocurren en el mundo. La reanimación neonatal disminuye la mortalidad en estos Recién Nacidos (RN). 10 por ciento de los RN requieren maniobras de reanimación, de éstos, 1 por ciento requiere reanimación avanzada. OBJETIVOS: Caracterizar los RN reanimados durante el año 2011 en un hospital público. Materiales y métodos: Estudio descriptivo retrospectivo, con historias clínicas correspondientes a la totalidad de RN durante el 2011 en el Hospital Clínico Regional de Concepción. Se seleccionaron RN que requirieron maniobras de reanimación desde ventilación a presión positiva. Se analizaron datos demográficos, Apgar, maniobras realizadas y antecedentes maternos. RESULTADOS: Del total de RN vivos (4095) fueron reanimados 130 (3,17 por ciento), de estos últimos un 57,69 por ciento de término. El 11,5 por ciento fue de muy bajo peso y el 11,5 por ciento de extremo bajo peso al nacer. Hubo parto vaginal en 49,6 por ciento y cesárea urgencia 40,8 por ciento. En relación al Apgar al (1’) resultó <7 en 93,18 por ciento de los RN. Se utilizó Ventilación a Presión Positiva (VPP) en 66,15 por ciento; reanimándose sólo con aire un 12,9 por ciento de RN de término y todos los RN Pretérmino fueron reanimados con oxígeno, regulado por oximetría de pulso. Se realizó intubación endotraqueal en 26,92 por ciento; 6,92 por ciento requirió masaje cardiaco y medicamentos. El 96,15 por ciento sobrevivió y 48,15 por ciento fueron hospitalizados en UCI. DISCUSIÓN: El porcentaje de RN reanimados fue bajo en comparación a lo señalado en la literatura, pese a ser un centro de referencia. La mayoría de los reanimados fue de término. La maniobra más utilizada fue la VPP.

INTRODUCTION: Asphyxia is responsible for 19 percent of neonatal deaths that occur worldwide. Neonatal resuscitation contributes to lower morbidity and mortality in newborns. 10 percent of newborns require some assistance to begin breathing at birth; of this group less than 1 percent require extensive resuscitative measures. OBJECTIVE: To characterize newborns resuscitated during2011 in a public hospital. Material and method: Descriptive retrospective study, including all infants born during 2011 in Regional Clinical Hospital of Concepción. Neonates that required resuscitation measures were selected from positive ventilation pressure. Demographic data, Apgar score, resuscitation measures and maternal history were analyzed. RESULTS: Out of the 4095 living newborns, 130 of them (3.17 percent) were resuscitated. Of this group, 57.69 percent were of term gestation, 11.5 percent of them were very low weight and 11.5 percent extremely low weight. Vaginal delivery ocurred in 49.6 percent and urgency cesarean section in 40.8 percent. Apgar score at (1’) resulted <7 in 93.18 percent of neonates. Positive-pressure ventilation was used in 66.15 percent; using air in 12.9 percent of term infants. All preterm infants were resuscitated with oxygen, regulated by pulse oximetry. Endotracheal intubation was used in 6.92 percent; whereas 6.92 percent required cardiac massage and drugs. 96.15 percent survived and 48.15 percent were admitted to ICU. DISCUSSION: The percentage of resuscitated neonates was low in comparison to the pointed out in literature, despite being a reference center. The majority of resuscitated infants had term gestation. The most used resuscitation measure was positive pressure ventilation.

[Relative bioavailability study of two oral formulations of mycophenolate mofetil in healthy volunteers]. / Estudio de biodisponibilidad relativa entre dos formulaciones orales de micofenolato mofetilo en voluntarios sanos.

BACKGROUND: The bioequivalence of different formulations of a same pharmaceutical product must be tested empirically. AIM: To evaluate the relative bioavailability for an oralformulation of mycophenolate mofetil (MMF) (Linfonex™) compared to the reference formulation (Cellcept™) to determine the bioequivalence between both formulations. MATERIAL AND METHODS: A randomized, crossover, double-blind trial in 22 healthy male volunteers, who received a single oral dose of 1000 mg of Linfonex and Cellcept with a washout period of 10 days. Plasma levels of the drug were determined by high performance liquid chr ornatography. Plasma concentrations were plotted and maximum concentration, area under the plasma concentration versus time between 0 and 12 hours after administration and área under plasma concentration curve versus time after administration between 0 and infinity, were calculated for both products. RESULTS: The active compound, mycophenolic acid, was similarly absorbed in both formulations. No statistically significant differences were found in calculated pharmacokinetic parameters between both formulations. CONCLUSIONS: Linfonex™ 500 mg is bioequivalent to Cellcept™ 500 mg.

Estudio de biodisponibilidad relativa entre dos formulaciones orales de micofenolato mofetilo en voluntarios sanos / Relative bioavailability study of two oral formulations of mycophenolate mofetil in healthy volunteers

Background: The bioequivalence of different formulations of a same pharmaceutical product must be tested empirically. Aim: To evaluate the relative bioavailability for an oralformulation of mycophenolate mofetil (MMF) (Linfonex™) compared to the reference formulation (Cellcept™) to determine the bioequivalence between both formulations. Material and Methods: A randomized, crossover, double-blind trial in 22 healthy male volunteers, who received a single oral dose of 1000 mg of Linfonex and Cellcept with a washout period of 10 days. Plasma levels of the drug were determined by high performance liquid chr ornatography. Plasma concentrations were plotted and maximum concentration, area under the plasma concentration versus time between 0 and 12 hours after administration and área under plasma concentration curve versus time after administration between 0 and infinity, were calculated for both products. Results: The active compound, mycophenolic acid, was similarly absorbed in both formulations. No statistically significant differences were found in calculated pharmacokinetic parameters between both formulations. Conclusions: Linfonex™ 500 mg is bioequivalent to Cellcept™ 500 mg.

Estudios de bioexención (in vitro) para establecer equivalencia de medicamentos / Biowaiver studies (in vitro) to establish equivalence of drugs

En el presente trabajo se hace un análisis de los conceptos, normativas y propuestas sobre la equivalencia terapéutica de medicamentos similares con respecto a los innovadores, desde una perspectiva internacional y nacional, explicando las bases científicas de los estudios de bioexención in vitro para determinar la intercambiabilidad de aquellos medicamentos similares provenientes de diferentes fuentes que se han liberado de los estudios de bioequivalencia (in vivo). Además, se presentan algunos resultados de estudios de test de disolución para dar a conocer la metodología usada en la bioexención y se detallan los requisitos para aprobar un Centro de Bioequivalencia in vitro.

In this review, the concepts, guidelines and proposals regarding the determination of therapeutic equivalence of similar drug products are analyzed from a national and international point of view. The scientific background of the in vitro biowaiver studies that may result in the interchange ability of multisource drug product that have been waived from the demonstration of in vivo bioequivalence studies is also explained. In order to explain the methods in biowaiver studies, results of dissolution kinetics are shown as well as the requirements to approve an in vitro biopharmaceutic center.

Estudios de biodisponibilidad para establecer bioequivalencia de medicamentos / Bioavailability studies to establish the drugs bioequivalence

Se hace un análisis de los conceptos, normativas y propuestas sobre la equivalencia terapéutica de los medicamentos similares, desde una perspectiva internacional y nacional, explicando las bases científicas de los estudios de biodisponibilidad y bioequivalencia para determinar la intercambiabilidad de los medicamentos provenientes de diferentes fuentes.

A concept, rules and proposals research about therapeutic bioequivalence of similar drugs, from an international and national perspective, explaining the scientific bases of bioavailability and bioequivalence studies to determine the drugs of different sources exchangeability.

Papel de las enzimas citocromo p450 en el metabolismo de fármacos antineoplásicos: situación actual y perspectivas terapéuticas: [revisión] / Role of cytochrome P450 enzymes in the metabolism of antineoplastic drugs: [review]

Cytochrome P450 enzymes are very important to metabolize anti-carcinogenic agents. Therefore, understanding the role of these enzymes and their allele variants in the bioactivation or detoxification of drugs could greatiy benefit antineoplastic pharmacotherapy. The aim of thís manuscrípt is to give information about metabohzing enzymes for antineoplastic agents and to relate the current situation in antitumoral pharmacotherapy with recent knowledge about cytochrome P450 enzymes. This is crucial for the future perspectives towards personalized pharmacotherapy. We summarize the role of cytochrome P450 enzymes in the resistance and bioactivation of several antitumor agents, their induction and repression mechanisms and the effect of genetic polymorphisms on variability of drug metabolization. The understanding of genetic variability will help to develop new research Unes on innovative therapeutic possibilities.

Farmacocinética de medicamentos de uso pediátrico, visión actual / Pediatric drugs pharmacokinetics

Pharmacokinetics corresponds to the branch of pharmacology that studies the absorption, distribution, biotransformation and excretion of drugs in the body, in order to proportionate a reference line for interpretation of drug concentration in biological fluids, fundamental for clinical therapy. While adult pharmacology has increase greatly, advances in pediatric pharmacology have been poor. Therefore, drug prescription in children is essentially empirical on the basis of an inmature organism. An effective, secure and rational pediatric pharmacology requires exhaustive knowledgement of the developmental changes in relation to absorption, distribution, metabolism and excretion affecting pharmacokinetics parameters; therefore, the effective dose. This review describes fundamental differences between adult and pediatric pharmacokinetics. These differences must be considered when therapeutic strategies develop for newborns and children.

La farmacocinética, rama de la farmacología que estudia el paso de las drogas a través del organismo en función del tiempo y la dosis tiene por finalidad el proporcionar un marco de referencia para interpretar la concentración de los fármacos en los líquidos biológicos por el bien del paciente, lo que es fundamental para una correcta terapéutica clínica. Mientras los avances en farmacología clínica del adulto en las últimas décadas tuvieron un gran adelanto, no ha ocurrido lo mismo en farmacología pediátrica donde la mayoría de las veces la prescripción de medicamentos se realiza sobre una base empírica en un organismo inmaduro. Una terapéutica farmacológica efectiva, segura y racional en neonatos, lactantes y niños requiere el exhaustivo conocimiento de las diferencias en la absorción, distribución, metabolismo y excreción, las que aparecen durante el crecimiento y desarrollo, debido a que virtualmente, todos los parámetros farmacocinéticos se modifican con la edad. Esta revisión describe las diferencias fundamentales en la farmacocinética de los medicamentos en el niño cuando se compara con el adulto. Estas diferencias y los cambios en estos procesos deben ser cuidadosamente considerados cuando se desarrollan estrategias terapéuticas en recién nacidos y niños pequeños.

[Role of cytochrome P450 enzymes in the metabolism of antineoplastic drugs]. / Papel de las enzimas citocromo p450 en el metabolismo de fármacos antineoplásicos: situación actual y perspectivas terapéuticas.

Cytochrome P450 enzymes are very important to metabolize anti-carcinogenic agents. Therefore, understanding the role of these enzymes and their allele variants in the bioactivation or detoxification of drugs could greatly benefit antineoplastic pharmacotherapy. The aim of this manuscript is to give information about metabolizing enzymes for antineoplastic agents and to relate the current situation in antitumoral pharmacotherapy with recent knowledge about cytochrome P450 enzymes. This is crucial for the future perspectives towards personalized pharmacotherapy. We summarize the role of cytochrome P450 enzymes in the resistance and bioactivation of several antitumor agents, their induction and repression mechanisms and the effect of genetic polymorphisms on variability of drug metabolization. The understanding of genetic variability will help to develop new research lines on innovative therapeutic possibilities.

Intercambiabilidad de medicamentos de origen biológico (biofármacos): Consideraciones acerca de la aprobación de formulaciones biosimilares (biogenéricos) en Chile / Interchangeability of biological drugs: Considerations about the approval of biogeneric formulations in Chile

Once drug patents expire, the health authorities can approve the registry of similar products. They must request to the manufacturer, the bibliographic background of the original product and the analytical results that certify drug quality. An inspection of the premises of the manufacturer is also required. The main goal of this approval is to decrease cost, considering that the original product is usually more expensive. This is a current situation due to the imminent expiration of the patents of many biopharmaceutical products. Therefore, in Chile, the Public Health (ISP) and the Ministry of Health should consider that for this kind of products, until now, there are no interchangeable generic drugs, and that the similar drugs that are offered have a different chemical composition, since they have been manufactured through different processes. In the case of biological drugs (e.g. erythropoietir, somatotropin, heparin) the quality and homogeneity depend from the manufacture process. Its complete composition can not be absolutely elucidated; therefore small impurities or conformational variants can elicit an altered immune response or unexpected adverse reactions. This indicates that the approval of a biogeneric drug requires in addition to pharmacokinetic studies, preclinical and clinical analytical studies such as physicochemical assays, biological and immunological test. This issues have been established by WHO and have been incorporated for the main drug registry entities all over the world (FDA, EMEA, ANVISA) to approve biogeneric products.

Medicamentos genéricos / Generic medicines

Se analiza la actual definición de la Organización Mundial de la Salud (OMS) para medicamento genéricobioequivalente, la adopción de este concepto por parte de los países de mayor desarrollo sanitario y la situación de Chile al respecto. A través de ejemplos de estudios de biodisponibilidad y bioequivalencia (BD/BE) hechos en Chile, se discuten los conceptos de equivalencia terapéutica, calidad, seguridad y eficacia del medicamento y se da a conocer el listado de drogas que, de acuerdo a la legislación chilena, deberán ser sometidos a este tipo de estudios para probar equivalencia terapéutica y aquellos de la bioexención que podrán optar al estudio in vitro o test de disolución.También se discute la situación de los medicamentos a los cuales no es necesario hacerles estudios de BD/BE para demostrar equivalencia, como los inyectables endovenosos, jarabes y otros y también qué se recomienda hacer con los productos de origen biotecnológico para demostrar su intercambiabilidad con el original.

The present definition of the World Health Organization (WHO) for generic bioequivalent drug, the adoption of this concept by the countries of best sanitary development and the situation of Chile on the matter, are analyzed. Through examples of studies of bioavailability and bioequivalence (BD/BE) done in Chile we discuss the concepts of therapeutic equivalence, quality, safety and effectiveness of the drugs. We also list drugs that according to Chilean legislation must be submitted to this kind of studies and those will be able to choose in vitro studies (for example dissolution tests) in order to prove therapeutic equivalence. Also the situation ofthe drugs which do not require BD/BE studies, as for example intravenous injections, syrups and others is discussed. Finally, we recommended what to do with products of biotechnological origin.

[Interchangeability of biological drugs: considerations about the approval of biogeneric formulations in Chile]. / Intercambiabilidad de medicamentos de origen biológico (biofármacos): consideraciones acerca de la aprobación de formulaciones biosimilares (biogenéricos) en Chile.

Once drug patents expire, the health authorities can approve the registry of similar products. They must request to the manufacturer, the bibliographic background of the original product and the analytical results that certify drug quality. An inspection of the premises of the manufacturer is also required. The main goal of this approval is to decrease cost, considering that the original product is usually more expensive. This is a current situation due to the imminent expiration of the patents of many biopharmaceutical products. Therefore, in Chile, the Public Health (ISP) and the Ministry of Health should consider that for this kind of products, until now, there are no interchangeable generic drugs, and that the similar drugs that are offered have a different chemical composition, since they have been manufactured through different processes. In the case of biological drugs (e.g. erythropoietir, somatotropin, heparin) the quality and homogeneity depend from the manufacture process. Its complete composition can not be absolutely elucidated; therefore small impurities or conformational variants can elicit an altered immune response or unexpected adverse reactions. This indicates that the approval of a biogeneric drug requires in addition to pharmacokinetic studies, preclinical and clinical analytical studies such as physicochemical assays, biological and immunological test. This issues have been established by WHO and have been incorporated for the main drug registry entities all over the world (FDA, EMEA, ANVISA) to approve biogeneric products.

Bioequivalencia entre dos formulaciones de claritromicina comprimidos de liberación modificada existentes en el mercado chileno / Bioequivalence of two brands of clarithromycin in modified-release tablets available in the chilean pharmacopeia

Se realizó un estudio comparativo de biodisponibilidad, para evaluar la bioequivalencia entre dos formulaciones de claritromicina de 500 mg en comprimidos de liberación modificada, una nacional (Pre-Clar UD (R)), y el innovador del mercado (Klaricid UD (R)). Se utilizó un ensayo microbiológico para determinar las concentraciones plasmáticas del antimicrobiano. El ensayo está basado en la correlación entre la inhibición del crecimiento bacteriano y la concentración plasmática de claritromicina. Un total de 16 voluntarios, jóvenes sanos, no fumadores, participaron y completaron el protocolo del estudio, el cual fue aprobado por el Comité de Ética de la Facultad de Medicina de la Universidad de Chile. Los parámetros farmacocinéticos de: concentración plasmática máxima (Cmáx,), tiempo de vida media (t1/2), área bajo la curva de concentraciones plasmáticas versus tiempo desde cero a infinito (ABC0-Ñ) ,constante de velocidad de absorción (Kabs), no mostraron diferencias estadísticamente significativas entre los productos utilizados. De acuerdo a los criterios recomendados por la FDA y en base a nuestros resultados, se concluye que las formulaciones Pre-Clar UD® y Klaricid UD® son bioequivalentes, asumiéndose que tendrán igual eficacia clínica.

Bioequivalencia entre dos formulaciones de claritromicina en suspensión pediátrica existentes en el mercado chileno / Bioequivalence evaluation of two brands of clarithromycin suspension available in the chilean pharmacopeia

Se realizó un estudio comparativo de biodisponibilidad, para evaluar la bioequivalencia entre dos formulaciones de claritromicina en suspensión de 250 mg/5 mL, una nacional (Pre-Clar(R)), y el innovador del mercado (Klaricid(R)). En ambos casos, se administró una dosis de 500 mg. Se utilizó un ensayo microbiológico para determinar las concentraciones plasmáticas del antimicrobiano. El ensayo está basado en la correlación entre la inhibición del crecimiento bacteriano y la concentración plasmática de claritromicina. Un total de 12 voluntarios, jóvenes sanos, participaron y completaron el protocolo del estudio, el cual fue aprobado por el Comité de Ética de la Facultad de Medicina de la Universidad de Chile. Los parámetros farmacocinéticos de concentración plasmática máxima (Cmáx), tiempo de vida media (t1/2), área bajo la curva concentraciones plasmáticas versus tiempo, desde cero a infinito (ABC0-Ñ) y la constante de velocidad de absorción (Kabs), no mostraron diferencias estadísticamente significativas entre los productos utilizados. De acuerdo a los criterios recomendados por la FDA y sobre la base de nuestros resultados, se concluye que las formulaciones en suspensión pediátrica de 250 mg/5 mL Pre-Clar® y Klaricid® son bioequivalentes asumiéndose que tendrán igual eficacia clínica.

Biodisponibilidad de cuatro preparados de teofilina de liberación sostenida del mercado nacional / Bioavailability of 4 sustained release teophylline preparations

We evaluated pharmacokynetic parameters and bioavailability of 4 sustained release teophylline preparations. A crossover design was used in 12 healthy males aged 22 to 27 years old. each individual recived 250 mg iv followed by 250 mg orally of each preparation, and then 400mg rapid acting aminophylline. A 7 day period was allowed between drug courses. HPLC was used to determine plasma levels of teophylline at regular intervals up to 48 hr following drug administration. Significant (p < 0.05) differences in pharmacokynetic parameters were found among preparations, 2 of them having larger integrals of plasma levels and one of them different times to peak plasma level and peak plasma concentration, compared to both remaining preparations

Carbamazepina: biodisponibilidad de cuatro productos farmacéuticos orales / Bioavailability of carbamazepine from 4 products

The bioavailability of carba,azepine from 4 comercially available products was evaluated in 12 healthy volonteers. A crossover design was used and each patients received 400 mg of each product. Plasma levels of the drug were determined periodically for 72 h using a gas-liquid chromatographic method. An open model of one compartment for first-order absortion was assumed to derive pharmacokinetic parameters. Dissolution kinetics was also evaluated in each product. Significant differences in biovailability were shown for one product. Results correlated with the in vitro dissolution findings