ABSTRACT Local irritability studies for inhaled products constitute a fundamental link in the chain of regulatory requirements for preclinical toxicological studies. For this reason, the objective of the work was to determine the irritation potential of SURFACEN® in repeated doses by intranasal route. Thirty Cenp: Sprague Dawley rats (15/sex) were divided into two experimental groups: control (0.9 % NaCl solution) and treated (SURFACEN®). Both groups received the same treatment scheme with two daily intranasal applications spaced four to six hours apart, for 14 days. The dose to be applied was 13.27 mg/kg. Clinical observations, body weight, post mortem body weight, absolute and relative weight of the selected organs (lungs, brain) of each animal and pathological study were the variables to be studied. The design and implementation of the research was carried out according to the animal welfare principles. All animals survived the study. No statistically significant differences were evidenced between both groups regarding the variables studied. There were no signs of overt toxicity after SURFACEN® administration, and no anatomopathological alterations that could be associated with the administration of the drug were detected. It was evidenced that the application of repeated doses of SURFACEN® by intranasal route did not alter the cell morphology of the nasal mucosa, did not cause histopathological damage in the organs studied and did not produce signs of local irritation, thus it is considered potentially non-toxic for humans.

RESUMEN Los estudios de irritabilidad local para los productos inhalados constituyen un eslabón fundamental en la cadena de requisitos regulatorios de los estudios preclínicos toxicológicos, por este motivo el objetivo del trabajo fue determinar el potencial irritante de SURFACEN® en dosis repetidas por vía intranasal. Se utilizaron 30 ratas Cenp: Sprague Dawley (15 de cada sexo) distribuidas en dos grupos experimentales: control (solución de NaCl 0,9 %) y tratado (SURFACEN®). Ambos grupos recibieron el mismo esquema de tratamiento con dos aplicaciones diarias espaciadas entre sí, de cuatro a seis horas por vía intranasal, durante 14 días. La dosis a aplicar fue de 13,27 mg/kg. Las variables a evaluar fueron la observación clínica, el peso corporal, el peso corporal post mortem, el peso absoluto y relativo de los órganos seleccionados (pulmones, encéfalo) de cada animal y los estudios anatomopatológicos. El diseño y la conducción de la investigación se realizó según los principios de bienestar animal. Todos los animales sobrevivieron al estudio. No se evidenciaron diferencias estadísticamente significativas entre ambos grupos en las variables estudiadas. No hubo signos de toxicidad manifiestos tras la administración de SURFACEN® y no se detectaron alteraciones anatomopatológicas que pudieran estar asociadas a la administración del medicamento. Se evidenció que la aplicación de dosis repetidas por vía intranasal de SURFACEN® no alteró la morfología celular de la mucosa nasal, no causó daños histopatológicos en los órganos estudiados y no produjo signos de irritación local, por lo que se considera potencialmente no tóxico para humanos.

ABSTRACT INTRODUCTION Acute respiratory distress syndrome is a complex heterogeneous disorder with low incidence but high case fatality in children. Treatment with pulmonary surfactants is a possible option. Surfacen, a Cuban exogenous pulmonary surfactant, has been proven safe and effective in premature newborns with hyaline membrane disease, but evidence regarding its efficacy in older children is still inconclusive. OBJECTIVE Determine Surfacen’s efficacy in improving oxygenation and increasing survival in children with acute respiratory distress syndrome. METHODS A multicenter (five pediatric intensive care units in four provinces), open-label, controlled, randomized phase III clinical trial with two treatment groups was conducted from November 2009 through August 2013, with 19 girls and 23 boys aged 1 month to 18 years. The experimental group (20 patients) received conventional treatment (oxygenation and mechanical ventilation) plus intratracheal instillation of Surfacen (100 mg/4 mL) every eight hours for three days. The control group (22 patients) received only conventional treatment. The primary dependent outcome was patient vital status (alive or deceased) 28 days after study enrollment. Other variables and outcomes analyzed were age, sex, ARDS presentation, Kirby index (arterial oxygen tension over inspired oxygen fraction), oxygenation index, static lung compliance, transcutaneous oxygen saturation, radiographic course, mechanical ventilation time and length of stay in neonatal intensive care. Statistical tests used were the chi-square test and Fisher exact test. RESULTS On day 28, there was 80% survival in the experimental group versus 38.1% in the control group. There were significant differences between the experimental and the control group in Kirby index, oxygenation index, static lung compliance and radiographic course, all favoring the experimental group. For every 2.38 patients treated in total, there was one additional survivor in the experimental group. CONCLUSIONS When combined with conventional therapy in the regimen employed, Surfacen improves oxygenation and increases survival in children with ARDS.

Surfacen®, a clinical preparation of exogenous pulmonary surfactant, and pulmonary surfactant protein A (SP-A) were evaluated in relation to their in vitro effect on the growth of a clinical isolate of Streptococcus pneumoniae. The bacterium was incubated in a normal saline solution for 5 h at 37ºC, together with Surfacen® and SP-A. Surfacen® showed antibacterial activity against the clinical isolate of Streptococcus pneumonia at 10 or 25 mg/ml with one logarithm of reduction of the bacterial growth; also SP-A had the same effect at concentrations of 0.25, 0.5 or 1 mg/ml. Porcine SP-A addition at the highest Surfacen® concentration (25 mg/ml) showed a higher antibacterial activity by reducing two logarithms of bacterial growth.

Surfacen®, una preparación clínica de surfactante pulmonar exógeno, y la proteína A del surfactante pulmonar (SP-A), se evaluaron en relación a su efecto in vitro sobre el crecimiento de un aislado clínico de Streptococcus pneumoniae. La bacteria fue incubada en solución salina durante 5 h a 37ºC junto a Surfacen® y la SP-A. Los resultados mostraron que Surfacen®, a las concentraciones de 10 y 25 mg/ml, logró una reducción de un logaritmo del crecimiento bacteriano; a su vez la SP-A porcina tuvo igual efecto a las concentraciones de 0,25; 0,5 y 1 mg/ml. La adición de SP-A porcina a la máxima concentración de Surfacen® (25 mg/ml) mostró una mayor actividad antibacteriana al reducir dos logaritmos del crecimiento bacteriano.

Pulmonary surfactant is one multi-component system of vital importance for breathing of organisms with lungs. When this surfactant is negatively affected, this is associated with the development of respiratory diseases with several degrees of severity, being the acute respiratory distress syndrome one of the unsolved health problems worldwide. The present article reviews the present situation of knowledge about this syndrome including definition, etiology, epidemiology, determining factors, making special emphasis on inflammatory/oxidative mechanisms involved, mainly secretory A2 phospholipase enzyme, as well as the research prospects around search of more efficient drugs to treat this condition.

El surfactante pulmonar constituye un sistema multicomponente de vital importancia para la respiración de los organismos pulmonados. Su afectación se asocia al desarrollo de enfermedades respiratorias de diversas gravedades, siendo el síndrome de dificultad respiratoria agudo uno de los problemas de salud no resueltos a nivel mundial. El presente artículo revisa el estado actual del conocimiento de este síndrome, se incluye su definición, etiología, epidemiología, factores que lo determinan con especial énfasis en los mecanismos inflamatorios/oxida-tivos involucrados, fundamentalmente en la enzima fosfolipasa A2 de secreción así como las perspectivas en la investigación en cuanto a la búsqueda de medicamentos más eficaces para su tratamiento.