RESUMEN
BACKGROUND: Necrotizing enterocolitis (NEC) is a frequent cause of mortality and morbidity in very low birth weight (VLBW) infants. Human milk (HM) feeding has been associated with lower risk of NEC. However, mothers of VLBW infants often experience insufficient milk production, resulting in mixed feedings of HM and formula. Moreover, medical complications often limit the volume of feeding they can be given. OBJECTIVE: To determine if high proportions of (50% or greater) HM enteral feeding within the first 14 days of life are protective against NEC. METHOD: This was a prospective cohort study of VLBW infants who were grouped according to the HM proportion of enteral feeding in the first 14 days: <50% (low human milk, LHM, n=46) and > or =50% (high human milk, HHM, n=156). The outcome of interest was development of NEC (Bell stage 2 or 3). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) and to assess potential confounding due to perinatal risk factors. RESULT: Two hundred and two infants were studied. Confirmed NEC occurred in 5/46 (10.6%) of the LHM group, as compared with 5/156 (3.2%) of the HHM. Gestational age was the only perinatal factor associated with risk of NEC. After adjustment for gestational age, HHM was associated with a lower risk of NEC ((OR=0.17, 95% CI: 0.04 to 0.68), P=0.01). CONCLUSION: Enteral feeding containing at least 50% HM in the first 14 days of life was associated with a sixfold decrease in the odds of NEC.
Asunto(s)
Enterocolitis Necrotizante/prevención & control , Recién Nacido de muy Bajo Peso , Leche Humana , Estudios de Cohortes , Enterocolitis Necrotizante/etiología , Humanos , Fenómenos Fisiológicos Nutricionales del Lactante , Recién Nacido , Oportunidad Relativa , Estudios ProspectivosRESUMEN
Statistics has a role to play in the establishment of specification limits. This is particularly true in bioassays where the levels of uncertainty in the process and assay can be substantial. The use of statistical approaches can aid manufacturers in setting meaningful specifications and help to evaluate the ability of their processes to meet specifications long-term.
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Bioensayo/normas , Bioensayo/métodos , Estadística como AsuntoRESUMEN
Gastrointestinal bleeding in Turner's syndrome can represent vascular lesions that are frequently beyond standard endoscopic reach and often life threatening. This report describes the successful use of intraoperative endoscopy to identify the souce of bleeding in an adolescent with Turner's syndrome and significant intestinal hemorrhage. J Pediatr Surg 36:951-952.
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Endoscopía Gastrointestinal , Hemorragia Gastrointestinal/diagnóstico , Intestino Delgado , Síndrome de Turner/complicaciones , Adolescente , Femenino , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/cirugía , Humanos , Cuidados Intraoperatorios , LaparotomíaRESUMEN
OBJECTIVE: To analyze the association between chronic lung disease (CLD) and clinically diagnosed gastroesophageal reflux (GER) in very low birth weight (VLBW) infants, and between GER and outcomes at 1 year adjusted age. METHODS: A total of 375 consecutively born VLBW infants with CLD and 345 gestational age-matched controls were studied. Records were reviewed to ascertain which infants were diagnosed with GER (based on clinical suspicion or confirmatory tests) and which infants had delayed growth or development at 1 year adjusted age. RESULTS: Infants with CLD were treated for GER more frequently than controls (CLD: 27% versus controls: 9%; p < 0.0001). Among infants with CLD, those with and without GER were comparable in terms of the days on supplemental oxygen [124 (64 to 93) vs 121 (47 to 394)] and the proportion with cystic changes on chest radiograph (44% vs 47%). Comparing outcomes at 1 year for infants with and without GER, no differences were found in the rates of Bayley Mental Developmental and Psychomotor Developmental Indices of < 70, cerebral palsy, and measurements below the 10th percentile. CONCLUSION: Among VLBW infants, an association exists between CLD and GER, although this association might be due to greater diagnostic suspicion in infants with CLD. In VLBW infants, GER does not appear to increase the risk of delayed growth or development.
Asunto(s)
Desarrollo Infantil , Reflujo Gastroesofágico/epidemiología , Recién Nacido de muy Bajo Peso , Enfermedades Pulmonares/epidemiología , Estudios de Casos y Controles , Preescolar , Enfermedad Crónica , Comorbilidad , Intervalos de Confianza , Femenino , Reflujo Gastroesofágico/diagnóstico , Humanos , Lactante , Recién Nacido , Enfermedades Pulmonares/diagnóstico , Masculino , North Carolina/epidemiología , Oportunidad Relativa , Prevalencia , Valores de Referencia , Factores de Riesgo , Índice de Severidad de la Enfermedad , Distribución por SexoRESUMEN
INTRODUCTION: Providing the high calcium intake necessary for normal bone mineralization in rapidly growing very low birth weight infants is difficult because calcium and phosphorus solubility is limited in the range of parenteral nutrition pH. A major determinant of calcium and phosphorus solubility in vitro is solution pH. The objective of this study was to develop and assess the accuracy of a method to predict the final parenteral solution pH as a linear function of the individual parenteral component concentrations. METHODS: pH values were measured for 205 neonatal parenteral nutrition solutions prepared during a 5-week period. Concentrations of the 13 components used to synthesize parenteral nutrition were determined for each solution. Data from 135 samples were used to develop a linear regression coefficient model with pH as the dependent variable. From the regression model the pH was predicted for the remaining 70 samples using the seven significant solution component concentrations, and the predicted and measured solution pH values were compared. RESULTS: The mean measured parenteral nutrition pH for all solutions was 5.364 +/- 0.110 (mean +/- SD, range 5.03-5.73). The absolute mean pH difference between the predicted and measured value for the 70 test samples was 0.04 +/- 0.04. pH estimated with the model correlated highly with measured pH (r2 = 0.77). The seven components in the regression model accounted for 81% of the pH variance. CONCLUSION: The pH of neonatal parenteral nutrition solutions can be predicted accurately as a linear function of the solution concentrations of the following seven components: sodium acetate, sodium phosphate, potassium phosphate, potassium acetate, magnesium sulphate, amino acid solution and dextrose. The absolute mean difference between measured pH and predicted pH was 0.04. Applying this method to estimate pH with the interactive properties of computer-based ordering systems could enhance calcium and phosphorus administration to very low birth weight infants.
Asunto(s)
Calcio/química , Nutrición Parenteral , Fósforo/química , Calcificación Fisiológica , Calcio/administración & dosificación , Predicción , Humanos , Concentración de Iones de Hidrógeno , Recién Nacido , Modelos Lineales , Fósforo/administración & dosificación , SolubilidadRESUMEN
OBJECTIVE: Ventilator-dependent preterm infants are often treated with a prolonged tapering course of dexamethasone to decrease the risk and severity of chronic lung disease. The objective of this study was to assess the effect of this therapy on developmental outcome at 1 year of age. METHODS: Study participants were 118 very low birth weight infants who, at 15 to 25 days of life, were not weaning from assisted ventilation and were then enrolled in a randomized, placebo-controlled, double-blind trial of a 42-day tapering course of dexamethasone. Infants were examined at 1 year of age, adjusted for prematurity, by a pediatrician and a child psychologist. A physical and neurologic examination was performed, and the Bayley Scales of Infant Development were administered. All examiners were blind to treatment group. RESULTS: Groups were similar in terms of birth weight, gestational age, gender, and race. A higher percentage of dexamethasone recipients had major intracranial abnormalities diagnosed by ultrasonography (21% vs 11%). Group differences were not found for Bayley Mental Development Index (median [range] for dexamethasone-treated group, 94 [50-123]; for placebo group, 90 [28-117]) or Psychomotor Development Index Index (median [range]) for dexamethasone-treated group, 78 (50-109); for placebo-treated group, 81 [28-117]). More dexamethasone-treated infants had cerebral palsy (25% vs 7%) and abnormal neurologic examination findings (45% vs 16%). In stratified analyses, adjusted for major cranial ultrasound abnormalities, these associations persisted (OR values for cerebral palsy, 5.3; 95% CI: 1.3-21.4; OR values for neurologic abnormality 3.6; 95% CI: 1.2-11.0). CONCLUSIONS: A 42-day tapering course of dexamethasone was associated with an increased risk of cerebral palsy. Possible explanations include an adverse effect of this therapy on brain development and/or improved survival of infants who either already have neurologic injury or who are at increased risk for such injury.
Asunto(s)
Desarrollo Infantil/efectos de los fármacos , Dexametasona/farmacología , Glucocorticoides/farmacología , Recién Nacido de muy Bajo Peso , Desconexión del Ventilador/métodos , Parálisis Cerebral/epidemiología , Factores de Confusión Epidemiológicos , Dexametasona/uso terapéutico , Método Doble Ciego , Femenino , Glucocorticoides/uso terapéutico , Humanos , Lactante , Recién Nacido , Masculino , North Carolina/epidemiología , Oportunidad Relativa , Modelos de Riesgos Proporcionales , Síndrome de Dificultad Respiratoria del Recién Nacido/epidemiología , Síndrome de Dificultad Respiratoria del Recién Nacido/terapia , Estadísticas no ParamétricasRESUMEN
OBJECTIVE: To assess the effect on duration of ventilator dependency of a 42-day tapering course of dexamethasone in very low birth weight neonates. METHODS: Infants (N = 118) were assigned randomly, within birth weight/gender strata, to treatment with either a 42-day tapering course of dexamethasone or an equal volume of saline as placebo. Entry criteria were 1) birth weight <1501 g; 2) age between 15 and 25 days; 3) <10% decrease in ventilator settings for 24 hours and FIO2 >/=0.3; 4) absence of patent ductus arteriosus, sepsis, major congenital malformation, congenital heart disease; and 5) no evidence of maternal HIV or hepatitis B infection. The dosage schedule was 0.25 mg/kg bid for 3 days, then 0.15 mg/kg bid for 3 days, then a 10% reduction in the dose every 3 days until a dose of 0.1 mg/kg had been given for 3 days, from which time a dose of 0.1 mg/kg qod was continued until 42 days after entry. The primary endpoint was the number of days on assisted ventilation after study entry. Secondary outcomes of interest included days on supplemental oxygen, days of hospitalization, and potential adverse effects, such as infection, gastrointestinal bleeding, left ventricular hypertrophy, and severe retinopathy of prematurity. RESULTS: Infants in the dexamethasone- and placebo-treated groups were similar in terms of baseline attributes, including birth weight, gestational age, gender, race, and ventilator settings at entry. Infants treated with dexamethasone were on assisted ventilation and supplemental oxygen for fewer days after study entry (median days on ventilator, 5th and 95th percentiles, 13 [1-64] vs 25 [6-104]; days on oxygen, 59 [6-247] vs 100 [11-346]). No differences were found in risk of death, infection, or severe retinopathy. In subgroup analyses, the association of dexamethasone with more rapid weaning from the ventilator was weaker among infants enrolled before the 16th day of life, infants with chest radiographs showing cystic changes and/or hyperinflation, and infants requiring an FIO2 >/=0.7 or a peak inspiratory pressure >/=19 at study entry. CONCLUSIONS: A 42-day tapering course of dexamethasone decreases the duration of ventilator and oxygen dependency in very low birth weight infants and is not associated with an increased risk of short-term adverse effects.
Asunto(s)
Dexametasona/uso terapéutico , Glucocorticoides/uso terapéutico , Recién Nacido de muy Bajo Peso , Desconexión del Ventilador/métodos , Factores de Confusión Epidemiológicos , Método Doble Ciego , Femenino , Humanos , Recién Nacido , Masculino , Oportunidad Relativa , Modelos de Riesgos Proporcionales , Síndrome de Dificultad Respiratoria del Recién Nacido/terapia , Estadísticas no Paramétricas , Factores de TiempoRESUMEN
LY315920 is a potent, selective inhibitor of recombinant human, group IIA, nonpancreatic secretory PLA2 (sPLA2). In a chromogenic isolated enzyme assay, LY315920 inhibited sPLA2 activity with an IC50 of 9 +/- 1 nM or 7.3 x 10(-6) mole fraction, which approached the stiochiometric limit of this assay. The true potency of LY315920 was defined using a deoxycholate/phosphatidylcholine assay with a mole fraction of 1.5 x 10(-6). LY315920 was 40-fold less active against human, group IB, pancreatic sPLA2 and was inactive against cytosolic PLA2 and the constitutive and inducible forms of cyclooxygenase. Human sPLA2-induced release of thromboxane A2 (TXA2) from isolated guinea pig lung bronchoalveolar lavage cells was inhibited by LY315920 with an IC50 of 0.79 microM. The release of TXA2 from these cells by N-formyl-methionyl-leucyl-phenylalanine or arachidonic acid was not inhibited. The i.v. administration of LY315920, 5 min before harvesting the bronchoalveolar lavage cells, resulted in the inhibition of sPLA2-induced production of TXA2 with an ED50 of 16.1 mg/kg. Challenge of guinea pig lung pleural strips with sPLA2 produced contractile responses that were suppressed in a concentration-dependent manner by LY315920 with an apparent KB of 83 +/- 14 nM. Contractile responses induced by arachidonic acid were not altered. Intravenous or oral administration of LY315920 to transgenic mice expressing the human sPLA2 protein inhibited serum sPLA2 activity in a dose-related manner over a 4-h time course. LY315920 is a potent and selective sPLA2 inhibitor and represents a new class of anti-inflammatory agent designated SPI. This agent is currently undergoing clinical evaluation and should help to define the role of sPLA2 in various inflammatory disease states.
Asunto(s)
Acetatos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Indoles/farmacología , Fosfolipasas A/antagonistas & inhibidores , Animales , Ácido Araquidónico/farmacología , Línea Celular , Clonación Molecular , Cricetinae , Fosfolipasas A2 Grupo II , Cobayas , Humanos , Cetoácidos , Masculino , Mesocricetus , Ratones , Ratones Transgénicos , Músculo Liso/efectos de los fármacos , Fosfolipasas A/biosíntesis , Fosfolipasas A/sangre , Fosfolipasas A2 , Pleura/efectos de los fármacos , Pleura/metabolismo , Conejos , Ratas , Proteínas Recombinantes/biosíntesis , Tromboxano A2/biosíntesisRESUMEN
A case-control study was performed to identify perinatal events associated with intraparenchymal echodensity on cranial ultrasonography--an important antecedent of cerebral palsy in very-low-birthweight infants. Forty-eight infants with birthweight < 1500 g and intraparenchymal echodensity on cranial ultrasound examination and 90 controls with normal cranial ultrasounds were identified within a cohort of 1791 consecutive very-low-birthweight infants born at a regional obstetric referral centre. Data about potential risk factors were obtained from medical records of cases and controls. Among prenatal factors, chorioamnionitis (odds ratio[OR]: 3.2; 95% confidence interval: 1.3, 8.1) and placental abruption (OR 2.6 [1.0, 6.6]) were associated most strongly with an increased risk of intraparenchymal echodensity and pre-eclampsia (OR 0.3 [0.1, 0.8]) was associated most strongly with a decreased risk. When controlling for gestational age, multiple gestation was also associated with an increased risk (OR 2.7 [1.0, 7.5]). Neonatal factors independently associated with an increased risk included low systolic blood pressure (< 33 mmHg in the first 12 h of life; odds ratio 8.0 [2.0, 31.3]), receipt of a fluid bolus in the first 12 h of life (OR 19.7 [4.6, 84.3]), need for cardiopulmonary resuscitation in the first 72 h (OR 6.9 [1.5, 31.3]) and pneumothorax in the first 72 h of life (OR 27.0 [4.3, 167.2]). When analyses were restricted to infants who were not given a fluid bolus, the associations with chorioamnionitis and placental abruption were attenuated. When excluding infants who had a pneumothorax, the associations with placental abruption and multiple gestation were attenuated. Restriction of infants with systolic blood pressure < 33 mmHg resulted in attenuation of associations with pre-eclampsia and multiple gestation. These analyses suggest the possibility that potentially modifiable postnatal events may be involved as intervening factors linking chorioamnionitis, placental abruption and multiple gestation with subsequent intraparenchymal echodensity.
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Parálisis Cerebral/diagnóstico por imagen , Parálisis Cerebral/etiología , Enfermedades del Prematuro/diagnóstico por imagen , Enfermedades del Prematuro/etiología , Recién Nacido de muy Bajo Peso , Desprendimiento Prematuro de la Placenta/complicaciones , Estudios de Casos y Controles , Hemorragia Cerebral/complicaciones , Parálisis Cerebral/patología , Corioamnionitis/complicaciones , Factores de Confusión Epidemiológicos , Femenino , Humanos , Recién Nacido , Enfermedades del Prematuro/patología , Modelos Logísticos , Análisis Multivariante , Oportunidad Relativa , Paridad , Preeclampsia/complicaciones , Embarazo , Factores de Riesgo , UltrasonografíaRESUMEN
OBJECTIVE: To analyze whether the increasing survival of very low birth weight infants during the 1980s and 1990s has increased the risk of cerebral palsy among survivors. METHODS: The study cohort consisted of 2076 consecutively born infants, with birth weights of 500 to 1500 g and no major anomaly, born July 1, 1982, through June 30, 1994, to residents of a 17-county region in North Carolina. These infants had a mean birth weight of 1096 g (standard deviation, 251 g) and a mean gestational age of 29 weeks (standard deviation, 3 weeks). One thousand five hundred sixty-eight infants (76%) survived to 1 year adjusted age, at which point 1282 infants (82%) were examined at our medical center. The diagnosis of cerebral palsy was made only if the examining pediatrician and a pediatric physical therapist agreed on the diagnosis. To analyze trends across time, the Cochran-Armitage chi2 test and logistic regression were applied to data for infants categorized into six 2-year epochs according to year of birth. RESULTS: Mortality did not change significantly through 1990, and then began to decrease in 1990 to 1994. During the study period, mortality decreased from 36.8% between 1982 and 1984, to 13.8% between 1992 and 1994. The prevalence of cerebral palsy among survivors was constant from 1982 to 1988 (11.3%), decreased slightly from 1988 to 1990 (9.2%), and was lowest in 1990 to 1994 (5.2%). These secular trends in mortality and cerebral palsy risk remained significant when adjusted for gestational age, gender, and race. When adjusted for surfactant use, the trend in mortality was no longer significant, whereas the trend in cerebral palsy risk persisted. CONCLUSIONS: The increasing survival of very low birth weight infants in the 1980s and 1990s has not resulted in an increased prevalence of cerebral palsy among survivors.
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Parálisis Cerebral/epidemiología , Mortalidad Infantil/tendencias , Recién Nacido de muy Bajo Peso , Distribución de Chi-Cuadrado , Estudios de Cohortes , Femenino , Humanos , Lactante , Recién Nacido , Modelos Logísticos , Masculino , North Carolina/epidemiología , Prevalencia , Surfactantes Pulmonares/uso terapéutico , Riesgo , Sesgo de SelecciónRESUMEN
The purpose of this study was to analyze associations between prenatal factors and cerebral palsy in a geographically based cohort of very low birth weight infants. Cases (n = 80) and controls had birth weights of 500-1,500 g and were born in 1978-1989, to a resident of one of 17 counties in northwest North Carolina. Medical records were reviewed for data about prenatal and neonatal factors. Associations were analyzed separately for three clinical forms of spastic cerebral palsy (hemiplegia, diplegia, and quadriplegia) and for cerebral palsy with and without antecedent major cranial ultrasound abnormalities. The following factors were associated most strongly with an increased risk of cerebral palsy: multiple gestation, chorioamnionitis, maternal antibiotics, antepartum vaginal bleeding, and labor lasting less than 4 hours. Preeclampsia and delivery without labor were associated with a decreased risk. Evidence of confounding was found for each of these associations, except for those with chorioamnionitis and labor lasting less than 4 hours. The association with chorioamnionitis was stronger for diplegia (compared with hemiplegia and quadriplegia) and for cerebral palsy without major cranial ultrasound abnormalities. Associations with antepartum vaginal bleeding (increased risk) and preeclampsia (decreased risk) were stronger for cerebral palsy occurring with major cranial ultrasound abnormality.
Asunto(s)
Parálisis Cerebral/epidemiología , Recién Nacido de muy Bajo Peso , Antibacterianos/uso terapéutico , Estudios de Casos y Controles , Corioamnionitis/epidemiología , Factores de Confusión Epidemiológicos , Femenino , Humanos , Trabajo de Parto , North Carolina/epidemiología , Preeclampsia/epidemiología , Embarazo , Complicaciones del Embarazo/epidemiología , Embarazo Múltiple , Análisis de Regresión , Factores de Riesgo , Factores de Tiempo , Hemorragia Uterina/epidemiologíaRESUMEN
Very low-birthweight infants constitute more than one-quarter of all new cases of cerebral palsy. We performed a case-control study of associations between antenatal maternal infection and cerebral palsy in very low-birthweight infants. Cases and controls were selected from a cohort of 1238 consecutive infants who: (1) had birthweights between 500 and 1500 g and no major congenital anomaly; (2) were born 1 January 1986 to 31 December 1993 to a mother residing in 1 of 17 counties in north-west North Carolina; and (3) were delivered at the only tertiary obstetric referral centre in those same 17 counties. A total of 984 of these infants (79%) survived to 1 year of age (adjusted for degree of prematurity) and were scheduled for a multidisciplinary examination; 815 (83%) came as scheduled. Excluding two cases attributable to post-neonatal events, 62 cases of cerebral palsy were identified. Controls were the two infants, without cerebral palsy, born closest in time to each case. Medical records were reviewed by a nurse who was not aware of which subjects were cases. Among possible markers of intra-amniotic infection, those associated most strongly with cerebral palsy were chorioamnionitis diagnosed by an obstetrician (odds ratio [OR] adjusted for gestational age [95% confidence limits] = 2.6 [1.0, 6.5]), antepartum maternal temperature > 37.8 degrees C (OR = 2.6 [1.1, 6.0]), uterine tenderness (OR = 2.6 [0.8, 9.3]), maternal receipt of antibiotics (OR = 2.2 [1.0, 4.7]) and neonatal sepsis in the first week of life (OR = 2.9 [0.9, 8.9]). All of these associations were stronger for diplegia than the other clinical subtypes of cerebral palsy. The association with chorioamnionitis and spastic diplegia persisted when adjusted for maternal magnesium sulphate receipt, maternal betamethasone receipt, method of delivery (vaginal vs. abdominal), acidosis on the neonate's initial arterial blood gas, systolic blood pressure < 30 mmHg and the diagnosis of major neonatal neurosonographic abnormality.
Asunto(s)
Parálisis Cerebral/etiología , Corioamnionitis/complicaciones , Recién Nacido de muy Bajo Peso , Complicaciones Infecciosas del Embarazo , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Recién Nacido , Modelos Logísticos , Masculino , Embarazo , Resultado del Embarazo , Factores de RiesgoRESUMEN
OBJECTIVE: Because the survival rate has increased for extremely low birth weight neonates, many have raised the concern that the rate of developmental disability among survivors will also increase. To address this concern, we analyzed changes over time in survival and major neurosensory impairment in a sample of extremely low birth weight infants born between July 1, 1979, and June 30, 1994. METHODS: The study sample included 513 infants with birth weights of 501 to 800 g who were cared for in either of the two neonatal intensive care units that serve a 17-county region in northwest North Carolina and who were born to mothers residing in that region. At 1 year of age (corrected for gestation), survivors were examined by a pediatrician and were tested using the Bayley Scales of Infant Development. Major neurosensory impairment was defined as cerebral palsy, a Bayley Mental Developmental Index <68, or blindness. A total of 209/216 (97%) of survivors were examined at 1 year of age. Epoch of birth was defined as follows: epoch 1, July 1, 1979 to June 30, 1984; epoch 2, July 1, 1984 to June 30, 1989; and epoch 3, July 1, 1989 to June 30, 1994. RESULTS: Survival rates for epochs 1, 2, and 3 were, respectively, 24/120 (20%), 63/175 (36%), and 129/218 (59%). In contrast, the proportions with a major neurosensory impairment did not increase over time; rates for successive epochs were 6/24 (25%), 17/61 (28%), and 26/124 (21%). Rates of cerebral palsy were 3/24 (13%), 12/61 (20%), and 9/124 (7%); rates of delayed mental development were 4/24 (17%), 12/61 (20%), and 17/124 (14%); and rates of blindness were 2/24 (8%), 0/62, and 5/124 (4%), respectively. CONCLUSIONS: This analysis suggests that the increasing survival of extremely low birth weight neonates since the late 1970s has not resulted in an increased rate of major developmental problems identifiable at 1 year of age.
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Discapacidades del Desarrollo/epidemiología , Recién Nacido de muy Bajo Peso , Ceguera/epidemiología , Parálisis Cerebral/epidemiología , Estudios de Seguimiento , Humanos , Lactante , Mortalidad Infantil/tendencias , Tasa de SupervivenciaRESUMEN
Phospholipases (PLAs) produce rate-limiting precursors in the biosynthesis of various types of biologically active lipids involved in inflammatory processes. Increased levels of human nonpancreatic secretory phospholipase A2 (hnps-PLA2) have been detected in several pathological conditions. An inhibitor of this enzyme could have therapeutic utility. A broad screening program was carried out to identify chemical structures which could inhibit hnps-PLA2. One of the lead compounds generated by the screening program was 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (13a). We describe the syntheses, structure--activity relationships, and pharmacological activities of a series of indole-3-acetamides and related compounds derived from this lead. This SAR was undertaken with the aid of X-ray crystal structures of complexes between the inhibitors and hnps-PLA2 which were of great value in directing the SAR.
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Inhibidores Enzimáticos/farmacología , Ácidos Indolacéticos/farmacología , Fosfolipasas A/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Cobayas , Humanos , Técnicas In Vitro , Ácidos Indolacéticos/química , Pulmón/efectos de los fármacos , Pulmón/enzimología , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Fosfolipasas A2 , Relación Estructura-ActividadRESUMEN
As reported in our previous paper, a series of indole-3-acetamides which possessed potency and selectivity as inhibitors of human nonpancreatic secretory phospholipase A2(hnps-PLA2) was developed. The design of these compounds was based on information derived from x-ray crystal structures determined for complexes between the enzyme and its inhibitors. We describe here the further implementation of this structure-based design strategy and continued SAR development to produce indole-3-acetamides with additional functionalities which provide increased interaction with important residues within the enzyme active site. These efforts led to inhibitors with substantially enhanced potency and selectivity.
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Ácidos Indolacéticos/química , Ácidos Indolacéticos/farmacología , Fosfolipasas A/antagonistas & inhibidores , Cristalografía por Rayos X , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Fosfolipasas A2 , Relación Estructura-ActividadRESUMEN
The preceding papers of this series detail the development of functionalized indole-3-acetamides as inhibitors of hnps-PLA2. We describe here the extension of the structure-activity relationship to include a series of indole-3-glyoxamide derivatives. Functionalized indole-3-glyoxamides with an acidic substituent appended to the 4- or 5-position of the indole ring were prepared and tested as inhibitors of hnps-PLA2. It was found that the indole-3-glyoxamides with a 4-oxyacetic acid substituent had optimal inhibitory activity. These inhibitors exhibited an improvement in potency over the best of the indole-3-acetamides, and LY315920 (6m) was selected for evaluation clinically as an hnps-PLA2 inhibitor.
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Fosfolipasas A/antagonistas & inhibidores , Compuestos de Sulfonilurea/química , Compuestos de Sulfonilurea/farmacología , Cristalografía por Rayos X , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Fosfolipasas A2 , Relación Estructura-ActividadRESUMEN
Outcomes were compared for 31 very-low-birthweight children recovered from chronic lung disease and 31 very-low-birthweight controls. All children had been free of major abnormalities on neonatal cranial ultrasonography. At 4 to 5 years of age, children were examined by a pediatrician and tested by a psychologist who administered the Wechsler Preschool and Primary Scale of Intelligence-Revised. Despite similar medical outcomes, the children who had had neonatal chronic lung disease had lower Full-scale IQs (median 83 vs 87) and Performance IQs (79 vs 90). Median Verbal IQ was similar in the two groups (85 vs 87). A higher proportion of children who had had chronic lung disease had Full-scale IQ < 70 (8/31 [26%] vs 1/31 [3%]) and Performance IQ < 70 (8/31 [26%] vs 0/31). These effects persisted after adjustment for confounding factors.
Asunto(s)
Convalecencia , Enfermedades del Recién Nacido , Enfermedades Pulmonares , Preescolar , Enfermedad Crónica , Trastornos del Conocimiento/diagnóstico , Femenino , Humanos , Recién Nacido , MasculinoRESUMEN
We compared the response to prolonged treatment with dexamethasone in two groups of ventilated preterm infants: one whose chest radiographs showed homogenous opacity, and one whose radiographs showed cystic changes and hyperinflation. Forty-nine infants were treated with dexamethasone for 42 days, beginning when they were 15 to 27 days old, had no evidence of sepsis or patent ductus arteriosus, and had experienced no decrease in ventilator support for 24 hours. Forty-nine controls were selected who met these criteria for dexamethasone treatment. All had birthweights of 500 to 1250 g. Two radiographs made between 14 and 28 days of age were reviewed. Among infants with homogeneous opacity (19 dexamethasone, 26 controls), dexamethasone was associated with fewer days on assisted ventilation (median [interquartile range]: 7 [3-11] versus 23 [9-40]; p = 0.001). Among those with cystic changes and hyperexpansion (30 dexamethasone, 23 controls), no difference was found between dexamethasone treated infants and controls (17 [7-34] versus 32 [16-47]; p = 0.9). Thus, the effect of dexamethasone on days of ventilation was attenuated in infants with cystic changes and hyperinflation.
Asunto(s)
Displasia Broncopulmonar/diagnóstico por imagen , Displasia Broncopulmonar/tratamiento farmacológico , Dexametasona/uso terapéutico , Glucocorticoides/uso terapéutico , Respiración Artificial , Displasia Broncopulmonar/terapia , Estudios de Casos y Controles , Femenino , Humanos , Recién Nacido , Recien Nacido Prematuro , Pulmón/diagnóstico por imagen , Masculino , RadiografíaRESUMEN
Transgenic mice were created which overexpress human secretory non-pancreatic phospholipase A2 (sPLA2) pansomatically as a potential disease and drug-testing model. The mice were produced using a DNA construct in which the inducible mouse metallothionein gene promoter drives expression of a human sPLA2 minigene. High levels of sPLA2 were detected in several tissues by immunofluorescence localization. Expression in the testes caused hypospermia and male infertility. Circulating catalytically active sPLA2 could be induced to levels observed in patients undergoing a systemic inflammatory response but had no detectable effect on the mice. Therefore, these results suggest that sPLA2 hyperphospholipasemia alone may have only limited pathophysiological consequences. We further show that 3-[3-acetamide-1-benzyl-2-ethylindolyl-5-oxy]propane phosphonic acid LY311727), a potent new inhibitor of phospholipase A2 catalysis developed by our group, dramatically suppresses the circulating enzyme activity in these animals whereas 3-[3-acetamide-1-benzyl-2-propylindolyl-5-oxy]propane phosphonic acid (LY314024), a substantially less potent LY311727 analog, is without effect. These later results thus motivate the further development of this compound as a potential new therapeutic agent and valuable research tool.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Fosfolipasas A/antagonistas & inhibidores , Fosfolipasas A/genética , Animales , Northern Blotting , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Indoles/farmacología , Masculino , Ratones , Ratones Transgénicos , Fosfolipasas A/análisis , Fosfolipasas A2 , Testículo/química , Testículo/patologíaRESUMEN
The primary objective of this study was to develop a functional assay that could provide rapid and reliable information on some pharmacologic characteristics of a novel inhibitor of human secretory phospholipase A2 (sPLA2). Guinea pig bronchoalveolar lavage (BAL) fluid, containing predominantly macrophages, eosinophils and epithelial cells, released thromboxane A2, as measured by thromboxane B2, in a concentration-dependent manner on exposure to recombinant human sPLA2 (rh-sPLA2). Similarly, n-formyl-L-methionyl-L-leucyl-L-phenylalanine (n-F-Met-Leu-Phe) or arachidonic acid also released this lipid mediator. Indomethacin, a cyclooxygenase inhibitor, blocked synthesis of thromboxane in response to these agents. p-Bromophenacylbromide-inactivated rh-sPLA2 was substantially less effective than the untreated enzyme in causing release of thromboxane. LY311727 is a potent indole-derived inhibitor of the isolated enzyme (IC50 = 23 nM). Incubation of this agent with BAL cells, just before addition of rh-sPLA2, reduced release of thromboxane with an IC50 = 1.8 x 10(-6) M. Specificity for sPLA2 was demonstrated in that LY311727, unlike indomethacin, did not reduce synthesis and subsequent release of thromboxane A2 in response to arachidonic acid. Using this technique as a basis, we determined whether LY311727 could sufficiently accumulate in lung after i.v. administration to inhibit rh-sPLA2-induced thromboxane A2 release from BAL cells. The compound, given i.v. to guinea pigs 5 min before collecting BAL fluid, produced a dose-dependent inhibition of rh-sPLA2 with an ED50 = 50 mg/kg. Thus, new in vitro and ex vivo assays were developed that permit functional evaluation of novel sPLA2 inhibitors. These techniques should serve as secondary assays for evaluation of human sPLA2 inhibitory activity from a chemical series and in addition provide initial data related to metabolic stability and distribution to the lung.