RESUMEN

OBJECTIVE: To examine the effects of early echocardiography-targeted ibuprofen treatment of large patent ductus arteriosus (PDA) on survival without cerebral palsy at 24 months of corrected age. STUDY DESIGN: We enrolled infants born at <28 weeks of gestation with a large PDA on echocardiography at 6-12 hours after birth to ibuprofen or placebo by 12 hours of age in a multicenter, double blind, randomized-controlled trial. Open-label ibuprofen was allowed for prespecified criteria of a hemodynamically significant PDA. The primary outcome was survival without cerebral palsy at 24 months of corrected age. RESULTS: Among 337 enrolled infants, 109 had a small or closed ductus and constituted a reference group; 228 had a large PDA and were randomized. The primary outcome was assessed at 2 years in 108 of 114 (94.7%) and 102 of 114 (89.5%) patients allocated to ibuprofen or placebo, respectively. Survival without cerebral palsy occurred in 77 of 108 (71.3%) after ibuprofen, 73 of 102 (71.6%) after placebo (adjusted relative risk 0.98, 95% CI 0.83-1.16, P = .83), and 77 of 101 (76.2%) in reference group. Infants treated with ibuprofen had a lower incidence of PDA at day 3. Severe pulmonary hemorrhage during the first 3 days occurred in 2 of 114 (1.8%) infants treated with ibuprofen and 9 of 114 (7.9%) infants treated with placebo (adjusted relative risk 0.22, 95% CI 0.05-1.00, P = .05). Open-label rescue treatment with ibuprofen occurred in 62.3% of infants treated with placebo and 17.5% of infants treated with ibuprofen (P < .001), at a median (IQR) age of 4 (3, 5) and 4 (4, 12) days, respectively. CONCLUSIONS: Early echocardiography-targeted ibuprofen treatment of a large PDA did not change the rate of survival without cerebral palsy. TRIAL REGISTRATION: Eudract 2011-003063-30 and ClinicalTrials.gov: NCT01630278.

Asunto(s)

Parálisis Cerebral/epidemiología , Inhibidores de la Ciclooxigenasa/uso terapéutico , Conducto Arterioso Permeable/tratamiento farmacológico , Ibuprofeno/uso terapéutico , Recien Nacido Extremadamente Prematuro , Preescolar , Método Doble Ciego , Conducto Arterioso Permeable/mortalidad , Humanos , Lactante , Recién Nacido

RESUMEN

OBJECTIVE: To compare early routine pharmacologic treatment of moderate-to-large patent ductus arteriosus (PDA) at the end of week 1 with a conservative approach that requires prespecified respiratory and hemodynamic criteria before treatment can be given. STUDY DESIGN: A total of 202 neonates of <28 weeks of gestation age (mean, 25.8 ± 1.1 weeks) with moderate-to-large PDA shunts were enrolled between age 6 and 14 days (mean, 8.1 ± 2.2 days) into an exploratory randomized controlled trial. RESULTS: At enrollment, 49% of the patients were intubated and 48% required nasal ventilation or continuous positive airway pressure. There were no differences between the groups in either our primary outcome of ligation or presence of a PDA at discharge (early routine treatment [ERT], 32%; conservative treatment [CT], 39%) or any of our prespecified secondary outcomes of necrotizing enterocolitis (ERT, 16%; CT, 19%), bronchopulmonary dysplasia (BPD) (ERT, 49%; CT, 53%), BPD/death (ERT, 58%; CT, 57%), death (ERT,19%; CT, 10%), and weekly need for respiratory support. Fewer infants in the ERT group met the rescue criteria (ERT, 31%; CT, 62%). In secondary exploratory analyses, infants receiving ERT had significantly less need for inotropic support (ERT, 13%; CT, 25%). However, among infants who were ≥26 weeks gestational age, those receiving ERT took significantly longer to achieve enteral feeding of 120 mL/kg/day (median: ERT, 14 days [range, 4.5-19 days]; CT, 6 days [range, 3-14 days]), and had significantly higher incidences of late-onset non-coagulase-negative Staphylococcus bacteremia (ERT, 24%; CT,6%) and death (ERT, 16%; CT, 2%). CONCLUSIONS: In preterm infants age <28 weeks with moderate-to-large PDAs who were receiving respiratory support after the first week, ERT did not reduce PDA ligations or the presence of a PDA at discharge and did not improve any of the prespecified secondary outcomes, but delayed full feeding and was associated with higher rates of late-onset sepsis and death in infants born at ≥26 weeks of gestation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01958320.

Asunto(s)

Acetaminofén/uso terapéutico , Tratamiento Conservador , Inhibidores de la Ciclooxigenasa/uso terapéutico , Conducto Arterioso Permeable/terapia , Ibuprofeno/uso terapéutico , Indometacina/uso terapéutico , Presión de las Vías Aéreas Positiva Contínua , Conducto Arterioso Permeable/clasificación , Femenino , Edad Gestacional , Humanos , Recien Nacido Extremadamente Prematuro , Recién Nacido , Masculino , Estudios Prospectivos , Método Simple Ciego , Resultado del Tratamiento

RESUMEN

OBJECTIVE: To evaluate whether the presence of patent ductus arteriosus (PDA) in preterm infants worsens long-term neurodevelopmental outcomes. STUDY DESIGN: This was a secondary observational analysis of data from 1090 preterm low-birthweight infants in the Infant Health and Development Program (IHDP), a multicenter longitudinal cohort study of outcomes assessed from 3 to 18 years of age. Multivariable analysis was adjusted for IHDP treatment group (intervention or follow-up), birth weight, maternal race, maternal education, infant sex, maternal preconception weight, Home Observation Measurement of the Environment (HOME) total score at 12 months, neonatal health index, and gestational age. RESULTS: Of the 1090 patients (49% male) included in the analysis, 135 had a PDA. Mean birth weight (1322 g vs 1871 g; P < .0001) and gestational age (30.2 weeks vs 33.4 weeks, P < .0001) were lower and mean ventilator days (11.8 vs 1.3; P < .0001), vasopressor use (12.6% vs 1.2%; P < .0001), and congestive heart failure (8.9% vs 0.1%; P < .0001) were higher in the PDA group. There were no differences between the PDA and no-PDA groups in maternal education level and HOME total score at age 12 months. Multivariable analysis demonstrated no between-group differences in cognitive development or behavioral competence at age 3, 8, and 18 years. CONCLUSIONS: The presence of a PDA in moderately preterm, low-birthweight infants does not impact long-term neurodevelopmental outcomes.

Asunto(s)

Conducto Arterioso Permeable/diagnóstico , Conducto Arterioso Permeable/tratamiento farmacológico , Recién Nacido de Bajo Peso , Recien Nacido Prematuro , Trastornos del Neurodesarrollo/diagnóstico , Adolescente , Factores de Edad , Niño , Preescolar , Inhibidores de la Ciclooxigenasa/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Ibuprofeno/uso terapéutico , Incidencia , Indometacina/uso terapéutico , Lactante , Recién Nacido , Estudios Longitudinales , Masculino , Trastornos del Neurodesarrollo/epidemiología , Medición de Riesgo , Tiempo , Factores de Tiempo

RESUMEN

The objective of this work was to obtain and evaluate anti-inflammatory in vitro, in vivo and in silico potential of novel indole-N-acylhydrazone derivatives. In total, 10 new compounds (3a-j) were synthesized in satisfactory yields, through a condensation reaction in a single synthesis step. In the lymphoproliferation assay, using mice splenocytes, 3a and 3b showed inhibition of lymphocyte proliferation of 62.7% (±3.5) and 50.7% (±2), respectively, while dexamethasone presented an inhibition of 74.6% (±2.4). Moreover, compound 3b induced higher Th2 cytokines production in mice splenocytes cultures. The results for COX inhibition assays showed that compound 3b is a selective COX-2 inhibitor, but with less potency when compared to celecoxib, and compound 3a not presented selectivity towards COX-2. The molecular docking results suggest compounds 3a and 3b interact with the active site of COX-2 in similar conformations, but not with the active site of COX-1, and this may be the main reason to the COX-2 selectivity of compound 3b. In vivo carrageenan-induced paw edema assays were adopted for the confirmation of the anti-inflammatory activity. Compound 3b showed better results in suppressing edema at all tested concentrations and was able to induce an edema inhibition of 100% after 5 h of carrageenan injection at the 30 mg kg-1 dosage, corroborating with the COX inhibition and lymphoproliferation results. I addition to our experimental results, in silico analysis suggest that compounds 3a and 3b present a well-balanced profile between pharmacodynamics and pharmacokinetics. Thus, our preliminary results revealed the potentiality of a new COX-2 selective derivative in the modulation of the inflammatory process.

Asunto(s)

Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacología , Hidrazonas/química , Hidrazonas/farmacología , Acilación , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Carragenina , Línea Celular , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/uso terapéutico , Edema/inducido químicamente , Edema/tratamiento farmacológico , Edema/enzimología , Femenino , Humanos , Hidrazonas/síntesis química , Hidrazonas/uso terapéutico , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Indoles/uso terapéutico , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular

RESUMEN

OBJECTIVE: To test the hypothesis that neonatal intensive care unit (NICU)-specific changes in patent ductus arteriosus (PDA) management are associated with changes in local outcomes in preterm infants. STUDY DESIGN: This retrospective repeated-measures study of aggregated data included infants born 400-1499 g admitted within 2 days of delivery to NICUs participating in the California Perinatal Quality Care Collaborative. The period 2008-2015 was divided into four 2-year epochs. For each epoch and NICU, we calculated proportions of infants receiving cyclooxygenase inhibitor (COXI) or PDA ligation and determined NICU-specific changes in these therapies between consecutive epochs. Generalized estimating equations were used to examine adjusted relationships between NICU-specific changes in PDA management and contemporaneous changes in local outcomes. RESULTS: We included 642 observations of interepoch change at 119 hospitals summarizing 32 094 infants. NICU-specific changes in COXI use and ligation showed significant dose-response associations with contemporaneous changes in adjusted local outcomes. Each percentage point decrease in NICU-specific proportion treated with either COXI or ligation was associated with a 0.21 percentage point contemporaneous increase in adjusted local in-hospital mortality (95% CI 0.06, 0.33; P = .005) among infants born 400-749 g. In contrast, decreasing NICU-specific ligation rate among infants 1000-1499 g was associated with decreasing adjusted local bronchopulmonary dysplasia (P = .009) and death or bronchopulmonary dysplasia (P = .01). CONCLUSIONS: NICU-specific outcomes of preterm birth co-vary with local PDA management. Treatment for PDA closure may benefit some infants born 400-749 g. Decreasing NICU-specific rates of COXI use or ligation were not associated with increases in local adjusted rates of examined adverse outcomes in larger preterm infants.

Asunto(s)

Displasia Broncopulmonar/mortalidad , Conducto Arterioso Permeable/mortalidad , Conducto Arterioso Permeable/terapia , Mortalidad Hospitalaria , Unidades de Cuidado Intensivo Neonatal/organización & administración , Nacimiento Prematuro , Displasia Broncopulmonar/diagnóstico por imagen , Displasia Broncopulmonar/terapia , California , Causas de Muerte , Estudios de Cohortes , Inhibidores de la Ciclooxigenasa/uso terapéutico , Conducto Arterioso Permeable/diagnóstico por imagen , Femenino , Humanos , Recién Nacido , Ligadura/métodos , Masculino , Análisis Multivariante , Evaluación de Resultado en la Atención de Salud , Embarazo , Estudios Retrospectivos , Medición de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento

RESUMEN

ABSTRACT: Pain is a major symptom in many dental procedures. Studies show consistently that pain, including dental pain, is not effectively treated; management of pain is a critical and challenging component in dentistry. Improvement and efficacy on the treatment depends on knowing which treatments are the most effective. Knowing how well an analgesic works and its associated adverse effects is fundamental to clinical decision. The aim of this review is to provide information to the dentistry field on the treatment of dental pain specifically with COX-2 inhibitors providing a useful guide to dentist on controlling pain. Therefore, nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed analgesic agents in surgical outpatients. Major limitations of NSAIDs are their gastrointestinal (GI) adverse events (perforation, ulceration, and bleeding), impairment of hemostatic function, and renal failure (with long-term therapy). A new class of NSAIDs, COX2 selective inhibitors (Coxibs), have been developed with the aim of reducing the GI adverse events of traditional NSAIDs while maintaining their effective anti-inflammatory and analgesic properties.

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RESUMEN: El dolor es un síntoma principal en muchos procedimientos dentales. Los estudios demuestran consistentemente que el dolor, incluido el dolor dental, no se trata de manera efectiva; el manejo del dolor es un componente crítico y desafiante en odontología. La mejora y la eficacia en el tratamiento depende de saber qué tratamientos son los más efectivos. Saber qué tan bien funciona un analgésico y sus efectos adversos asociados es fundamental para la decisión clínica. El objetivo de esta revisión es proporcionar información al campo de la odontología sobre el tratamiento del dolor dental específicamente con los inhibidores de la COX-2, proporcionando una guía útil para el control del dolor por parte del dentista. Por lo tanto, los fármacos antiinflamatorios no esteroideos (AINE) son los agentes analgésicos más comúnmente prescritos en pacientes ambulatorios quirúrgicos. Las principales limitaciones de los AINE son los eventos adversos gastrointestinales (perforación, ulceración y hemorragia), deterioro de la función hemostática e insuficiencia renal (con terapia a largo plazo). Una nueva clase de AINE, los inhibidores selectivos de la COX-2 (Coxibs), se han desarrollado con el objetivo de reducir los eventos adversos gastrointestinales de los AINE tradicionales mientras se mantienen sus propiedades antiinflamatorias y analgésicas efectivas.

Asunto(s)

Humanos , Cuidados Paliativos/métodos , Inhibidores de la Ciclooxigenasa/uso terapéutico , Isoenzimas/antagonistas & inhibidores , Dolor/etiología , Dolor/tratamiento farmacológico , Extracción Dental/efectos adversos , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2

RESUMEN

CONTEXT: Inflammatory disorders are common in modern life, and medicinal plants provide an interesting source for new compounds bearing anti-inflammatory properties. In this regard, Brazilian medicinal plants are considered to be a promising supply of such compounds due to their great biodiversity. OBJECTIVES: To undertake a review on Brazilian medicinal plants with corroborated anti-inflammatory activities by selecting data from the literature reporting the efficacy of plants used in folk medicine as anti-inflammatory, including the mechanisms of action of their extracts and isolated compounds. METHODS: A search in the literature was undertaken by using the following Web tools: Web of Science, SciFinder, Pub-Med and Science Direct. The terms 'anti-inflammatory' and 'Brazilian medicinal plants' were used as keywords in search engine. Tropicos and Reflora websites were used to verify the origin of the plants, and only the native plants of Brazil were included in this review. The publications reporting the use of well-accepted scientific protocols to corroborate the anti-inflammatory activities of Brazilian medicinal plants with anti-inflammatory potential were considered. RESULTS: We selected 70 Brazilian medicinal plants with anti-inflammatory activity. The plants were grouped according to their anti-inflammatory mechanisms of action. The main mechanisms involved inflammatory mediators, such as interleukins (ILs), nuclear factor kappa B (NF-κB), prostaglandin E2 (PGE2), cyclooxygenase (COX) and reactive oxygen species (ROS). CONCLUSIONS: The collected data on Brazilian medicinal plants, in the form of crude extract and/or isolated compounds, showed significant anti-inflammatory activities involving different mechanisms of action, indicating Brazilian plants as an important source of anti-inflammatory compounds.

Asunto(s)

Antiinflamatorios/uso terapéutico , Inflamación/prevención & control , Medicina Tradicional , Extractos Vegetales/uso terapéutico , Animales , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Antioxidantes/aislamiento & purificación , Antioxidantes/uso terapéutico , Brasil , Inhibidores de la Ciclooxigenasa/aislamiento & purificación , Inhibidores de la Ciclooxigenasa/uso terapéutico , Dinoprostona/metabolismo , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Interleucinas/metabolismo , Estructura Molecular , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fitoterapia , Extractos Vegetales/aislamiento & purificación , Plantas Medicinales , Prostaglandina-Endoperóxido Sintasas/metabolismo , Relación Estructura-Actividad Cuantitativa , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

Dual 5-LOX/COX inhibitors are potential new dual drugs to treat inflammatory conditions. This research aimed to design, synthesis and to evaluate the anti-inflammatory and antinociceptive effects of the new compound, which is derived from nimesulide and darbufelone lead compounds. The new dual inhibitor 5-LOX/COX has the possible advantage of gastrointestinal safety. A voltammetric experiment was conducted to observe the drug's antioxidative effect. A formalin test, a hot plate test and carrageenan-induced mechanical hyperalgesia were employed to evaluate the analgesic nature of LQFM-091. To evaluate anti-inflammatory activity, we measured edema, leukocyte count, myeloperoxidase activity and cytokines levels in carrageenan-induced inflammation tests. We elucidated the underlying mechanisms by assessing the interaction the with COXs and LOX enzymes by colorimetric screening assay and molecular docking. The lethal dose (LD50) was estimated using 3T3 Neutral Red Uptake assay. Our results indicate that the LQFM-091 prototype is a powerful antioxidant, as well as able to inhibit COX-1, COX-2 and LOX activities. LQFM091 was classified in GHS category 4 (300

Asunto(s)

Inhibidores de la Ciclooxigenasa/uso terapéutico , Inhibidores de la Lipooxigenasa/uso terapéutico , Fenoles/uso terapéutico , Células 3T3 , Animales , Carragenina , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Ciclooxigenasa/farmacología , Citocinas/inmunología , Edema/inducido químicamente , Edema/tratamiento farmacológico , Femenino , Calor , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Recuento de Leucocitos , Lipooxigenasa/metabolismo , Inhibidores de la Lipooxigenasa/farmacología , Ratones , Simulación del Acoplamiento Molecular , Dimensión del Dolor , Peroxidasa/inmunología , Fenoles/farmacología , Estimulación Física , Pleuresia/inducido químicamente , Pleuresia/tratamiento farmacológico , Pleuresia/inmunología , Prostaglandina-Endoperóxido Sintasas/metabolismo , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Sulfonamidas

RESUMEN

OBJECTIVE: To identify changes in the diagnosis, pharmacotherapy, and surgical ligation of patent ductus arteriosus (PDAs) in infants born premature and report on temporal changes in mortality and morbidity from a large volume of neonatal intensive care units (NICUs) in the US. STUDY DESIGN: We queried the Pediatrix Clinical Data Warehouse for all inborn infants without major anomalies born between 23 and 30 weeks' gestation from 2006 to 2015 for a diagnosis of PDA, use of indomethacin or ibuprofen, history of ductal ligation, mortality, and major morbidities. RESULTS: There were 829 091 infants entered in the Clinical Data Warehouse; 61 520 infants from 280 NICUs met our inclusion criteria. The diagnosis of PDA declined from 51% to 38% (P < .001), use of indomethacin or ibuprofen decreased from 32% to 18%, and PDA ligation decreased from 8.4% to 2.9% (both P < .001). During the study period, mortality decreased with no increase in any measured morbidity. Of the 163 sites with data for both periods, 128 (79%) showed a decrease in the diagnosis of PDA, and 132 (81%) showed a decrease in the use indomethacin and/or ibuprofen when 2011-2015 was compared with 2006-2010. Of 103 sites with at least 1 PDA ligation, 85 (83%) showed a decrease in PDA ligation in a similar comparison. CONCLUSIONS: In this large population of infants <30 weeks' gestation from 280 NICUs across the US, there were significant decreases in the diagnosis and treatment of the PDA. Although there was no evidence of increased morbidities, it remains uncertain how these changes may directly affect infant outcomes.

Asunto(s)

Inhibidores de la Ciclooxigenasa/uso terapéutico , Conducto Arterioso Permeable/diagnóstico , Unidades de Cuidado Intensivo Neonatal/estadística & datos numéricos , Ligadura/métodos , Bases de Datos Factuales , Conducto Arterioso Permeable/mortalidad , Conducto Arterioso Permeable/terapia , Humanos , Ibuprofeno/uso terapéutico , Indometacina/uso terapéutico , Recién Nacido , Recien Nacido Prematuro , Ligadura/estadística & datos numéricos , Estados Unidos

RESUMEN

OBJECTIVE: To determine whether prophylactic indomethacin (PINDO) has more or less morbidity than delayed conservative management of the moderate-to-large patent ductus arteriosus (PDA). STUDY DESIGN: We performed a prospective double cohort controlled study of infants delivered at ≤276/7 weeks gestation (n = 397). From January 2005 through April 2011, all infants were treated with PINDO (n = 247). From May 2011 through August 2016, no infant was treated with indomethacin until at least 8 postnatal days (conservative epoch, n = 150). Echocardiograms were performed on day 7 and at planned intervals until the PDA was small or closed. A single neonatologist prospectively collected all data. RESULTS: The incidence of moderate-to-large PDA on day 7 and duration of exposure to moderate-to-large PDA were significantly less in the PINDO epoch (incidence = 10%, median = 2 days) than the conservative epoch (incidence = 67%, median = 14 days). Ligation rates were low in both epochs (PINDO = 14%, conservative = 5%). In multivariate analyses, PINDO infants had a significantly lower incidence of bronchopulmonary dysplasia (BPD) (risk ratio = 0.68, CI: 0.46-0.89) and BPD or death (risk ratio= 0.78, CI: 0.62-0.95) than conservative infants. There were no differences between the epochs in death, intraventricular hemorrhage grades 3 and 4, necrotizing enterocolitis, or retinopathy of prematurity receiving treatment. The effects of PINDO on BPD and BPD or death were no longer significant when analyses were adjusted for presence of a moderate-to-large PDA on day 7. The significant effects of PINDO were independent of whether or not a ligation was performed. CONCLUSIONS: PINDO decreases BPD and BPD or death compared with delayed conservative PDA management. These effects are mediated by closure of the PDA.

Asunto(s)

Displasia Broncopulmonar/prevención & control , Inhibidores de la Ciclooxigenasa/uso terapéutico , Conducto Arterioso Permeable/tratamiento farmacológico , Indometacina/uso terapéutico , Displasia Broncopulmonar/epidemiología , Estudios de Cohortes , Tratamiento Conservador/métodos , Conducto Arterioso Permeable/epidemiología , Ecocardiografía , Femenino , Humanos , Incidencia , Recien Nacido Extremadamente Prematuro , Recién Nacido , Masculino , Estudios Prospectivos , Resultado del Tratamiento

RESUMEN

We have investigated the mechanisms involved in the genesis of edema and nociception induced by Philodryas patagoniensis venom (PpV) injected into the footpad of mice. PpV induced dose-related edema and nociceptive effects. Pretreatment of mice with cyclooxygenase inhibitor (indomethacin), but not with cyclooxygenase 2 inhibitor (celecoxib) markedly inhibited both effects. Pretreatments with H1 receptor antagonist (promethazine) or with dual histamine-serotonin inhibitor (cyproheptadine) failed in inhibiting both effects. In groups pretreated with captopril (angiotensin-converting enzyme inhibitor) the edema was unaltered, but nociception was clearly increased, suggesting the participation of kinins in the pathophysiology of the nociception but not of the edema-forming effect of PpV. When PpV was treated with EDTA, the nociception was similar to the one induced by untreated venom, but edema was markedly reduced. We concluded that PpV-induced edema and nociception have cyclooxygenase eicosanoids as the main mediators and no participation of vasoactive amines. Kinins seem to participate in nociception but not in edema induced by PpV. The results also suggest that metalloproteinases are the main compounds responsible for the edema, but not for the nociception induced by this venom.

Asunto(s)

Colubridae , Inhibidores de la Ciclooxigenasa/uso terapéutico , Edema/inducido químicamente , Edema/tratamiento farmacológico , Nocicepción/efectos de los fármacos , Venenos de Serpiente/toxicidad , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Dexametasona/uso terapéutico , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Indometacina/uso terapéutico , Masculino , Ratones , Nocicepción/fisiología , Mordeduras de Serpientes/inducido químicamente , Mordeduras de Serpientes/tratamiento farmacológico , Resultado del Tratamiento

RESUMEN

OBJECTIVE: To describe the clinical course and risk factors for pulmonary arterial hypertension (PAH) after ibuprofen treatment to close patent ductus arteriosus. STUDY DESIGN: All neonates weighing < 1500 g at birth who received ibuprofen to close patent ductus arteriosus and were admitted to Seoul National University Children's Hospital's neonatal intensive care unit in 2010-2014 were eligible for this study. The study population was divided into the PAH and non-PAH groups, and medical records were retrospectively reviewed. RESULTS: Of the 144 eligible infants, 10 developed PAH (6.9%). Relative to the non-PAH group, the PAH group exhibited greater respiratory severity and more frequent severe bronchopulmonary dysplasia or death before 36 weeks postmenstrual age. Multivariable analysis demonstrated that lower gestational age, birth weight in less than the third percentile for age, maternal hypertension of pregnancy, and oligohydramnios were risk factors for developing PAH after ibuprofen treatment. CONCLUSION: A high incidence of PAH after ibuprofen treatment was observed in the study population. Furthermore, younger gestational age and several prenatal conditions were identified as risk factors for developing PAH after ibuprofen treatment. Additional large cohort studies are necessary to confirm our results.

Asunto(s)

Inhibidores de la Ciclooxigenasa/uso terapéutico , Conducto Arterioso Permeable/tratamiento farmacológico , Hipertensión Pulmonar/inducido químicamente , Ibuprofeno/efectos adversos , Estudios de Cohortes , Femenino , Humanos , Recién Nacido , Recién Nacido de muy Bajo Peso , Masculino , Estudios Retrospectivos

RESUMEN

OBJECTIVE: To determine whether a nonintervention approach for treating hemodynamically significant patent ductus arteriosus (PDA) is associated with decreased mortality and/or morbidity compared with a mandatory closure approach in extremely low birth weight infants. STUDY DESIGN: We reviewed the medical records of 178 infants of 23-26 weeks' gestational age with PDA, requiring ventilator treatment, and with hemodynamically significant PDA ≥2 mm in size. Mandatory closure was used during period I (July 2009 to December 2011, n = 81), and nonintervention was used during period II (January 2012 to June 2014, n = 97). RESULTS: During period I, 64% of infants were first treated with indomethacin, and 82% were ultimately ligated surgically. During period II, no infant was treated with indomethacin and/or ligation. The average postnatal day of PDA closure was day 13 and day 44 during periods I and II, respectively. There was significantly more use of diuretics and fluid restriction during period II compared with period I. There was no difference in mortality or morbidities such as necrotizing enterocolitis or intraventricular hemorrhage. The incidence of bronchopulmonary dysplasia (BPD) and the propensity score adjusted OR of BPD were significantly lower during period II compared with period I. CONCLUSIONS: Despite longer PDA exposure, nonintervention was associated with significantly less BPD compared with mandatory closure. Additional study is warranted to determine the benefits and risks of non-intervention for the hemodynamically significant PDA in extremely low birth weight infants.

Asunto(s)

Inhibidores de la Ciclooxigenasa/uso terapéutico , Conducto Arterioso Permeable/terapia , Indometacina/uso terapéutico , Recien Nacido Prematuro , Procedimientos de Cirugía Plástica/métodos , Conducto Arterioso Permeable/tratamiento farmacológico , Conducto Arterioso Permeable/cirugía , Femenino , Edad Gestacional , Humanos , Recién Nacido , Recién Nacido de muy Bajo Peso , Masculino , Puntaje de Propensión , Procedimientos de Cirugía Plástica/efectos adversos , Estudios Retrospectivos

RESUMEN

This study assessed the effect of the combination of anethole and ibuprofen in comparison with monotherapy by either drug alone, using two in vivo inflammatory models, namely the pleurisy and paw edema in rats. We also measured the levels of the TNF protein in plasma, and the ability of anethole to inhibit, in vitro, the activity of the cyclooxygenase 1 and cyclooxygenase 2 enzymes. The test drugs (anethole; ibuprofen; anethole + ibuprofen), at different doses, were administered once (p.o.) 60 min before the induction of the inflammatory response. The association of anethole + ibuprofen inhibited the development of the inflammatory response in both models used. This effect can be partially explained by the inhibitory action on the production of TNF and of COX isoforms. The isobologram analysis evidenced a synergistic effect between ibuprofen and anethole, because the combination of drugs showed a higher inhibitory potential than either drug alone.

Asunto(s)

Anisoles/farmacología , Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Ibuprofeno/farmacología , Derivados de Alilbenceno , Animales , Anisoles/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Carragenina/efectos adversos , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/uso terapéutico , Sinergismo Farmacológico , Ibuprofeno/uso terapéutico , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Masculino , Nitritos/metabolismo , Pleuresia/inducido químicamente , Pleuresia/tratamiento farmacológico , Pleuresia/metabolismo , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

OBJECTIVE: The aim of this study was to determine the effects of some polyunsaturated fatty acids plus phytomelatonin from walnuts in the development of mammary gland adenocarcinoma. METHODS: BALB/c mice were fed a semisynthetic diet supplemented with either 6% walnut oil and 8% walnut flour containing phytomelatonin (walnut diet: WD); or 6% corn oil plus commercial melatonin (melatonin diet: MD), or the control group (CD), which received only 6% of corn oil. Membrane fatty acids of tumor cells (TCs) were analyzed by gas liquid chromatography, cyclooxygenase (COX) and lipoxygenase (LOX) derivatives, and plasma melatonin by high-performance liquid chromatography; apoptosis and tumor-infiltrating lymphocytes by flow cytometry. RESULTS: TCs from the MD and WD mice showed significant decreases in linoleic acid compared with the CD group (P < 0.05). Significantly lower levels of LOX-[13(S)-HODE] were found in TCs from the MD and WD group than in CD (P < 0.0001). COX-[12(S)-HHT] was lower and 12 LOX-[12(S)-HETE] was higher in TCs from the MD group than form the WD and CD arms (P < 0.05). Plasma melatonin, apoptosis, tumor infiltration, and survival time were significantly lower in CD mice than in MD and WD mice (P < 0.05). CONCLUSIONS: This study shows that melatonin, along with polyunsaturated fatty acids, exerts a selective inhibition of some COX and LOX activities and has a synergistic anti-tumor effect on a mammary gland adenocarcinoma model.

Asunto(s)

Adenocarcinoma/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Ácidos Grasos Omega-3/uso terapéutico , Juglans/química , Melatonina/uso terapéutico , Nueces/química , Fitoterapia , Adenocarcinoma/metabolismo , Animales , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Apoptosis , Neoplasias de la Mama/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Inhibidores de la Ciclooxigenasa/uso terapéutico , Dieta , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Ácidos Grasos Omega-3/farmacología , Femenino , Ácido Linoleico/metabolismo , Lipooxigenasa/metabolismo , Masculino , Melatonina/sangre , Melatonina/farmacología , Ratones Endogámicos BALB C , Prostaglandina-Endoperóxido Sintasas/metabolismo

RESUMEN

INTRODUCTION: Stroke is the second leading cause of death and the first cause of disability in the world, with more than 85% of the cases having ischemic origin. OBJECTIVE: To evaluate in an embolism model of stroke the effect of atorvastatin and meloxicam on neurons, astrocytes and microglia. This evaluation was done administering each medication individually and in association. MATERIALS AND METHODS: Wistar rats were subjected to carotid arterial embolism and treatment with meloxicam and atorvastatin at 6, 24, 48 and 72 hours. Using immunohistochemistry, we evaluated the immunoreactivity of COX-2 protein, GFAP and OX-42 in neurons, astrocytes and microglia by densitometric and morphological studies. Data were evaluated by variance analysis and non-parametric multiple comparison. RESULTS: Cerebral ischemia by arterial embolism increased significantly the reactivity of microglia and astrocytes (p<0.001), whereas it was reduced by atorvastatin, meloxicam and their association. Ischemia produced astrocytic shortening, cellular thickening, protoplasmic rupture expansions (clasmatodendrosis) and microglial morphological changes characteristic of various activity stages. In perifocal areas, immunoreactivity of COX-2 was increased and in the ischemic focus it was reduced, while meloxicam and atorvastatin significantly reduced (p<0.001) perifocal immunoreactivity, restoring the marking of cyclooxygenase in the ischemic focus. CONCLUSION: These results suggest that the meloxicam-atorvastatin association attenuates astrocytic and microglial response in the inflammatory process after cerebral ischemia by arterial embolism, reducing neurodegeneration and restoring the morphological and functional balance of nervous tissue .

Asunto(s)

Isquemia Encefálica/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Embolia Intracraneal/complicaciones , Degeneración Nerviosa/prevención & control , Pirroles/uso terapéutico , Tiazinas/uso terapéutico , Tiazoles/uso terapéutico , Animales , Astrocitos/efectos de los fármacos , Astrocitos/patología , Atorvastatina , Biomarcadores , Isquemia Encefálica/etiología , Isquemia Encefálica/patología , Antígeno CD11b/análisis , Estenosis Carotídea/complicaciones , Estenosis Carotídea/patología , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/administración & dosificación , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Proteína Ácida Fibrilar de la Glía/análisis , Ácidos Heptanoicos/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inflamación , Embolia Intracraneal/patología , Meloxicam , Microglía/efectos de los fármacos , Microglía/patología , Proteínas del Tejido Nervioso/análisis , Pirroles/administración & dosificación , Distribución Aleatoria , Ratas , Ratas Wistar , Tiazinas/administración & dosificación , Tiazoles/administración & dosificación

RESUMEN

People who suffer from traumatic brain injury (TBI) often experience cognitive deficits in spatial reference and working memory. The possible roles of cyclooxygenase-1 (COX-1) in learning and memory impairment in mice with TBI are far from well known. Adult mice subjected to TBI were treated with the COX-1 selective inhibitor SC560. Performance in the open field and on the beam walk was then used to assess motor and behavioral function 1, 3, 7, 14, and 21 days following injury. Acquisition of spatial learning and memory retention was assessed using the Morris water maze on day 15 post-TBI. The expressions of COX-1, prostaglandin E2 (PGE2), interleukin (IL)-6, brain-derived neurotrophic factor (BDNF), platelet-derived growth factor BB (PDGF-BB), synapsin-I, and synaptophysin were detected in TBI mice. Administration of SC560 improved performance of beam walk tasks as well as spatial learning and memory after TBI. SC560 also reduced expressions of inflammatory markers IL-6 and PGE2, and reversed the expressions of COX-1, BDNF, PDGF-BB, synapsin-I, and synaptophysin in TBI mice. The present findings demonstrated that COX-1 might play an important role in cognitive deficits after TBI and that selective COX-1 inhibition should be further investigated as a potential therapeutic approach for TBI.

Asunto(s)

Animales , Lesiones Encefálicas/complicaciones , Corteza Cerebral/lesiones , Ciclooxigenasa 1/fisiología , Inhibidores de la Ciclooxigenasa/uso terapéutico , Aprendizaje/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Pirazoles/uso terapéutico , Western Blotting , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Decorticación Cerebral , Ciclooxigenasa 1/metabolismo , Modelos Animales de Enfermedad , Dinoprostona/análisis , Dinoprostona/metabolismo , Ensayo de Inmunoadsorción Enzimática , Hipocampo/metabolismo , /sangre , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/etiología , Trastornos de la Memoria/metabolismo , Proteínas Proto-Oncogénicas c-sis/metabolismo , Recuperación de la Función/efectos de los fármacos , Sinaptofisina/análisis , Sinaptofisina/metabolismo

RESUMEN

People who suffer from traumatic brain injury (TBI) often experience cognitive deficits in spatial reference and working memory. The possible roles of cyclooxygenase-1 (COX-1) in learning and memory impairment in mice with TBI are far from well known. Adult mice subjected to TBI were treated with the COX-1 selective inhibitor SC560. Performance in the open field and on the beam walk was then used to assess motor and behavioral function 1, 3, 7, 14, and 21 days following injury. Acquisition of spatial learning and memory retention was assessed using the Morris water maze on day 15 post-TBI. The expressions of COX-1, prostaglandin E2 (PGE2), interleukin (IL)-6, brain-derived neurotrophic factor (BDNF), platelet-derived growth factor BB (PDGF-BB), synapsin-I, and synaptophysin were detected in TBI mice. Administration of SC560 improved performance of beam walk tasks as well as spatial learning and memory after TBI. SC560 also reduced expressions of inflammatory markers IL-6 and PGE2, and reversed the expressions of COX-1, BDNF, PDGF-BB, synapsin-I, and synaptophysin in TBI mice. The present findings demonstrated that COX-1 might play an important role in cognitive deficits after TBI and that selective COX-1 inhibition should be further investigated as a potential therapeutic approach for TBI.

Asunto(s)

Lesiones Encefálicas/complicaciones , Corteza Cerebral/lesiones , Ciclooxigenasa 1/fisiología , Inhibidores de la Ciclooxigenasa/uso terapéutico , Aprendizaje/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Pirazoles/uso terapéutico , Animales , Becaplermina , Western Blotting , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Decorticación Cerebral , Ciclooxigenasa 1/metabolismo , Dinoprostona/análisis , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Hipocampo/metabolismo , Interleucina-6/sangre , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/etiología , Trastornos de la Memoria/metabolismo , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-sis/metabolismo , Recuperación de la Función/efectos de los fármacos , Sinaptofisina/análisis , Sinaptofisina/metabolismo

RESUMEN

Introducción. El accidente cerebrovascular es la segunda causa de muerte y la primera de discapacidad en el mundo, y más de 85 % es de origen isquémico. Objetivo. Evaluar en un modelo de infarto cerebral por embolia arterial el efecto de la atorvastatina y el meloxicam, administrados por separado y de forma conjunta, sobre la respuesta neuronal, los astrocitos y la microglia. Materiales y métodos. Se sometieron ratas Wistar a embolia de la arteria carótida y a tratamiento con meloxicam y atorvastatina, administrados por separado y conjuntamente, a las 6, 24, 48 y 72 horas. Se evaluó la reacción de las proteínas COX-2, GFAP y OX-42 en las neuronas, los astrocitos y la microglia mediante inmunohistoquímica y estudios morfológicos y de densitometría. Los datos obtenidos se evaluaron por medio de un análisis de varianza y de pruebas no paramétricas de comparación múltiple. Resultados. La isquemia cerebral por embolia arterial incrementó significativamente (p<0,001) la reacción de los astrocitos y la microglia, en tanto que la atorvastatina y el meloxicam, administrados por separado y de forma conjunta, la redujeron. La isquemia produjo acortamiento de las proyecciones de los astrocitos, engrosamiento celular, ruptura de las expansiones protoplásmicas (clasmatodendrosis) y cambios morfológicos en la microglia propios de diversas etapas de actividad. En las zonas circundantes del foco se incrementó la reacción inmunológica de la COX-2 y se redujo en el foco isquémico, en tanto que el meloxicam y la atorvastatina redujeron significativamente (p<0,001) la reacción inmunológica en la zona circundante del foco, restableciendo la marcación de la ciclooxigenasa en el foco isquémico. Conclusión. La combinación de meloxicam y atorvastatina atenúa la respuesta de los astrocitos y la microglia en el proceso inflamatorio posterior a la isquemia cerebral por embolia arterial, reduciendo la degeneración neuronal y restableciendo el equilibrio morfológico y funcional del tejido nervioso.

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Introduction: Stroke is the second leading cause of death and the first cause of disability in the world, with more than 85% of the cases having ischemic origin. Objective: To evaluate in an embolism model of stroke the effect of atorvastatin and meloxicam on neurons, astrocytes and microglia. This evaluation was done administering each medication individually and in association. Materials and methods: Wistar rats were subjected to carotid arterial embolism and treatment with meloxicam and atorvastatin at 6, 24, 48 and 72 hours. Using immunohistochemistry, we evaluated the immunoreactivity of COX-2 protein, GFAP and OX-42 in neurons, astrocytes and microglia by densitometric and morphological studies. Data were evaluated by variance analysis and non-parametric multiple comparison. Results: Cerebral ischemia by arterial embolism increased significantly the reactivity of microglia and astrocytes (p<0.001), whereas it was reduced by atorvastatin, meloxicam and their association. Ischemia produced astrocytic shortening, cellular thickening, protoplasmic rupture expansions (clasmatodendrosis) and microglial morphological changes characteristic of various activity stages. In perifocal areas, immunoreactivity of COX-2 was increased and in the ischemic focus it was reduced, while meloxicam and atorvastatin significantly reduced (p<0.001) perifocal immunoreactivity, restoring the marking of cyclooxygenase in the ischemic focus. Conclusion: These results suggest that the meloxicam-atorvastatin association attenuates astrocytic and microglial response in the inflammatory process after cerebral ischemia by arterial embolism, reducing neurodegeneration and restoring the morphological and functional balance of nervous tissue .

Asunto(s)

Animales , Femenino , Ratas , Isquemia Encefálica/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Embolia Intracraneal/complicaciones , Degeneración Nerviosa/prevención & control , Pirroles/uso terapéutico , Tiazinas/uso terapéutico , Tiazoles/uso terapéutico , Atorvastatina , /análisis , Astrocitos/efectos de los fármacos , Astrocitos/patología , Biomarcadores , Isquemia Encefálica/etiología , Isquemia Encefálica/patología , Estenosis Carotídea/complicaciones , Estenosis Carotídea/patología , Inhibidores de la Ciclooxigenasa/administración & dosificación , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Proteína Ácida Fibrilar de la Glía/análisis , Ácidos Heptanoicos/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inflamación , Embolia Intracraneal/patología , Microglía/efectos de los fármacos , Microglía/patología , Proteínas del Tejido Nervioso/análisis , Pirroles/administración & dosificación , Distribución Aleatoria , Ratas Wistar , Tiazinas/administración & dosificación , Tiazoles/administración & dosificación

RESUMEN

Objective: To describe the results of a long-term follow-up of Bartter syndrome patients treated with different drugs. Method: Patients were diagnosed according to clinical and laboratory data. Treatment protocol was potassium supplementation, sodium, spironolactone, and non-steroidal anti-inflammatory drug. Patients who developed proteinuria were converted to angiotensin conversion enzyme inhibitor. The variables evaluated for each drug were Z-score for weight and stature, proteinuria, creatinine clearance, gastrointestinal complaints, amount of potassium supplementation, serum potassium and bicarbonate levels, and findings of upper digestive endoscopy. Results: 20 patients were included. Follow-up was 10.1 ± 5.2 years. 17 patients received indomethacin for 5.9 ± 5.3 years; 19 received celecoxib, median of 35 months; and five received enalapril, median of 23 months. During indomethacin, a statistically significant increase was observed in the Z-score for stature and weight, without a change in the creatinine clearance. Seven of 17 patients had gastrointestinal symptoms, and upper digestive endoscopy evidenced gastritis in three patients and gastric ulcer in four patients. During celecoxib use, a significant increase was detected in the Z-score for stature and weight and a reduction of hyperfiltration; seven patients presented gastrointestinal symptoms, and upper digestive endoscopy evidenced mild gastritis in three. During enalapril use, no significant changes were observed in the Z-score for stature, weight and creatinine clearance. The conversion to enalapril resulted in a significant reduction in proteinuria. Conclusion: The authors suggest starting the treatment with celecoxib, and replacing by ACEi if necessary, monitoring the renal function. The safety and efficacy of celecoxib need to be assessed in larger controlled studies. .

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Objetivo: Descrever os resultados de um acompanhamento de longo prazo de pacientes com síndrome de Bartter tratados com diferentes medicamentos. Método: Pacientes diagnosticados segundo os dados clínicos e laboratoriais. Protocolo de tratamento: suplementação de potássio, sódio, espironolactona e medicamento anti-inflamatório não esteroidal. Os pacientes que desenvolveram proteinúria foram submetidos a inibidor da enzima de conversão da angiotensina. As variáveis avaliadas durante o uso de cada medicamento foram: escore Z para peso e estatura, proteinúria, depuração da creatinina, queixas gastrointestinais, quantidade da suplementação de potássio, níveis séricos de potássio e bicarbonato e achados da endoscopia digestiva alta. Resultados: Foram incluídos 20 pacientes. O acompanhamento foi de 10,1 ± 5,2 anos. No total, 17 pacientes receberam indometacina por 5,9 ± 5,3 anos, 19 receberam celecoxib por aproximadamente 35 meses e cinco receberam enalapril por aproximadamente 23 meses. Durante o uso de indometacina, observamos um aumento estatístico significativo no escore Z para estatura e peso, sem alteração na depuração da creatinina. 7/17 pacientes apresentaram sintomas gastrointestinais, e a endoscopia digestiva alta mostrou gastrite em três pacientes e úlcera gástrica em quatro. Durante o uso de celecoxib, detectamos um aumento significativo no escore Z para estatura e peso e uma redução da hiperfiltração; sete pacientes apresentaram sintomas gastrointestinais e a endoscopia digestiva alta mostrou gastrite leve em três pacientes. Durante o uso de enalapril, não observamos alterações significativas no escore Z para estatura, peso e depuração da creatinina. A mudança da medicação para enalapril resultou em uma ...

Asunto(s)

Femenino , Humanos , Lactante , Masculino , Síndrome de Bartter/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Enalapril/uso terapéutico , Indometacina/uso terapéutico , Pirazoles/uso terapéutico , Sulfonamidas/uso terapéutico , Síndrome de Bartter/complicaciones , Bicarbonatos/sangre , Estatura/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Creatinina/análisis , Estudios de Seguimiento , Potasio/sangre , Proteinuria/tratamiento farmacológico , Proteinuria/etiología , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento