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PURPOSE: To investigate the feasibility of a study based on treatment with topiramate (TPM) added to moderate hypothermia in newborns with hypoxic ischemic encephalopathy (HIE). MATERIALS AND METHODS: Multicenter randomized controlled trial. Term newborns with precocious metabolic, clinical and electroencephalographic (EEG) signs of HIE were selected according to their amplified integrated EEG pattern and randomized to receive either TPM (10 mg/kg once a day for the first three days of life) plus moderate hypothermia or hypothermia alone. Safety was assessed by monitoring cardiorespiratory parameters and blood samples collected to check renal, liver, metabolic balance and TPM pharmacokinetics. Efficacy was evaluated by the combined frequency of mortality and severe neurological disability as primary outcome. Incidence of magnetic resonance injury, epilepsy, blindness, hearing loss, neurodevelopment at 18-24 months of life was assessed as secondary outcomes. RESULTS: Forty-four asphyxiated newborns were enrolled in the study. Twenty one newborns (10 with moderate and 11 with severe HIE) were allocated to hypothermia plus TPM and 23 (12 moderate and 11 severe HIE) to hypothermia. No statistically or clinically significant differences were observed for safety, primary or secondary outcomes. However, a reduction in the prevalence of epilepsy was observed in newborns co-treated with TPM. CONCLUSIONS: Results of this pilot trial suggest that administration of TPM in newborns with HIE is safe but does not reduce the combined frequency of mortality and severe neurological disability. The role of TPM co-treatment in preventing subsequent epilepsy deserves further studies.
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Fructosa/análogos & derivados , Hipotermia Inducida , Hipoxia-Isquemia Encefálica/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Estudios de Factibilidad , Femenino , Fructosa/farmacocinética , Fructosa/uso terapéutico , Humanos , Hipoxia-Isquemia Encefálica/diagnóstico por imagen , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Neuroimagen , Fármacos Neuroprotectores/farmacocinética , Topiramato , Resultado del TratamientoRESUMEN
BACKGROUND: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. This study evaluated safety and efficacy of propranolol eye micro-drops in preterm newborns with ROP. METHODS: A multicenter open-label trial, planned according to the Simon optimal two-stage design, was performed to analyze safety and efficacy of propranolol micro-drops in newborns with stage 2 ROP. To this end, hemodynamic and respiratory parameters were monitored, and blood samples were collected weekly, for 3 wk. Propranolol plasma levels were also monitored. The progression of the disease was evaluated with serial ophthalmologic examinations. RESULTS: Twenty-three newborns were enrolled. Since the fourth of the first 19 newborns enrolled in the first stage of the study showed a progression to stage 2 or 3 with plus, the second stage was prematurely discontinued. Even though the objective to complete the second stage was not achieved, the percentage of ROP progression (26%) was similar to that obtained previously with oral propranolol administration. However, no adverse effects were observed and propranolol plasma levels were significantly lower than those measured after oral administration. CONCLUSION: Propranolol 0.1% eye micro-drops are well tolerated, but not sufficiently effective. Further studies are required to identify the optimal dose and administration schedule.
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Propranolol/administración & dosificación , Retinopatía de la Prematuridad/tratamiento farmacológico , Administración Oftálmica , Administración Oral , Administración Tópica , Progresión de la Enfermedad , Femenino , Hemodinámica , Humanos , Recién Nacido , Masculino , Neovascularización Fisiológica/efectos de los fármacos , Seguridad del Paciente , Proyectos Piloto , Propranolol/sangre , RespiraciónRESUMEN
Children affected by hemodynamically significant congenital heart disease (HSCHD) experience severe respiratory complications that can increase the frequency of hospitalizations. The aim of the SINERGY study was to describe the incidence of respiratory diseases and to collect information on active and passive immunoprophylaxis in the first 2 years of life. In this retrospective, multicenter, and epidemiologic study, children with HSCHD were enrolled across 11 Italian sites. Children born between December 31, 2007, and December 31, 2012, were observed during their first 2 years of life. Data were collected through hospital database searches and parent interviews. Four hundred twenty children were enrolled: 51.7 % were female, 79.5 % were born full-term (≥37 weeks), and 77.6 % weighed >2500 g at birth. The most frequent heart defects were ventricular septal defect (23.1 %) and coarctation of the aorta (14.3 %). The incidence of respiratory diseases was 63.1 %. Frequent respiratory diseases not requiring hospitalization were upper respiratory tract infections (76.4 %), acute bronchitis (43.3 %), and influenza (22.1 %), while those requiring hospitalization were bronchitis and bronchiolitis (8.3 % each one). While active immunoprophylaxis was applied with wide compliance (diphtheria/pertussis/tetanus, 99.5 %; Haemophilus influenzae type b, 72.5 %; pneumococcus, 79.9 %; meningococcus, 77.4 %), only 54 % of children received respiratory syncytial virus (RSV) passive prophylaxis (palivizumab). Of the 35 hospitalizations due to bronchiolitis, 27 (77.1 %) did not receive prophylaxis against RSV, compared with 8 (22.9 %) who received prophylaxis (P < 0.0001). Children with HSCHD are at major risk of respiratory diseases. Passive immunoprophylaxis can help to prevent hospitalizations for bronchiolitis.
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Cardiopatías Congénitas , Anticuerpos Monoclonales , Anticuerpos Monoclonales Humanizados , Antivirales , Niño , Femenino , Hospitalización , Humanos , Incidencia , Italia , Masculino , Infecciones por Virus Sincitial Respiratorio , Estudios RetrospectivosRESUMEN
PURPOSE: In infants aged less than 12 months, there are few data on pharmacokinetics of high-dose methotrexate (MTX) for brain tumors at the dose of 8 g/m(2). Consolidated knowledges are present only with the dose of 5 g/m(2) in acute lymphoblastic leukemia. METHODS: We collected data on 8 infants at the time of their first treatment with high-dose MTX, 8 g/m(2), to evaluate the pharmacokinetic profile. All children had a dose adjustment with a weight-based prescription (1 m(2) = 30 kg). RESULTS: The median age was 4.5 months (range 0-9). The median weight was 5.63 kg (range 3.12-9.0). The median steady-state MTX concentration at the end of 6-hr infusion was 486 µM/L (range 227-790). The median systemic MTX clearance was 4.14 L/h/m(2) (range 1.98-9.35). The median MTX concentration after 24 h from the beginning of infusion was 3.29 µM/L (range 1.14-100.44). Three (37.5 %) patients had a delayed elimination of MTX (delayed early, delayed late, or total delayed: one for each). These altered elimination occurred principally in children weighing less than 4 kg (p: 0.0179). Moreover, a systemic MTX clearance at the end of infusion minor than 3 L/h/m(2) can predict a delayed elimination (p: 0.0179). Patients with altered elimination underwent rescue measures (leucovorin supplement and/or exchange transfusion). CONCLUSIONS: Our data suggest that a higher dose of MTX for the treatment of aggressive brain tumors in early infants had an acceptable pharmacokinetic profile. Greater attention must be used in the treatment of children weighing less than 4 kg.
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Antimetabolitos Antineoplásicos/farmacocinética , Neoplasias Encefálicas/tratamiento farmacológico , Metotrexato/farmacocinética , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Estudios RetrospectivosAsunto(s)
Aeromonas caviae/aislamiento & purificación , Bacteriemia/microbiología , Infecciones por Bacterias Gramnegativas/microbiología , Plásmidos/análisis , Resistencia betalactámica , beta-Lactamasas/genética , Aeromonas caviae/enzimología , Aeromonas caviae/genética , Antibacterianos/farmacología , Humanos , Recién Nacido , Pruebas de Sensibilidad MicrobianaRESUMEN
Centronuclear myopathies (CNMs) are a group of clinically and genetically heterogeneous muscle disorders. To date, mutation in 7 different genes has been reported to cause CNMs but 30 % of cases still remain genetically undefined. Genetic investigations are often expensive and time consuming. Clinical and morphological clues are needed to facilitate genetic tests and to choose the best approach for genetic screening. We aimed to describe genotype-phenotype correlation in an Italian cohort of patients affected by CNMs, to define the relative frequencies of its defined genetic forms and to draw a diagnostic algorithm to address genetic investigations. We recruited patients with CNMs from all the Italian tertiary neuromuscular centers following clinical and histological criteria. All selected patients were screened for the four 'canonical' genes related to CNMs: MTM1, DNM2, RYR1 and BIN1. Pathogenetic mutations were found in 38 of the 54 screened patients (70 %), mostly in patients with congenital onset (25 of 30 patients, 83 %): 15 in MTM1, 6 in DNM2, 3 in RYR1 and one in TTN. Among the 13 patients with a childhood-adolescence onset, mutations were found in 6 patients (46 %), all in DNM2. In the group of the 11 patients with adult onset, mutations were identified in 7 patients (63 %), again in DNM2, confirming that variants in this gene are relatively more common in late-onset phenotypes. The present study provides the relative molecular frequency of centronuclear myopathy and of its genetically defined forms in Italy and also proposes a diagnostic algorithm to be used in clinical practice to address genetic investigations.
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Conectina/genética , Dinamina II/genética , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Miopatías Estructurales Congénitas/genética , Canal Liberador de Calcio Receptor de Rianodina/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Niño , Preescolar , Estudios de Cohortes , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Recién Nacido , Italia/epidemiología , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Miopatías Estructurales Congénitas/fisiopatología , Fenotipo , Proteínas Tirosina Fosfatasas no Receptoras/genética , Adulto JovenRESUMEN
We describe the case of a newborn presenting with multicystic encephalomalacy, hydrocephalus and bilateral hemovitreous. An underlying coagulation disorder was suspected and laboratory tests revealed severe protein C deficiency. At 25 days of life, after the appearance of purpura fulminans, replacement therapy with intravenous protein C concentrate (Ceprotin; Baxter, Vienna, Austria) was started.Due to difficulties in getting peripheral venous access and to repeated loss of the venous access, continuous subcutaneous infusion of protein C was started with an insulin pump (VEO 754; Medtronic, Minneapolis, Minnesota, USA), normally adopted in patients with type 1 diabetes mellitus. Protein C values increased into the normal range and the resolution of the purpuric skin lesion was achieved. Chronic prophylaxis with low-molecular-weight heparin failed and, due to cutaneous and cerebral recrudescence, replacement therapy with the pump was started again. The insulin pump allowed us to reduce the number of injections per day and to deal with the difficulties in getting peripheral venous access, permitting medical and paramedical staff an easier management of the therapy. The dosing schedule could be easily adapted with the insulin pump and the continuous subcutaneous administration of small amounts of protein C concentrate prevented fluctuation in trough levels of protein C. This is the first reported case of a novel, successful use of an insulin pump in an extremely rare disease, to administer a drug different from insulin, which needs to be further analyzed, underlining the importance of a multidisciplinary team approach in order to provide effective and efficient care in high-complexity diseases.
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Deficiencia de Proteína C/tratamiento farmacológico , Proteína C/uso terapéutico , Femenino , Humanos , Recién Nacido , Infusiones Subcutáneas , Sistemas de Infusión de Insulina , Proteína C/administración & dosificaciónRESUMEN
Retinopathy of prematurity (ROP) is a disease that can cause blindness in very low birthweight infants. The incidence of ROP is closely correlated with the weight and the gestational age at birth. Despite current therapies, ROP continues to be a highly debilitating disease. Our advancing knowledge of the pathogenesis of ROP has encouraged investigations into new antivasculogenic therapies. The purpose of this article is to review the findings on the pathophysiological mechanisms that contribute to the transition between the first and second phases of ROP and to investigate new potential therapies. Oxygen has been well characterized for the key role that it plays in retinal neoangiogenesis. Low or high levels of pO2 regulate the normal or abnormal production of hypoxia-inducible factor 1 and vascular endothelial growth factors (VEGF), which are the predominant regulators of retinal angiogenesis. Although low oxygen saturation appears to reduce the risk of severe ROP when carefully controlled within the first few weeks of life, the optimal level of saturation still remains uncertain. IGF-1 and Epo are fundamentally required during both phases of ROP, as alterations in their protein levels can modulate disease progression. Therefore, rhIGF-1 and rhEpo were tested for their abilities to prevent the loss of vasculature during the first phase of ROP, whereas anti-VEGF drugs were tested during the second phase. At present, previous hypotheses concerning ROP should be amended with new pathogenetic theories. Studies on the role of genetic components, nitric oxide, adenosine, apelin and ß-adrenergic receptor have revealed new possibilities for the treatment of ROP. The genetic hypothesis that single-nucleotide polymorphisms within the ß-ARs play an active role in the pathogenesis of ROP suggests the concept of disease prevention using ß-blockers. In conclusion, all factors that can mediate the progression from the avascular to the proliferative phase might have significant implications for the further understanding and treatment of ROP.
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Retinopatía de la Prematuridad/fisiopatología , Edad Gestacional , Humanos , Factor 1 Inducible por Hipoxia/metabolismo , Lactante , Recién Nacido , Recién Nacido de muy Bajo Peso , Oxígeno/fisiología , Retinopatía de la Prematuridad/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
We report a case of fatal intra-abdominal bleeding in a term newborn delivered by vacuum extractor and Kristeller manouvre. Although autopsy was not performed in compliance with the parents' wishes, there is strong evidence of a massive abdominal haemorrhage due to injuries of the hypochondriac organs probably leading to disconnection of a vascular pedicle.
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OBJECTIVE: To evaluate safety and efficacy of oral propranolol administration in preterm newborns affected by an early phase of retinopathy of prematurity (ROP). STUDY DESIGN: Fifty-two preterm newborns with Stage 2 ROP were randomized to receive oral propranolol (0.25 or 0.5 mg/kg/6 hours) added to standard treatment or standard treatment alone. To evaluate safety of the treatment, hemodynamic and respiratory variables were continuously monitored, and blood samples were collected weekly to check for renal, liver, and metabolic balance. To evaluate efficacy of the treatment, the progression of the disease (number of laser treatments, number of bevacizumab treatments, and incidence of retinal detachment) was evaluated by serial ophthalmologic examinations, and plasma soluble E-selectin levels were measured weekly. RESULTS: Newborns treated with propranolol showed less progression to Stage 3 (risk ratio 0.52; 95% CI 0.47-0.58, relative reduction of risk 48%) or Stage 3 plus (relative risk 0.42 95% CI 0.31-0.58, relative reduction of risk 58%). The infants required fewer laser treatments and less need for rescue treatment with intravitreal bevacizumab (relative risk 0.48; 95% CI 0.29-0.79, relative reduction of risk 52 %), a 100% relative reduction of risk for progression to Stage 4. They also had significantly lower plasma soluble E-selectin levels. However, 5 of the 26 newborns treated with propranolol had serious adverse effects (hypotension, bradycardia), in conjunction with episodes of sepsis, anesthesia induction, or tracheal stimulation. CONCLUSION: This pilot study suggests that the administration of oral propranolol is effective in counteracting the progression of ROP but that safety is a concern.
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Antagonistas Adrenérgicos beta/uso terapéutico , Propranolol/uso terapéutico , Retinopatía de la Prematuridad/tratamiento farmacológico , Antagonistas Adrenérgicos beta/efectos adversos , Femenino , Humanos , Recien Nacido Prematuro , Masculino , Proyectos Piloto , Propranolol/efectos adversos , Factores de Riesgo , Método Simple CiegoRESUMEN
Whole-body deep hypothermia (DH) could be a new therapeutic strategy for asphyxiated newborn. This retrospective study describes how DH modified the heart rate and arterial blood pressure if compared to mild hypothermia (MH). Fourteen in DH and 17 in MH were cooled within the first six hours of life and for the following 72 hours. Hypothermia criteria were gestational age ≥36 weeks; birth weight ≥1800 g; clinical signs of moderate/severe hypoxic-ischemic encephalopathy. Rewarming was obtained in the following 6-12 hours (0.5°C/h) after cooling. Heart rates were the same between the two groups; there was statistically significant difference at the beginning of hypothermia and during rewarming. Three babies in the DH group and 2 in the MH group showed HR < 80 bpm and QTc > 520 ms. Infant submitted to deep hypothermia had not bradycardia or Qtc elongation before cooling and after rewarming. Blood pressure was significantly lower in DH compared to MH during the cooling, and peculiar was the hypotension during rewarming in DH group. Conclusion. The deeper hypothermia is a safe and feasible, only if it is performed by a well-trained team. DH should only be associated with a clinical trial and prospective randomized trials to validate its use.
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ß-adrenergic receptors (ß-ARs) are G protein-coupled receptors that activate signal transduction pathways involved in angiogenesis, resulting in enhanced tumor vascularization and more aggressive growth. In this study, we evaluated the expression of ß-ARs in a population of 12 children affected by malignant primary brain tumors. We found a significant expression of ß1- and ß2-ARs in all 12 samples as well as the 3 cell lines tested (U87MG, T98G and DAOY). The mean absolute ß1-AR mRNA level standardized to GAPDH was 5.81 (range, -7.91 to 11.29) for brain tumors and 8.59 (range, 6.046 to 12.59) for cell lines (U87MG, DAOY and T98G), respectively. The mean absolute ß2-AR mRNA level was 4.74 (range, -9.30 to 8.45) for tumor specimens and 7.64 (range, 5.85 to 8.88) for cell lines. These real-time quantitative (qRT)-PCR expression data were confirmed by immunohistochemical analysis. Our study evaluated the presence of ß1- and ß2-ARs in malignant pediatric brain tumors and brain tumor cell lines.
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BACKGROUND: Despite progresses in neonatal care, the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements. In countries with a high level of perinatal care, the incidence of asphyxia responsible for moderate or severe encephalopathy is still 2-3 per 1000 term newborns. Recent trials have demonstrated that moderate hypothermia, started within 6 hours after birth and protracted for 72 hours, can significantly improve survival and reduce neurologic impairment in neonates with hypoxic-ischemic encephalopathy. It is not currently known whether neuroprotective drugs can further improve the beneficial effects of hypothermia. Topiramate has been proven to reduce brain injury in animal models of neonatal hypoxic ischemic encephalopathy. However, the association of mild hypothermia and topiramate treatment has never been studied in human newborns. The objective of this research project is to evaluate, through a multicenter randomized controlled trial, whether the efficacy of moderate hypothermia can be increased by concomitant topiramate treatment. METHODS/DESIGN: Term newborns (gestational age ≥ 36 weeks and birth weight ≥ 1800 g) with precocious metabolic, clinical and electroencephalographic (EEG) signs of hypoxic-ischemic encephalopathy will be randomized, according to their EEG pattern, to receive topiramate added to standard treatment with moderate hypothermia or standard treatment alone. Topiramate will be administered at 10 mg/kg once a day for the first 3 days of life. Topiramate concentrations will be measured on serial dried blood spots. 64 participants will be recruited in the study. To evaluate the safety of topiramate administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of topiramate, the neurologic outcome of enrolled newborns will be evaluated by serial neurologic and neuroradiologic examinations. Visual function will be evaluated by means of behavioural standardized tests. DISCUSSION: This pilot study will explore the possible therapeutic role of topiramate in combination with moderate hypothermia. Any favourable results of this research might open new perspectives about the reduction of cerebral damage in asphyxiated newborns.
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Fructosa/análogos & derivados , Hipotermia Inducida , Hipoxia-Isquemia Encefálica/terapia , Fármacos Neuroprotectores/uso terapéutico , Terapia Combinada , Fructosa/efectos adversos , Fructosa/uso terapéutico , Humanos , Recién Nacido , Fármacos Neuroprotectores/efectos adversos , TopiramatoRESUMEN
OBJECTIVE: To report our experience in the selection of newborns candidate to therapeutic hypothermia. METHODS: Retrospective study involving 47 newborns suffering from perinatal asphyxia from January 2008 to September 2011. RESULTS: Thirty-five of 47 newborns admitted to our hospital fulfilled metabolic and neurological criteria for recruitment and were cooled. aEEG was carried out in 26 of them and resulted always abnormal. In three of the 12 newborns with only metabolic criteria, aEEG was moderately abnormal. They were cooled and their outcome (evaluated by General Movements and Griffiths Mental Development Scales for children aged 0-2 years) is good. Three additional newborns who only met the metabolic criterion reached our hospital after the therapeutic window for hypothermia and exhibited seizures; their outcome is poor. CONCLUSIONS: In our experience, the inclusion of aEEG in the entry criteria would not have precluded newborns with neurological criteria from cooling. On the contrary, without an early aEEG, we would have excluded from hypothermia infants with moderate hypoxic-ischemic encephalopathy without precocious neurological signs who exhibited only the metabolic criterion, but with abnormal aEEG. If further studies will confirm that early aEEG might identify newborns suitable for cooling even in the absence of clinical signs, a revision of the entry criteria should be considered.
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Asfixia Neonatal/terapia , Electroencefalografía , Hipotermia Inducida , Hipoxia-Isquemia Encefálica/terapia , Selección de Paciente , Asfixia Neonatal/diagnóstico , Preescolar , Estudios de Cohortes , Frío , Diagnóstico Precoz , Electroencefalografía/métodos , Femenino , Humanos , Hipotermia Inducida/métodos , Hipotermia Inducida/estadística & datos numéricos , Hipoxia-Isquemia Encefálica/congénito , Hipoxia-Isquemia Encefálica/diagnóstico , Lactante , Recién Nacido , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: To present the results of a strategy designed to reduce the incidence of skin complications in newborns with hypoxic-ischemic encephalopathy treated with moderate whole-body hypothermia. DESIGN: Retrospective study. SETTING: Neonatal Intensive Care Unit (NICU). PATIENTS: Thirty-nine neonates cooled in the considered period. INTERVENTION: Starting from January 2008, for neonates treated with moderate whole-body hypothermia (33.5 °C), the cooling system was set in "automatic servo-controlled mode (ACM)", where the temperature of the circulating water could vary between 4 °C and 42 °C. Starting from January 2009, cooling blankets were used in another type of automatic mode, the "gradient variable mode (GVM)", where the circulating water was maintained at a specific pre-set gradient towards the patient's body temperature, and a specific nursing protocol (NP) was adopted. MEASUREMENTS AND MAIN RESULTS: Two of the eleven newborns treated with the "ACM" exhibited skin complications compatible with subcutaneous fat necrosis (SFN). None of the twenty-eight newborns treated with the "GVM" exhibited skin complications. A comparison of the biochemical and hematological data between these two groups revealed that newborns treated after the adopting of a NP and the "GVM" showed lower serum protein C and calcium levels, and higher platelet levels. CONCLUSIONS: Our data suggest that newborns undergoing therapeutic cooling may benefit from a specific NP and correct cooling unit setting. Should further studies confirm our data, this nursing approach could be easily adopted.
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Necrosis Grasa/prevención & control , Hipotermia Inducida/métodos , Hipoxia-Isquemia Encefálica/terapia , Paniculitis/prevención & control , Grasa Subcutánea/patología , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Calcio/sangre , Necrosis Grasa/sangre , Necrosis Grasa/etiología , Femenino , Humanos , Hipotermia Inducida/efectos adversos , Hipotermia Inducida/instrumentación , Hipotermia Inducida/enfermería , Recién Nacido , Masculino , Paniculitis/sangre , Paniculitis/etiología , Estudios RetrospectivosRESUMEN
Oxygen-induced retinopathy (OIR) is a model for human retinopathy of prematurity. In mice with OIR, beta-adrenergic receptor (ß-AR) blockade with propranolol has been shown to ameliorate different aspects of retinal dysfunction in response to hypoxia. In the present study, we used the OIR model to investigate the role of distinct ß-ARs on retinal proangiogenic factors, pathogenic neovascularization and electroretinographic responses. Our results demonstrate that ß(2) -AR blockade with ICI 118,551 decreases retinal levels of proangiogenic factors and reduces pathogenic neovascularization, whereas ß(1) - and ß(3) -AR antagonists do not. Determination of retinal protein kinase A activity is indicative of the fact that ß-AR blockers are indeed effective at the receptor level. In addition, the specificity of ICI 118,551 on retinal angiogenesis has been demonstrated by the finding that in mouse retinal explants, ß(2) -AR silencing prevents ICI 118,551 effects on hypoxia-induced vascular endothelial growth factor accumulation. In OIR mice, ICI 118,551 is effective in increasing electroretinographic responses suggesting that activation of ß(2) -ARs constitutes an important part of the retinal response to hypoxia. Lastly, immunohistochemical studies demonstrate that ß(2) -ARs are localized to several retinal cells, particularly to Müller cells suggesting the possibility that ß(2) -ARs play a role in regulating vascular endothelial growth factor production by these cells. The present results suggest that pathogenic angiogenesis, a key change in many hypoxic/ischemic vision-threatening retinal diseases, depends at least in part on ß(2) -AR activity and indicate that ß(2) -AR blockade can be effective against retinal angiogenesis.
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Antagonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Inhibidores de la Angiogénesis/uso terapéutico , Modelos Animales de Enfermedad , Oxígeno/efectos adversos , Retinopatía de la Prematuridad/inducido químicamente , Retinopatía de la Prematuridad/tratamiento farmacológico , Antagonistas Adrenérgicos beta/uso terapéutico , Animales , Animales Recién Nacidos , Atenolol/uso terapéutico , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Electrorretinografía , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/genética , Humanos , Recién Nacido , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Técnicas de Cultivo de Órganos , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Propanolaminas/uso terapéutico , ARN Mensajero , ARN Interferente Pequeño/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Neovascularización Retiniana/tratamiento farmacológico , Retinopatía de la Prematuridad/fisiopatología , Estadísticas no Paramétricas , Transfección , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Hyperammonemia is a true neonatal emergency with high toxicity for the central nervous system and developmental delay. The causes of neonatal hyperammonemia are genetic defects of urea cycle enzymes, organic acidemias, lysinuric protein intolerance, hyperammonemia-hyperornithinemia- homocitrullinemia syndrome, transient hyperammonemia of the newborn, and congenital hyperinsulinism with hyperammonemia. In some of these conditions the high blood ammonia levels are due to the reduction of N-acetylglutamate, an essential cofactor necessary for the function of the urea cycle, or to the reduction of carbamoyl-phosphate synthase-I activity. In these cases, N-carbamylglutamate (carglumic acid) can be administered together with the conventional therapy. Carglumic acid is an analog of N-acetylglutamate that has a direct action on carbamoyl-phosphate synthase-I. Its effects are reactivation of the urea cycle and reduction of plasma ammonia levels. As a consequence it improves the traditional treatment, avoiding the need of hemodialysis and peritoneal dialysis. In this review we evaluate the possible field of application of carglumic acid and its effectiveness and safety.
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PURPOSE: Therapeutic hypothermia has recently been introduced to treat term newborns with hypoxic-ischemic encephalopathy, of whom more than half have seizures. Phenobarbital is widely used to treat neonatal seizures, but it is unknown whether its pharmacokinetics is affected by hypothermia. We evaluated the influence of hypothermia on phenobarbital pharmacokinetics in asphyxiated newborns. METHODS: Nineteen term asphyxiated newborns treated with mild whole body hypothermia, started within 6 h after birth and protracted for 72 h, received phenobarbital for clinical seizures. Treatment schedule consisted of a loading dose of 20 mg/kg, titrated to response, up to a maximum dose of 40 mg/kg, followed by a maintenance dose of 2.5 or 1.5 mg/kg every 12 h. Phenobarbital concentrations were measured on 28 dried blood spots in each newborn. KEY FINDINGS: Eighteen newborns showed plasma concentrations within the reference range after receiving a loading dose of 20 mg/kg. In the remaining newborn, who had received a loading dose of 35 mg/kg, phenobarbital concentrations exceeded the upper reference limit. Phenobarbital concentrations reached a virtual steady state in all newborns. Pharmacokinetic parameters were then calculated. Minimum and maximum concentration (24.7 ± 8.8 and 30.63 ± 10.3 mg/L), average plasma concentration (27.37 ± 9.4 mg/L), and half-life (173.9 ± 62.5 h) were considerably higher than reported in literature for normothermic newborns. Pharmacokinetic parameters did not differ significantly between infants receiving different maintenance doses. SIGNIFICANCE: Phenobarbital administered to newborns under whole body hypothermia results in higher plasma concentrations and longer half-lives than expected in normothermic newborns.
Asunto(s)
Asfixia Neonatal/terapia , Hipoxia-Isquemia Encefálica/terapia , Fenobarbital/farmacocinética , Convulsiones/tratamiento farmacológico , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/farmacocinética , Asfixia Neonatal/complicaciones , Temperatura Corporal/efectos de los fármacos , Temperatura Corporal/fisiología , Humanos , Hipotermia Inducida/efectos adversos , Hipotermia Inducida/métodos , Hipoxia-Isquemia Encefálica/complicaciones , Recién Nacido , Evaluación de Resultado en la Atención de Salud/métodos , Fenobarbital/administración & dosificación , Convulsiones/etiología , Resultado del TratamientoRESUMEN
OBJECTIVE: Terlipressin has been successfully used as rescue treatment in hypotensive adults and children with septic shock, but only exceptionally in neonates. The aim of this study is to describe original clinical scenarios in which terlipressin, in newborns and infants, resolved the catecholamine-refractory hypotension. DESIGN: Retrospective study. SETTING: Neonatal intensive care unit. PATIENTS: All newborns with hypotension unresponsive to volume replacement and catecholamines, and treated with terlipressin, from January 2008 to December 2009. In this study, also an infant (11 months old) born extremely preterm was included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Four hypotensive patients received as rescue therapy terlipressin, which produced a dramatic increase in mean arterial pressure, diuresis, and reduction of lactate levels. In three newborns, hypotension, associated with pulmonary hypertension, was resolved with terlipressin. Two of them (one with systemic inflammatory response syndrome, the other with congenital diaphragmatic hernia) died in the following days for causes unrelated to hypotension; the third (on mild hypothermia for hypoxic-ischemic encephalopathy) recovered. We report furthermore an infant with septic shock and on treatment with ß-blockers in whom terlipressin normalized blood pressure. In two patients, cranial Doppler ultrasonography showed the recovery of diastolic cerebral flow in the anterior cerebral artery and the normalization of resistance index within 30 mins from the first dose of terlipressin. In two infants, hyponatremia was detected. CONCLUSION: Although the number of reported infants is little, terlipressin appears to be an effective rescue treatment in different scenarios of refractory neonatal hypotension. Further controlled studies are required to confirm its efficacy and safety.