RESUMEN

Therapeutic hypothermia is only partially protective for neonatal encephalopathy; there is an urgent need to develop treatments that augment cooling. Our objective was to assess safety, efficacy and pharmacokinetics of 5 and 15 mg/kg/24 h melatonin (proprietary formulation) administered at 2 h and 26 h after hypoxia-ischemia (HI) with cooling in a piglet model. Following moderate cerebral HI, 30 piglets were eligible and randomized to: i) Hypothermia (33.5 °C, 2-26 h) and vehicle (HT + V;n = 13); b) HT and 5 mg/kg melatonin over 6 h at 2 h and 26 h after HI (HT + Mel-5;n = 4); c) HT and 15 mg/kg melatonin over 6 h at 2 h and 26 h after HI (HT + Mel-15;n = 13). Intensive care was maintained for 48 h; brain MRS was acquired and cell death (TUNEL) evaluated at 48 h. Comparing HT + V with HT + Mel-5 and HT + Mel-15, there was no difference in blood pressure or inotropic support needed, brain Lactate/N Acetylaspartate at 24 h and 48 h was similar, ATP/phosphate pool was higher for HT + Mel-15 versus HT + V at 24 h (p = 0.038) but not 48 h. A localized reduction in TUNEL positive cell death was observed in the sensorimotor cortex in the 15 mg/kg melatonin group (HT + Mel-15 versus HT + V; p < 0.003) but not in the 5 mg/kg melatonin group (HT + Mel-5 versus HT + V; p = 0.808). Putative therapeutic melatonin levels were reached 8 h after HI (104 increase from baseline; ~15-30 mg/l). Mean ±â€¯SD peak plasma melatonin levels after the first infusion were 0.0014 ±â€¯0.0012 mg/l in the HT + V group, 3.97 ±â€¯1.53 mg/l in the HT + Mel-5 group and 16.8 ±â€¯8.3 mg/l in the HT + Mel-15 group. Protection was dose dependent; 15 mg/kg melatonin started 2 h after HI, given over 6 h, was well tolerated and augmented hypothermic protection in sensorimotor cortex. Earlier attainment of therapeutic plasma melatonin levels may optimize protection by targeting initial events of reperfusion injury. The time window for intervention with melatonin, as adjunct therapy with cooling, is likely to be narrow and should be considered in designing future clinical studies.

Asunto(s)

Encéfalo/efectos de los fármacos , Hipotermia Inducida/métodos , Hipoxia-Isquemia Encefálica/terapia , Melatonina/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Hipoxia-Isquemia Encefálica/complicaciones , Hipoxia-Isquemia Encefálica/metabolismo , Melatonina/farmacología , Fármacos Neuroprotectores/farmacología , Sus scrofa , Investigación Biomédica Traslacional

RESUMEN

BACKGROUND AND OBJECTIVES: To compare in vitro characteristics and pharmacokinetics of Bramitob, a preservative-free tobramycin solution for nebulization, and Tobi in patients with cystic fibrosis (CF) and Pseudomonas aeruginosa infection. METHODS: In vitro characteristics of Bramitob and Tobi were evaluated using Pari TurboBoy/LC Plus and the Systam 290 LS nebulizers. In the randomized, double-blind, two-way crossover pharmacokinetic study, 11 patients with CF received a single nebulized dose (300mg) of Bramitob or Tobi, separated by a 7-day washout period. Plasma and sputum tobramycin concentrations were measured immediately before and over 24 hours after administration. RESULTS: Bramitob and Tobi performed alike during nebulization. The fine particle fraction was 33-37% and the mass median aerodynamic diameter was <5microm. Nine patients completed the pharmacokinetic study. Tobramycin plasma profiles after administration of Bramitob or Tobi were similar, with a peak at 90 and 72 minutes after inhalation of Bramitob and Tobi, respectively. The elimination half-life was ~5 hours for both products. The relative bioavailability of Bramitob to Tobi was 1.01, indicating comparable systemic exposure. Peak sputum concentration of tobramycin was 816 +/- 681 microg/g for Tobi and 1289 +/- 851 microg/g for Bramitob and was >400 microg/g (threshold sufficient for an antibacterial effect against P. aeruginosa) in 5 out of 9 patients receiving Tobi and 8 out of 9 patients receiving Bramitob. All adverse events were considered mild and judged not related to the study drugs. CONCLUSIONS: In vitro performance of Bramitob((R)) was similar when nebulized with Pari TurboBoy k/LC Plus and Systam 290 LS nebulizers and comparable to that of TobiThe systemic bioavailability of tobramycin was similar after administration of either Bramitob or Tobi; however, in sputum samples the tobramycin peak concentration was slightly greater after administration of Bramitob than after Tobi.

Asunto(s)

Antibacterianos/farmacocinética , Fibrosis Quística/tratamiento farmacológico , Infecciones por Pseudomonas/tratamiento farmacológico , Tobramicina/farmacocinética , Administración por Inhalación , Adolescente , Adulto , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Disponibilidad Biológica , Enfermedad Crónica , Estudios Cruzados , Fibrosis Quística/complicaciones , Método Doble Ciego , Femenino , Humanos , Masculino , Nebulizadores y Vaporizadores , Tamaño de la Partícula , Infecciones por Pseudomonas/complicaciones , Pseudomonas aeruginosa , Equivalencia Terapéutica , Tobramicina/administración & dosificación , Tobramicina/efectos adversos