METHOD: This is a single-center, single-dose, open-label, randomized, 2-treatment, 2-sequence and 2-period crossover study with a washout period of 7 days. Paracetamol/Orphenadrine tablets were administered after a 10-h fast. Blood samples for pharmacokinetic analysis were collected at scheduled time intervals prior to and up to 72 h after dosing. Blood samples were centrifuged, and separated plasma were kept frozen (- 15 °C to - 25 °C) until analysis. Plasma concentrations of orphenadrine and paracetamol were quantified using liquid-chromatography-tandem mass spectrometer using diphenhydramine as internal standard. The pharmacokinetic parameters AUC0-∞, AUC0-t and Cmax were determined using plasma concentration time profile for both preparations. Bioequivalence was assessed according to the ASEAN guideline acceptance criteria for bioequivalence which is the 90% confidence intervals of AUC0-∞, AUC0-t and Cmax ratio must be within the range of 80.00-125.00%.
RESULTS: There were 28 healthy subjects enrolled, and 27 subjects completed this trial. There were no significant differences observed between the AUC0-∞, AUC0-t and Cmax of both test and reference preparations in fasted condition. The 90% confidence intervals for the ratio of AUC0-t (100.92-111.27%), AUC0-∞ (96.94-108.08%) and Cmax (100.11-112.50%) for orphenadrine (n = 25); and AUC0-t (94.29-101.83%), AUC0-∞ (94.77-101.68%) and Cmax (87.12-101.20%) for paracetamol (n = 27) for test preparation over reference preparation were all within acceptable bioequivalence range of 80.00-125.00%.
CONCLUSION: The test preparation is bioequivalent to the reference preparation and can be used interchangeably.
TRIAL REGISTRATION: NMRR- 17-1266-36,001; registered and approved on 12 September 2017.
OBJECTIVES: To determine the overall effectiveness and safety of dexmedetomidine for sedation and analgesia in newborn infants receiving mechanical ventilation compared with other non-opioids, opioids, or placebo.
SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and two trial registries in September 2023.
SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) and quasi-RCTs evaluating the effectiveness of dexmedetomidine compared with other non-opioids, opioids, or placebo for sedation and analgesia in neonates (aged under four weeks) requiring mechanical ventilation.
DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were level of sedation and level of analgesia. Our secondary outcomes included days on mechanical ventilation, number of infants requiring additional medication for sedation or analgesia (or both), hypotension, neonatal mortality, and neurodevelopmental outcomes. We planned to use GRADE to assess the certainty of evidence for each outcome.
MAIN RESULTS: We identified no eligible studies for inclusion. We identified four ongoing studies, two of which appear to be eligible for inclusion; they will compare dexmedetomidine with fentanyl in newborn infants requiring surgery. We listed the other two studies as awaiting classification pending assessment of full reports. One study will compare dexmedetomidine with morphine in asphyxiated newborns undergoing hypothermia, and the other (mixed population, age up to three years) will evaluate dexmedetomidine versus ketamine plus dexmedetomidine for echocardiography. The planned sample size of the four studies ranges from 40 to 200 neonates. Data from these studies may provide some evidence for dexmedetomidine efficacy and safety.
AUTHORS' CONCLUSIONS: Despite the increasing use of dexmedetomidine, there is insufficient evidence supporting its routine use for analgesia and sedation in newborn infants on mechanical ventilation. Furthermore, data on dexmedetomidine safety are scarce, and there are no data available on its long-term effects. Future studies should address the efficacy, safety, and long-term effects of dexmedetomidine as a single drug therapy for sedation and analgesia in newborn infants.