Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method

Desfrère, Luc; Zohar, Sarah; Morville, P; Brunhes, Anne; Chevret, Sylvie; Pons, Gérard; Moriette, G; Rey, Elisabeth; Tréluyer, J.M.

doi:10.1111/j.1365-2710.2005.00630.x

Cited by 109 publications

(78 citation statements)

References 40 publications

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“…5 Ϯ 11.2 mg/L were reported with the same dose on day 3 of life (29). With 20 mg/kg median concentrations reached 68 g/mL (30). Plasma half-life was prolonged 10 times in preterm infants compared with infants of more than 3 mo of age (28).…”

Section: Discussionmentioning

confidence: 85%

Ibuprofen Augments Bilirubin Toxicity in Rat Cortical Neuronal Culture

et al. 2009

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Premature infants are at risk for bilirubin-associated brain damage. In cell cultures bilirubin causes neuronal apoptosis and necrosis. Ibuprofen is used to close the ductus arteriosus, and is often given when hyperbilirubinemia is at its maximum. Ibuprofen is known to interfere with bilirubin-albumin binding. We hypothesized that bilirubin toxicity to cultured rat embryonic cortical neurons is augmented by coincubation with ibuprofen. Incubation with ibuprofen above a concentration of 125 g/mL reduced cell viability, measured by methylthiazole tetrazolium reduction, to 68% of controls (p Ͻ 0.05). Lactate dehydrogenase (LDH) release increased from 29 to 38% (p Ͻ 0.01). The vehicle solution did not affect cell viability. Coincubation with 10 M unconjugated bilirubin (UCB)/human serum albumin in a molar ratio of 3:1 and 250 g/mL ibuprofen caused additional loss of cell viability and increased LDH release (p Ͻ 0.01), DNA fragmentation, and activated caspase-3. Preincubation with the pan-caspase inhibitor z-val-alaasp-fluoromethyl ketone abolished ibuprofen-and UCB-induced DNA fragmentation. The study demonstrates that bilirubin in low concentration of 10 M reduces neuron viability and ibuprofen increases this effect. Apoptosis is the underlying cell death mechanism. (Pediatr Res 65: 392-396, 2009)

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Section: Discussionmentioning

confidence: 85%

Ibuprofen Augments Bilirubin Toxicity in Rat Cortical Neuronal Culture

et al. 2009

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“…The reported closure rate using IBU is between 57 and 89% and is inversely related to gestational age [8]. Increased and earlier doses of IBU have recently been recommended in an effort to improve its efficacy [9,10,11], but the tolerability and safety of these regimens need to be assessed in larger populations. Also, the oral route has been tested, but the results need to be confirmed in larger trials, especially in extremely low birth weight infants [12].…”

Section: Introductionmentioning

confidence: 99%

Continuous Infusion of Ibuprofen for Treatment of Patent Ductus Arteriosus in Very Low Birth Weight Infants

et al. 2013

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Background: Ibuprofen (IBU) has proved as effective as indomethacin in the pharmacological closure of hemodynamically significant patent ductus arteriosus (HsPDA), with an efficacy inversely related to gestational age (57-89%). Objective: This study aimed to establish whether continuous infusions of IBU could be more effective in very low birth weight infants with no additional adverse effects and reduce the need for surgical ligation. Methods: A prospective, randomized, double-dummy study was conducted on 112 very low birth weight infants (mean gestational age 27.2 weeks, SD 2; birth weight 1,019 g, SD 330) with HsPDA, 56 of whom were given IBU in conventional 15-min intermittent boluses, while the other 56 were administered IBU as a 24-hour continuous infusion, both at standard doses (10/5/5 mg/kg). Extensive echocardiography was performed before and after treatment, and adverse effects were monitored. Results: Pharmacological PDA closure was achieved after 1 or 2 IBU courses in 36 of 56 infants (64.3%) after bolus administration and in 46 of 55 (83.6%) after continuous infusion (p = 0.020), and in 9 of 26 (34.6%) and 24 of 30 (80.0%), respectively, in the infants with a gestational age of 23-27 weeks (p = 0.006). Sustained pharmacological closure was observed in 38 of 56 infants (67.9%) after bolus IBU and in 47 of 55 (85.5%) after continuous infusion (p = 0.029). Surgical ligation was used less after continuous infusion than after bolus IBU (5.5 vs. 19.6%; p = 0.024). The continuous infusion group had fewer symptoms of necrotizing enterocolitis (NEC), especially in the more preterm infants, while other neonatal morbidity and mortality rates were similar. Conclusion: Continuous IBU infusion is more effective than standard boluses for sustained closure of HsPDA, with fewer NEC symptoms and less need for surgical ligation in very low birth weight infants.

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“…Sophisticated designs based on Bayesian reasoning to minimize the number of participants, e.g. the continual reassessment method, have been conducted in neonates [45]. These studies inform subsequent development, e.g.…”

Section: Protocol: Trial Design and Drug Development In Neonatesmentioning

confidence: 99%

Clinical trials of medicines in neonates: the influence of ethical and practical issues on design and conduct

Turner

2015

Brit J Clinical Pharma

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In the past, there has been a perception that ethical and practical problems limit the opportunities for research in neonates. This perception is no longer appropriate. It is now clear that research about the medicines used in neonates is an ethical requirement. It is possible to conduct high quality research in neonates if the research team adapt to the characteristics of this population. Good practice involves respecting the specific needs of newborn babies and their families by adopting relevant approaches to study design, recruitment, pharmacokinetic studies and safety assessment. Neonatal units have a unique culture that requires careful development in a research setting. Clinical investigators need to recognize the clinical and ethical imperative to conduct rigorous research. Industry needs to engage with neonatal networks early in the process of drug development, preferably before contacting regulatory agencies. Follow-up over 3-5 years is essential for the evaluation of medicines in neonates and explicit funding for this is required for the assessment of the benefit and risk of treatments given to sick newborn babies. The views of parents must be central to the development of studies and the research agenda. Ethical and practical problems are no longer barriers to research in neonates. The current challenges are to disseminate good practice and maximize capacity in order to meet the need for research among newborn babies.

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Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method

Cited by 109 publications

References 40 publications

Ibuprofen Augments Bilirubin Toxicity in Rat Cortical Neuronal Culture

Ibuprofen Augments Bilirubin Toxicity in Rat Cortical Neuronal Culture

Continuous Infusion of Ibuprofen for Treatment of Patent Ductus Arteriosus in Very Low Birth Weight Infants

Clinical trials of medicines in neonates: the influence of ethical and practical issues on design and conduct

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