Neonatal medicines research: challenges and opportunities

Samardžić, Janko; Turner, Mark A.; Bax, Ralph; Allegaert, Karel

doi:10.1517/17425255.2015.1046433

Cited by 12 publications

(9 citation statements)

References 87 publications

(123 reference statements)

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“…Hence, only a brief overview will be provided to illustrate its impact. Body water content is proportionally larger, body fat content is proportionally smaller in neonates in comparison to adults (impact on distribution), and liver and kidney function are not fully developed at birth, which is an important factor considering metabolism and elimination of many drugs [3,4]. Generally, the maturation of DMEs does not follow a single, uniform pattern, but displays iso-enzyme-specific maturation.…”

Section: Introductionmentioning

confidence: 99%

Drug metabolism in early infancy: opioids as an illustration

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Tibboel

et al. 2018

Expert Opinion on Drug Metabolism & Toxicology

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Drug dosing in infants frequently depends on body weight as a crude indicator for maturation. Fentanyl (metabolized by Cytochrome P450 3A4) and morphine (glucuronidated by UDP-glucuronosyltransferase-2B7) served as model drugs to provide insight in maturation patterns of these enzymes and provide understanding of the impact of non-maturational factors to optimize dosing in infants. Areas covered: Systematic searches on metabolism and population pharmacokinetic (Pop-PK) models for fentanyl and morphine were performed. Pre- and post-model selection criteria were applied to assess and evaluate the validity of these models. It was observed that maturational changes have been rather well investigated, be it with variability in the maturational function estimates. The same holds true for Pop-PK models, where non-maturational covariates have also been reported (pharmacogenetics, disease state or external influences), although less incorporated in the PK models and with limited knowledge on mechanisms involved. Expert opinion: PK models for fentanyl and morphine are currently available. Consequently, we suggest that researchers should not continue to develop new models, but should investigate whether collected data fit in already existing models and provide additional value concerning the impact of (non)-maturational factors like drug-drug interactions or pharmacogenetics.

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Section: Introductionmentioning

confidence: 99%

Drug metabolism in early infancy: opioids as an illustration

Donge

Mian

Tibboel

et al. 2018

Expert Opinion on Drug Metabolism & Toxicology

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“…In addition to the complex and unique aspects of perinatal-neonatal pharmacokinetics [ 37 , 39 ], pharmacodynamic changes associated with development may present a challenge for pharmacotherapeutic interventions. Therefore, drug targets (including ion channels) that are present and functional in adults may be absent or may have not yet reached a functional mature state, which considerably undermines their pharmacological value during the fetal and neonatal period [ 39 – 40 ].…”

Section: Discussionmentioning

confidence: 99%

Large conductance voltage- and calcium-gated potassium channels (BK) in cerebral artery myocytes of perinatal fetal primates share several major characteristics with the adult phenotype

et al. 2018

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Large conductance voltage- and calcium-gated channels (BK) control fundamental processes, including smooth muscle contractility and artery diameter. We used a baboon (Papio spp) model of pregnancy that is similar to that of humans to characterize BK channels in the middle cerebral artery and its branches in near-term (165 dGa) primate fetuses and corresponding pregnant mothers. In cell-attached patches (K+pipette = 135 mM) on freshly isolated fetal cerebral artery myocytes, BK currents were identified by large conductance, and voltage- and paxilline-sensitive effects. Their calcium sensitivity was confirmed by a lower Vhalf (transmembrane voltage needed to reach half-maximal current) in inside-out patches at 30 versus 3 μM [Ca2+]free. Immunostaining against the BK channel-forming alpha subunit revealed qualitatively similar levels of BK alpha protein-corresponding fluorescence in fetal and maternal myocytes. Fetal and maternal BK currents recorded at 3 μM [Ca2+]free from excised membrane patches had similar unitary current amplitude, and Vhalf. However, subtle differences between fetal and maternal BK channel phenotypes were detected in macroscopic current activation kinetics. To assess BK function at the organ level, fetal and maternal artery branches were pressurized in vitro at 30 mmHg and probed with the selective BK channel blocker paxilline (1 μM). The degree of paxilline-induced constriction was similar in fetal and maternal arteries, yet the constriction of maternal arteries was achieved sooner. In conclusion, we present a first identification and characterization of fetal cerebral artery BK channels in myocytes from primates. Although differences in BK channels between fetal and maternal arteries exist, the similarities reported herein advance the idea that vascular myocyte BK channels are functional near-term, and thus may serve as pharmacological targets during the perinatal-neonatal period.

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“…However, few of these refer to neonates, which remain one of the last therapeutic orphans [19]. Design and reporting of RCTs in neonates seem to be of poor quality without any substantial improvement during the past years, as identified by Kaguelidou et al in a systematic review of RCTs of antibiotics for neonatal infections [20].…”

Section: High Variability In Antibiotic Dosingmentioning

confidence: 99%