Clinical Pharmacology Studies in Critically Ill Children

Developmental and physiological changes in children contribute to variation in drug disposition with age. Additionally, critically ill children suffer from various life-threatening conditions that can lead to pathophysiological alterations that further affect pharmacokinetics (PK). Some factors that can alter PK in this patient population include variability in tissue distribution caused by protein binding changes and fluid shifts, altered drug elimination due to organ dysfunction, and use of medical interventions that can affect drug disposition (e.g., extracorporeal membrane oxygenation and continuous renal replacement therapy). Performing clinical studies in critically ill children is challenging because there is large inter-subject variability in the severity and time course of organ dysfunction; some critical illnesses are rare, which can affect subject enrollment; and critically ill children usually have multiple organ failure, necessitating careful selection of a study design. As a result, drug dosing in critically ill children is often based on extrapolations from adults or non-critically ill children. Dedicated clinical studies in critically ill children are urgently needed to identify optimal dosing of drugs in this population. This review will summarize the effect of critical illness on pediatric PK, the challenges associated with performing studies in this vulnerable subpopulation, and the clinical PK studies performed to date for commonly used drugs

Effects of Strength Training on the Physiological Determinants of Middle- and Long-Distance Running Performance: A Systematic Review

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background: Middle- and long-distance running performance is constrained by several important aerobic and anaerobic parameters. The efficacy of strength training (ST) for distance runners has received considerable attention in the literature. However, to date, the results of these studies have not been fully synthesized in a review on the topic. Objectives: This systematic review aimed to provide a comprehensive critical commentary on the current literature that has examined the effects of ST modalities on the physiological determinants and performance of middle- and long-distance runners, and offer recommendations for best practice. Methods: Electronic databases were searched using a variety of key words relating to ST exercise and distance running. This search was supplemented with citation tracking. To be eligible for inclusion, a study was required to meet the following criteria: participants were middle- or long-distance runners with ≥ 6 months experience, a ST intervention (heavy resistance training, explosive resistance training, or plyometric training) lasting ≥ 4 weeks was applied, a running only control group was used, data on one or more physiological variables was reported. Two independent assessors deemed that 24 studies fully met the criteria for inclusion. Methodological rigor was assessed for each study using the PEDro scale. Results: PEDro scores revealed internal validity of 4, 5, or 6 for the studies reviewed. Running economy (RE) was measured in 20 of the studies and generally showed improvements (2–8%) compared to a control group, although this was not always the case. Time trial (TT) performance (1.5–10 km) and anaerobic speed qualities also tended to improve following ST. Other parameters [maximal oxygen uptake (V˙ O 2 max), velocity at V˙ O 2 max, blood lactate, body composition] were typically unaffected by ST. Conclusion: Whilst there was good evidence that ST improves RE, TT, and sprint performance, this was not a consistent finding across all works that were reviewed. Several important methodological differences and limitations are highlighted, which may explain the discrepancies in findings and should be considered in future investigations in this area. Importantly for the distance runner, measures relating to body composition are not negatively impacted by a ST intervention. The addition of two to three ST sessions per week, which include a variety of ST modalities are likely to provide benefits to the performance of middle- and long-distance runners

Pharmacokinetics and Pharmacodynamics of Antibacterials, Antifungals, and Antivirals Used Most Frequently in Neonates and Infants

Antimicrobials and antivirals are widely used in young infants and neonates. These patients have historically been largely excluded from clinical trials and, as a consequence, the pharmacokinetics and pharmacodynamics of commonly used antibacterials, antifungals, and antivirals are incompletely understood in this population. This review summarizes the current literature specific to neonates and infants regarding pharmacokinetic parameters and changes in neonatal development that affect antimicrobial and antiviral pharmacodynamics. Specific drug classes addressed include aminoglycosides, aminopenicillins, cephalosporins, glycopeptides, azole antifungals, echinocandins, polyenes, and guanosine analogs. Within each drug class, the pharmacodynamics, pharmacokinetics, and clinical implications and future directions for prototypical agents are discussed. β-Lactam antibacterial activity is maximized when the plasma concentration exceeds the minimum inhibitory concentration for a prolonged period, suggesting that more frequent dosing may optimize β-lactam therapy. Aminoglycosides are typically administered at longer intervals with larger doses in order to maximize exposure (i.e., area under the plasma concentration–time curve) with gestational age and weight strongly influencing the pharmacokinetic profile. Nonetheless, safety concerns necessitate therapeutic drug monitoring across the entire neonatal and young infant spectrum. Vancomycin, representing the glycopeptide class of antibacterials, has a long history of clinical utility, yet there is still uncertainty about the optimal pharmacodynamic index in neonates and young infants. The high degree of pharmacokinetic variability in this population makes therapeutic drug monitoring essential to ensure adequate therapeutic exposure. Among neonates treated with the triazole agent fluconazole, it has been speculated that loading doses may improve pharmacodynamic target attainment rates. The use of voriconazole necessitates therapeutic drug monitoring and dose adjustments for patients with hepatic dysfunction. Neonates treated with lipid-based formulations of the polyene amphotericin B may be at an increased risk of death, such that alternative antifungal agents should be considered for neonates with invasive fungal infections. Alternative antifungal agents such as micafungin and caspofungin also exhibit unique pharmacokinetic considerations in this population. Neonates rapidly eliminate micafungin and require nearly three times the normal adult dose to achieve comparable levels of systemic exposure. Conversely, peak caspofungin concentrations have been reported to be similar among neonates and adults. However, both of these drugs feature favorable safety profiles. Recent studies with acyclovir have suggested that current dosing regimens may not result in therapeutic central nervous system concentrations and more frequent dosing may be required for neonates at later postmenstrual ages. Though ganciclovir and valganciclovir demonstrate excellent activity against cytomegalovirus, they are associated with significant neutropenia. In summary, many pharmacokinetic and pharmacodynamic studies have been conducted in this vulnerable population; however, there are also substantial gaps in our knowledge that require further investigation. These studies will be invaluable in determining optimal neonatal dosing regimens that have the potential to improve clinical outcomes and decrease adverse effects associated with antimicrobial and antiviral treatments