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Background: Postpartum hemorrhage remains a significant contributor to morbidity and mortality of women of childbearing age worldwide. Trends in both incidence and severity of postpartum hemorrhage are increasing which makes it imperative to identify drugs that could target prevention and/or treatment of these postpartum hemorrhages for women living in high, middle and low-income countries., Methods: We have reviewed current advances in the medical management of postpartum hemorrhage focusing on non-uterotonic therapy. We specifically describe the use and mechanism of action of tranexamic acid (TXA) and fibrinogen concentrate. Furthermore, we address the existing data for using these medications in postpartum hemorrhage, highlighting both strengths and limitations., Results: This review describes a new generation of medications that are promising for the prevention and/or treatment of postpartum hemorrhage. For patients at risk for significant hemorrhage, TXA has been shown to reduce intraoperative blood loss and can be given as a prophylactic agent. For the treatment of postpartum hemorrhage, early use of TXA has the potential to reduce mortality. In addition, some data exists supporting the use of fibrinogen concentrate, though more studies are required to help formulate guidelines for its use., Conclusion: A promising new approach for the management of severe postpartum hemorrhage is using medications that alter coagulation. More data are needed to describe ideal patient populations, dosing, the time of administration, and infusion rate., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Therapeutic drug monitoring (TDM) refers to the interpretation of quantified drug concentrations in strategically timed samples of bodily fluids, with the aim to maximize therapeutic benefit, while minimizing toxicity. In essence, TDM criteria for neonates are similar to those for adults, but specific issues should be considered. This review focusses on the relevance of these specific issues: larger variability in pharmacokinetics (PK), and non-PK related factors, sampling opportunities, analytical techniques, therapeutic range. Specific issues: Larger variability in PK, and non-PK related factors in neonates compared to adults result in a less clear relation between the administered dose and the concentration measured. Sophisticated dosing regimens derived from population PK-models can partly overcome this variability, thereby reducing the need for TDM. Dosing can be further individualized using Bayesian forecasting as a tool for TDM. Besides PK related factors, concentrations of endogenous substances (e.g. immunoglobulin A, plasma protein) in neonates differ from those in adults, which may complicate interpretation of measured drug concentrations. Blood sampling opportunities in neonates are limited by the small blood volume and the need to minimize painful procedures. Dried blood spot sampling may be less invasive. This method has been facilitated by more sensitive analytical techniques, such as chromatography followed by mass spectrometry. For the same reason, saliva is gaining attention as an alternative non-invasive bodily fluid. Lastly, reference values for therapeutic ranges of drugs in neonates are mostly adapted from adult studies, although pharmacodynamics may be quite different in neonates. This review concludes with recommendations for future research on these specific issues., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: β-lactams are among the most frequently prescribed antibiotics for the treatment of neonatal sepsis. Survival of extremely preterm neonates necessitates an improved understanding of how β-lactams should be used in this vulnerable population. Appropriate dosing regimens for neonates remain unclear. We reviewed available data on the pharmacokinetics (PK) of β -lactam drugs in neonates. Pharmacokinetic/ pharmacodynamic (PK/PD) efficacy index surrogates and minimum inhibitory concentrations (MICs) used to support dosing regimens recommendation in the studies were also investigated., Methods: A comprehensive literature search was undertaken to identify studies that have investigated the PK/PD of β-lactam drugs in neonates., Results: Data available for the PK/PD of β-lactams in neonates are limited but confirm the importance of weight, gestational age and postnatal age as markers of growth and renal maturation. The contribution of tubular secretion in addition to glomerular filtration is highlighted. The development of methods to assay β-lactam protein binding in vivo has added greater understanding. Modelling and simulation techniques have aided dosing optimisation. However, there remains a gap in the understanding of PD parameters and the appropriate PK/PD index to target for improved clinical outcome which partly explains the various dosing recommendations. Improved data on the efficacy of β -lactams are needed in a context of increasing global antimicrobial resistance and variable geographic MIC distribution., Conclusion: Prospective in vivo studies are required to validate PK/PD indexes associated with clinical efficacy. Current antimicrobial stewardship efforts should integrate PK/PD principles and dosing optimization, taking into account susceptibility of isolated microorganisms., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Effective and safe pharmacotherapy in an individual neonate necessitates understanding the pharmacokinetic (PK) and pharmacodynamic (PD) properties of a specific drug together with the characteristics of this neonate., Methods: Developmental PK hereby provides estimates of the concentration-time profile. Multiple maturational, disease and treatment related differences can result in differences in PK and probably also in PD in neonates compared to other populations. All these PK processes (absorption, distribution, metabolism and elimination, ADME) display maturation but are also affected by non-maturational covariates. Maturational covariates relate to age or weight dependent changes, while non-maturational covariates relate to variables in disease, environment, treatment - including co-medications - or genetic background., Results: We will describe general PK related aspects of ADME in neonates with emphasis on both maturational and non-maturational covariates of the variability observed, followed by compound specific illustrations (tramadol, amikacin) to further underscore the impact and interaction of these maturational and non-maturational changes., Conclusion: Future efforts should focus on integration of the already available knowledge and the collection of data on the impact of non-maturational covariates. These kinds of PK efforts will become clinically important when subsequently linked to PD, ultimately covering both wanted effects and undesired side-effects., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Therapeutic hypothermia (HT) is frequently used in neonates with hypoxic-ischemic encephalopathy and young infants during cardiopulmonary bypass (CPB). Hypothermia and CPB result in physiological changes contributing to pharmacokinetic (PK) and pharmacodynamic (PD) changes. Changes in the absorption, the volume of distribution (Vd) and the total body clearance (CL) of drugs used during hypothermia and CPB might lead to the interindividual PK variability resulting in either insufficient or toxic plasma concentrations and have an impact on the biodisposition and action of drugs. Both under- or overdosing of medicines in these critically ill patients may contribute to a worse overall outcome. Overall, hypothermia decreases CL but may decrease or increase Vd by changing intravascular blood volume, organ perfusion and enzymatic metabolic processes. In addition, maturational as well as organ specific changes may occur during hypothermia superimposed on the underlying disease and/or procedures such as extracorporeal membrane oxygenation (ECMO) or CPB. This paper will provide an overview of variables and potential covariates (e.g., asphyxia, sepsis, multiorgan dysfunction syndrome, cardiac arrest) determining the PK of frequently used drugs. In addition, the effects of hypothermia on individual drugs are described as well as alternative ways for future study designs such as the use of population PK-PD and opportunistic sampling. Ultimately, these investigations are warranted to obtain specific dosing nomograms of medicines for use in clinical practice and to improve the treatment results of this vulnerable group of pediatric patients.

Once daily dosing of aminoglycosides has been introduced and validated in non-neonatal patient cohorts. This is because aminoglycosides display peak concentration dependent bacterial killing, have a postantibiotic effect and adaptive resistance. In addition, this strategy reduces toxicity. Although aminoglycosides are also frequently administered to neonates, there is still debate about how to integrate and extrapolate these extended interval dosing regimens into dosing schedules tailored for neonates. There is a growing body of knowledge on aminoglycoside disposition and its covariates (e.g. asphyxia, ibuprofen or indomethacin exposure, serum creatinine, sepsis, dose accuracy) in neonates. In essence, integration of developmental physiology with clinical pharmacology unveils a discrepancy between aspects related to either body composition (higher distribution volume necessitates higher dose, to attain peak concentration) or to elimination clearance (lower renal clearance necessitates prolonged time interval between administrations). Such discrepancy can be solved by introducing more complex dosing guidelines (based on weight, postnatal age, serum creatinine, ibuprofen, asphyxia) in neonates. However, the introduction of more complex dosing guidelines should be balanced with its clinical feasibility. At least, there are reports that these more complex dosing guidelines result in a higher incidence of dosing errors. Besides errors in prescription, these errors also relate to the number of dilutions or manipulations needed before the prescribed dose can be administered. Since an integrated approach is needed, we discuss in this overview both the available pharmacokinetic data in support of the use of extended dosing regimens in neonates as well as the strategies suggested to reduce dosing errors.

To attain effective and safe pharmacotherapy in neonates, caregivers have to consider both the clinical characteristics of the newborn and the pharmacokinetic estimates of a given compound during prescription and administration. Overall, clearance in neonates is low when compared to other pediatric subpopulations. Despite this overall low clearance, there is already extensive between individual variability in clearance in early life. As a consequence, neonates are in urgent need of tailored drug product development that considers the need for both low and flexible dosing to maintain dose accuracy. During the development of such formulations tailored for neonates, there is also a need for guidance on excipient exposure. The available knowledge on the safety or toxicity of excipients is limited and difficult to retrieve, but there are initiatives (e.g. Safety and Toxicity of Excipients for Pediatrics [STEP] database initiative) to improve the present situation. In addition, population focussed studies on aspects of clinical pharmacology of excipients in neonates should be conducted. The propylene glycol research project and the European Study for Neonatal Excipient Exposure (ESNEE) initiative illustrate its feasibility. Finally, until tailored formulations make it to the market, compounding practices for drug formulations in neonates should be evaluated to guarantee correct dosing, product stability, safety and to support pharmacists in their daily practice.

Background: The paucity of marketed drug products that have been adequately studied in infants and children and subsequently, licensed (or labeled) for pediatric use has caused abundant use of off-label and unauthorized products in this patient population. In those instances where insufficient pharmacologic or therapeutic information exists for children, the potential for off-label use of medicines to result in therapeutic misadventure does as well. In the USA, a series of regulatory measures have been introduced since 1997 which have increased both the number and scope of pediatric drug trials and also, fostered the development of ageappropriate drug formulations by pharmaceutical companies. Provisions of these regulations for previously marketed drugs include the potential for a company to be granted 6 months of marketing exclusivity, thereby providing them with a financial incentive. For new drugs being developed that have potential pediatric use, the regulations mandate the inclusion of children in the drug development process. In the EU comparable measures have been very recently (Jan 2007) signed into European law to overcome the therapeutic orphan status of the infants and children of Europe., Method: The aims of this study was to compare the availability of age-appropriate oral formulations labeled for use in children less than 12 years of age in Serbia, Germany and USA in 2007, and to investigate if certain drug groups of therapeutic importance to children had fewer medicines appropriately labeled for pediatric patients available. The primary sources of information for determining the ageappropriate oral dosage forms, and their licensing and labeling status were the official manuals on drug information and national formularies in 2007., Finding: The general availability of oral drugs was the highest in the USA (304), followed by Germany (235) and Serbia (156). From all these oral drugs the availability of labeled age-appropriate pediatric dosage formulations was only between 21.2% and 47.7%. Moreover, there were striking differences between the three countries in the availability of labeled age-appropriate formulations for certain drug groups such as cardiovascular (absent in Serbia) and antiparasitic drugs (absent in Serbia and Germany)., Interpretation: Our data suggest that significant country-to-country differences continue to exist in both the number and type of oral drug formulations that have pediatric labeling. Potential contributing factors include country-specific differences in the drug regulatory process, capacity for pharmaceutical development and the regulatory lag time associated with the implementation of drug regulation specifically addressing pediatric product development and labeling. We hypothesize that the new European regulation concerning medicines and children will improve the current unacceptable situation.

Obesity represents one of the most important public health issues according to the World Health Organization. Additionally, in a recent National Health and Nutrition Survey of 2011-2012, approximately 17 % of children and adolescents in the United States were considered obese. The obesity rate is higher within the adolescent age group as compared to preschool children. Childhood obesity is particularly problematic, because the co-morbid disease states which accompany obesity may require frequent pharmacotherapy and/ or surgical intervention. Despite the potential for increased pharmacotherapy among obese patients, there is a paucity of dosing guidelines for this special population. Optimal drug dosing in obese pediatric patients has not been sufficiently explored as the present data available are mostly specific for obese adults. In this review, we present an overview concerning what is currently known about the pharmacokinetics and pharmacogenetics of frequently used drugs including midazolam, fentanyl and its newer derivatives, morphine, ketamine, acetaminophen, dexmedetomidine and enoxaparin in obese adolescents undergoing bariatric surgery. We will also summarize the current dosing recommendations of anesthetic drugs in bariatric anesthesia.

Aminoglycosides have played a major role in antimicrobial therapy since their discovery in the 1940s. Their bactericidal efficacy in gram-negative infections, synergism with beta-lactam antibiotics, limited bacterial resistance, and low cost have given these agents a firm place in antimicrobial treatment. After penicillins, aminoglycosides are the most commonly used drugs in the neonatal intensive care unit. While the pharmacodynamic action on the bacterial target is obviously the same in neonates as compared to children and adults, dramatic differences exist in terms of pharmacokinetics. Renal function is the most important determinant in respect to the elimination of aminoglycosides and, depending on the age and development of the newborn infant, dramatic changes in renal clearing capacity have been documented. The incorporation of this knowledge about the developing kidney has, very recently, resulted in a revised aminoglycoside dosing guideline for use in newborn infants. This article will therefore address the rationale behind this new dosing regimen and also explain why this has resulted in clinically important changes in how to perform therapeutic drug monitoring of aminoglycosides in neonates to ensure safe and effective use of these frequently used medicines in this vulnerable population.

Aminoglycosides have played a major role in antimicrobial therapy since their discovery in the 1940s. Their bactericidal efficacy in gram-negative infections, synergism with beta-lactam antibiotics, limited bacterial resistance, and low cost have given these agents a firm place in antimicrobial treatment. After penicillins, aminoglycosides are the most commonly used drugs in the neonatal intensive care unit. While the pharmacodynamic action on the bacterial target is obviously the same in neonates as compared to children and adults, dramatic differences exist in terms of pharmacokinetics. Renal function is the most important determinant in respect to the elimination of aminoglycosides and, depending on the age and development of the newborn infant, dramatic changes in renal clearing capacity have been documented. The incorporation of this knowledge about the developing kidney has, very recently, resulted in a revised aminoglycoside dosing guideline for use in newborn infants. This article will therefore address the rationale behind this new dosing regimen and also explain why this has resulted in clinically important changes in how to perform therapeutic drug monitoring of aminoglycosides in neonates to ensure safe and effective use of these frequently used medicines in this vulnerable population.