Prospective study of serum and ionized magnesium pharmacokinetics in the treatment of children with severe acute asthma.

PURPOSE: Intravenous (IV) magnesium sulfate (MgSO4) is clinically useful as adjunct therapy in treating acute asthma exacerbations. Despite its clinical utility, the disposition of magnesium in children is poorly described. The purpose of this study is to describe the pharmacokinetics (PK) of ionized and total serum magnesium following IV MgSO4 administration in children with severe acute asthma. METHODS: Thirty-two children receiving 50 mg/kg IV MgSO4 for acute asthma exacerbations at Primary Children's Hospital in Salt Lake City, UT, were prospectively enrolled in the study. Blood samples were collected before, as well as 30 min and 2 h after each child's IV MgSO4 dose, and used to determine total serum and ionized magnesium concentrations. The collected data were analyzed using population PK techniques using NONMEM® software. RESULTS: Total serum magnesium concentrations were used to externally validate our previously published model constructed with retrospective data (median prediction error 10.3%, median absolute prediction error 18.1%). The mean (%CV) observed endogenous ionized magnesium concentration was calculated to be 6.0 mg/L (12%), approximately one third of the same value for endogenous total serum magnesium (17.6 mg/L (22%)) in this dataset. Weight was a significant predictor of both clearance and volume in a population PK model describing ionized magnesium concentrations. No adverse events were observed in this pediatric cohort. CONCLUSIONS: This prospective study supports and extends our previous PK analysis of total serum magnesium concentrations. Ionized and total serum magnesium followed similar PK profiles following IV MgSO4 administration in children. A single bolus infusion of IV MgSO4 was safe in this small sample of children receiving it for acute asthma.

The impact of exposure to antidepressant medications during pregnancy on neonatal outcomes: a review of retrospective database cohort studies.

INTRODUCTION: Concerns with prescription antidepressant use in pregnant women have instigated the examination of potential associations between fetal exposure to antidepressant medication and outcomes including preterm delivery, congenital malformations, perinatal and post-natal adverse events, persistent pulmonary hypertension, and mortality. The retrospective cohort model is an often utilized study design. The objective of this review is to evaluate the literature on antidepressant use in pregnancy conducted as retrospective cohorts in national/regional medical, or claims databases that assess neonatal and infant outcomes for agreement between studies, ultimately providing a methodological and outcomes summary for future scientific endeavors. METHODS: PubMed was searched for literature relating to antidepressant use and infant outcomes from the earliest available date through July 15, 2016. Studies with a retrospective cohort design and conducted in national/regional medical or claims databases were included. Searched outcomes included preterm delivery, congenital malformations, low birth weight, small for gestational age, persistent pulmonary hypertension of the newborn, and other select adverse events comprising low Apgar score (5 min), convulsions/seizures, respiratory distress/problems, fetal mortality, and infant mortality. RESULTS: Of the 784 studies identified, 36 retrospective cohort studies met eligibility criteria. An increase in preterm delivery and respiratory distress/problems and no increase in congenital malformation or fetal and infant death were associated with prenatal use of prescription antidepressants by majority consensus (at least 2/3 [67%] of studies). CONCLUSIONS: While consensus indicates that perinatal prescription antidepressant use has consequences for the fetus and infant, there are notable inconsistencies in the literature. More investigations that address prenatal exposure to depression and other important covariates are needed.

The Biomechanical Effects of Resuscitation Colloids on the Compromised Lung Endothelial Glycocalyx.

BACKGROUND: The endothelial glycocalyx is an important component of the vascular permeability barrier, forming a scaffold that allows serum proteins to create a gel-like layer on the endothelial surface and transmitting mechanosensing and mechanotransduction information that influences permeability. During acute inflammation, the glycocalyx is degraded, changing how it interacts with serum proteins and colloids used during resuscitation and altering its barrier properties and biomechanical characteristics. We quantified changes in the biomechanical properties of lung endothelial glycocalyx during control conditions and after degradation by hyaluronidase using biophysical techniques that can probe mechanics at (1) the aqueous/glycocalyx interface and (2) inside the glycocalyx. Our goal was to discern the location-specific effects of albumin and hydroxyethyl starch (HES) on glycocalyx function. METHODS: The effects of albumin and HES on the mechanical properties of bovine lung endothelial glycocalyx were studied using a combination of atomic force microscopy and reflectance interference contrast microscopy. Logistic regression was used to determine the odds ratios for comparing the effects of varying concentrations of albumin and HES on the glycocalyx with and without hyaluronidase. RESULTS: Atomic force microscopy measurements demonstrated that both 0.1% and 4% albumin increased the thickness and reduced the stiffness of glycocalyx when compared with 1% albumin. The effect of HES on glycocalyx thickness was similar to albumin, with thickness increasing significantly between 0.1% and 1% HES and a trend toward a softer glycocalyx at 4% HES. Reflectance interference contrast microscopy revealed a concentration-dependent softening of the glycocalyx in the presence of albumin, but a concentration-dependent increase in stiffness with HES. After glycocalyx degradation with hyaluronidase, stiffness was increased only at 4% albumin and 1% HES. CONCLUSIONS: Albumin and HES induced markedly different effects on glycocalyx mechanics and had notably different effects after glycocalyx degradation by hyaluronidase. We conclude that HES is not comparable with albumin for studies of vascular permeability and glycocalyx-dependent signaling. Characterizing the molecular and biomechanical effects of resuscitation colloids on the glycocalyx should clarify their indicated uses and permit a better understanding of how HES and albumin affect vascular function.

Effects of Chicory (Cichorium intybus L.) Extract on Male Rat Reproductive System, Pregnancy and Offspring Development.

BACKGROUND: We recently reported that extract prepared from the aerial part of Cichorium intybus L. (CE) possesses hepatoprotective, hypolipidemic, and hypoglycemic properties. This paper focuses on the effects of CE on the male rat reproductive system and the effects of this treatment on pregnancy and offspring development. METHODS: The experimental male rats received 100 mg/kg bw/day, 500 mg/kg bw/day, and 1000 mg/kg bw/day of CE orally for 60 consecutive days. Rats that received tap water were used as controls. After treatment, we evaluated the effects of CE on the male reproductive system, fertility, and offspring development. RESULTS: For CE-treated male rats, there was a significant increase in the (1) diameter of seminiferous tubules, (2) spermatogenic index, (3) number of total and motile spermatozoa, and (4) testosterone levels. Additionally, there was a decrease in the pre- and post-implantation death of the embryos in the CE-treated group. All pups born from CE-treated males demonstrated normal development. CONCLUSIONS: CE treatment significantly improved male reproductive functions. No adverse effects on pregnancy and offspring development were observed when males were treated with CE. Further clinical evaluation of CE should lead to the development of a safe and effective phytodrug for treating male infertility.

Results of a Pilot Trial Assessing the Effects of Proper Oral Hygiene and a Probiotic Dietary Supplement on Oral Health in Volunteers with Oral Malodor.

Persistent malodor affects many people worldwide and is usually associated with poor dental hygiene. This pilot trial aimed to determine whether proper dental hygiene (DH) and a probiotic dietary supplement support oral health in volunteers with persistent malodor. Volunteers (n = 35) were randomly assigned to the probiotic or placebo cohort. The probiotic cohort (n = 20) brushed and flossed their teeth twice daily and used probiotics for 30 days; the placebo cohort (n = 15) followed the same hygiene practices and used the placebo. The intervention phase was followed by a 30-day follow-up period. Measured outcomes were malodor and tongue-coating scores, probiotic DNA levels, salivary cytokines, and salivary pH. DH and probiotics significantly decreased malodor (~50% during intervention) and tongue coating scores (~45% during intervention). These changes remained through the course of the trial. The probiotic DNA levels increased in the probiotic cohort and dropped in the placebo cohort after the intervention started. The malodor moderately correlated with the tongue coating P. acidilactici level. The addition of probiotics increased IL-10 levels during the intervention and decreased IL-8, TNF-α, and IL-6 by the end of the study. People with malodor may benefit from using DH and probiotics. Additional trials are needed to definitively establish the benefits of probiotic dietary supplements.

Current use of complementary and conventional medicine for treatment of pediatric patients with gastrointestinal disorders.

Infants, children, and adolescents are at risk of experiencing a multitude of gastrointestinal disorders (GID). These disorders can adversely affect the quality of life or be life-threatening. Various interventions that span the conventional and complementary therapeutic categories have been developed. Nowadays, parents increasingly seek complementary options for their children to use concurrently with conventional therapies. Due to the high prevalence and morbidity of diarrhea, constipation, and irritable bowel syndrome (IBS) in children, in this review, we decided to focus on the current state of the evidence for conventional and complementary therapies used for the treatment of these diseases in children. Diarrhea treatment focuses on the identification of the cause and fluid management. Oral rehydration with supplementation of deficient micronutrients, especially zinc, is well established and recommended. Some probiotic strains have shown promise in reducing the duration of diarrhea. For the management of constipation, available clinical trials are insufficient for conclusive recommendations of dietary modifications, including increased use of fruit juice, fiber, and fluid. However, the role of laxatives as conventional treatment is becoming more established. Polyethylene glycol is the most studied, with lactulose, milk of magnesia, mineral oil, bisacodyl, and senna presenting as viable alternatives. Conventional treatments of the abdominal pain associated with IBS are poorly studied in children. Available studies investigating the effectiveness of antidepressants on abdominal pain in children with IBS were inconclusive. At the same time, probiotics and peppermint oil have a fair record of benefits and safety. The overall body of evidence indicates that a careful balance of conventional and complementary treatment strategies may be required to manage gastrointestinal conditions in children.

Drug exposure during pregnancy: Current understanding and approaches to measure maternal-fetal drug exposure.

Prescription drug use is prevalent during pregnancy, yet there is limited knowledge about maternal-fetal safety and efficacy of this drug use because pregnant individuals have historically been excluded from clinical trials. Underrepresentation has resulted in a lack of data available to estimate or predict fetal drug exposure. Approaches to study fetal drug pharmacology are limited and must be evaluated for feasibility and accuracy. Anatomic and physiological changes throughout pregnancy fluctuate based on gestational age and can affect drug pharmacokinetics (PK) for both mother and fetus. Drug concentrations have been studied throughout different stages of gestation and at or following delivery in tissue and fluid biospecimens. Sampling amniotic fluid, umbilical cord blood, placental tissue, meconium, umbilical cord tissue, and neonatal hair present surrogate options to quantify and characterize fetal drug exposure. These sampling methods can be applied to all therapeutics including small molecule drugs, large molecule drugs, conjugated nanoparticles, and chemical exposures. Alternative approaches to determine PK have been explored, including physiologically based PK modeling, in vitro methods, and traditional animal models. These alternative approaches along with convenience sampling of tissue or fluid biospecimens can address challenges in studying maternal-fetal pharmacology. In this narrative review, we 1) present an overview of the current understanding of maternal-fetal drug exposure; 2) discuss biospecimen-guided sampling design and methods for measuring fetal drug concentrations throughout gestation; and 3) propose methods for advancing pharmacology research in the maternal-fetal population.

Use of reflectance interference contrast microscopy to characterize the endothelial glycocalyx stiffness.

Reflectance interference contrast microscopy (RICM) was used to study the mechanics of the endothelial glycocalyx. This technique tracks the vertical position of a glass microsphere probe that applies very light fluctuating loads to the outermost layer of the bovine lung microvascular endothelial cell (BLMVEC) glycocalyx. Fluctuations in probe vertical position are used to estimate the effective stiffness of the underlying layer. Stiffness was measured before and after removal of specific glycocalyx components. The mean stiffness of BLMVEC glycocalyx was found to be ~7.5 kT/nm(2) (or ~31 pN/nm). Enzymatic digestion of the glycocalyx with pronase or hyaluronan with hyaluronidase increased the mean effective stiffness of the glycocalyx; however, the increase of the mean stiffness on digestion of heparan sulfate with heparinase III was not significant. The results imply that hyaluronan chains act as a cushioning layer to distribute applied forces to the glycocalyx structure. Effective stiffness was also measured for the glycocalyx exposed to 0.1%, 1.0%, and 4.0% BSA; glycocalyx compliance increased at two extreme BSA concentrations. The RICM images indicated that glycocalyx thickness increases with BSA concentrations. Results demonstrate that RICM is sensitive to detect the subtle changes of glycocalyx compliance at the fluid-fiber interface.

Medication based machine learning to identify subpopulations of pediatric hemodialysis patients in an electronic health record database.

Electronic health records (EHRs) have given rise to large and complex databases of medical information that have the potential to become powerful tools for clinical research. However, differences in coding systems and the detail and accuracy of the information within EHRs can vary across institutions. This makes it challenging to identify subpopulations of patients and limits the widespread use of multi-institutional databases. In this study, we leveraged machine learning to identify patterns in medication usage among hospitalized pediatric patients receiving renal replacement therapy and created a predictive model that successfully differentiated between intermittent (iHD) and continuous renal replacement therapy (CRRT) hemodialysis patients. We trained six machine learning algorithms (logistical regression, Naïve Bayes, k-nearest neighbor, support vector machine, random forest, and gradient boosted trees) using patient records from a multi-center database (n = 533) and prescribed medication ingredients (n = 228) as features to discriminate between the two hemodialysis types. Predictive skill was assessed using a 5-fold cross-validation, and the algorithms showed a range of performance from 0.7 balanced accuracy (logistical regression) to 0.86 (random forest). The two best performing models were further tested using an independent single-center dataset and achieved 84-87% balanced accuracy. This model overcomes issues inherent within large databases and will allow us to utilize and combine historical records, significantly increasing population size and diversity within both iHD and CRRT populations for future clinical studies. Our work demonstrates the utility of using medications alone to accurately differentiate subpopulations of patients in large datasets, allowing codes to be transferred between different coding systems. This framework has the potential to be used to distinguish other subpopulations of patients where discriminatory ICD codes are not available, permitting more detailed insights and new lines of research.

Examination of Complementary Medicine for Treating Urinary Tract Infections Among Pregnant Women and Children.

Urinary tract infections (UTIs) are a significant clinical problem that pregnant women and children commonly experience. Escherichia coli is the primary causative organism, along with several other gram-negative and gram-positive bacteria. Antimicrobial drugs are commonly prescribed to treat UTIs in these patients. Conventional treatment can range from using broad-spectrum antimicrobial drugs for empirical or prophylactic therapy or patient-tailored therapy based on urinary cultures and sensitivity to prospective antibiotics. The ongoing emergence of multi-drug resistant pathogens has raised concerns related to commonly prescribed antimicrobial drugs such as those used routinely to treat UTIs. Consequently, several natural medicines have been explored as potential complementary therapies to improve health outcomes in patients with UTIs. This review discusses the effectiveness of commonly used natural products such as cranberry juice/extracts, ascorbic acid, hyaluronic acid, probiotics, and multi-component formulations intended to treat and prevent UTIs. The combination of natural products with prescribed antimicrobial treatments and use of formulations that contained high amounts of cranberry extracts appear to be most effective in preventing recurrent UTIs (RUTIs). The incorporation of natural products like cranberry, hyaluronic acid, ascorbic acid, probiotics, Canephron® N, and Cystenium II to conventional treatments of acute UTIs or as a prophylactic regimen for treatment RUTIs can benefit both pregnant women and children. Limited information is available on the safety of natural products in these patients' populations. However, based on limited historical information, these remedies appear to be safe and well-tolerated by patients.

Development of a Generic Physiologically-Based Pharmacokinetic Model for Lactation and Prediction of Maternal and Infant Exposure to Ondansetron via Breast Milk.

Ondansetron is commonly used in breastfeeding mothers to treat nausea and vomiting. There is limited information in humans regarding safety of ondansetron exposure to nursing infants and no adequate study looking at ondansetron pharmacokinetics during lactation. We developed a generic physiologically-based pharmacokinetic lactation model for small molecule drugs and applied this model to predict ondansetron transfer into breast milk and characterize infant exposure. Drug-specific model inputs were parameterized using data from the literature. Population-specific inputs were derived from a previously conducted systematic literature review of anatomic and physiologic changes in postpartum women. Model predictions were evaluated using ondansetron plasma and breast milk concentration data collected prospectively from 78 women in the Commonly Used Drugs During Lactation and infant Exposure (CUDDLE) study. The final model predicted breast milk and plasma exposures following a single 4 mg dose of intravenous ondansetron in 1,000 simulated women who were 2 days postpartum. Model predictions showed good agreement with observed data. Breast milk median prediction error (MPE) was 18.4% and median absolute prediction error (MAPE) was 53.0%. Plasma MPE was 32.5% and MAPE was 43.2%. The model-predicted daily and relative infant doses were 0.005 mg/kg/day and 3.0%, respectively. This model adequately predicted ondansetron passage into breast milk. The calculated low relative infant dose indicates that mothers receiving ondansetron can safely breastfeed. The model building blocks and population database are open-source and can be adapted to other drugs.

Stiffness and heterogeneity of the pulmonary endothelial glycocalyx measured by atomic force microscopy.

The mechanical properties of endothelial glycocalyx were studied using atomic force microscopy with a silica bead (diameter ∼18 µm) serving as an indenter. Even at indentations of several hundred nanometers, the bead exerted very low compressive pressures on the bovine lung microvascular endothelial cell (BLMVEC) glycocalyx and allowed for an averaging of stiffness in the bead-cell contact area. The elastic modulus of BLMVEC glycocalyx was determined as a pointwise function of the indentation depth before and after enzymatic degradation of specific glycocalyx components. The modulus-indentation depth profiles showed the cells becoming progressively stiffer with increased indentation. Three different enzymes were used: heparinases III and I and hyaluronidase. The main effects of heparinase III and hyaluronidase enzymes were that the elastic modulus in the cell junction regions increased more rapidly with the indentation than in BLMVEC controls, and that the effective thickness of glycocalyx was reduced. Cytochalasin D abolished the modulus increase with the indentation. The confocal profiling of heparan sulfate and hyaluronan with atomic force microscopy indentation data demonstrated marked heterogeneity of the glycocalyx composition between cell junctions and nuclear regions.

Treatment optimization of maintenance immunosuppressive agents in pediatric renal transplant recipients.

Introduction: Graft survival in pediatric kidney transplant patients has increased significantly within the last three decades, correlating with the discovery and utilization of new immunosuppressants as well as improvements in patient care. Despite these developments in graft survival for patients, there is still improvement needed, particularly in long-term care in pediatric patients receiving grafts from deceased donor patients. Maintenance immunosuppressive therapies have narrow therapeutic indices and are associated with high inter-individual and intra-individual variability.Areas covered: In this review, we examine the impact of pharmacokinetic variability on renal transplantation and its association with age, genetic polymorphisms, drug-drug interactions, drug-disease interactions, renal insufficiency, route of administration, and branded versus generic drug formulation. Pharmacodynamics are outlined in terms of the mechanism of action for each immunosuppressant, potential adverse effects, and the utility of pharmacodynamic biomarkers.Expert opinion: Acquiring abetter quantitative understanding of immunosuppressant pharmacokinetics and pharmacodynamic components should help clinicians implement treatment regimens to maintain the balance between therapeutic efficacy and drug-related toxicity.

Valuable Hepatoprotective Plants - How Can We Optimize Waste Free Uses of Such Highly Versatile Resources?

Humans used plants for thousand of years as food, drugs, or fuel to keep homes warm. People commonly used fruits and roots, and other parts of the plant were often wasted. This review aims to discuss the potential of rational stem-to-stern use of three highly versatile and valuable plants with hepatoprotective properties. Milk thistle (Silybum marianum L. Gaertn.), artichoke (Cynara cardunculus), and chicory (Cichorium intybus L.) have well-characterized hepatoprotective properties. These plants have been chosen since liver diseases are significant diseases of concern worldwide, and all parts of plants can be potentially utilized. Artichoke and chicory are commonly used as food or dietary supplements and less often as phytodrugs. Various dietary supplements and phytodrugs prepared from milk thistle (MT) fruits/seeds are well-known to consumers as remedies supporting liver functions. However, using these plants as functional food, farm animal feed, is not well-described in the literature. We also discuss bioactive constituents present in various parts of these plants, their pharmacological properties. Distinct parts of MT, artichoke, and chicory can be used to prepare remedies and food for humans and animals. Unused plant parts are potentially wasted. To achieve waste-free use of these and many other plants, the scientific community needs to analyze the complex use of plants and propose strategies for waste-free technologies. The government must stimulate companies to utilize by-products. Another problem associated with plant use as a food or source of phytodrug is the overharvesting of wild plants. Consequently, there is a need to use more active cultivation techniques for plants.

Effects of a new thyrotropic drug isolated from Potentilla alba on the male reproductive system of rats and offspring development.

BACKGROUND: The dysfunction of the thyroid gland is a common medical condition. Nowadays, patients frequently use medicinal herbs as complementary or alternative options to conventional drug treatments. These patients may benefit from treatment of thyroid dysfunctions with Potentilla alba L. preparations. While it has been reported that Potentilla alba preparations have low toxicity, nothing is known about their ability to affect reproductive functions in patients of childbearing age. METHODS: Male Wistar rats were orally treated with a thyrotrophic botanical drug, standardized Potentilla alba Dry Extract (PADE), at doses 8 and 40 times higher than the median therapeutic dose recommended for the clinical trials, for 60 consecutive days. Male Wistar rats receiving water (H2O) were used as controls. After completing treatment, half of the PADE-treated and control males were used to determine PADE gonadotoxicity, and the remaining half of PADE-treated and control males were mated with intact females. Two female rats were housed with one male for two estrus cycles. PADE effects on fertility and fetal/offspring development were evaluated. RESULTS: Herein, we report that oral treatment of male Wistar rats with PADE before mating with intact females instigated marked effects on male reproductive organs. Treatment significantly decreased the motility of the sperm and increased the number of pathological forms of spermatozoa. Additionally, a dose-dependent effect on Leydig cells was observed. However, these PADE effects did not significantly affect male fertility nor fetal and offspring development when PADE-treated males were mated with intact females. CONCLUSIONS: PADE treatment of male rates negatively affected sperm and testicular Leydig cell morphology. However, these changes did not affect male fertility and offspring development. It is currently not known whether PADE treatment may affect human male fertility and offspring development. Therefore, these results from an animal study need to be confirmed in humans. Results from this animal study can be used to model the exposure-response relationship and adverse outcomes in humans.

How can we improve the safe use of herbal medicine and other natural products? A clinical pharmacologist mission.

INTRODUCTION: Three major classes of natural products (NPs) for medicinal purposes or improving wellbeing are generally available in the US: conventional drugs of herbal origin, botanical drugs, and dietary supplements (DSs). Consumer consumption of DSs is growing annually. The U.S. FDA regulates conventional and botanical drugs for safety and efficacy; however, DSs are minimally regulated. AREAS COVERED: This article will: i) highlight the importance of NP as a significant source of prescription drugs; ii) discuss differences in the regulation of conventional drugs of NP product, botanical drugs, and DSs; iii) discuss the safety and efficacy of DSs and iv) make recommendations for improvement of safety for minimally regulated NPs. EXPERT OPINION: Toxicities associated with the use of NPs, including vitamins and DSs, are mainly due to excessive use and interactions with conventional drug(s) and may represent challenges for clinicians. Conventional and botanical-based prescription drugs are rarely associated with unknown toxicities. However, DSs are minimally regulated and can produce severe adverse effects. We believe that clinical pharmacologists can have a role in developing criteria for DS safety analysis. There is also the potential for a standardized NP stewardship program(s) and the development of NP policies and practices nationally and globally.

Therapeutic Potential of Citrulline as an Arginine Supplement: A Clinical Pharmacology Review.

Supplemental arginine has shown promise as a safe therapeutic option to improve endogenous nitric oxide (NO) regulation in cardiovascular diseases associated with endothelial dysfunction. In clinical studies in adults, L-arginine, an endogenous amino acid, was reported to improve cardiovascular function in hypertension, pulmonary hypertension, preeclampsia, angina, and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome. L-citrulline, a natural precursor of L-arginine, is more bioavailable than L-arginine because it avoids hepatic first-pass metabolism and has a longer circulation time. Although not yet well-studied, arginine/citrulline has immense therapeutic potential in some life-threatening diseases in children. However, the optimal clinical development of arginine or citrulline in children requires more information about pharmacokinetics and exposure-response relationships at appropriate ages and under relevant disease states. This article summarizes the preclinical and clinical studies of arginine/citrulline in both adults and children, including currently available pharmacokinetic information. The pharmacology of arginine/citrulline is confounded by several patient-specific factors such as variations in baseline arginine/citrulline due to developmental ages and disease states. Currently available pharmacokinetic studies are insufficient to inform the optimal design of clinical studies, especially in children. Successful bench-to-bedside clinical translation of arginine supplementation awaits information from well-designed pharmacokinetic/pharmacodynamic studies, along with pharmacometric approaches.

Pediatric Age Groups and Approach to Studies.

Pediatric clinical trials are often requested according to specific age ranges. In the past and still today, these ages may correspond to developmental stages, such as newborn, infancy, childhood, and adolescence. Selection of ages for pediatric participation in medication studies should correspond to ages of rapid changes in pharmacokinetics and pharmacodynamics. Age-related changes in several enzymes involved in drug metabolism and glomerular filtration are described as examples of optimal ages for study of specific drugs according to their pathways of disposition.

Use of Herbal Medicine by Pregnant Women: What Physicians Need to Know.

About 80% of the consumers worldwide use herbal medicine (HMs) or other natural products. The percentage may vary significantly (7%-55%) among pregnant women, depending upon social status, ethnicity, and cultural traditions. This manuscript discusses the most common HMs used by pregnant women, and the potential interactions of HMs with conventional drugs in some medical conditions that occur during pregnancy (e.g., hypertension, asthma, epilepsy). It also includes an examination of the characteristics of pregnant HM consumers, the primary conditions for which HMs are taken, and a discussion related to the potential toxicity of HMs taken during pregnancy. Many cultures have used HMs in pregnancy to improve wellbeing of the mother and/or baby, or to help decrease nausea and vomiting, treat infection, ease gastrointestinal problems, prepare for labor, induce labor, or ease labor pains. One of the reasons why pregnant women use HMs is an assumption that HMs are safer than conventional medicine. However, for pregnant women with pre-existing conditions like epilepsy and asthma, supplementation of conventional treatment with HMs may further complicate their care. The use of HMs is frequently not reported to healthcare professionals. Providers are often not questioning HM use, despite little being known about the HM safety and HM-drug interactions during pregnancy. This lack of knowledge on potential toxicity and the ability to interact with conventional treatments may impact both mother and fetus. There is a need for education of women and their healthcare professionals to move away from the idea of HMs not being harmful. Healthcare professionals need to question women on whether they use any HMs or natural products during pregnancy, especially when conventional treatment is less efficient and/or adverse events have occurred as herbal-drug interactions could be the reason for these observations. Additionally, more preclinical and clinical studies are needed to evaluate HM efficacy and toxicity.