Effectiveness of atropine in managing sialorrhea: A systematic review and meta-analysis.

OBJECTIVES: To describe the efficacy of atropine in controlling salivary flow in patients with sialorrhea or drooling. MATERIALS AND METHODS: We included randomized controlled studies, quasi-randomized trials, case reports, clinical trials, systematic reviews, and meta-analyses assessing the use of atropine in patients with sialorrhea or drooling. The endpoints were reduction in salivary flow rate, amount of saliva secreted, reduction in clinical symptoms of sialorrhea, death rattle intensity, or reduction in drooling intensity as measured by an objective scale such as the drooling intensity scale. RESULTS: A total of 56 studies with 2,378 patients were included in the systematic review. The underlying disease states included brain injury, amyotrophic lateral sclerosis, cerebral palsy, clozapine- and perphenazine-induced sialorrhea, Parkinson's disease, and terminal illness. The routes of atropine administration included sublingual, intravenous, subcutaneous, oral tablet or solution, and direct injection of atropine into parotid glands or at the base of the tongue. The generalized estimated equation regression models showed that sublingual administration is superior to oral and subcutaneous routes. CONCLUSION: Atropine is efficacious in managing sialorrhea in most disease states. Sublingual administration of atropine is superior to other routes of administration in reducing salivary flow in patients with sialorrhea.

Mapping the Evidence for Opioid-Mediated Changes in Malignancy and Chemotherapeutic Efficacy: Protocol for a Scoping Review.

BACKGROUND: Numerous reports contend opioids can augment or inhibit malignancy. At present, there is no consensus on the risk or benefit posed by opioids on malignancy or chemotherapeutic activity. Distinguishing the consequences of opioid use from pain and its management is challenging. Additionally, opioid concentration data is often lacking in clinical studies. A scoping review approach inclusive of preclinical and clinical data will improve our understanding of the risk-benefit relationship concerning commonly prescribed opioids and cancer and cancer treatment. OBJECTIVE: The aim of the study is to map diverse studies spanning from preclinical to clinical regarding opioids with malignancy and its treatment. METHODS: This scoping review will use the Arksey six stages framework to (1) identify the research question; (2) identify relevant studies; (3) select studies meeting criteria; (4) extract and chart data; (5) collate, summarize, and report results; and (6) conduct expert consultation. An initial pilot study was undertaken to (1) parameterize the extent and scale of existing data for an evidence review, (2) identify key factors to be extracted in systematic charting efforts, and (3) assess opioid concentration as a variable for its relevance to the central hypothesis. Six databases will be searched with no filters: MEDLINE, Embase, CINAHL Complete, Cochrane Library, Biological Sciences Collection, and International Pharmaceutical Abstracts. Trial registries will include ClinicalTrials.gov, Cochrane CENTRAL, International Standard Randomised Controlled Trial Number Registry, European Union Clinical Trials Register, and World Health Organization International Clinical Trials Registry. Eligibility criteria will include preclinical and clinical study data on opioids effects on tumor growth or survival, or alteration on the antineoplastic activity of chemotherapeutics. We will chart data on (1) opioid concentration from human subjects with cancer, yielding a "physiologic range" to better interpret available preclinical data; (2) patterns of opioid exposure with disease and treatment-related patient outcomes; and (3) the influence of opioids on cancer cell survival, as well as opioid-related changes to cancer cell susceptibility for chemotherapeutics. RESULTS: This scoping review will present results in narrative forms as well as with the use of tables and diagrams. Initiated in February 2021 at the University of Utah, this protocol is anticipated to generate a scoping review by August 2023. The results of the scoping review will be disseminated through scientific conference proceedings and presentations, stakeholder meetings, and by publication in a peer-reviewed journal. CONCLUSIONS: The findings of this scoping review will provide a comprehensive description of the consequences of prescription opioids on malignancy and its treatment. By incorporating preclinical and clinical data, this scoping review will invite novel comparisons across study types that could inform new basic, translational, and clinical studies regarding risks and benefits of opioid use among patients with cancer. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/38167.

Dronabinol Prescribing and Exposure Among Children and Young Adults Diagnosed with Cancer.

Purpose: The therapeutic utility of Cannabis in cancer is a topic of intense interest. Dronabinol is synthetic Δ9-tetrahydrocannabinol (THC), the primary psychoactive component of Cannabis sativa, and is approved for treating refractory chemotherapy-induced nausea and vomiting. Little is known about dronabinol prescribing in children and young adults, and no published concentration data are available. This study evaluated national level dronabinol use and assessed concentrations of THC and its primary metabolites in patients with cancer <27 years of age prescribed dronabinol. Methods: Observational review of records from the Pediatric Health Information System (PHIS) and a regional network of hospitals in the Intermountain West, including a tertiary care children's hospital, Primary Children's Hospital (PCH), for inpatients <27 years of age prescribed dronabinol. Prospective blood samples were collected from children with cancer at PCH. Results: Across PHIS institutions, overall dronabinol prescribing aligned with the pharmacy records for those with cancer (p < 0.0001), and of these, 10.4% received dronabinol as inpatients. Blood collected within 72 hours of dronabinol administration was available from 10 children with a median age of 12.5 (range 6-17) years. Quantifiable concentrations were found in 4 (13%), 6 (20%), and 1 (3%) samples assayed for THC, 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (COOH-THC), and 11-hydroxy-Δ9-tetrahydrocannabinol (OH-THC), respectively. THC concentrations ranged between 0.100 and 0.128 ng/mL and were not associated with dose. Conclusion: Dronabinol prescribing appears exclusive to patients diagnosed with cancer, and its use has increased steadily in the past decade. In a small sample of children administered dronabinol, THC and metabolite concentrations were consistently low or undetectable.

Predicting Resolvin D1 Pharmacokinetics in Humans with Physiologically-Based Pharmacokinetic Modeling.

Sjögren's syndrome (SS) is an autoimmune disease with no effective treatment options. Resolvin D1 (RvD1) belongs to a class of lipid-based specialized pro-resolving mediators that showed efficacy in preclinical models of SS. We developed a physiologically-based pharmacokinetic (PBPK) model of RvD1 in mice and optimized the model using plasma and salivary gland pharmacokinetic (PK) studies performed in NOD/ShiLtJ mice with SS-like features. The predictive performance of the PBPK model was also evaluated with two external datasets from the literature reporting RvD1 PKs. The PBPK model adequately captured the observed concentrations of RvD1 administered at different doses and in different species. The PKs of RvD1 in virtual humans were predicted using the verified PBPK model at various doses (0.01-10 mg/kg). The first-in-human predictions of RvD1 will be useful for the clinical trial design and translation of RvD1 as an effective treatment strategy for SS.

Supportive care medications coinciding with chemotherapy among children with hematologic malignancy.

Pharmacokinetic (PK) conflicts can arise between supportive care medications (SCM) and chemotherapy in children with hematologic malignancy (HM). In this retrospective study, medical records for children (28 days-18 years) diagnosed with HM and receiving an SCM antimicrobial were collected from a hospital network between 1 May 2000 and 31 December 2014. PK drug-gene associations were obtained from a curated pharmacogenomics database. Among 730 patients (median age of 7.5 (IQR 3.7-13.9) years), primarily diagnosed with lymphoid leukemia (52%), lymphoma (28%), or acute myeloid leukemia (16%), chemotherapy was administered in 2846 hospitalizations. SCM accounted for 90.5% (n = 448) of distinct drugs with 93% (n = 679) of children, receiving ≥5 different SCM/hospitalization. Same-day SCM/chemotherapeutic PK gene overlap occurred in 48.3% of hospitalizations and was associated with age (p = 0.026), number of SCM, HM subtype, surgery, and hematopoietic stem cell transplant (p < 0.0001). A high and variable SCM burden among children with HM receiving chemotherapy poses a risk for unanticipated PK conflicts.

Pharmacokinetics, pharmacodynamics and pharmacogenetics associated with nonsteroidal anti-inflammatory drugs and opioids in pediatric cancer patients.

INTRODUCTION: Advancing appropriate and adequate analgesic pharmacotherapy in pediatric patients with cancer is an area of clinical need. Few studies have been performed to evaluate the selection of an analgesic and appropriate dosing corresponding to analgesic effect among pediatric cancer patients. This review describes information related to pharmacokinetic, pharmacodynamic, and pharmacogenomic (when applicable) considerations for analgesics that are commonly used to manage pain experienced by pediatric patients with cancer. Areas covered: Analgesics commonly used to treat pediatric patients with malignancy patterned after the World Health Organization's 'analgesic ladder' for cancer pain management. Expert opinion: Addressing pain management safely and effectively in pediatric patients with cancer will require advances in both drug development, to increase the armament of analgesics available for children, and our pharmacologic understanding of those analgesics in current use. However, performing the necessary types of studies to develop new analgesics, or gain knowledge of existing therapy, within a population that is relatively small, diverse, and who experience pain originating from a variety of sources, is a tremendous challenge.

Herbal medicines: challenges in the modern world. Part 4. Canada and United States.

INTRODUCTION: Similar to other nations North American people used herbs for thousands of years to treat diseases and purify their spirits. By the middle of the 1900s, evidence-based conventional medicine received wide acceptance in Canada and the United States (US). Nowadays, people are going back to their roots and actively using herbal medicines (HMs) and natural health products (NHPs). Areas covered: This article is focusing on use and regulation of the HMs and NHPs in Canada and the US, raises concerns regarding HM and NHP safety and efficacy, offers suggestions on how to overcome these problems. Materials available from legislative and governmental websites, PubMed and news media were used. Expert commentary: Use of HMs, especially dietary supplements is widespread among adults in Canada and US. HMs and NHPs are regulated in both countries, but minimum criteria for product approval and post-market surveillance have been set. Concerns of quality, contamination, adulteration, and efficacy in are of central importance in the discussion of HMs and NHPs. Detailed product description and research are of vital importance to ensure safety and efficacy of these products. Additionally, 'herbal' education of healthcare providers and patients is needed to guarantee further successful integration of HM and conventional medicines.

Pharmacodynamic studies of voriconazole: informing the clinical management of invasive fungal infections.

INTRODUCTION: Voriconazole is a broad-spectrum antifungal agent commonly used to treat invasive fungal infections (IFI), including aspergillosis, candidiasis, Scedosporium infection, and Fusarium infection. IFI often occur in immunocompromised patients, leading to increased morbidity and mortality. AREAS COVERED: The objective of this review is to summarize the pharmacodynamic properties of voriconazole and to provide considerations for potential optimal dosing strategies. Studies have demonstrated superior clinical response when an AUC/MIC >25 or Cmin/MIC >1 is attained in adult patients, correlating to a trough concentration range as narrow as 2-4.5 mg/L; however, these targets are poorly established in the pediatric population. Topics in this discussion include voriconazole use in multiple age groups, predisposing patient factors for IFI, and considerations for clinicians managing IFI. Expert commentary: The relationship between voriconazole dosing and exposure is not well defined due to the large inter- and intra-subject variability. Development of comprehensive decision support tools for individualizing dosing, particularly in children who require higher dosing, will help to increase the probability of achieving therapeutic efficacy and decrease sub-therapeutic dosing and adverse events.

A propensity-matched cohort study of vancomycin-associated nephrotoxicity in neonates.

BACKGROUND: The incidence of nephrotoxicity among vancomycin-treated neonates has been reported to range from 2% to 20%. These widely varying estimates have led to confusion and controversy regarding the safety of vancomycin among neonates. OBJECTIVE: Evaluate the incidence of nephrotoxicity among neonates receiving vancomycin concomitantly with gentamicin. DESIGN: Retrospective observational cohort study using propensity score matching to provide covariate balance between neonates who did or did not receive vancomycin based on factors known to be related to the development of renal dysfunction. SETTING: Hospitals (n=22) throughout the Intermountain West, including a quaternary care children's hospital. PATIENTS: Neonates ≤44 postmenstrual weeks (median gestational age: 31 (IQR 28-36) weeks) receiving intravenous gentamicin with or without exposure to vancomycin from January 2006 to December 2012. MAIN OUTCOME MEASURES: Nephrotoxicity based on the modified Acute Kidney Injury Network criteria for acute kidney injury (AKI) or serum creatinine concentration ≥1.5 mg/dL persisting for ≥48 h. RESULTS: The final cohort was comprised of 1066 neonates (533 receiving vancomycin and gentamicin vs 533 receiving gentamicin). In a propensity score-matched cohort that was well balanced across 16 covariates, AKI was not associated with vancomycin use (16 neonates receiving vancomycin vs 7 controls experienced AKI; OR 1.5; 95% CI 0.6 to 4.0). However, the presence of a patent ductus arteriosus, concomitant non-steroidal anti-inflammatory drug use, ≥1 positive blood cultures, low birth weight and higher severity of illness and risk of mortality scores were associated with an increased risk of nephrotoxicity. CONCLUSIONS: These results corroborate several earlier reports and much anecdotal evidence describing the infrequent occurrence of nephrotoxicity in neonates receiving concomitant vancomycin and gentamicin.

Renal Function Descriptors in Neonates: Which Creatinine-Based Formula Best Describes Vancomycin Clearance?

Growth and maturational changes have been identified as significant covariates in describing variability in clearance of renally excreted drugs such as vancomycin. Because of immaturity of clearance mechanisms, quantification of renal function in neonates is of importance. Several serum creatinine (SCr)-based renal function descriptors have been developed in adults and children, but none are selectively derived for neonates. This review summarizes development of the neonatal kidney and discusses assessment of the renal function regarding estimation of glomerular filtration rate using renal function descriptors. Furthermore, identification of the renal function descriptors that best describe the variability of vancomycin clearance was performed in a sample study of a septic neonatal cohort. Population pharmacokinetic models were developed applying a combination of age-weight, renal function descriptors, or SCr alone. In addition to age and weight, SCr or renal function descriptors significantly reduced variability of vancomycin clearance. The population pharmacokinetic models with Léger and modified Schwartz formulas were selected as the optimal final models, although the other renal function descriptors and SCr provided reasonably good fit to the data, suggesting further evaluation of the final models using external data sets and cross validation. The present study supports incorporation of renal function descriptors in the estimation of vancomycin clearance in neonates.

Pharmacokinetic considerations in the use of antivirals in neonates.

INTRODUCTION: Neonatal patients, because of the inability of their immune system to properly respond to microbial challenge, are highly susceptible to viral infections. Immunoglobulins, monoclonal antibody and antiviral drugs are used for prophylaxis and treatment of viral diseases in neonates. Neonates and, especially, preterm infants differ in drug absorption, distribution, metabolism and excretion from adults and older children. AREAS COVERED: This review will evaluate deficiencies of neonatal immune responses to microbial challenge that predispose newborns to viral infections, clinical manifestations and the treatment of viral diseases in neonates. We focus on published studies describing antiviral drug pharmacokinetics in neonates and make recommendations on the dosing of these drugs, allowing achievement of maximal clinical benefits in neonates. EXPERT OPINION: While some efforts were undertaken to study pharmacokinetics and pharmacodynamics of antiviral drugs, much more needs to be done. Current data indicate that the pharmacokinetics of antiviral drugs may vary significantly depending on gestational age, maturation processes of drug-metabolizing enzymes and renal clearance. Specifics of pharmacokinetics of antiviral drugs need to be taken into consideration when they are prescribed to neonates and infants.

Special population considerations and regulatory affairs for clinical research.

Special populations, including women (non-pregnant and pregnant), pediatrics, and the elderly, require additional consideration with regard to clinical research. There are very specific regulatory laws, which protect these special populations, that need to be understood and adhered to in order to perform clinical research. This review provides a broad overview of some of the physiological differences in special populations and discusses how these differences may affect study design and regulatory considerations. These various special populations, with respect to regulatory affairs, are clearly defined within the Code of Federal Regulations. The definition of "special population" exists to provide enhanced awareness of their vulnerabilities, thereby allowing the creation of regulatory guidance aimed to decrease injury or outright harm. Currently, progress is being made to be more inclusive of special populations in clinical trials. This reflects changing attitudes towards drug information, with it being more representative of those patients that will ultimately be prescribed or exposed to the therapy. However, all research undertaken in these populations should be performed in a manner that ensures all protections of each participant are upheld.

Pediatric vancomycin dosing: Trends over time and the impact of therapeutic drug monitoring.

Monitoring of vancomycin trough concentrations is recommended for pediatric patients in the product label and by several professional societies. However, among a network of freestanding children's hospitals vancomycin therapeutic drug monitoring (TDM) practices were reported to be highly variable. In this study, we sought to evaluate whether trends in vancomycin use and TDM changed across a large healthcare delivery system in Utah and Idaho from 2006 to 2012. Children ≤18 years who received ≥2 vancomycin doses were included. Overall, vancomycin TDM was performed during 5,035 (80%) of 6,259 hospital encounters, in which 85,442 doses were administered and 7,935 concentrations were obtained. Across this time period, the median trough concentration increased from 10.9 to 13.7 µg/mL (P < .001), which temporally coincided with recommendations published by the Infectious Disease Society of America that recommend targeting higher trough concentrations. Two or more abnormally low trough concentrations were accompanied by an increase in the dose 75% of the time. Similarly, ≥2 abnormally high trough concentrations were followed by a decrease in the dose 35% of the time. In aggregate, these data suggest that vancomycin TDM is commonly performed among children and the majority of abnormal trough concentrations were associated with an appropriate modification to the dosing regimen.

An extensive pharmacokinetic, metabolic and toxicological review of elderly patients under intensive chemotherapy for acute myeloid leukemia.

INTRODUCTION: Acute myeloid leukemia (AML) is a clonal hematological malignancy characterized by accumulation of poorly differentiated and immature blast cells in bone marrow and blood circulation. The initiation of intensive chemotherapy is necessary to control further progression of the disease. Therapeutic success is less common in older patients (> 65 years) than it is in younger patients with AML. Cytarabine in combination with an anthracycline has been the mainstays of AML therapy for many years and continues to serve as the foundation for the current standard therapeutic regimen. AREAS COVERED: This review discusses the pharmacokinetic (PK), metabolic and toxicological issues associated with antileukemic agents used to treat elderly patients (> 60 years) with AML. EXPERT OPINION: Profound and predictable changes often occur with age and can have effects on drug metabolism, PK and toxicity with consequences bearing on overall efficacy. Few studies focus specifically on elderly patients with AML, but modifications to intensive induction therapy may be beneficial as the current number and rate of individuals achieving complete remission of the disease remains low. Therapeutic options, for the treatment of AML, have remained static for many years, but it has become clear that among elderly patients with AML, improved antileukemic therapy is greatly needed.

Vancomycin pharmacokinetic models: informing the clinical management of drug-resistant bacterial infections.

This review aims to critically evaluate the pharmacokinetic literature describing the use of vancomycin in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Guidelines recommend that trough concentrations be used to guide vancomycin dosing for the treatment of MRSA infections; however, numerous in vitro, animal model and clinical studies have demonstrated that the therapeutic effectiveness of vancomycin is best described by the area under the concentration versus time curve (AUC) divided by the minimum inhibitory concentration (MIC) of the infecting organism (AUC/MIC). Among patients with lower respiratory tract infections, an AUC/MIC ≥400 was associated with a superior clinical and bacteriological response. Similarly, patients with MRSA bacteremia who achieved an Etest AUC/MIC ≥320 within 48 h were 50% less likely to experience treatment failure. For other patient populations and different clinical syndromes (e.g., children, the elderly, patients with osteomyelitis, etc.), pharmacokinetic/pharmacodynamic studies and prospective clinical trials are needed to establish appropriate therapeutic targets.

Epidemiological Evaluation of Blood Culture Patterns among Neonates Receiving Vancomycin.

The objective of this study was to assess the frequency of blood culture (BC) collection among neonates who received vancomycin. Demographic, clinical, microbiologic, and pharmacy data were collected for 1275 neonates (postnatal age 0-27 days) who received vancomycin at an Intermountain Healthcare facility between 1/2006 and 9/2011. Neonates treated with vancomycin had a BC collected 94 % (n = 1198) of the time, of which 37 % (n = 448) grew one or more bacterial organisms (BC positive). Of these, 1 % (n = 5) grew methicillin-resistant Staphylococcus aureus (MRSA), 71 % (n = 320) grew coagulase-negative Staphylococci (CoNS), 9 % (n = 40) grew methicillin-sensitive Staphylococcus aureus (MSSA), and 22 % (n = 97) grew other bacterial species (total exceeds 100 % due to co-detection). In patients with negative BC or no BC, vancomycin therapy was extended beyond 72 h 52 % of the time. The median duration of vancomycin therapy for patients with a negative BC was 4 (IQR: 2-10) days. BCs were frequently obtained among neonates who received vancomycin. Vancomycin therapy beyond the conventional 'empiric' treatment window of 48-72 h was common without isolation of resistant gram-positive bacteria.

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. ß-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 ß-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.

Pharmacokinetics and pharmacodynamics of antifungals in children and their clinical implications.

Invasive fungal infections are a significant cause of morbidity and mortality in children. Successful management of these systemic infections requires identification of the causative pathogen, appropriate antifungal selection, and optimisation of its pharmacokinetic and pharmacodynamic properties to maximise its antifungal activity and minimise toxicity and the emergence of resistance. This review highlights salient scientific advancements in paediatric antifungal pharmacotherapies and focuses on pharmacokinetic and pharmacodynamic studies that underpin current clinical decision making. Four classes of drugs are widely used in the treatment of invasive fungal infections in children, including the polyenes, triazoles, pyrimidine analogues and echinocandins. Several lipidic formulations of the polyene amphotericin B have substantially reduced the toxicity associated with the traditional amphotericin B formulation. Monotherapy with the pyrimidine analogue flucytosine rapidly promotes the emergence of resistance and cannot be recommended. However, when used in combination with other antifungal agents, therapeutic drug monitoring of flucytosine has been shown to reduce high peak flucytosine concentrations, which are strongly associated with toxicity. The triazoles feature large inter-individual pharmacokinetic variability, although this pattern is less pronounced with fluconazole. In clinical trials, posaconazole was associated with fewer adverse effects than other members of the triazole family, though both posaconazole and itraconazole display erratic absorption that is influenced by gastric pH and the gastric emptying rate. Limited data suggest that the clinical response to therapy may be improved with higher plasma posaconazole and itraconazole concentrations. For voriconazole, pharmacokinetic studies among children have revealed that children require twice the recommended adult dose to achieve comparable blood concentrations. Voriconazole clearance is also affected by the cytochrome P450 (CYP) 2C19 genotype and hepatic impairment. Therapeutic drug monitoring is recommended as voriconazole pharmacokinetics are highly variable and small dose increases can result in marked changes in plasma concentrations. For the echinocandins, the primary source of pharmacokinetic variability stems from an age-dependent decrease in clearance with increasing age. Consequently, young children require larger doses per kilogram of body weight than older children and adults. Routine therapeutic drug monitoring for the echinocandins is not recommended. The effectiveness of many systemic antifungal agents has been correlated with pharmacodynamic targets in in vitro and in murine models of invasive candidiasis and aspergillosis. Further study is needed to translate these findings into optimal dosing regimens for children and to understand how these agents interact when multiple antifungal agents are used in combination.

Characteristics and publication patterns of obstetric studies registered in ClinicalTrials.gov.

Physiologic changes during pregnancy alter the pharmacokinetics, safety, and efficacy of many drugs. For clinicians, there is often uncertainty regarding the safety of these drugs due to a scarcity of published data. This study aimed to comprehensively evaluate the characteristics and publication patterns of obstetric studies registered in ClinicalTrials.gov from 2007 to 2012. Primary outcome measures, funding sources, inclusion criteria, and the reporting of study results were evaluated. A manual review of Medline/PubMed was performed to identify publications associated with studies registered in ClinicalTrials.gov. Of 93,709 total studies, there were 5,203 (6%) obstetric studies registered in ClinicalTrials.gov. Interventional studies accounted for 70% and 30% were observational. Clinical trials of drugs (49%), procedures (13%), and behavioral interventions (12%) were most common. Among interventional drug trials, 84% featured randomized allocation to study arms and 93% included measures of safety and/or efficacy as primary endpoints. Of 946 (18%) studies completed more than 2 years ago, only 11% had reported results and <7% had been published. In an area with a great need for evidence of safe and effective therapies, the low publication rate of completed studies incorporating elements of high-quality trial design is concerning. The sources of this trend should be closely investigated.