Alpha-2-adrenergic agonists reduce resting energy expenditure in humans during external cooling.

Intravenous alpha-2-adrenergic receptor agonists reduce energy expenditure and lower the temperature when shivering begins in humans, allowing a decrease in core body temperature. Because there are few data about similar effects from oral drugs, we tested whether single oral doses of the sedative dexmedetomidine (1 µg/kg sublingual or 4 µg/kg swallowed) or the muscle relaxant tizanidine (8 mg or 16 mg), combined with surface cooling, reduce energy expenditure and core body temperature in humans. A total of 26 healthy participants completed 41 one-day laboratory studies measuring core body temperature using an ingested telemetry capsule and measuring energy expenditure using indirect calorimetry for up to 6 hours after drug ingestion.

A Population Pharmacokinetic Assessment of the Effect of Food on Selumetinib in Patients with Neurofibromatosis Type 1-Related Plexiform Neurofibromas and Healthy Volunteers.

Selumetinib is clinically used for pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas. Until recently, selumetinib had to be taken twice daily, after 2 hours of fasting and followed by 1 hour of fasting, which could be inconvenient. This population analysis evaluated the effect of low- and high-fat meals on the pharmacokinetic (PK) parameters of selumetinib and its active metabolite N-desmethyl selumetinib.

Hemorheological, cardiorespiratory, and cerebrovascular effects of pentoxifylline following acclimatization to 3,800 m.

Pentoxifylline is a nonselective phosphodiesterase inhibitor used for the treatment of peripheral artery disease. Pentoxifylline acts through cyclic adenosine monophosphate, thereby enhancing red blood cell deformability, causing vasodilation and decreasing inflammation, and potentially stimulating ventilation. We conducted a double-blind, placebo-controlled, crossover, counter-balanced study to test the hypothesis that pentoxifylline could lower blood viscosity, enhance cerebral blood flow, and decrease pulmonary artery pressure in lowlanders following 11-14 days at 3,800 m.

Complement blockade with eculizumab for treatment of severe Coronavirus Disease 2019 in pregnancy: A case series.

Problem: We evaluated eculizumab, a complement protein C5 inhibitor, for treatment of severe COVID-19 in pregnant and postpartum individuals.

Method Of Study: Protocol ECU-COV-401 (clinicaltrials.gov NCT04355494) is an open label, multicenter, Expanded Access Program (EAP), evaluating eculizumab for treatment of severe COVID-19.

Eculizumab Pharmacokinetics and Pharmacodynamics in Patients With Generalized Myasthenia Gravis.

To investigate the pharmacokinetics, pharmacodynamics, and exposure-response of the approved 900/1,200 mg dosing regimen for the terminal complement component 5 (C5) inhibitor eculizumab in patients with generalized myasthenia gravis (gMG). The analysis used data from 62 patients aged ≥ 18 years with anti-acetylcholine receptor (AChR) antibody-positive refractory gMG who received eculizumab during the REGAIN study (ClinicalTrials.gov: NCT01997229).

Pharmacokinetic and Pharmacodynamic Evaluation of Ravulizumab in Adults with Severe Coronavirus Disease 2019.

Introduction: Terminal complement amplification is hypothesized to be a key contributor to the clinical manifestations of severe coronavirus disease 2019 (COVID-19). Ravulizumab, a humanized monoclonal antibody that binds with high affinity to complement protein C5 and inhibits terminal complement activation, is being evaluated as a treatment for COVID-19-related severe pneumonia, acute lung injury, and acute respiratory distress syndrome in an ongoing phase 3 randomized controlled trial (ALXN1210-COV-305). To address the overactivation of terminal complement in severe COVID-19 compared to the diseases in which ravulizumab is currently approved, a modified dosing regimen was adopted.

São Paulo State Liver Transplantation Supply Chain Study.

Background: The number of liver transplantations is increasing worldwide, and Brazil ranks in the second position. It has one of the biggest public health care systems, which is responsible for the coordination and financial funding of transplantation procedures. Meeting the demands of such a large system of transplantation has become a challenge, particularly when attempting to minimize costs of scarce and expensive resources.

Solid Organ Transplantation Activities Evolution in Brazil: Analysis of 20 Years.

Background: From 1968 until 1997, transplantation-related activities were not properly regulated and were informally practiced. During 20 years, many legal and political changes influenced it.

Objective: To provide a historical overview of the 20 years with a descriptive data analysis of a 20-year data set.

Bioactivity Improvement of Olea europaea Leaf Extract Biotransformed by Wickerhamomyces anomalus Enzymes.

Olive leaves represent a quantitatively significant by-product of agroindustry. They are rich in phenols, mainly oleuropein, which can be hydrolyzed into several bioactive compounds, including hydroxytyrosol. In this study, water extract from olive leaves 'Biancolilla' was analyzed for polyphenol profile, DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging activity and protective effect on differentiated Caco-2 cells.

Olive Leaf Extract from Sicilian Cultivar Reduced Lipid Accumulation by Inducing Thermogenic Pathway during Adipogenesis.

Olive leaves contain a wide variety of phenolic compounds belonging to phenolic acids, phenolic alcohols, flavonoids, and secoiridoids, and include also many other pharmacological active compounds. They could play an important role in human diet and health because of their ability to lower blood pressure, increase coronary arteries blood flow and decrease the risk of cardiovascular diseases. The aim of this study was to investigate the effect of olive leaf extract (OLE) from Sicilian cultivar on adipogenic differentiation of human adipose derived mesenchymal stem cells and its impact on lipid metabolism.

Stochastic nonlinear mixed effects: a metformin case study.

In nonlinear mixed effect (NLME) modeling, the intra-individual variability is a collection of errors due to assay sensitivity, dosing, sampling, as well as model misspecification. Utilizing stochastic differential equations (SDE) within the NLME framework allows the decoupling of the measurement errors from the model misspecification. This leads the SDE approach to be a novel tool for model refinement.

Effect of talc addition on the extraction yield and quality of extra virgin olive oils from Coratina cultivar after production and during storage.

An experimental investigation was carried out with the aim to evaluate the effect of talc on the extraction yield and quality of extra virgin olive oils from Coratina olives after production and during storage. A significant effect of talc, added in the malaxer, on both yield and oil quality was observed. The addition of 1% talc lead to a 15% decrease of the residual oil in the olive-pomace, while higher amounts of talc did not determine further significant variations.

Modeling and simulation of bone mineral density response from a phase 2 study of ONO-5334, a new cathepsin K inhibitor, to support dose selection in osteoporosis.

ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this modeling study were to (1) develop exposure-response (E-R) models to relate ONO-5334 exposure to bone mineral density (BMD), (2) predict BMD responses to various doses of ONO-5334 for both immediate release tablet (IRT) and sustained release tablet (SRT) formulations where only BMD response after administration of IRT had been studied to date, (3) inform selection of appropriate formulation/dose using simulation for future clinical trials. A population pharmacokinetic (PK) model was developed to simultaneously analyze data for both IRT and SRT.

Population pharmacokinetic modeling and dosing simulations of nitrogen-scavenging compounds: disposition of glycerol phenylbutyrate and sodium phenylbutyrate in adult and pediatric patients with urea cycle disorders.

Sodium phenylbutyrate and glycerol phenylbutyrate mediate waste nitrogen excretion in the form of urinary phenylacetylglutamine (PAGN) in patients with urea cycle disorders (UCDs); rare genetic disorders characterized by impaired urea synthesis and hyperammonemia. Sodium phenylbutyrate is approved for UCD treatment; the development of glycerol phenylbutyrate afforded the opportunity to characterize the pharmacokinetics (PK) of both compounds. A population PK model was developed using data from four Phase II/III trials that collectively enrolled patients ages 2 months to 72 years.

Pharmacology and safety of glycerol phenylbutyrate in healthy adults and adults with cirrhosis.

Unlabelled: Phenylbutyric acid (PBA), which is approved for treatment of urea cycle disorders (UCDs) as sodium phenylbutyrate (NaPBA), mediates waste nitrogen excretion via combination of PBA-derived phenylacetic acid with glutamine to form phenylactylglutamine (PAGN) that is excreted in urine. Glycerol phenylbutyrate (GPB), a liquid triglyceride pro-drug of PBA, containing no sodium and having favorable palatability, is being studied for treatment of hepatic encephalopathy (HE). In vitro and clinical studies have been performed to assess GPB digestion, safety, and pharmacology in healthy adults and individuals with cirrhosis.

Position paper on fatal abusive head injuries in infants and young children.

This article represents the work of the National Association of Medical Examiners Ad Hoc Committee on shaken baby syndrome. Abusive head injuries include injuries caused by shaking as well as impact to the head, either by directly striking the head or by causing the head to strike another object or surface. Because of anatomic and developmental differences in the brain and skull of the young child, the mechanisms and types of injuries that affect the head differ from those that affect the older child or adult.

Simulation of clinical trials.

Computer simulation of clinical trials has evolved over the past two decades from a simple instructive game to "full" simulation models yielding pharmacologically sound, realistic trial outcomes. The need to make drug development more efficient and informative and the awareness that many industries make extensive use of simulation in product development have advanced considerably the use of simulation of clinical trials in pharmaceutical product development over the past decade. The structural and stochastic components of trial simulation models are explained as a prelude to a listing of representative simulation projects, reflecting investigative applications of statistical methods, trial design comparisons, and full simulation of new drugs being developed.

Features and toxicokinetics of clozapine in overdose.

One hundred patients were commenced on clozapine in the Hunter region of Australia from July 1993 to September 1995. Of these, one ingested clozapine as a self-poisoning on two occasions. Over the same period, there were four other self-poisonings with clozapine in the region.

Human papillomavirus screening in pediatric victims of sexual abuse.

Objective: To evaluate for the presence of subclinical human papillomavirus (HPV) in cases of suspected sexual abuse in children.

Design: Prospective data collection via interviews, physical examination, colposcopic examination, and tissue sampling by a surface swab technique.

Setting: A total of 40 pediatric patients ranging in age from 1 to 16 years who were referred to the Special Assessment and Management Clinic at Cardinal Glennon Children's Hospital, St Louis, MO, for probable or confirmed sexual abuse.

Persistent pseudohypoaldosteronism in a 7-year-old boy.

Pseudohypoaldosteronism has been described as a syndrome presenting early in life with profound salt wastage, failure to thrive, and lethargy. The mechanism of sodium loss is renal, not related to aldosterone production. Previous cases have been transient, responding to supplemental salt therapy which was discontinued after one to two years.