Probenecid inhibits SARS-CoV-2 replication in vivo and in vitro

Effective vaccines are slowing the COVID-19 pandemic, but SARS-CoV-2 will likely remain an issue in the future making it important to have therapeutics to treat patients. There are few options for treating patients with COVID-19. We show probenecid potently blocks SARS-CoV-2 replication in mammalian cells and virus replication in a hamster model. Furthermore, we demonstrate that plasma concentrations up to 50-fold higher than the protein binding adjusted IC(90) value are achievable for 24 h following a single oral dose. These data support the potential clinical utility of probenecid to control SARS-CoV-2 infection in humans

Multi-Locus Phylogeographic and Population Genetic Analysis of Anolis carolinensis: Historical Demography of a Genomic Model Species

The green anole (Anolis carolinensis) has been widely used as an animal model in physiology and neurobiology but has recently emerged as an important genomic model. The recent sequencing of its genome has shed new light on the evolution of vertebrate genomes and on the process that govern species diversification. Surprisingly, the patterns of genetic diversity within natural populations of this widespread and abundant North American lizard remain relatively unknown. In the present study, we use 10 novel nuclear DNA sequence loci (N = 62 to 152) and one mitochondrial locus (N = 226) to delimit green anole populations and infer their historical demography. We uncovered four evolutionarily distinct and geographically restricted lineages of green anoles using phylogenetics, Bayesian clustering, and genetic distance methods. Molecular dating indicates that these lineages last shared a common ancestor ∼2 million years ago. Summary statistics and analysis of the frequency distributions of DNA polymorphisms strongly suggest range-wide expansions in population size. Using Bayesian Skyline Plots, we inferred the timing of population size expansions, which differ across lineages, and found evidence for a relatively recent and rapid westward expansion of green anoles across the Gulf Coastal Plain during the mid-Pleistocene. One surprising result is that the distribution of genetic diversity is not consistent with a latitudinal shift caused by climatic oscillations as is observed for many co-distributed taxa. This suggests that the most recent Pleistocene glacial cycles had a limited impact on the geographic distribution of the green anole at the northern limits of its range

Population pharmacokinetic and pharmacodynamic analysis in allergic diseases

In this chapter, we introduce the concepts and methodologies of population analysis as applied to analyzing pharmacokinetic and pharmacodynamic data. One of the key determining characteristics of the population approach is that through it, one seeks not only to characterize deterministic trends in the data, but also to identify and estimate the magnitudes of the important sources of variability within the data. The first section of this chapter provides an introduction to the primary concepts of, and motivation for, population modeling by way of a hypothetical case study. Then, the various methodologies that have been employed throughout the history of population analysis are described in further detail. Of these, the most commonly employed today is nonlinear mixed-effects (NLME) modeling. Finally, notable examples of the application of population PK and PK/PD modeling to treatments for allergies and asthma are discussed. Population PK models have frequently been used to extrapolate exposures to special populations, such as pediatrics, as well as to optimize treatment regimens and trial designs for these populations. Population PK/PD models have most frequently been applied to analyzing and interpreting data from wheal and flare trials, but are also becoming increasingly important in the analysis of PD data from monoclonal antibodies

Population Pharmacokinetic Modeling and Probability of Pharmacodynamic Target Attainment for Ceftazidime-Avibactam in Pediatric Patients Aged 3 Months and Older.

Increasing prevalence of infections caused by antimicrobial-resistant gram-negative bacteria represents a global health crisis, and while several novel therapies that target various aspects of antimicrobial resistance have been introduced in recent years, few are currently approved for children. Ceftazidime-avibactam is a novel β-lactam β-lactamase inhibitor combination approved for adults and children 3 months and older with complicated intra-abdominal infection, and complicated urinary tract infection or hospital-acquired ventilator-associated pneumonia (adults only in the United States) caused by susceptible gram-negative bacteria. Extensive population pharmacokinetic (PK) data sets for ceftazidime and avibactam obtained during the adult clinical development program were used to iteratively select, modify, and validate the approved adult dosage regimen (2,000-500 mg by 2-hour intravenous (IV) infusion every 8 hours (q8h), with adjustments for renal function). Following the completion of one phase I (NCT01893346) and two phase II ceftazidime-avibactam studies (NCT02475733 and NCT02497781) in children, adult PK data sets were updated with pediatric PK data. This paper describes the development of updated combined adult and pediatric population PK models and their application in characterizing the population PK of ceftazidime and avibactam in children, and in dose selection for further pediatric evaluation. The updated models supported the approval of ceftazidime-avibactam pediatric dosage regimens (all by 2-hour IV infusion) of 50-12.5 mg/kg (maximum 2,000-500 mg) q8h for those ≥6 months to 18 years old, and 40-10 mg/kg q8h for those ≥3 to 6 months old with creatinine clearance > 50 mL/min/1.73 m2

Population pharmacokinetics of cabotegravir following administration of oral tablet and long‐acting intramuscular injection in adult HIV‐1‐infected and uninfected subjects

AimTo characterize cabotegravir population pharmacokinetics using data from phase 1, 2 and 3 studies and evaluate the association of intrinsic and extrinsic factors with pharmacokinetic variability.MethodsAnalyses were implemented in NONMEM and R. Concentrations below the quantitation limit were modelled with likelihood-based approaches. Covariate relationships were evaluated using forward addition (P < .01) and backward elimination (P < .001) approaches. The impact of each covariate on trough and peak concentrations was evaluated through simulations. External validation was performed using prediction-corrected visual predictive checks.ResultsThe model-building dataset included 23 926 plasma concentrations from 1647 adult HIV-1-infected (72%) and uninfected (28%) subjects in 16 studies at seven dose levels (oral 10-60 mg, long-acting [LA] intramuscular injection 200-800 mg). A two-compartment model with first-order oral and LA absorption and elimination adequately described the data. Clearances and volumes were scaled to body weight. Estimated relative bioavailability of oral to LA was 75.6%. Race and age were not significant covariates. LA absorption rate constant (KALA ) was 50.9% lower in females and 47.8% higher if the LA dose was given as two split injections. KALA decreased with increasing BMI and decreasing needle length. Clearance was 17.4% higher in current smokers. The impact of any covariate was ≤32% on trough and peak concentrations following LA administration. The final model adequately predicted 5097 plasma concentrations from 647 subjects who were not included in the model-building dataset.ConclusionsA cabotegravir population pharmacokinetic model was developed that can be used to inform dosing strategies and future study design. No dose adjustment based on subject covariates is recommended

The ecotoxicology of nanoparticles and nanomaterials: current status, knowledge gaps, challenges, and future needs

This paper introduces a special issue on the ecotoxicology and environmental chemistry of nanoparticles (NPs), and nanomaterials (NMs), in the journal Ecotoxicology. There are many types of NMs and the scientific community is making observations on NP ecotoxicity to inform the wider debate about the risks and benefits of these materials. Natural NPs have existed in the environment since the beginning of Earth’s history, and natural sources can be found in volcanic dust, most natural waters, soils and sediments. Natural NPs are generated by a wide variety of geological and biological processes, and while there is evidence that some natural NPs can be toxic, organisms have also evolved in an environment containing natural NPs. There are concerns that natural nano-scale process could be influenced by the presence of pollution. Manufactured NPs show some complex colloid and aggregation chemistry, which is likely to be affected by particle shape, size, surface area and surface charge, as well as the adsorption properties of the material. Abiotic factors such as pH, ionic strength, water hardness and the presence of organic matter will alter aggregation chemistry; and are expected to influence toxicity. The physico-chemistry is essential to understanding of the fate and behaviour of NPs in the environment, as well as uptake and distribution within organisms, and the interactions of NPs with other pollutants. Data on biological effects show that NPs can be toxic to bacteria, algae, invertebrates and fish species, as well as mammals. However, much of the ecotoxicological data is limited to species used in regulatory testing and freshwater organism. Data on bacteria, terrestrial species, marine species and higher plants is particularly lacking. Detailed investigations of absorption, distribution, metabolism and excretion (ADME) remain to be performed on species from the major phyla, although there are some data on fish. The environmental risk assessment of NMs could be performed using the existing tiered approach and regulatory framework, but with modifications to methodology including chemical characterisation of the materials being used. There are many challenges ahead, and controversies (e.g., reference substances for ecotoxicology), but knowledge transfer from mammalian toxicology, colloid chemistry, as well as material and geological sciences, will enable ecotoxicology studies to move forward in this new multi-disciplinary field

The ecotoxicology and chemistry of manufactured nanoparticles

The emerging literature on the ecotoxicity of nanoparticles and nanomaterials is summarised, then the fundamental physico-chemistry that governs particle behaviour is explained in an ecotoxicological context. Techniques for measuring nanoparticles in various biological and chemical matrices are also outlined. The emerging ecotoxicological literature shows toxic effects on fish and invertebrates, often at low mg l−1 concentrations of nanoparticles. However, data on bacteria, plants, and terrestrial species are particularly lacking at present. Initial data suggest that at least some manufactured nanoparticles may interact with other contaminants, influencing their ecotoxicity. Particle behaviour is influenced by particle size, shape, surface charge, and the presence of other materials in the environment. Nanoparticles tend to aggregate in hard water and seawater, and are greatly influenced by the specific type of organic matter or other natural particles (colloids) present in freshwater. The state of dispersion will alter ecotoxicity, but many abiotic factors that influence this, such as pH, salinity, and the presence of organic matter remain to be systematically investigated as part of ecotoxicological studies. Concentrations of manufactured nanoparticles have rarely been measured in the environment to date. Various techniques are available to characterise nanoparticles for exposure and dosimetry, although each of these methods has advantages and disadvantages for the ecotoxicologist. We conclude with a consideration of implications for environmental risk assessment of manufactured nanoparticles