A Lipid Prodrug Strategy Enhances Targeted Protein Degrader CNS Pharmacokinetics.

Targeted protein degraders that recruit the von Hippel-Lindau E3-ligase complex often have poor physicochemical properties, requiring extensive medicinal chemistry optimization prior to use in hypothesis-testing experiments and with few blood-brain barrier permeable examples disclosed. In this study, we systematically examine a panel of fatty acid promoieties as agents to enhance degrader pharmacokinetics and BBB-exposure. We characterize effects on cellular E3-ligase engagement, cellular BRD4 degradation kinetics, murine plasma stability, and murine blood plasma and brain pharmacokinetics and pharmacodynamics.

Variability in Meropenem Distribution and Clearance in Children with Sepsis: Population-Based Pharmacokinetics with Assessment of Renal Biomarkers.

Background And Objective: Meropenem dosing to achieve therapeutic exposure in critically ill children with sepsis is challenging due to a spectrum of renal function, from augmented renal clearance (ARC) to acute kidney injury (AKI). The objective of this study was to define meropenem plasma concentrations and pharmacodynamic exposure metrics in children with septic shock during the first 3 days of PICU hospitalization.

Methods: We prospectively evaluated meropenem clearance (CL) and volume of distribution (V), innovatively assessing renal biomarkers (serum creatinine [SCr], serum cystatin C [SCys], and neutrophil gelatinase-associated lipocalin [SNgal]), in infants aged ≥ 4 weeks and children on intravenous (IV) meropenem 20 mg/kg every 8 h from 2019 to 2023.

Double-Blind, Randomized, Placebo-Controlled, Crossover Study of Oral Cannabidiol and Tetrahydrocannabinol for Essential Tremor.

Background: Essential tremor (ET) is characterized by often disabling action tremors. No pharmacological agent has been developed specifically for symptomatic treatment. Anecdotal reports describe tremor improvement with cannabis, but no evidence exists to support these claims.

-Cystamine: A Deuterated Cystamine Derivative with Improved Anti-Inflammatory and Anti-Fibrotic Activities in a Murine Model of Fibrosing Steatohepatitis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial chronic disease that can progress to metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis, ultimately leading to liver cirrhosis and hepatocellular carcinoma. Oxidative stress is believed to play an important role in the development of MASH. Small aminothiol compounds such as cysteamine and its oxidized precursor, cystamine, are known pleiotropic compounds that exhibit relatively potent antioxidant and other effects.

Clinical Trial to Assess the Safety and Tolerability of Anti-IL 23 Monoclonal Antibody Guselkumab in Patients With Alcohol-Associated Liver Disease.

Background: There are no FDA-approved therapies for alcohol-associated liver disease (ALD). Preclinical studies indicate that blocking IL-23/IL-17 signalling may reverse liver injury. Guselkumab, an IL-23-specific antibody approved for psoriasis, may be beneficial for ALD.

Identification of Substituted 4-Aminocinnolines as Broad-Spectrum Antiparasitic Agents.

Neglected tropical diseases such as Chagas disease, human African trypanosomiasis, leishmaniasis, and schistosomiasis have a significant global health impact in predominantly developing countries, although these diseases are spreading due to increased international travel and population migration. Drug repurposing with a focus on increasing antiparasitic potency and drug-like properties is a cost-effective and efficient route to the development of new therapies. Here we identify compounds that have potent activity against and , and the latter were progressed into the murine model of infection.

Measurement of Whole Blood Tacrolimus Concentrations by LC-MS/MS and Immunoassay Methods: Influence of Immediate-Release vs Extended-Release Tacrolimus Formulations.

Background: Therapeutic drug monitoring of the immunosuppressant tacrolimus is commonly performed by immunoassay or LC-MS/MS. Measurement biases between these methodologies have been characterized for immediate-release tacrolimus (IR-tac; Prograf) but have not been performed for extended-release formulations such as Envarsus. These discrepancies can impact patient care, as appropriate dosing is required to maintain therapeutic concentrations and immunosuppression.

Pharmacokinetics and Safety of Bictegravir in Pregnant and Postpartum Persons With HIV and Their Infants.

Background: Limited data exist on bictegravir pharmacokinetics in pregnancy among persons with HIV (PWH) and infant washout.

Setting: Nonrandomized, open-label, multicenter phase-IV prospective study of bictegravir pharmacokinetics and safety in pregnant PWH and their infants.

Methods: Steady-state 24-hour pharmacokinetic sampling of oral bictegravir 50 mg once daily (a component of fixed-dose combination bictegravir/emtricitabine/tenofovir alafenamide) during the second and third trimesters and postpartum was performed.

Development of a physiologically-based pharmacokinetic model for Ritonavir characterizing exposure and drug interaction potential at both acute and steady-state conditions.

Ritonavir (RTV) is a potent CYP3A inhibitor that is widely used as a pharmacokinetic (PK) enhancer to increase exposure to select protease inhibitors. However, as a strong and complex perpetrator of CYP3A interactions, RTV can also enhance the exposure of other co-administered CYP3A substrates, potentially causing toxicity. Therefore, the prediction of drug-drug interactions (DDIs) and estimation of dosing requirements for concomitantly administered drugs is imperative.

Interaction of milrinone with extracorporeal life support.

Background: Milrinone is commonly prescribed to critically ill patients who need extracorporeal life support such as extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). Currently, the effect of ECMO and CRRT on the disposition of milrinone is unknown.

Methods: Ex vivo ECMO and CRRT circuits were primed with human blood and then dosed with milrinone to study drug extraction by the circuits.

Evaluation of Effective Half-Life and Its Impact on Time to Steady State for Oral MeltDose Tacrolimus (LCPT) in De Novo Kidney Transplant Recipients.

Background: For extended-release drug formulations, effective half-life (t 1/2eff ) is a relevant pharmacokinetic parameter to inform dosing strategies and time to reach steady state. Tacrolimus, an immunosuppressant commonly used for the prophylaxis of organ rejection in transplant patients, is available as both immediate- and extended-release formulations. To the best of our knowledge, the t 1/2eff of tacrolimus from these different formulations has not yet been assessed.

In Vivo Regulation of Small Molecule Natural Products, Antioxidants, and Nutrients by OAT1 and OAT3.

The organic anion transporters OAT1 (SLC22A6) and OAT3 (SLC22A8) are drug transporters that are expressed in the kidney, with well-established roles in the in vivo transport of drugs and endogenous metabolites. A comparatively unexplored potential function of these drug transporters is their contribution to the in vivo regulation of natural products (NPs) and their effects on endogenous metabolism. This is important for the evaluation of potential NP interactions with other compounds at the transporter site.

Distinguishing Molecular Properties of OAT, OATP, and MRP Drug Substrates by Machine Learning.

The movement of organic anionic drugs across cell membranes is partly governed by interactions with SLC and ABC transporters in the intestine, liver, kidney, blood-brain barrier, placenta, breast, and other tissues. Major transporters involved include organic anion transporters (OATs, SLC22 family), organic anion transporting polypeptides (OATPs, SLCO family), and multidrug resistance proteins (MRPs, ABCC family). However, the sets of molecular properties of drugs that are necessary for interactions with OATs (OAT1, OAT3) vs.

Pharmacokinetics, Fecal Output, and Grimace Scores in Rabbits Given Long-acting Buprenorphine or Fentanyl for Postsurgical Analgesia.

The New Zealand white rabbit (Oryctolagus cuniculus) is a frequently used surgical model. Pain management after surgery is a critical aspect of animal welfare. Recently, a long-acting buprenorphine formulation (Ethiqa XR; EXR) was approved for use in rats and mice but has not yet been investigated in rabbits.

Concentrations of remdesivir and GS-441524 in human milk from lactating individuals diagnosed with COVID-19.

Findings from this study provide further reassuring evidence that infant exposure through human milk received from lactating individuals who require treatment with remdesivir is negligible.

Brief Report: Dolutegravir Plasma Protein Binding and Unbound Concentrations During Pregnancy and Postpartum.

Background: Clinical interpretation of the reduced dolutegravir (DTG) plasma concentrations reported during pregnancy is complicated by its high plasma protein binding. Plasma proteins significantly decrease during pregnancy, and understanding changes in DTG protein binding and its therapeutically active unbound concentrations are necessary to evaluate the impact of pregnancy changes on DTG pharmacokinetics.

Methods: Retrospective assessment of plasma samples from pregnant women living with HIV enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s study receiving 50 mg DTG film-coated tablets once daily as part of clinical care.

Directed evolution unlocks oxygen reactivity for a nicotine-degrading flavoenzyme.

The flavoenzyme nicotine oxidoreductase (NicA2) is a promising injectable treatment to aid in the cessation of smoking, a behavior responsible for one in ten deaths worldwide. NicA2 acts by degrading nicotine in the bloodstream before it reaches the brain. Clinical use of NicA2 is limited by its poor catalytic activity in the absence of its natural electron acceptor CycN.

Cannabidiol Exposure Through Maternal Marijuana Use: Predictions in Breastfed Infants.

Background And Objective: Knowledge about exposure to cannabidiol (CBD) in breastfed infants can provide an improved understanding of potential risk. The aim was to predict CBD exposure in breastfed infants from mothers taking CBD and CBD-containing products.

Methods: Cannabidiol concentrations in milk previously attained from data collected through an existing human milk research biorepository were used to simulate infant doses and identify subgroups.

Evaluation of bumetanide as a potential therapeutic agent for Alzheimer's disease.

Therapeutics discovery and development for Alzheimer's disease (AD) has been an area of intense research to alleviate memory loss and the underlying pathogenic processes. Recent drug discovery approaches have utilized computational strategies for drug candidate selection which has opened the door to repurposing drugs for AD. Computational analysis of gene expression signatures of patients stratified by the APOE4 risk allele of AD led to the discovery of the FDA-approved drug bumetanide as a top candidate agent that reverses APOE4 transcriptomic brain signatures and improves memory deficits in APOE4 animal models of AD.

Translating Clinical Pharmacology Data in Pregnancy to Evidence-Based Guideline Recommendations: Perspectives From the HIV Field.

Pharmacokinetic (PK) studies in pregnant, postpartum, and breastfeeding people are critical to informing appropriate medication use and dosing. A key component of translating PK results in these complex populations into clinical practice involves the systematic review and interpretation of data by guideline panels, composed of clinicians, scientists, and community members, to leverage available data for informed decision making by clinicians and patients and offer clinical best practices. Interpretation of PK data in pregnancy involves evaluation of multiple factors such as the study design, target population, and type of sampling performed.

Variable Delta-9-Tetrahydrocannabinol Pharmacokinetics and Pharmacodynamics After Cannabis Smoking in Regular Users.

Background: Despite its federally restricted status, cannabis is widely used medicinally and recreationally. The pharmacokinetics (PK) and central nervous system (CNS) effects of tetrahydrocannabinol (THC), the major psychoactive cannabinoid, are not well understood. The objective of this study was to develop a population PK model of inhaled THC, including sources of variability, and to conduct an exploratory analysis of potential exposure-response relationships.

Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis.

Ferroptosis is a regulated form of cell death associated with the iron-dependent accumulation of phospholipid hydroperoxides. Inducing ferroptosis is a promising approach to treat therapy-resistant cancer. Ferroptosis suppressor protein 1 (FSP1) promotes ferroptosis resistance in cancer by generating the antioxidant form of coenzyme Q10 (CoQ).

Comparative Pharmacokinetics and Injection Site Histopathology in Nude Mice Treated with Long-acting Buprenorphine Formulations.

Two long-acting formulations of buprenorphine are commercially available as analgesics for rodents. However, these drugs have not yet been studied in nude mice. We sought to investigate whether the manufacturer-recommended or labeled mouse doses of either drug would provide and sustain the purported therapeutic plasma concentration of buprenorphine (1 ng/mL) over 72 h in nude mice and to characterize the injection site histopathology.