Research priorities towards precision antibiotic therapy to improve patient care.

Antibiotic resistance presents an incessant threat to our drug armamentarium that necessitates novel approaches to therapy. Over the past several decades, investigation of pharmacokinetic and pharmacodynamic (PKPD) principles has substantially improved our understanding of the relationships between the antibiotic, pathogen, and infected patient. However, crucial gaps in our understanding of the pharmacology of antibacterials and their optimal use in the care of patients continue to exist; simply attaining antibiotic exposures that are considered adequate based on traditional targets can still result in treatment being unsuccessful and resistance proliferation for some infections.

Microdialysis sampling to monitor target-site vancomycin concentrations in septic infants: a feasible way to close the knowledge gap.

Unlabelled: This work is dedicated to the memory of Hartmut Derendorf (1953-2020), a pioneer of modern pharmacokinetics and valued mentor of this project.

Objectives: Septic infants/neonates need effective antibiotic exposure, but dosing recommendations are challenging as the pharmacokinetics in this age are highly variable. For vancomycin, which is used as a standard treatment, comprehensive pharmacokinetic knowledge especially at the infection site is lacking.

Pharmacokinetics and Determination of Tumor Interstitial Distribution of a Therapeutic Monoclonal Antibody Using Large-Pore Microdialysis.

R7072 is a fully human monoclonal antibody (mAb) exerting anti-tumor activity via blockade of insulin like growth factor 1 receptor. The tumoral interstitial concentrations are anticipated to be better surrogates of active site concentrations than commonly used serum concentrations for pharmacokinetic-pharmacodynamic correlation of anti-tumor mAbs. Previously, a large-pore microdialysis technique for measuring tissue interstitial concentrations of R7072 in non-tumor bearing mice was established.

Model-Informed Drug Development for Anti-Infectives: State of the Art and Future.

Model-informed drug development (MIDD) has a long and rich history in infectious diseases. This review describes foundational principles of translational anti-infective pharmacology, including choice of appropriate measures of exposure and pharmacodynamic (PD) measures, patient subpopulations, and drug-drug interactions. Examples are presented for state-of-the-art, empiric, mechanistic, interdisciplinary, and real-world evidence MIDD applications in the development of antibacterials (review of minimum inhibitory concentration-based models, mechanism-based pharmacokinetic/PD (PK/PD) models, PK/PD models of resistance, and immune response), antifungals, antivirals, drugs for the treatment of global health infectious diseases, and medical countermeasures.

Tobacco smoke exposure enhances reward sensitivity in male and female rats.

Rationale: Systemic administration of the tobacco smoke constituent nicotine stimulates brain reward function in rats. However, it is unknown if the inhalation of tobacco smoke affects brain reward function.

Objectives: These experiments investigated if exposure to smoke from high-nicotine SPECTRUM research cigarettes increases reward function and affects the rewarding effects of nicotine in adult male and female Wistar rats.

Plasma l-indospicine and 3-nitropropionic acid in ponies fed creeping indigo: Comparison with results from an episode of presumptive creeping indigo toxicosis.

Background: Creeping indigo (Indigofera spicata) toxicosis is an emerging problem among horses in Florida and bordering states.

Objectives: To quantify the putative toxins l-indospicine (IND) and 3-nitropropionic acid (NPA) in creeping indigo collected from multiple sites and to measure plasma toxin concentrations in ponies fed creeping indigo and horses with presumptive creeping indigo toxicosis.

Study Design: Experimental descriptive study with descriptive observational field investigation.

Evaluation of the Effects of Maytenus ilicifolia on the Activities of Cytochrome P450 3A and P-glycoprotein.

Background: Maytenus ilicifolia is a Brazilian popular medicine commonly used to treat ulcer and gastritis. Despite the absence of toxicity regarding its consumption, possible interactions when co-administrated with conventional drugs, are unknown.

Objective: This study aimed to evaluate the effects of M.

Excessive lysosomal ion-trapping of hydroxychloroquine and azithromycin.

A recent report identified significant reductions or disappearance of viral load in COVID-19 patients given a combination of hydroxychloroquine and azithromycin. The present communication discusses some common pharmacokinetic properties of these two drugs that may be linked to a potential underlying mechanism of action for these antiviral effects. The physicochemical properties of both hydroxychloroquine and azithromycin are consistent with particularly high affinity for the intracellular lysosomal space, which has been implicated as a target site for antiviral activity.

Calculated initial parenteral treatment of bacterial infections: Pharmacokinetics and pharmacodynamics.

This is the third chapter of the guideline "Calculated initial parenteral treatment of bacterial infections in adults - update 2018" in the 2 updated version. The German guideline by the Paul-Ehrlich-Gesellschaft für Chemotherapie e.V.

Carvacrol loaded nanostructured lipid carriers as a promising parenteral formulation for leishmaniasis treatment.

Leishmaniasis are a group of neglected infectious diseases caused by protozoa of the genus Leishmania with distinct presentations. The available leishmaniasis treatment options are either expensive and/or; cause adverse effects and some are ineffective for resistant Leishmania strains. Therefore, molecules derived from natural products as the monoterpene carvacrol, have attracted interest as promising anti-leishmania agents.

Pharmacokinetic and Pharmacodynamic Characterization of Tetrahydrocannabinol-Induced Cannabinoid Dependence After Chronic Passive Cannabis Smoke Exposure in Rats.

Cannabis is the most widely used illicit drug in the US, and cannabis use among young adults continues to rise. Previous studies have shown that chronic administration of delta 9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, induces dependence in animal models. Because smoking is the most frequent route of THC self-administration, it is critical to investigate the effects of cannabis smoke inhalation.

Medications in Space: In Search of a Pharmacologist's Guide to the Galaxy.

Medications have been used during space missions for more than half a century, yet our understanding of the effects of spaceflight on drug pharmacokinetics and pharmacodynamics is poor. The space environment induces time-dependent alterations in human physiology that include fluid shifts, cardiovascular deconditioning, bone and muscle density loss, and impaired immunity. This review presents the current knowledge on the physiological effects of spaceflight that can translate into altered drug disposition and activity and eventually to inadequate treatment.

Determination of Dermal Pharmacokinetics by Microdialysis Sampling in Rats.

The evaluation of absorption and availability at the site of action of a drug candidate is an important element of drug discovery and development, as clinical response is a function of the bioavailability of the active agent and its continued presence at the site of action. Evaluation of dermal pharmacokinetics facilitates the selection of new compounds or chemical structures for advancement as possible clinical candidates. An advantage of microdialysis is that it allows the measurement of compound concentrations at the site of action without disturbing the tissue milieu, making it possible to determine the relationship between this important variable and plasma concentrations of the agent.

Impact of Ethnicity-Specific Hepatic Microsomal Scaling Factor, Liver Weight, and Cytochrome P450 (CYP) 1A2 Content on Physiologically Based Prediction of CYP1A2-Mediated Pharmacokinetics in Young and Elderly Chinese Adults.

Background: The vast majority of physiological and biological data required for physiologically based predictions are primarily available in Caucasians rather than other ethnic populations, which leads to a lack of confidence in the application of physiologically based pharmacokinetic (PBPK) modeling for ethnicity-specific prediction of pharmacokinetics in the Chinese population.

Objectives: In this study we recalibrate the system parameters of Chinese-specific PBPK modeling and explore for the first time the relative importance of ethnicity-specific microsomal protein per gram of liver (MPPGL), liver weight, and cytochrome P450 (CYP) 1A2 abundance to the projection of drug disposition mediated by CYP1A2 in young and elderly Chinese adults.

Methods: Chinese MPPGL levels and associated variability were parameterized and incorporated for the first time into ethnicity-specific PBPK models for the Chinese adults.

Gastric-acid-mediated drug-drug interactions with direct-acting antiviral medications for hepatitis C virus infection: clinical relevance and mitigation strategies.

Drug-drug interactions (DDIs) between direct-acting antiviral (DAA) medications and acid-reducing agents mediated by gastric acid represent an important issue in drug development and treatment, which could lead to impaired bioavailability and subtherapeutic plasma concentrations of DAA drugs and subsequently compromised treatment outcomes. However, identification of clinically relevant drug interactions associated with elevated gastric pH is not well characterized. Here, we present the first comprehensive analysis of the gastric-acid-mediated drug interactions with all novel DAA medications by analyzing and revisiting in vitro data, prospective DDI trials and retrospective assessments based upon Phase II and III studies, aiming toward an in-depth understanding of the clinical implications and mitigation strategies to circumvent such interactions.

Bioanalytical method development and validation for determination of fibroblast growth factor peptide and its application to pharmacokinetic studies.

Fibroblast growth factor peptide (FGF-P) is a polypeptide analog of FGF-2 that could be a potential mitigation and treatment agent for radiation syndromes. Prior to conducting preclinical pharmacokinetics, we developed and validated the LC-MS/MS bioanalytical method for determination of FGF-P in rat plasma for the first time. FGF-P was extracted from rat plasma using the protein precipitation technique followed liquid-liquid extraction using dichloromethane as a solvent.

Dose optimization of moxifloxacin and linezolid against tuberculosis using mathematical modeling and simulation.

Introduction: There is an urgent need for new anti-tuberculosis (TB) drugs and optimization of current TB treatment. Moxifloxacin and linezolid are valuable options for the treatment of drug-resistant TB; however, it is crucial to find a dose at which these drugs not only show high efficacy but also suppress the development of further drug resistance.

Methods: Activity of moxifloxacin and linezolid against Mycobacterium tuberculosis was studied in the hollow-fiber infection model system in log-phase growth under neutral pH and slow growth in an acidic environment.

Development of clinical pharmacy services in Australia, Austria, Belgium, Bosnia-Herzegovina, Canada, Germany, Japan, Kosovo, Switzerland, the Netherlands, Thailand, USA and correlation with educational standards, level of research, and implemen.

Objective: This study aimed to compare determinants of professional development between different countries to identify barriers and facilitators of development towards clinical pharmacy services and stimulate discussion of under-used potential and opportunities.

Materials: The study was conceived as a survey. The questionnaire was administered to a group of experts.

Clinical Pharmacokinetics and Pharmacodynamics of Ceftazidime-Avibactam Combination: A Model-Informed Strategy for its Clinical Development.

Avibactam is a non-β-lactam, β-lactamase inhibitor of the diazabicyclooctane class that covalently acylates its β-lactamase targets, encompassing extended spectrum of activities that cover serine β-lactamases but not metallo-β-lactamases. Ceftazidime and avibactam have complementary pharmacokinetic (PK) profiles. Both drugs have a half-life of approximately 2 h, making them suitable to be combined in a fixed-dose combination ratio of 4:1 (ceftazidime:avibactam).

Simultaneous quantification of cannabinoids tetrahydrocannabinol, cannabidiol and CB1 receptor antagonist in rat plasma: An application to characterize pharmacokinetics after passive cannabis smoke inhalation and co-administration of rimonabant.

A highly sensitive and selective liquid chromatography-tandem mass spectrometry method for the determination of tetrahydrocannabinol (THC), cannabidiol, and rimonabant in rat plasma was developed. Analytes and the internal standard were extracted from plasma using a combination of protein precipitation followed by liquid-liquid extraction. Chromatographic separation was done using Waters Symmetry C18, 4.

Development of apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent and its preliminary evaluation in an orthotopic patient-derived xenograft (PDX) model.

Despite the significant progress in the field of cancer therapeutics, the incidence of pancreatic cancer (PC) has continuously increased. One possible mechanism for this increasing burden is impaired drug delivery and drug resistance resulting from a unique tumor microenvironment and genetic mutations. Apratoxins are potent anticancer agents and cotranslational translocation inhibitors with potential therapeutic applications to treat cancers with active secretory pathways.