Annual review of pharmacology and toxicology最新文献

Toluene intoxication constitutes a persistent public health problem worldwide. While most organs can be damaged, the brain is a primary target whether exposure is accidental, occupational, or recreational. Interventions to prevent/revert brain damage by toluene are curtailed by the scarce information on the molecular targets and mechanisms mediating toluene's brain toxicity and the common exposure to other neurotoxins and/or coexistence of neurological/psychiatric disorders. We examine (a) the physicochemical properties of toluene that allow this inhalant to primarily target the lipid-rich brain; (b) the cell types targeted by toluene (neurons, different types of glia), while considering a cerebrovascular component; and (c) putative molecular mechanisms by which toluene may modify receptor function while analyzing structural features that allow toluene to directly interact with membrane lipids or specific proteins. This information constitutes a stepping stone to design pharmacotherapies that counteract toluene brain intoxication.

Pharmacogenetics (PGx) aims to optimize drug treatment outcomes by using a patient's genetic profile for individualized drug and dose selection. Currently, reactive and pretherapeutic single-gene PGx tests are increasingly applied in clinical practice in several countries and institutions. With over 95% of the population carrying at least one actionable PGx variant, and with drugs impacted by these genetic variants being in common use, pretherapeutic or preemptive PGx panel testing appears to be an attractive option for better-informed drug prescribing. Here, we discuss the current state of PGx panel testing and explore the potential for clinical implementation. We conclude that available evidence supports the implementation of pretherapeutic PGx panel testing for drugs covered in the PGx guidelines, yet identification of specific patient populations that benefit most and cost-effectiveness data are necessary to support large-scale implementation.

Obesity is a global health concern. Progress in understanding the physiology of obesity and weight reduction has provided new drug targets. Development and testing of new antiobesity medications (AOMs) has the potential to quickly expand options for treatment. In this review, we briefly summarize the physiology of obesity and weight reduction, as well as medications currently approved for weight management. We highlight the increasing use of incretin and nutrient-stimulated hormone-based therapies. We conclude with an overview of AOMs progressing through the pipeline and discuss their implications for the rapidly evolving field of obesity management.

The last two decades have witnessed substantial advances in identifying synaptic plasticity responsible for behavioral changes in animal models of substance use disorder. We have learned the most about cocaine-induced plasticity in the nucleus accumbens and its relationship to cocaine seeking, so that is the focus in this review. Synaptic plasticity pointing to potential therapeutic targets has been identified mainly using two drug self-administration models: extinction-reinstatement and abstinence models. A relationship between cocaine seeking and potentiated AMPAR transmission in nucleus accumbens is indicated by both models. In particular, an atypical subpopulation-Ca2+-permeable or CP-AMPARs-mediates cue-induced seeking that persists even after long periods of abstinence, modeling the persistent vulnerability to relapse that represents a major challenge in treating substance use disorder. We review strategies to reverse CP-AMPAR plasticity; strategies targeting other components of excitatory synapses, including dysregulated glutamate uptake and release; and behavioral interventions that can be augmented by harnessing synaptic plasticity.

Castration-resistant prostate cancer (CRPC) presents significant challenges in clinical management due to its resistance to conventional androgen receptor (AR)-targeting therapies. The advent of proteolysis targeting chimeras (PROTACs) has revolutionized cancer therapy by enabling the targeted degradation of key molecular players implicated in CRPC progression. In this review we discuss the developments of PROTACs for CRPC treatment, focusing on AR and other CRPC-associated regulators. We provide an overview of the strategic trends in AR PROTAC development from the aspect of targeting site selection and preclinical antitumor evaluation, as well as updates on AR degraders in clinical applications. Additionally, we briefly address the current status of selective AR degrader development. Furthermore, we review new developments in PROTACs as potential CRPC treatment paradigms, highlighting those targeting chromatin modulators BRD4, EZH2, and SWI/SNF; transcription regulator SMAD3; and kinases CDK9 and PIM1. Given the molecular targets shared between CRPC and neuroendocrine prostate cancer (NEPC), we also discuss the potential of PROTACs in addressing NEPC.

Drugs represent our first, and sometimes last, line of defense for many diseases, yet despite decades of research we still do not fully understand why a given drug works in one patient and fails in the next. The human gut microbiome is one of the missing puzzle pieces, due to its ability to parallel and extend host pathways for drug metabolism, along with more complex host-microbiome interactions. Herein, we focus on the well-established links between the gut microbiome and drugs for heart disease and cancer, plus emerging data on neurological disease. We highlight the interdisciplinary methods that are available and how they can be used to address major remaining knowledge gaps, including the consequences of microbial drug metabolism for treatment outcomes. Continued progress in this area promises fundamental biological insights into humans and their associated microbial communities and strategies for leveraging the microbiome to improve the practice of medicine.

Snakebite envenoming kills and maims hundreds of thousands of people every year, especially in the rural settings of tropical regions. Envenomings are still treated with animal-derived antivenoms, which have prevented many lives from being lost but which are also medicines in need of innovation. Strides are being made to improve envenoming therapies, with promising efforts made toward optimizing manufacturing and quality aspects of existing antivenoms, accelerating research and development of recombinant antivenoms based on monoclonal antibodies, and repurposing of small-molecule inhibitors that block key toxins. Here, we review the most recent advances in these fields and discuss therapeutic opportunities and limitations for different snakebite treatment modalities. Finally, we discuss challenges related to preclinical and clinical evaluation, regulatory pathways, large-scale manufacture, and distribution and access that need to be addressed to fulfill the goals of the World Health Organization's global strategy to prevent and control snakebite envenoming.

Phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze cyclic nucleotides. While the 11 PDE subfamilies share common features, key differences confer signaling specificity. The differences include substrate selectivity, enzymatic activity regulation, tissue expression, and subcellular localization. Selective inhibitors of each subfamily have elucidated the protean role of PDEs in normal cell function. PDEs are also linked to diseases, some of which affect the immune, cardiac, and vascular systems. Selective PDE inhibitors are clinically used to treat these specific disorders. Ongoing preclinical studies and clinical trials are likely to lead to the approval of additional PDE-targeting drugs for therapy in human disease. In this review, we discuss the structure and function of PDEs and examine current and evolving therapeutic uses of PDE inhibitors, highlighting their mechanisms and innovative applications that could further leverage this crucial family of enzymes in clinical settings.

G protein-coupled receptors (GPCRs) are a superfamily of transmembrane signal transducers that facilitate the flow of chemical signals across membranes. GPCRs are a desirable class of drug targets, and the activation and deactivation dynamics of these receptors are widely studied. Multidisciplinary approaches for studying GPCRs, such as downstream biochemical signaling assays, cryo-electron microscopy structural determinations, and molecular dynamics simulations, have provided insights concerning conformational dynamics and signaling mechanisms. However, new approaches including biosensors that use luminescence- and fluorescence-based readouts have been developed to investigate GPCR-related protein interactions and dynamics directly in cellular environments. Luminescence- and fluorescence-based readout approaches have also included the development of GPCR biosensor platforms that utilize enabling technologies to facilitate multiplexing and miniaturization. General principles underlying the biosensor platforms and technologies include scalability, orthogonality, and kinetic resolution. Further application and development of GPCR biosensors could facilitate hit identification in drug discovery campaigns. The goals of this review are to summarize developments in the field of GPCR-related biosensors and to discuss the current available technologies.

Ryanodine receptor type 2 (RyR2) is the principal intracellular calcium release channel in the cardiac sarcoplasmic reticulum (SR). Pathological RyR2 hyperactivity generates arrhythmia risk in genetic and structural heart diseases. RYR2 gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia. In structural heart diseases (i.e., heart failure), posttranslation modifications render RyR2 channels leaky, resulting in pathologic calcium release during diastole, contributing to arrhythmogenesis and contractile dysfunction. Hence, RyR2 represents a therapeutic target in arrhythmogenic heart diseases. We provide an overview of the structure and function of RyR2, and then review US Food and Drug Administration-approved and investigational RyR2 inhibitors. A therapeutic classification of RyR2 inhibitors is proposed based on their mechanism of action. Class I RyR2 inhibitors (e.g., flecainide) do not change SR calcium content and are primarily antiarrhythmic. Class II RyR2 inhibitors (e.g., dantrolene) increase SR calcium content, making them less effective as antiarrhythmics but preferable in conditions with reduced SR calcium content such as heart failure.