Annual review of pharmacology and toxicology最新文献

Although human genetics has substantial potential to illuminate novel disease pathways and facilitate drug development, identifying causal variants and deciphering their mechanisms remain challenging. We believe these challenges can be addressed, in part, by creatively repurposing the results of molecular trait genome-wide association studies (GWASs). In this review, we introduce techniques related to molecular GWASs and unconventionally apply them to understanding SVEP1, a human coronary artery disease risk locus. Our analyses highlight SVEP1's causal link to cardiometabolic disease and glaucoma, as well as the surprising discovery of SVEP1 as the first known physiologic ligand for PEAR1, a critical receptor governing platelet reactivity. We further employ these techniques to dissect the interactions between SVEP1, PEAR1, and the Ang/Tie pathway, with therapeutic implications for a constellation of diseases. This review underscores the potential of molecular GWASs to guide drug discovery and unravel the complexities of human health and disease by demonstrating an integrative approach that grounds mechanistic research in human biology.

G protein-coupled receptors (GPCRs) represent the largest family of plasma membrane proteins targeted for therapeutic development. For decades, GPCRs were investigated as monomeric entities during analysis of their pharmacology or signaling and during drug development. However, a considerable body of evidence now indicates that GPCRs function as dimers or higher-order oligomers. Greater acceptance of oligomerization occurred with the recognition that GPCR interactions form heteromeric receptor complexes, which was validated in vivo, often with pharmacologic, signaling, and functional properties distinct from the constituent protomers. GPCR heteromerization is reviewed in the context of brain disorders, with examples illustrating their functional implication in diverse neuropsychiatric and neurodegenerative disorders, making them an enormous unexploited resource for selective pharmacotherapy target identification. The strategies for development of heteromer-selective ligands are discussed as a new opportunity to precisely target the function of a receptor complex with greater specificity, in contrast to the classical ligands targeting individual receptors.

The use of pharmaceuticals has grown substantially and their consequential release via wastewaters poses a potential threat to aquatic and terrestrial environments. While transportation prediction models for aquatic environments are well established, they cannot be universally extrapolated to terrestrial systems. Pharmaceuticals and their metabolites are, for example, readily detected in the excreta of terrestrial organisms (including humans). Furthermore, the trophic transfer of pharmaceuticals to and from food webs is often overlooked, which in turn highlights a public health concern and emphasizes the pressing need to elucidate how today's potpourri of pharmaceuticals affect the terrestrial system, their biophysical behaviors, and their interactions with soil metazoans. This review explores the existing knowledge base of pharmaceutical exposure sources, mobility, persistence, (bio)availability, (bio)accumulation, (bio)magnification, and trophic transfer of pharmaceuticals through the soil and terrestrial food chains.

Genetically driven clinical trial enrichment has been proposed to accelerate and reduce the cost of developing new therapeutics. Usage of this approach has not been comprehensively reviewed. We searched Ovid MEDLINE, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, and WHO ICTRP for articles published between 2010 and 2023. Excluding absorption, distribution, metabolism, and elimination pharmacogenetic studies and anti-infectives, we found 95 completed, 4 terminated, and 22 ongoing prospective genetically enriched trials on 110 drugs for 48 nononcology, nonrare syndromic indications. Trial sizes ranged from 4 to 6,147 participants (median 72) and covered numerous disease areas, particularly neurology (30), metabolism (22), and psychiatry (17). Fifty-six completed studies (60%) met their primary end point. Overall, this scoping review demonstrates that genetically enriched trials are feasible and scalable across disease areas and provide critical information for further development, or attrition, of investigational drugs. Large, appropriately designed disease-, hospital-, or population-based biobanks will undoubtedly facilitate this type of precision drug development approach.

The study of the adverse effects of chemical substances on living organisms is an old and intense field of research. However, toxicological and environmental health sciences have long been dominated by descriptive approaches that enable associations or correlations but relatively few robust causal links and molecular mechanisms. Recent achievements have shown that structural biology approaches can bring this added value to the field. By providing atomic-level information, structural biology is a powerful tool to decipher the mechanisms by which toxicants bind to and alter the normal function of essential cell components, causing adverse effects. Here, using endocrine-disrupting chemicals as illustrative examples, we describe recent advances in the structure-based understanding of their modes of action and how this knowledge can be exploited to develop computational tools aimed at predicting properties of large collections of compounds.

The halogenated solvent trichloroethylene (TCE) has had many uses in medicine, construction, consumer products, and the military. Many of these uses have been discontinued or restricted due to its toxicity, which affects multiple target organs and includes both acute, high-dose toxicity and chronic, low-dose toxicity that also encompass several cancers. US and international agencies have conducted risk and hazard assessments for TCE, with comprehensive publications coming out in the last 10-15 years. Accordingly, the focus of this article is to review recently published data since that time (i.e., 2014) that clarify unsettled questions or provide additional insights into the metabolism and mechanisms of toxicity of TCE in several target organs. Besides metabolism, the review focuses on the kidneys, liver, immune system, nervous system, cardiovascular and pulmonary systems, the search for biomarkers, and recent analyses of human cancer risk and incidence from TCE exposure.

Pharmacogenetic variation is common and an established driver of response for many drugs. There has been tremendous progress in pharmacogenetics knowledge over the last 30 years and in clinical implementation of that knowledge over the last 15 years. But there have also been many examples where translation has stalled because of the lack of available data sets for discovery or validation research. The recent availability of data from very large cohorts with linked genetic, electronic health record, and other data promises new opportunities to advance pharmacogenetics research. This review presents the stages from pharmacogenetics discovery to widespread clinical adoption using prominent gene-drug pairs that have been implemented into clinical practice as examples. We discuss the opportunities that the All of Us Research Program and other large biorepositories with genomic and linked electronic health record data present in advancing and accelerating the translation of pharmacogenetics into clinical practice.

The increasing prevalence of Parkinson disease (PD) highlights the need to develop interventions aimed at slowing or halting its progression. As a result of sophisticated disease modeling in preclinical studies, and refinement of specific clinical/genetic/pathological profiles, our understanding of PD pathogenesis has grown over the years, leading to the identification of several targets for disease modification. This has translated to the development of targeted therapies, many of which have entered clinical trials. Nonetheless, up until now, none of these treatments have satisfactorily shown disease-modifying effects in PD. In this review, we present the most up-to-date disease-modifying pharmacological interventions in the clinical trial pipeline for PD. We focus on agents that have reached more advanced stages of clinical trials testing, highlighting both positive and negative results, and critically reflect on strengths, weaknesses, and challenges of current disease-modifying therapeutic avenues in PD.

New drug modalities offer life-saving benefits for patients through access to previously undruggable targets. Yet these modalities pose a challenge for the pharmaceutical industry, as side effects are complex, unpredictable, and often uniquely human. With animal studies having limited predictive value due to translatability challenges, the pharmaceutical industry seeks out new approach methodologies. Microphysiological systems (MPS) offer important features that enable complex toxicological processes to be modeled in vitro such as (a) an adjustable complexity of cellular components, including immune components; (b) a modifiable tissue architecture; (c) integration and monitoring of dynamic mechanisms; and (d) a multiorgan connection. Here we review MPS studies in the context of four clinical adverse events triggered by new drug modalities: peripheral neuropathy, thrombocytopenia, immune-mediated hepatotoxicity, and cytokine release syndrome. We conclude that while the use of MPS for testing new drug modality-induced toxicities is still in its infancy, we see strong potential going forward.

Chronic inflammation is a common trait in the pathogenesis of several diseases of the gut, including inflammatory bowel disease and celiac disease. Control of the inflammatory response is crucial in these pathologies to avoid tissue destruction and loss of intestinal function. Over the last 50 years, the identification of the mechanisms and mediators involved in the acute phase of the inflammatory response, which is characterized by massive leukocyte recruitment, has led to a number of therapeutic options. New drugs targeting inflammatory flares are still under development. However, interest on the other end of the spectrum-the resolution and repair phases-has emerged, as promoting tissue functional repair may maintain remission and counteract the chronicity of the disease. This review aims to discuss the current and future pharmacological approaches to the treatment of chronic intestinal inflammation and the restoration of functional tissues.