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Annual review of pharmacology and toxicology最新文献

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Apathy and Motivation: Biological Basis and Drug Treatment. 冷漠与动机：生物基础与药物治疗
IF 12.5 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2024-01-23 Epub Date: 2023-08-16 DOI: 10.1146/annurev-pharmtox-022423-014645
Harry Costello, Masud Husain, Jonathan P Roiser
{"title":"Apathy and Motivation: Biological Basis and Drug Treatment.","authors":"Harry Costello, Masud Husain, Jonathan P Roiser","doi":"10.1146/annurev-pharmtox-022423-014645","DOIUrl":"10.1146/annurev-pharmtox-022423-014645","url":null,"abstract":"<p><p>Apathy is a disabling syndrome associated with poor functional outcomes that is common across a broad range of neurological and psychiatric conditions. Currently, there are no established therapies specifically for the condition, and safe and effective treatments are urgently needed. Advances in the understanding of motivation and goal-directed behavior in humans and animals have shed light on the cognitive and neurobiological mechanisms contributing to apathy, providing an important foundation for the development of new treatments. Here, we review the cognitive components, neural circuitry, and pharmacology of apathy and motivation, highlighting converging evidence of shared transdiagnostic mechanisms. Though no pharmacological treatments have yet been licensed, we summarize trials of existing and novel compounds to date, identifying several promising candidates for clinical use and avenues of future drug development.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"313-338"},"PeriodicalIF":12.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10004518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
From Thalidomide to Rational Molecular Glue Design for Targeted Protein Degradation. 从沙利度胺到靶向蛋白质降解的合理分子胶设计
IF 12.5 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2024-01-23 Epub Date: 2023-08-16 DOI: 10.1146/annurev-pharmtox-022123-104147
Vladas Oleinikovas, Pablo Gainza, Thomas Ryckmans, Bernhard Fasching, Nicolas H Thomä
{"title":"From Thalidomide to Rational Molecular Glue Design for Targeted Protein Degradation.","authors":"Vladas Oleinikovas, Pablo Gainza, Thomas Ryckmans, Bernhard Fasching, Nicolas H Thomä","doi":"10.1146/annurev-pharmtox-022123-104147","DOIUrl":"10.1146/annurev-pharmtox-022123-104147","url":null,"abstract":"<p><p>Thalidomide and its derivatives are powerful cancer therapeutics that are among the best-understood molecular glue degraders (MGDs). These drugs selectively reprogram the E3 ubiquitin ligase cereblon (CRBN) to commit target proteins for degradation by the ubiquitin-proteasome system. MGDs create novel recognition interfaces on the surface of the E3 ligase that engage in induced protein-protein interactions with neosubstrates. Molecular insight into their mechanism of action opens exciting opportunities to engage a plethora of targets through a specific recognition motif, the G-loop. Our analysis shows that current CRBN-based MGDs can in principle recognize over 2,500 proteins in the human proteome that contain a G-loop. We review recent advances in tuning the specificity between CRBN and its MGD-induced neosubstrates and deduce a set of simple rules that govern these interactions. We conclude that rational MGD design efforts will enable selective degradation of many more proteins, expanding this therapeutic modality to more disease areas.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"291-312"},"PeriodicalIF":12.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10013249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Oral Anticoagulants Beyond Warfarin. 华法林之外的口服抗凝剂。
IF 12.5 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2024-01-23 Epub Date: 2023-09-27 DOI: 10.1146/annurev-pharmtox-032823-122811
Renske H Olie, Kristien Winckers, Bianca Rocca, Hugo Ten Cate
{"title":"Oral Anticoagulants Beyond Warfarin.","authors":"Renske H Olie, Kristien Winckers, Bianca Rocca, Hugo Ten Cate","doi":"10.1146/annurev-pharmtox-032823-122811","DOIUrl":"10.1146/annurev-pharmtox-032823-122811","url":null,"abstract":"<p><p>Direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists, mostly warfarin, for the main indications for oral anticoagulation, prevention and treatment of venous thromboembolism, and prevention of embolic stroke in atrial fibrillation. While DOACs offer practical, fixed-dose anticoagulation in many patients, specific restrictions or contraindications may apply. DOACs are not sufficiently effective in high-thrombotic risk conditions such as antiphospholipid syndrome and mechanical heart valves. Patients with cancer-associated thrombosis may benefit from DOACs, but the bleeding risk, particularly in those with gastrointestinal or urogenital tumors, must be carefully weighed. In patients with frailty, excess body weight, and/or moderate-to-severe chronic kidney disease, DOACs must be cautiously administered and may require laboratory monitoring. Reversal agents have been developed and approved for life-threatening bleeding. In addition, the clinical testing of potentially safer anticoagulants such as factor XI(a) inhibitors is important to further optimize anticoagulant therapy in an increasingly elderly and frail population worldwide.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"551-575"},"PeriodicalIF":12.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41091888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Artificial Intelligence for Drug Discovery: Are We There Yet? 用于药物发现的人工智能：我们已经实现了吗？
IF 12.5 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2024-01-23 Epub Date: 2023-09-22 DOI: 10.1146/annurev-pharmtox-040323-040828
Catrin Hasselgren, Tudor I Oprea
{"title":"Artificial Intelligence for Drug Discovery: Are We There Yet?","authors":"Catrin Hasselgren, Tudor I Oprea","doi":"10.1146/annurev-pharmtox-040323-040828","DOIUrl":"10.1146/annurev-pharmtox-040323-040828","url":null,"abstract":"<p><p>Drug discovery is adapting to novel technologies such as data science, informatics, and artificial intelligence (AI) to accelerate effective treatment development while reducing costs and animal experiments. AI is transforming drug discovery, as indicated by increasing interest from investors, industrial and academic scientists, and legislators. Successful drug discovery requires optimizing properties related to pharmacodynamics, pharmacokinetics, and clinical outcomes. This review discusses the use of AI in the three pillars of drug discovery: diseases, targets, and therapeutic modalities, with a focus on small-molecule drugs. AI technologies, such as generative chemistry, machine learning, and multiproperty optimization, have enabled several compounds to enter clinical trials. The scientific community must carefully vet known information to address the reproducibility crisis. The full potential of AI in drug discovery can only be realized with sufficient ground truth and appropriate human intervention at later pipeline stages.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"527-550"},"PeriodicalIF":12.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41092761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Hear and Now: Ongoing Clinical Trials to Prevent Drug-Induced Hearing Loss. 现在就听：预防药物性听力损失的现行临床试验。
IF 12.5 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2024-01-23 Epub Date: 2023-08-10 DOI: 10.1146/annurev-pharmtox-033123-114106
John Lee, Katharine Fernandez, Lisa L Cunningham
{"title":"Hear and Now: Ongoing Clinical Trials to Prevent Drug-Induced Hearing Loss.","authors":"John Lee, Katharine Fernandez, Lisa L Cunningham","doi":"10.1146/annurev-pharmtox-033123-114106","DOIUrl":"10.1146/annurev-pharmtox-033123-114106","url":null,"abstract":"<p><p>Each year over half a million people experience permanent hearing loss caused by treatment with therapeutic drugs with ototoxic side effects. There is a major unmet clinical need for therapies that protect against this hearing loss without reducing the therapeutic efficacy of these lifesaving drugs. At least 17 clinical trials evaluating 10 therapeutics are currently underway for therapies aimed at preventing aminoglycoside- and/or cisplatin-induced ototoxicity. This review describes the preclinical and clinical development of each of these approaches, provides updates on the status of ongoing trials, and highlights the importance of appropriate outcome measures in trial design and the value of reporting criteria in the dissemination of results.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"211-230"},"PeriodicalIF":12.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9964723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
LP(a): Structure, Genetics, Associated Cardiovascular Risk, and Emerging Therapeutics. LP（a）：结构、遗传学、相关心血管风险和新兴疗法。
IF 12.5 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2024-01-23 Epub Date: 2023-07-28 DOI: 10.1146/annurev-pharmtox-031023-100609
Erfan Tasdighi, Rishav Adhikari, Omar Almaadawy, Thorsten M Leucker, Michael J Blaha
{"title":"LP(a): Structure, Genetics, Associated Cardiovascular Risk, and Emerging Therapeutics.","authors":"Erfan Tasdighi, Rishav Adhikari, Omar Almaadawy, Thorsten M Leucker, Michael J Blaha","doi":"10.1146/annurev-pharmtox-031023-100609","DOIUrl":"10.1146/annurev-pharmtox-031023-100609","url":null,"abstract":"<p><p>Lipoprotein(a) [Lp(a)] is a molecule bound to apolipoprotein(a) with some similarity to low-density lipoprotein cholesterol (LDL-C), which has been found to be a risk factor for cardiovascular disease (CVD). Lp(a) appears to induce inflammation, atherogenesis, and thrombosis. Approximately 20% of the world's population has increased Lp(a) levels, determined predominantly by genetics. Current clinical practices for the management of dyslipidemia are ineffective in lowering Lp(a) levels. Evolving RNA-based therapeutics, such as the antisense oligonucleotide pelacarsen and small interfering RNA olpasiran, have shown promising results in reducing Lp(a) levels. Phase III pivotal cardiovascular outcome trials [Lp(a)HORIZON and OCEAN(a)] are ongoing to evaluate their efficacy in secondary prevention of major cardiovascular events in patients with elevated Lp(a). The future of cardiovascular residual risk reduction may transition to a personalized approach where further lowering of either LDL-C, triglycerides, or Lp(a) is selected after high-intensity statin therapy based on the individual risk profile and preferences of each patient.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"135-157"},"PeriodicalIF":12.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10246320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Orexin Receptor Antagonism: Normalizing Sleep Architecture in Old Age and Disease. 催产素受体拮抗剂：使老年和疾病患者的睡眠结构正常化
IF 12.5 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2024-01-23 Epub Date: 2023-09-14 DOI: 10.1146/annurev-pharmtox-040323-031929
Jarrah O-Z J Kron, Ryan J Keenan, Daniel Hoyer, Laura H Jacobson
{"title":"Orexin Receptor Antagonism: Normalizing Sleep Architecture in Old Age and Disease.","authors":"Jarrah O-Z J Kron, Ryan J Keenan, Daniel Hoyer, Laura H Jacobson","doi":"10.1146/annurev-pharmtox-040323-031929","DOIUrl":"10.1146/annurev-pharmtox-040323-031929","url":null,"abstract":"<p><p>Sleep is essential for human well-being, yet the quality and quantity of sleep reduce as age advances. Older persons (>65 years old) are more at risk of disorders accompanied and/or exacerbated by poor sleep. Furthermore, evidence supports a bidirectional relationship between disrupted sleep and Alzheimer's disease (AD) or related dementias. Orexin/hypocretin neuropeptides stabilize wakefulness, and several orexin receptor antagonists (ORAs) are approved for the treatment of insomnia in adults. Dysregulation of the orexin system occurs in aging and AD, positioning ORAs as advantageous for these populations. Indeed, several clinical studies indicate that ORAs are efficacious hypnotics in older persons and dementia patients and, as in adults, are generally well tolerated. ORAs are likely to be more effective when administered early in sleep/wake dysregulation to reestablish good sleep/wake-related behaviors and reduce the accumulation of dementia-associated proteinopathic substrates. Improving sleep in aging and dementia represents a tremendous opportunity to benefit patients, caregivers, and health systems.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"359-386"},"PeriodicalIF":12.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10233159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
High-Throughput Screening to Advance In Vitro Toxicology: Accomplishments, Challenges, and Future Directions. 推进体外毒理学的高通量筛选：成就、挑战和未来方向》。
IF 11.2 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2024-01-23 Epub Date: 2023-07-28 DOI: 10.1146/annurev-pharmtox-112122-104310
Caitlin Lynch, Srilatha Sakamuru, Masato Ooka, Ruili Huang, Carleen Klumpp-Thomas, Paul Shinn, David Gerhold, Anna Rossoshek, Sam Michael, Warren Casey, Michael F Santillo, Suzanne Fitzpatrick, Russell S Thomas, Anton Simeonov, Menghang Xia
{"title":"High-Throughput Screening to Advance In Vitro Toxicology: Accomplishments, Challenges, and Future Directions.","authors":"Caitlin Lynch, Srilatha Sakamuru, Masato Ooka, Ruili Huang, Carleen Klumpp-Thomas, Paul Shinn, David Gerhold, Anna Rossoshek, Sam Michael, Warren Casey, Michael F Santillo, Suzanne Fitzpatrick, Russell S Thomas, Anton Simeonov, Menghang Xia","doi":"10.1146/annurev-pharmtox-112122-104310","DOIUrl":"10.1146/annurev-pharmtox-112122-104310","url":null,"abstract":"<p><p>Traditionally, chemical toxicity is determined by in vivo animal studies, which are low throughput, expensive, and sometimes fail to predict compound toxicity in humans. Due to the increasing number of chemicals in use and the high rate of drug candidate failure due to toxicity, it is imperative to develop in vitro, high-throughput screening methods to determine toxicity. The Tox21 program, a unique research consortium of federal public health agencies, was established to address and identify toxicity concerns in a high-throughput, concentration-responsive manner using a battery of in vitro assays. In this article, we review the advancements in high-throughput robotic screening methodology and informatics processes to enable the generation of toxicological data, and their impact on the field; further, we discuss the future of assessing environmental toxicity utilizing efficient and scalable methods that better represent the corresponding biological and toxicodynamic processes in humans.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"191-209"},"PeriodicalIF":11.2,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10822017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10246325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pharmacogenomics Beyond Single Common Genetic Variants: The Way Forward. 药物基因组学超越单一常见基因变异：前进之路。
IF 12.5 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2024-01-23 Epub Date: 2023-07-28 DOI: 10.1146/annurev-pharmtox-051921-091209
Volker M Lauschke, Yitian Zhou, Magnus Ingelman-Sundberg
{"title":"Pharmacogenomics Beyond Single Common Genetic Variants: The Way Forward.","authors":"Volker M Lauschke, Yitian Zhou, Magnus Ingelman-Sundberg","doi":"10.1146/annurev-pharmtox-051921-091209","DOIUrl":"10.1146/annurev-pharmtox-051921-091209","url":null,"abstract":"<p><p>Interindividual variability in genes encoding drug-metabolizing enzymes, transporters, receptors, and human leukocyte antigens has a major impact on a patient's response to drugs with regard to efficacy and safety. Enabled by both technological and conceptual advances, the field of pharmacogenomics is developing rapidly. Major progress in omics profiling methods has enabled novel genotypic and phenotypic characterization of patients and biobanks. These developments are paralleled by advances in machine learning, which have allowed us to parse the immense wealth of data and establish novel genetic markers and polygenic models for drug selection and dosing. Pharmacogenomics has recently become more widespread in clinical practice to personalize treatment and to develop new drugs tailored to specific patient populations. In this review, we provide an overview of the latest developments in the field and discuss the way forward, including how to address the missing heritability, develop novel polygenic models, and further improve the clinical implementation of pharmacogenomics.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"33-51"},"PeriodicalIF":12.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10264298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Antiepileptic Drugs as Potential Dementia Prophylactics Following Traumatic Brain Injury. 抗癫痫药物作为创伤性脑损伤后潜在的痴呆预防药物。
IF 12.5 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2024-01-23 Epub Date: 2023-10-03 DOI: 10.1146/annurev-pharmtox-051921-013930
Laszlo F Locskai, Hadeel Alyenbaawi, W Ted Allison
{"title":"Antiepileptic Drugs as Potential Dementia Prophylactics Following Traumatic Brain Injury.","authors":"Laszlo F Locskai, Hadeel Alyenbaawi, W Ted Allison","doi":"10.1146/annurev-pharmtox-051921-013930","DOIUrl":"10.1146/annurev-pharmtox-051921-013930","url":null,"abstract":"<p><p>Seizures and other forms of neurovolatility are emerging as druggable prodromal mechanisms that link traumatic brain injury (TBI) to the progression of later dementias. TBI neurotrauma has both acute and long-term impacts on health, and TBI is a leading risk factor for dementias, including chronic traumatic encephalopathy and Alzheimer's disease. Treatment of TBI already considers acute management of posttraumatic seizures and epilepsy, and impressive efforts have optimized regimens of antiepileptic drugs (AEDs) toward that goal. Here we consider that expanding these management strategies could determine which AED regimens best prevent dementia progression in TBI patients. Challenges with this prophylactic strategy include the potential consequences of prolonged AED treatment and that a large subset of patients are refractory to available AEDs. Addressing these challenges is warranted because the management of seizure activity following TBI offers a rare opportunity to prevent the onset or progression of devastating dementias.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"577-598"},"PeriodicalIF":12.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41112201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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