Advances in pharmacology最新文献

Stimulant prodrugs: A pharmacological and clinical assessment of their role in treating ADHD and binge-eating disorder. 兴奋剂原药：对其在治疗多动症和暴食症方面作用的药理学和临床评估。

Advances in pharmacology Pub Date : 2024-01-01 Epub Date: 2023-10-25 DOI: 10.1016/bs.apha.2023.10.002

David J Heal, Jane Gosden, Sharon L Smith

{"title":"Stimulant prodrugs: A pharmacological and clinical assessment of their role in treating ADHD and binge-eating disorder.","authors":"David J Heal, Jane Gosden, Sharon L Smith","doi":"10.1016/bs.apha.2023.10.002","DOIUrl":"10.1016/bs.apha.2023.10.002","url":null,"abstract":"In this review, we critically evaluate the contribution of prodrugs to treating two related psychiatric disorders, attention-deficit hyperactivity disorder (ADHD) and binge-eating disorder (BED). ADHD is characterized by inattentiveness, distractibility, impulsiveness, and hyperactivity. BED is also an impulse-control disorder which leads to frequent, compulsive episodes of excessive eating (binges). Lisdexamfetamine (LDX; prodrug of d-amphetamine) is approved to treat both ADHD and BED. Serdexmethylphenidate (SDX; prodrug of d-threo-methylphenidate) is not clinically approved as monotherapy but, in a fixed-dose combination with immediate release d-threo-methylphenidate (Azstarys™), SDX is approved for managing ADHD in children/adolescents. The pharmacological actions of a stimulant mediate both its efficacy and side-effects. Therefore, daily management of ADHD or BED to maintain optimum efficacy and tolerability places highly restrictive requirements on the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of stimulant medications, especially prodrugs. Prodrugs must have good bioavailability and rapid metabolism to provide therapeutic efficacy soon after morning dosing combined with providing stimulant coverage throughout the day/evening. A wide selection of dosages and linear PK for the prodrug and its active metabolite are essential requirements for treatment of these conditions. The proposed neurobiological causes of ADHD and BED are described. The chemical, pharmacological and PK/PD properties responsible for the therapeutic actions of the prodrugs, LDX and SDX, are compared and contrasted. Finally, we critically assess their contribution as ADHD and BED medications, including advantages over their respective active metabolites, d-amphetamine and d-threo-methylphenidate, and also their potential for misuse and abuse.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"99 ","pages":"251-286"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140100827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural and functional perspectives on interactions between synthetic cathinones and monoamine transporters. 从结构和功能角度看合成卡西酮与单胺转运体之间的相互作用。

Advances in pharmacology Pub Date : 2024-01-01 Epub Date: 2023-10-20 DOI: 10.1016/bs.apha.2023.09.001

Vy T Nguyen, Alan C Harris, Jose M Eltit

{"title":"Structural and functional perspectives on interactions between synthetic cathinones and monoamine transporters.","authors":"Vy T Nguyen, Alan C Harris, Jose M Eltit","doi":"10.1016/bs.apha.2023.09.001","DOIUrl":"10.1016/bs.apha.2023.09.001","url":null,"abstract":"Synthetic cathinone derivatives comprise a family of psychoactive compounds structurally related to amphetamine. Over the last decade, clandestine chemists have synthesized a consistent stream of innovative cathinone derivatives to outpace governmental regulatory restrictions. Many of these unregulated substances are produced and distributed as designer drugs. Two of the principal chemical scaffolds exploited to expand the synthetic cathinone family are methcathinone and α-pyrrolidinopentiophenone (or α-pyrrolidinovalerophenone, α-PVP). These compounds' main physiological targets are monoamine transporters, where they promote addiction by potentiating dopaminergic neurotransmission. This chapter describes techniques used to study the pharmacodynamic properties of cathinones at monoamine transporters in vitro. Biochemical techniques described include uptake inhibition and release assays in rat brain synaptosomes and in mammalian expression systems. Electrophysiological techniques include current measurements using the voltage clamp technique. We describe a Ca2+ mobilization assay wherein voltage-gated Ca2+ channels function as reporters to study the action of synthetic cathinones at monoamine transporters. We discuss results from systematic structure-activity relationship studies on simple and complex cathinones at monoamine transporters with an emphasis on identifying structural moieties that modulate potency and selectivity at these transporters. Moreover, different profiles of selectivity at monoamine transporters directly predict compounds associated with behavioral and subjective effects within animals and humans. In conclusion, clarification of the structural aspects of compounds which modulate potency and selectivity at monoamine transporters is critical to identify and predict potential addictive drugs. This knowledge may allow prompt allocation of resources toward drugs that represent the greatest threats after drugs are identified by forensic laboratories.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"99 ","pages":"83-124"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140100828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of novel anti-infective agents. 发现新型抗感染药物。

Advances in pharmacology Pub Date : 2024-01-01 Epub Date: 2024-06-25 DOI: 10.1016/bs.apha.2024.05.001

Arnab K Chatterjee

引用次数: 0

IVT-mRNA reprogramming of myeloid cells for cancer immunotherapy. IVT-mRNA 重编程髓系细胞，用于癌症免疫疗法。

Advances in pharmacology Pub Date : 2024-01-01 Epub Date: 2024-05-18 DOI: 10.1016/bs.apha.2024.04.004

Kevon J Jolly, Fan Zhang

{"title":"IVT-mRNA reprogramming of myeloid cells for cancer immunotherapy.","authors":"Kevon J Jolly, Fan Zhang","doi":"10.1016/bs.apha.2024.04.004","DOIUrl":"https://doi.org/10.1016/bs.apha.2024.04.004","url":null,"abstract":"In the past decade, in vitro transcribed messenger RNAs (IVT-mRNAs) have emerged as promising therapeutic molecules. The clinical success of COVID-19 mRNA vaccines developed by Pfizer-BioNTech and Moderna, have demonstrated that IVT-mRNAs can be safely and successfully used in a clinical setting, and efforts are underway to develop IVT-mRNAs for therapeutic applications. Current applications of mRNA-based therapy have been focused on (1) mRNA vaccines for infectious diseases and cancer treatment; (2) protein replacement therapy; (3) gene editing therapy; and (4) cell-reprogramming therapies. Due to the recent clinical progress of cell-based immunotherapies, the last direction-the use of IVT-mRNAs as a therapeutic approach to program immune cells for the treatment of cancer has received extensive attention from the cancer immunotherapy field. Myeloid cells are important components of our immune system, and they play critical roles in mediating disease progression and regulating immunity against diseases. In this chapter, we discussed the progress of using IVT-mRNAs as a therapeutic approach to program myeloid cells against cancer and other immune-related diseases. Towards this direction, we first reviewed the pharmacology of IVT-mRNAs and the biology of myeloid cells as well as myeloid cell-targeting therapeutics. We then presented a few cases of current IVT-mRNA-based approaches to target and reprogram myeloid cells for disease treatment and discussed the advantages and limitations of these approaches. Finally, we presented our considerations in designing mRNA-based approaches to target myeloid cells for disease treatment.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"100 ","pages":"247-288"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Progress in the development of ERK1/2 inhibitors for treating cancer and other diseases. 用于治疗癌症和其他疾病的 ERK1/2 抑制剂的研发进展。

Advances in pharmacology Pub Date : 2024-01-01 Epub Date: 2024-04-24 DOI: 10.1016/bs.apha.2024.04.001

Lena Grogan, Paul Shapiro

{"title":"Progress in the development of ERK1/2 inhibitors for treating cancer and other diseases.","authors":"Lena Grogan, Paul Shapiro","doi":"10.1016/bs.apha.2024.04.001","DOIUrl":"10.1016/bs.apha.2024.04.001","url":null,"abstract":"The extracellular signal-regulated kinases-1 and 2 (ERK1/2) are ubiquitous regulators of many cellular functions, including proliferation, differentiation, migration, and cell death. ERK1/2 regulate cell functions by phosphorylating a diverse collection of protein substrates consisting of other kinases, transcription factors, structural proteins, and other regulatory proteins. ERK1/2 regulation of cell functions is tightly regulated through the balance between activating phosphorylation by upstream kinases and inactivating dephosphorylation by phosphatases. Disruption of homeostatic ERK1/2 regulation caused by elevated extracellular signals or mutations in upstream regulatory proteins leads to the constitutive activation of ERK1/2 signaling and uncontrolled cell proliferation observed in many types of cancer. Many inhibitors of upstream kinase regulators of ERK1/2 have been developed and are part of targeted therapeutic options to treat a variety of cancers. However, the efficacy of these drugs in providing sustained patient responses is limited by the development of acquired resistance often involving re-activation of ERK1/2. As such, recent drug discovery efforts have focused on the direct targeting of ERK1/2. Several ATP competitive ERK1/2 inhibitors have been identified and are being tested in cancer clinical trials. One drug, Ulixertinib (BVD-523), has received FDA approval for use in the Expanded Access Program for patients with no other therapeutic options. This review provides an update on ERK1/2 inhibitors in clinical trials, their successes and limitations, and new academic drug discovery efforts to modulate ERK1/2 signaling for treating cancer and other diseases.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"100 ","pages":"181-207"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Journey from lab to clinic: Design, preclinical, and clinical development of systemic, targeted dendrimer-N-acetylcysteine (D-NAC) nanomedicines. 从实验室到临床的旅程：系统性、靶向性树枝状聚合物-N-乙酰半胱氨酸（D-NAC）纳米药物的设计、临床前和临床开发。

Advances in pharmacology Pub Date : 2024-01-01 Epub Date: 2024-06-22 DOI: 10.1016/bs.apha.2024.05.003

Wathsala Liyanage, Narendra Kale, Sujatha Kannan, Rangaramanujam M Kannan

{"title":"Journey from lab to clinic: Design, preclinical, and clinical development of systemic, targeted dendrimer-N-acetylcysteine (D-NAC) nanomedicines.","authors":"Wathsala Liyanage, Narendra Kale, Sujatha Kannan, Rangaramanujam M Kannan","doi":"10.1016/bs.apha.2024.05.003","DOIUrl":"https://doi.org/10.1016/bs.apha.2024.05.003","url":null,"abstract":"Drug discovery is challenging task with numerous obstacles in translating drug candidates into clinical products. Dendrimers are highly adaptable nanostructured polymers with significant potential to improve the chances of clinical success for drugs. Yet, dendrimer-based drug products are still in their infancy. However, Hydroxyl polyamidoamine (PAMAM) dendrimers showed significant promise in drug discovery efforts, owning their remarkable potential to selectively target and deliver drugs specifically to activated microglia and astrocytes at the site of brain injury in several preclinical models. After a decade's worth of academic research and pre-clinical efforts, the hydroxyl PAMAM dendrimer-N-acetyl cysteine conjugate (OP-101) nanomedicine has made a significant advancement in the field of nanomedicine and targeted delivery. The OP-101 conjugate, primarily developed and validated in academic labs, has now entered clinical trials as a potential treatment for hyperinflammation in hospitalized adults with severe COVID-19 through Ashvattha Therapeutics. This chapter, we delve into the journey of the hydroxyl PAMAM dendrimer-N-acetylcysteine (NAC) OP-101 formulation from the laboratory to the clinic. It will specifically focus on the design, synthesis, preclinical, and clinical development of OP-101, highlighting the potential it holds for the future of medicine and the positive Phase 2a results for treating severe COVID-19.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"100 ","pages":"119-155"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Therapeutic resurgence of 6-diazo-5-oxo-l-norleucine (DON) through tissue-targeted prodrugs. 通过组织靶向原药使 6-重氮-5-氧代-1-正亮氨酸（DON）重新成为治疗药物。

Advances in pharmacology Pub Date : 2024-01-01 Epub Date: 2024-05-09 DOI: 10.1016/bs.apha.2024.04.003

Kateřina Novotná, Lukáš Tenora, Barbara S Slusher, Rana Rais

{"title":"Therapeutic resurgence of 6-diazo-5-oxo-l-norleucine (DON) through tissue-targeted prodrugs.","authors":"Kateřina Novotná, Lukáš Tenora, Barbara S Slusher, Rana Rais","doi":"10.1016/bs.apha.2024.04.003","DOIUrl":"https://doi.org/10.1016/bs.apha.2024.04.003","url":null,"abstract":"The recognition that rapidly proliferating cancer cells rely heavily on glutamine for their survival and growth has renewed interest in the development of glutamine antagonists for cancer therapy. Glutamine plays a pivotal role as a carbon source for synthesizing lipids and metabolites through the TCA cycle, as well as a nitrogen source for synthesis of amino acid and nucleotides. Numerous studies have explored the significance of glutamine metabolism in cancer, providing a robust rationale for targeting this metabolic pathway in cancer treatment. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) has been explored as an anticancer therapeutic for nearly six decades. Initial investigations revealed remarkable efficacy in preclinical studies and promising outcomes in early clinical trials. However, further advancement of DON was hindered due to dose-limiting gastrointestinal (GI) toxicities as the GI system is highly dependent on glutamine for regulating growth and repair. In an effort to repurpose DON and mitigate gastrointestinal (GI) toxicity concerns, prodrug strategies were utilized. These strategies aimed to enhance the delivery of DON to specific target tissues, such as tumors and the central nervous system (CNS), while sparing DON delivery to normal tissues, particularly the GI tract. When administered at low daily doses, optimized for metabolic inhibition, these prodrugs exhibit remarkable effectiveness without inducing significant toxicity to normal tissues. This approach holds promise for overcoming past challenges associated with DON, offering an avenue for its successful utilization in cancer treatment.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"100 ","pages":"157-180"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AXL: A novel therapeutic target in IBD. AXL：一种新型的 IBD 治疗靶点。

Advances in pharmacology Pub Date : 2024-01-01 Epub Date: 2024-10-22 DOI: 10.1016/bs.apha.2024.10.009

Bejan J Saeedi, Hannah E Carr, Peter D R Higgins, Calen A Steiner

引用次数: 0

Anti-fibrotics in inflammatory bowel diseases: Challenges and successes. 炎症性肠病中的抗纤维化药物：挑战与成功

Advances in pharmacology Pub Date : 2024-01-01 Epub Date: 2024-10-29 DOI: 10.1016/bs.apha.2024.10.012

Gaurav Chauhan, William J Massey, Ido Veisman, Florian Rieder

{"title":"Anti-fibrotics in inflammatory bowel diseases: Challenges and successes.","authors":"Gaurav Chauhan, William J Massey, Ido Veisman, Florian Rieder","doi":"10.1016/bs.apha.2024.10.012","DOIUrl":"https://doi.org/10.1016/bs.apha.2024.10.012","url":null,"abstract":"Stricture formation leading to obstruction in Crohn's disease (CD) remains one of the largest unmet needs in the field of inflammatory bowel diseases (IBD). Despite this need no selective anti-stricture drug has been approved for use in CD patients. This contrasts with other fibrotic diseases, such as in the lung, liver or kidney, where multiple drug development programs crossed the starting line and two anti-fibrotics are now being approved for pulmonary fibrosis. Strictures are composed of a mix of inflammation, excessive deposition of extracellular matrix (ECM) and smooth muscle hyperplasia, likely all ultimately being responsible for the luminal narrowing driving patient symptoms. Our understanding of the pathogenesis of stricturing CD has evolved and indicates a multifactorial process involving immune and non-immune cells and their soluble mediators. This understanding has rendered target pathways for anti-stricture drug development. Significant progress was made in creating consensus definitions and tools to enable clinical trials with two clinical development programs having been conceived to date. In this chapter, we discuss stricture pathogenesis with a focus on the pathways being tested in clinical trials, and clinical trial endpoints developed for this indication.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"101 ","pages":"85-106"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modeling methamphetamine use disorder in mammals: Sex differences in behavioral, biochemical, and transcriptional consequences. 哺乳动物甲基苯丙胺使用障碍模型：行为、生化和转录后果的性别差异。

Advances in pharmacology Pub Date : 2024-01-01 Epub Date: 2024-02-09 DOI: 10.1016/bs.apha.2023.08.002

Atul P Daiwile, Jean Lud Cadet

{"title":"Modeling methamphetamine use disorder in mammals: Sex differences in behavioral, biochemical, and transcriptional consequences.","authors":"Atul P Daiwile, Jean Lud Cadet","doi":"10.1016/bs.apha.2023.08.002","DOIUrl":"10.1016/bs.apha.2023.08.002","url":null,"abstract":"Methamphetamine (METH) is the most commonly misused amphetamine-type stimulant throughout the globe. METH is very rewarding, and its misuse can lead to a diagnosis of METH use disorder (MUD). Although METH use is observed in both sexes, there are, however, reported differences in the clinical manifestations of METH use and its consequences. These observations indicate the need for more research on the long-term sex-dependent consequences of METH taking in both preclinical and clinical settings. In effect, sex is a biological variable that can impact conclusions drawn from various basic and clinical studies. Thus, the present chapter provides a succinct review of the current state of the research on METH and its sex-associated consequences. In addition to behavioral and cognitive aspects of METH use, we discuss METH-induced changes in neurotransmitter systems and structures in the brain. Thus, the book chapter serves to highlight the significance of sex as a critical element that needs to be considered during discussions of novel therapeutic approaches to MUD.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"99 ","pages":"145-168"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11474929/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140100823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0