Current drug metabolism最新文献

{"title":"Artificial Intelligence in Drug Formulation and Development: Applications and Future Prospects.","authors":"Noorain, Varsha Srivastava, Bushra Parveen, Rabea Parveen","doi":"10.2174/0113892002265786230921062205","DOIUrl":"10.2174/0113892002265786230921062205","url":null,"abstract":"<p><p>Artificial Intelligence (AI) has emerged as a powerful tool in various domains, and the field of drug formulation and development is no exception. This review article aims to provide an overview of the applications of AI in drug formulation and development and explore its future prospects. The article begins by introducing the fundamental concepts of AI, including machine learning, deep learning, and artificial neural networks and their relevance in the pharmaceutical industry. Furthermore, the article discusses the network and tools of AI and its applications in the pharmaceutical development process, including various areas, such as drug discovery, manufacturing, quality control, clinical trial management, and drug delivery. The utilization of AI in various conventional as well as modified dosage forms has been compiled. It also highlights the challenges and limitations associated with the implementation of AI in this field, including data availability, model interpretability, and regulatory considerations. Finally, the article presents the future prospects of AI in drug formulation and development, emphasizing the potential for personalized medicine, precision drug targeting, and rapid formulation optimization. It also discusses the ethical implications of AI in this context, including issues of privacy, bias, and accountability.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41110163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolism Pathways of Major Therapeutics for Treating Monkeypox Mono- and Co-infection with Human Immunodeficient Virus or SARS-CoV-2.","authors":"Daisy Yan, Bingfang Yan","doi":"10.2174/1389200224666230607124102","DOIUrl":"10.2174/1389200224666230607124102","url":null,"abstract":"<p><p>Monkeypox is a zoonotic viral disease and remains endemic in tropical regions of Central and West Africa. Since May of 2022, cases of monkeypox have soared and spread worldwide. Confirmed cases have shown no travel history to the endemic regions as seen in the past. The World Health Organization declared monkeypox a global public health emergency in July 2022, and the United States government followed suit one month later. The current outbreak, in contrast to traditional epidemics, has high coinfection rates, particularly with HIV (human immunodeficiency virus), and to a lesser extent with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the pathogen of COVID-19. No drugs have been approved specifically for monkeypox. However, there are therapeutic agents authorized to treat monkeypox under the Investigational New Drug protocol, including brincidofovir, cidofovir, and tecovirimat. In contrast to limited options for monkeypox treatment, there are available drugs specifically for HIV or SARS-CoV-2 infection. Interestingly, these HIV and COVID-19 medicines share metabolism pathways with those authorized to treat monkeypox, particularly of hydrolysis, phosphorylation, and active membrane transport. This review discusses how these pathways shared by these medicines should be considered to gain therapeutic synergy and maximize safety for treating monkeypox coinfections.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11089469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10099718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Factors Influencing ADME Properties of Therapeutic Antisense Oligonucleotides: Physicochemical Characteristics and Beyond.","authors":"Rongrong Jiang,&nbsp;Shirin Hooshfar,&nbsp;Marsha Rebecca Eno,&nbsp;Cassandra Yun,&nbsp;Estevan Sonego Zimmermann,&nbsp;Raku Shinkyo","doi":"10.2174/1389200224666230418092626","DOIUrl":"10.2174/1389200224666230418092626","url":null,"abstract":"<p><p>Therapeutic antisense oligonucleotides (ASOs) represent a diverse array of chemically modified singlestranded deoxyribonucleotides that work complementarily to affect their mRNA targets. They vastly differ from conventional small molecules. These newly developed therapeutic ASOs possess unique absorption, distribution, metabolism, and excretion (ADME) processes that ultimately determine their pharmacokinetic, efficacy and safety profiles. The ADME properties of ASOs and associated key factors have not been fully investigated. Therefore, thorough characterization and in-depth study of their ADME properties are critical to support drug discovery and development processes for safe and effective therapeutic ASOs. In this review, we discussed the main factors affecting the ADME characteristics of these novels and evolving therapies. The major changes to ASO backbone and sugar chemistry, conjugation approaches, sites and routes of administration, <i>etc.,</i> are the principal determinants of ADME and PK profiles that consequentially impact their efficacy and safety profiles. In addition, species difference and DDI considerations are important in understanding ADME profile and PK translatability but are less studied for ASOs. We, therefore, have summarized these aspects based on current knowledge and provided discussions in this review. We also give an overview of the current tools, technologies, and approaches available to investigate key factors that influence the ADME of ASO drugs and provide future perspectives and knowledge gap analysis.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9420429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"State-of-the-art Application of Artificial Intelligence to Transporter-centered Functional and Pharmaceutical Research.","authors":"Jiayi Yin,&nbsp;Nanxin You,&nbsp;Fengcheng Li,&nbsp;Mingkun Lu,&nbsp;Su Zeng,&nbsp;Feng Zhu","doi":"10.2174/1389200224666230523155759","DOIUrl":"https://doi.org/10.2174/1389200224666230523155759","url":null,"abstract":"<p><p>Protein transporters not only have essential functions in regulating the transport of endogenous substrates and remote communication between organs and organisms, but they also play a vital role in drug absorption, distribution, and excretion and are recognized as major determinants of drug safety and efficacy. Understanding transporter function is important for drug development and clarifying disease mechanisms. However, the experimental-based functional research on transporters has been challenged and hinged by the expensive cost of time and resources. With the increasing volume of relevant omics datasets and the rapid evolution of artificial intelligence (AI) techniques, next-generation AI is becoming increasingly prevalent in the functional and pharmaceutical research of transporters. Thus, a comprehensive discussion on the state-of-the-art application of AI in three cutting-edge directions was provided in this review, which included (a) transporter classification and function annotation, (b) structure discovery of membrane transporters, and (c) drug-transporter interaction prediction. This study provides a panoramic view of AI algorithms and tools applied to the field of transporters. It is expected to guide a better understanding and utilization of AI techniques for in-depth studies of transporter-centered functional and pharmaceutical research.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10454515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Mini-review on Recent Strategies and Applications of Nanomedicines to Combat Antimicrobial Resistance.","authors":"Kanak Chahar,&nbsp;Yash Sharma,&nbsp;Preeti Patel,&nbsp;Vivek Asati,&nbsp;Balak Das Kurmi","doi":"10.2174/1389200224666230731093319","DOIUrl":"10.2174/1389200224666230731093319","url":null,"abstract":"<p><p>One of the key factors contributing to mortality and morbidity globally is infectious ailments. According to recent statistics from WHO, amplified antimicrobial resistance occurrence among bacteria signifies the utmost threat to global public health. Bacteria have developed various strategies to resist antimicrobials, including enzymatic inactivation of antibiotics, drug efflux, modifications of the antibiotic molecule or chemical alteration of the antibiotic, limited drug uptake, etc. Furthermore, the inefficiency of antimicrobial drugs against resistant bacteria due to low solubility, instability, and associated side effects augments challenges to combat these resistant pathogens. This has attracted the attention of researchers to create nano-delivery and targeting techniques. This review presents an overview of antimicrobial resistance (AMR), its various subtypes, as well as mechanisms involved in AMR. This review also describes current strategies and applications of various nanocarriers, including nanoparticles, liposomes, lipid-based nanoparticles, micelles, and polymeric nanoparticles.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9898275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational Structural Validation of <i>CYP2C9</i> Mutations and Evaluation of Machine Learning Algorithms in Predicting the Therapeutic Outcomes of Warfarin.","authors":"Kannan Sridharan,&nbsp;Thirumal Kumar D,&nbsp;Suchetha Manikandan,&nbsp;Gaurav Prasanna,&nbsp;Lalitha Guruswamy,&nbsp;Rashed Al Banna,&nbsp;George Priya Doss C","doi":"10.2174/1389200224666230705124329","DOIUrl":"10.2174/1389200224666230705124329","url":null,"abstract":"<p><strong>Aim: </strong>The study aimed to identify the key pharmacogenetic variable influencing the therapeutic outcomes of warfarin using machine learning algorithms and bioinformatics tools.</p><p><strong>Background: </strong>Warfarin, a commonly used anticoagulant drug, is influenced by cytochrome P450 (CYP) enzymes, particularly <i>CYP2C9</i>. MLAs have been identified to have great potential in personalized therapy.</p><p><strong>Objective: </strong>The purpose of the study was to evaluate MLAs in predicting the critical outcomes of warfarin therapy and validate the key predictor genotyping variable using bioinformatics tools.</p><p><strong>Methods: </strong>An observational study was conducted on adults receiving warfarin. Allele discrimination method was used for estimating the single nucleotide polymorphisms (SNPs) in <i>CYP2C9</i>, VKORC1, and CYP4F2. MLAs were used for identifying the significant genetic and clinical variables in predicting the poor anticoagulation status (ACS) and stable warfarin dose. Advanced computational methods (SNPs' deleteriousness and impact on protein destabilization, molecular dockings, and 200 ns molecular dynamics simulations) were employed for examining the influence of <i>CYP2C9</i> SNPs on structure and function.</p><p><strong>Results: </strong>Machine learning algorithms revealed <i>CYP2C9</i> to be the most important predictor for both outcomes compared to the classical methods. Computational validation confirmed the altered structural activity, stability, and impaired functions of protein products of <i>CYP2C9</i> SNPs. Molecular docking and dynamics simulations revealed significant conformational changes with mutations R144C and I359L in <i>CYP2C9</i>.</p><p><strong>Conclusion: </strong>We evaluated various MLAs in predicting the critical outcome measures associated with warfarin and observed <i>CYP2C9</i> as the most critical predictor variable. The results of our study provide insight into the molecular basis of warfarin and the <i>CYP2C9</i> gene. A prospective study validating the MLAs is urgently needed.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9746390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meropenem for the Pharmacological Treatment of Severe Infections in Critically Ill Pediatric Patients: Breakthrough Standard Treatment Strategies Based on PK/PD.","authors":"Xin He,&nbsp;Yaoyan Liu,&nbsp;Xiaodan Gong,&nbsp;Li Wang,&nbsp;Feng Chen","doi":"10.2174/1389200224666230325121729","DOIUrl":"https://doi.org/10.2174/1389200224666230325121729","url":null,"abstract":"<p><p>Meropenem, as a carbapenem antibiotic, is commonly used in critically ill pediatric patients with severe infection because of its broad antimicrobial spectrum, high penetration into tissues, and favorable safety profile. Due to pathophysiological changes in critically ill children, the available evidence has demonstrated that the standard dosage regimens of meropenem could not meet an appropriate pharmacodynamic (PD) target attainment in severely infected children. Therefore, we reviewed the pharmacokinetic (PK) profile of meropenem in critically ill children, therapeutic drug monitoring (TDM), and dose optimization based on PK/PD. Meropenem kills bacteria in a timedependent manner and its efficacy is positively correlated with the percentage of the time of dosing interval during which the free serum concentration of meropenem remains above the minimum inhibitory concentration (MIC) of the pathogen (%fT>MIC), which is related to PK/PD targets. For critically ill children, TDM-based dosage optimization and setting even higher PK/PD targets seem necessary to be considered. The currently available studies have revealed that increasing the dose and the application of the extended or continuous infusion of meropenem were able to achieve better PK/PD targets. According to limited clinical data on efficacy and safety, these treatment measures cannot yet be adopted as routine regimens only when serious infections caused by drug-resistant bacteria or strains with high values of MIC are suspected. Further high-quality randomized controlled trials (RCTs) or observational studies with sufficient sample sizes are required to confirm the efficacy and safety of these modes of administration.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9750502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Metabolic Pathways and Products of Ten <i>Aconitum</i> Alkaloids in Sanwujiao Pills from Eight Organs of Mice by UHPLC-Q-TOF-MS/MS.","authors":"Wen-Han Pei,&nbsp;Yu-Feng Huang,&nbsp;Ying Xie,&nbsp;Yuan Qu,&nbsp;Fan He,&nbsp;Hua Zhou","doi":"10.2174/1389200224666230505122353","DOIUrl":"https://doi.org/10.2174/1389200224666230505122353","url":null,"abstract":"<p><strong>Background: </strong>Sanwujiao pill (SWJP) is a Chinese herbal preparation widely used in China. It is an essential medicine for treating rheumatism and blood stasis. However, its safety in clinical use has always been the focus of patients because it contains toxic herbs of <i>Aconitum carmichaelii</i> Debx. and <i>A. vilmorinianum</i> Kom.</p><p><strong>Objective: </strong>To further reveal the pharmaceutical and toxic effect substances and the action mechanism of SWJPs, the metabolites and their pathways of ten <i>Aconitum</i> alkaloids (AAs) in the preparation at different time points after oral administration in eight organs of mice were investigated.</p><p><strong>Method: </strong>The biosamples were investigated by a four-step strategy of UPLC-Q-TOF-MS /MS technology.</p><p><strong>Results: </strong>Aconitine (AC), mesaconitine (MA), and hypaconitine (HA) were not detected in any organs. The highest concentrations of the other seven AAs occurred at 0.5 h. Yunaconitine (YAC) was not detected in the brain; all seven AAs had the lowest concentration in the brain, and the metabolism was slow in the stomach. Twelve predicted metabolites were identified, the kidney and stomach were their primary distribution locations, and the most metabolites were found at 0.5h. The main metabolic pathways of the ten AAs were demethylation, deethylation, deoxygenation, hydroxylation, and deacetylation.</p><p><strong>Conclusion: </strong>This is the first report about the metabolism of ten AAs in SWJPs in mice. Significantly, the metabolic pathways and products of four hidden toxic AAs were analyzed <i>in vivo</i> for the first time. The results were of great significance for the safety and effectiveness of SWJPs in clinical application.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10099968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Influence of Atorvastatin, Amlodipine and Ethoxidol on Ubiquinol and Ubiquinone Endogenous Plasma Concentrations in Patients with Chronic Heart Failure.","authors":"V I Zozina, S N Kondratenko, E V Shikh, L M Krasnykh, E S Melnikov, V G Kukes","doi":"10.2174/1389200224666230913133201","DOIUrl":"10.2174/1389200224666230913133201","url":null,"abstract":"<p><strong>Background: </strong>Coenzyme Q10 is a key component of the mitochondrial respiratory chain and a fat-soluble endogenous antioxidant performing many vital functions in the human body. Many researchers studied the plasma concentrations of ubiquinol, ubiquinone, total CoQ10 and the redox state (ubiquinol/ubiquinone ratio) of CoQ10 in healthy volunteers. However, these parameters in the plasma of patients with chronic heart failure (CHF) remain almost uninvestigated.</p><p><strong>Objective: </strong>The aim of this case-control study was to investigate the effect of atorvastatin, amlodipine and ethoxidol on endogenous plasma concentrations of ubiquinol, ubiquinone, total CoQ10 and its redox state in patients with CHF.</p><p><strong>Methods: </strong>The study included 62 patients with CHF divided into four groups depending on the prescribed therapy. For the quantitative determination of ubiquinol, ubiquinone, and total CoQ10 in the plasma of patients, HPLCMS/ MS was used.</p><p><strong>Results: </strong>It was established that the endogenous plasma concentration of total CoQ10 in patients with CHF is significantly lower than in healthy volunteers, and the ratio of reduced and oxidized forms of CoQ10 is shifted towards ubiquinone. It was a statistically significant effect of drugs with different physicochemical structures and pharmacological action on the plasma concentrations of ubiquinol, ubiquinone and total CoQ10: atorvastatin administration led to a decrease in the concentration of ubiquinol (-33.3Δ%), and total CoQ10 (-15Δ%), administration of amlodipine contributed to an increase in the levels of ubiquinol (+27.7Δ%) and total CoQ10 (+18.2Δ%), and the administration of ethoxidol caused an increase in the concentration of ubiquinol (+25Δ%), ubiquinone (+17.7Δ%) and total CoQ10 (+20.2Δ%).</p><p><strong>Conclusion: </strong>Amlodipine is able to neutralize the negative effect of atorvastin on the redox balance of CoQ10 in patients with CHF. An additional prescription of the antioxidant ethoxidol to standard therapy for patients with CHF was substantiated. Determination of the redox state of CoQ10 in plasma can be used to diagnose and assess the degree of oxidative stress in patients with cardiovascular diseases, as well as to assess the efficacy and safety of ongoing pharmacotherapy.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10241759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum: Intracellular Delivery: Exploiting Viral Membrane Topic Peptide.","authors":"Stefania Galdiero,&nbsp;Mariateresa Vitiello,&nbsp;Annarita Falanga,&nbsp;Marco Cantisani,&nbsp;Novella Incoronato,&nbsp;Massimiliano Galdiero","doi":"10.2174/138920022406230915142021","DOIUrl":"10.2174/138920022406230915142021","url":null,"abstract":"<p><p>The authors declare that after the publication of the article, it was noticed that two citations were inadvertently omitted. The references have now been included as [74b] and [74c]: [74] (b) Vitiello, M.; Galdiero, M.; Galdiero, M. Inhibition of Viral-Induced Membrane Fusion by Peptides. Protein Pep. Lett., 2009, 16(7), 786-793. (c) Galdiero, S.; Falanga, A.; Vitiello, M.; D'Isanto, M.; Cantisani, M.; Kampanaraki, A.; Benedetti, E.; Browne, H.; Galdiero, M. Peptides containing membrane-interacting motifs inhibit herpes simplex virus type 1 infectivity. Peptides, 2008, 29(9), 1461- 1471. The authors would like to include this reference in the online version of the article to ensure completeness.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41194137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}