Frontiers in drug discovery最新文献

{"title":"Effect of itraconazole on the safety and pharmacokinetics of antitumor SHR6390","authors":"Junyan Wu, H. Yao, X. Lv, Suiwen Ye, Nan Zhang","doi":"10.3389/fddsv.2022.963045","DOIUrl":"https://doi.org/10.3389/fddsv.2022.963045","url":null,"abstract":"The experimental drug SHR6390 has anti-tumor activity as a cyclin dependent kinase 4/6 inhibitor and is metabolized primarily by the cytochrome P450 3A4 enzyme. Therefore, The purpose of this trial was to evaluate the safety and pharmacokinetics of SHR6390, a potent cytochrome P450 3A4 inhibitor, in healthy Chinese subjects. In this trial study, 18 subjects received a single oral dose of SHR6390 50 mg on day 1, multiple doses of 200 mg itraconazole on days 12–24 for 13 days, and a single oral dose of SHR6390 50 mg on day 15. After coadministration with itraconazole, the maximum plasma concentration (Cmax) of SHR6390 increased by 70.7% (from 14.3 ng/ml to 24.5 ng/ml), and the area under the time curve from 0 to T (AUC0-T) increased by 110.8% from 468 h∙ng/mL to 988 h∙ng/mL. The area under the concentration-time curve extrapolated to ∞(AUC0-∞) increases from 509 H∙ng/mL to 1,040 h∙ng/mL, an increase of 105.1%. Oral gap (CL/F) decreased (47.9 L/h and 98.3 L/h) and apparent volume of distribution (Vz/F) decreased (4190 L and 5890 L). According to common terminology criteria, 15 32 adverse events were reported in 18 subjects (AEs) (27 SHR6390-related AEs and 15 Itraconazole-related AEs), AEs were all Class 1 adverse events. Overall, co-administration of Itraconazole increased the plasma exposure of SHR6390 in healthy subjects. Both SHR6390 alone and co-administration of Itraconazole showed acceptable safety profiles, which warrants further investigation. The experimental drug SHR-6390 of this clinical trial has been applied for registration, which is classified as Chemical drugs Class 1. The study drug SHR6390 registration number:ClinicalTrials.gov Identifier: NCT04423601 (https://clinicaltrials.gov/)","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43724388","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}

{"title":"Editorial: Development of COVID-19 therapies: Lessons learnt and ongoing efforts","authors":"B. Villoutreix, C. Cavasotto, J. Fernández-Recio","doi":"10.3389/fddsv.2022.1019705","DOIUrl":"https://doi.org/10.3389/fddsv.2022.1019705","url":null,"abstract":"INSERM Unit 1141, Hospital Robert Debré, University of Paris, Paris, France, Computational Drug Design and Biomedical Informatics Laboratory, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral-CONICET, Pilar, Argentina, Facultad de Ciencias Biomédicasand Facultad de Ingeniería, Universidad Austral, Pilar, Argentina, Austral Institute for Applied Artificial Intelligence, Universidad Austral, Pilar, Argentina, Institute of Vine and Wine Sciences, Spanish National Research Council (CSIC), Logroño, Spain","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48819812","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}

{"title":"Bismuth subsalicylate as potential treatment for Covid-19 pneumonia: A case series report","authors":"C. Kahlenborn, W. Severs, K. Nawab","doi":"10.3389/fddsv.2022.962988","DOIUrl":"https://doi.org/10.3389/fddsv.2022.962988","url":null,"abstract":"Various literature cited suggests that bismuth may have usefulness against Covid-19 both in vitro and in vivo. During the course of caring for Covid-19 patients we administered bismuth subsalicylate to those who displayed diarrhea and/or gastric complaints. Using relatively conservative criteria, upon retrospective review, we noted marked improvement in oxygen requirements in most of the cases. This improvement was observed even when prior therapy with standard anti-Covid drugs had failed. Our overall impression is that these positive results support a detailed evaluation of bismuth as an adjunct treatment for the treatment of Covid-19.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42269330","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}

{"title":"The challenges and opportunities for the development of COVID-19 therapeutics and preparing for the next pandemic","authors":"E. Ogbadoyi, Ndagi Umar","doi":"10.3389/fddsv.2022.925825","DOIUrl":"https://doi.org/10.3389/fddsv.2022.925825","url":null,"abstract":"The disease which is today known as COVID-19 is caused by severe acute respiratory. Syndrome coronavirus 2 (SARS-COV-2), was first reported in Wuhan, China in December 2019. The disease has claimed well over six million lives from over 500 million cases. Vaccine hesitancy militates against successful mass vaccination. There is the rapid emergence of new SARS-COV-2 variants, constituting a challenge to the effectiveness of vaccines. Moreover, none of the available vaccines offers 100% protection and even the protection offered is of short duration necessitating booster doses to be taken. Moving forward, the development of plant-based edible vaccines will be a remarkable strategic approach to overcome vaccine hesitancy and improve vaccine uptake. So far only about nine drugs for COVID-19 treatment have approvals by either or both the European Medicines Agency and the FDA. While drug repurposing to address the emerging need in the early period of the COVID-19 pandemic has been contextually very useful, investment in it remains relatively low for commercial reasons arising from patenting issues. Embarking on new drug discovery and development strategies targeting both the virus and host factors is a very appealing option. Targeting druggable targets that are present across viruses, particularly the coronaviruses, for drug discovery and development represents an important strategy for pandemic preparedness. Natural products are an important reservoir of chemical scaffolds with huge potential for the discovery of novel chemical entities for development of novel therapeutics. Phytopharming is an available technology that can be used for mass and accelerated production of therapeutic molecules that will be required within short periods of time as is the case in pandemic outbreaks. Nanotechnology provides excellent platforms for formulating multivalent vaccines and pan-viral medicines for the treatment of COVID-19. Taken together, this review discusses the potential for the development of therapeutics by using the tools of biocomputing, nanotechnology, and phytopharming for accelerated therapeutic development to achieve effective COVID-19 treatment and associated complications, including new and emerging variants of SARS-COV-2 and other viral pandemics that may emerge or re-emerge.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46722146","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}

{"title":"Current advances in our understanding of circular RNA (circRNA) in Alzheimer’s disease (AD); the potential utilization of synthetic circRNAs as a therapeutic strategy in the clinical management of AD","authors":"Yuhai Zhao, V. Jaber, W. Lukiw","doi":"10.3389/fddsv.2022.983030","DOIUrl":"https://doi.org/10.3389/fddsv.2022.983030","url":null,"abstract":"mRNA-mediated gene expression appears to be signi cantly in AD and CNS, our understanding of con fi guration and composition of circRNA is these ssRNAs are highly can in pathophysiological for extended periods, and therapeutically can be designed and synthesized to carry multiple ssRNA-mediated regulatory signals. Based on these and other very recent fi ndings this Opinion ” paper will: 1) address our current understanding of the emerging role of circRNAs in neurodegeneration with special reference to AD; and 2) discuss the intriguing possibility of using synthetic circRNAs containing multiple inserted miRNA, (AM; antagomir), anti-mRNA and/or other sequences in tandem combination with a personalized as an innovative for the and","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47640914","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}

{"title":"Modeling heart failure with preserved ejection fraction in rodents: Where do we stand?","authors":"Chun Chou, M. Chin","doi":"10.3389/fddsv.2022.948407","DOIUrl":"https://doi.org/10.3389/fddsv.2022.948407","url":null,"abstract":"Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by signs and symptoms of HF in the presence of a normal left ventricular systolic function. Over the past decade, HFpEF has become increasingly prevalent, accounting for greater than 50% of all clinical HF presentations. HFpEF is a complex disease with heterogeneous clinical presentations and multiple non-cardiac comorbidities, which frequently co-exist and contribute to its pathophysiology. To date, only a handful of therapies have been proven to improve, albeit marginally, the outcomes in HFpEF. The development of effective therapeutic agents is in part hampered by the lack of animal models that adequately recapitulate human HFpEF. Although numerous pre-clinical models developed over the years have been labeled as “HFpEF” specific, there has not been a consensus on the appropriate standards for pre-clinical HFpEF models. Thus, the extent to which they truly mirror human HFpEF cannot be systematically validated. Recently, a new algorithm (H2FPEF) was developed to standardize the clinical diagnosis of HFpEF. In this review, with the aid of the clinical H2FPEF scoring system, we evaluate the clinical applicability and translational values of various murine models of HFpEF.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44510927","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}

{"title":"Stemness inhibition by (+)-JQ1 in canine and human mammary cancer cells revealed by machine learning","authors":"Maycon Marção, S. Müller, Pedro Luiz P. Xavier, T. Malta","doi":"10.3389/fddsv.2022.953988","DOIUrl":"https://doi.org/10.3389/fddsv.2022.953988","url":null,"abstract":"Stemness is a phenotype associated with cancer initiation and progression, malignancy, and therapeutic resistance, exhibiting particular molecular signatures. Targeting stemness has been proposed as a promising strategy against breast cancer stem cells that can play a key role in breast cancer progression, metastasis, and multiple drug resistance. Here, using a previously published one-class logistic regression machine learning algorithm (OCLR) built on pluripotent stem cells to predict stemness in human cancer samples, we provide the stemness index (mRNAsi) of different canine non-tumor and mammary cancer cells. Then, we confirmed that inhibition of BET proteins by (+)-JQ1 reduces stemness in a high mRNAsi canine cancer cell. Furthermore, using public data, we observed that (+)-JQ1 can also decrease stemness in human triple-negative breast cancer cells. Our work suggests that mRNAsi can be used to estimate stemness in different species and confirm epigenetic modulation by BET inhibition as a promising strategy for modulating the stemness phenotype in canine and human mammary cancer cells.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44335983","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}

{"title":"Nanobodies: COVID-19 and Future Perspectives","authors":"Guillermo Valenzuela-Nieto, Zaray Miranda-Chacón, Constanza Salinas-Rebolledo, Ronald Jara, Alexei Cuevas, Anne D. Berking, A. Rojas-Fernandez","doi":"10.3389/fddsv.2022.927164","DOIUrl":"https://doi.org/10.3389/fddsv.2022.927164","url":null,"abstract":"The COVID-19 pandemic has driven biotechnological developments to provide new and more effective tools for prophylaxis, diagnosis, and therapy. Historically, monoclonal antibodies have been valuable tools; however, the pandemic has shown some weaknesses, such as production limitations at a global scale. An alternative to conventional monoclonal antibodies are nanobodies, recombinant fragments of the variable region of single-domain antibodies derived mainly from the Camelidae family. Nanobodies have multiple characteristic benefits: they are small (15 KDa) and have remarkable refolding capability and unlimited possibilities for modifications due to their recombinant nature. Here, we review the application of nanobodies in diagnosis and treatment of SARS-CoV-2 infection.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44316335","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}

{"title":"Reszinate—A Phase 1/2 Randomized Clinical Trial of Zinc and Resveratrol Utilizing Home Patient-Obtained Nasal and Saliva Viral Sampling","authors":"H. Kaplan, Kai Wang, Kimberly M. Reeves, J. Scanlan, Christopher C. Nunn, D. Kieper, Joshua L. Mark, Inyoul Y. Lee, Rachel Liu, R. Jin, Michael J. Bolton, J. Goldman","doi":"10.3389/fddsv.2022.910124","DOIUrl":"https://doi.org/10.3389/fddsv.2022.910124","url":null,"abstract":"Background: Safe, effective, and inexpensive treatment for COVID-19 is an urgent unmet medical need. Zinc and resveratrol have been reported to have antiviral activity, and resveratrol may increase zinc activity at the site of replication by increasing intracellular zinc concentrations.Methods: A 1:1 randomized, placebo-controlled trial of zinc 150 mg plus resveratrol 4 g daily for 5 days versus placebos in outpatients with SARS-CoV-2 was carried out from 9/21/2020–1/22/2021 in Seattle, Washington. Viral shedding was followed with patient self-collected nasal and saliva samples by measuring qRT-PCR for SARS-CoV-2 N gene days 1–7, 10, and 14. Patients filled out a web-based questionnaire on days 1–14 to report symptoms, vital signs and adherence to the study intervention. The study was posted as Clinical Trials.gov NCT04542993 on 9 September 2020.Results: A total of 30 participants (14 treatment; 16 placebos) had ≥1 day of the protocol treatment and were evaluable for the primary or secondary outcome. There was no difference in viral shedding between groups, nor in the resolution of symptoms. There was a trend toward a more rapid decrease in symptoms in the treatment group, though this was not statistically significant in the GLM model. Viral shedding was similar between patient self-collected mid-turbinate nasal swabs and expectorated saliva samples with a good correlation.Conclusion: SARS-CoV-2 shedding and COVID-19 symptoms were not statistically significantly decreased by treatment. Viral shedding correlates well between patient-obtained home nasal swabs and saliva sampling.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42536398","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}

{"title":"Overcoming Market Failures in Pandemic Drug Discovery Through Open Science: A Canadian Solution","authors":"E. Gold, A. Edwards","doi":"10.3389/fddsv.2022.898654","DOIUrl":"https://doi.org/10.3389/fddsv.2022.898654","url":null,"abstract":"Among the lessons learned from the COVID-19 pandemic is the need to develop antiviral drugs poised to treat the next pandemic. Unfortunately, traditional drug development economic models, centered principally on patents, are ineffective to induce private sector investment due to unpredictable timing and cause of the next pandemic. As a result, illustrated by the COVID-19 pandemic, it is the public and philanthropic sectors sectors that overwhelmingly fund the development of innovative vaccines and therapies. To meet the need for proactive antiviral medicines in advance of the next pandemic, new models of drug development are needed. Open science partnerships (OSPs) show promise in this regard. Rather than rely principally on patents and private investment, OSPs combine a variety of academic, philanthropic, governmental, and private sector incentives to share knowledge and develop and test antiviral drugs. Private sector investments are, within an OSP, not only leveraged against investments by other actors, but predicated on gaining regulatory data exclusivity, a known and secure form of commercial advantage. Building on domestic expertise in OSPs, Canadian leaders created the Viral Interruption Medicines Initiative, a not-for-profit OSP, to develop pandemic ready-antivirals and address other areas of market failure.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45960554","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}