Objective To identify the critical risks in the process of innovative drug research and development,and to provide reference for improving the efficiency of innovative drug development and risk control in China.Method...Objective To identify the critical risks in the process of innovative drug research and development,and to provide reference for improving the efficiency of innovative drug development and risk control in China.Methods Expert investigation and analytic hierarchy process were used to determine the weights of different risks.Results and Conclusion The research and analysis results showed that the risks at different stages of development had different effects on the success rate of drug development,among which the risk at the drug discovery stage influenced the most.In the drug discovery stage,inappropriate target selection had the greatest impact on the success rate of drug development.The lack of appropriate cell tissue or animal models had the greatest impact on the success rate of drug development from the discovery of a compound to the application for clinical trials.The difference in changes between nonclinical and clinical studies had the greatest impact on the success rate of drug development from early clinical studies to pivotal clinical studies.Incorrect dose selection had the greatest impact on the success rate of drug development from pivotal clinical studies to marketing authorization applications.The biggest impact from the marketing authorization application to the approval stage was inadequate communication with regulators.After investigating the weight of risk factors in the process of innovative drug development based on scientific methods,a new perspective for the risk control of new drug development and improving the research and development efficiency is provided.展开更多
Model-informed drug develop⁃ment(MIDD)is the application of a various math⁃ematical,statistical,and biological models to facilitate drug development,decision making and regulatory review.As a quantitative tool,MIDD ap...Model-informed drug develop⁃ment(MIDD)is the application of a various math⁃ematical,statistical,and biological models to facilitate drug development,decision making and regulatory review.As a quantitative tool,MIDD approaches allow an integration of information obtained from non-clinical studies and clinical trials in a drug development program.General understandings of the underlying biology,patho⁃physiology,and pharmacology can also be incor⁃porated into the model.MIDD is centered on knowledge and inferences generated from inte⁃grated models of the physicochemical character⁃istics of a molecule,its disposition in the body,and its mechanism of action,and how the drug might affect a disease from both an efficacy and a safety perspective.MIDD approaches have the potential to significantly streamline drug develop⁃ment,by improving clinical trial efficiency,opti⁃mizing dose and regimen and waive unneces⁃sary clinical studies.This presentation will use cases studies to demonstrate how to apply MIDD in early phase of clinical trials.展开更多
Since President Obama announced the Precision Medicine Initiative from a national strategy perspective in his State of the Union address,precision medicine has rapidly become a world-wide hotspot and drawn global atte...Since President Obama announced the Precision Medicine Initiative from a national strategy perspective in his State of the Union address,precision medicine has rapidly become a world-wide hotspot and drawn global attention in the medical field.Precision medicine aims at applying genetic information of individual diseases to guide his or her diagnosis and treatment.展开更多
Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia cases.Although there have been...Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia cases.Although there have been recent developments in tauopathy biomarkers and disease-modifying treatments,ongoing progress is required to ensure these are effective,economical,and accessible for the globally ageing population.As such,continued identification of new potential drug targets and biomarkers is critical."Big data"studies,such as proteomics,can generate information on thousands of possible new targets for dementia diagnostics and therapeutics,but currently remain underutilized due to the lack of a clear process by which targets are selected for future drug development.In this review,we discuss current tauopathy biomarkers and therapeutics,and highlight areas in need of improvement,particularly when addressing the needs of frail,comorbid and cognitively impaired populations.We highlight biomarkers which have been developed from proteomic data,and outline possible future directions in this field.We propose new criteria by which potential targets in proteomics studies can be objectively ranked as favorable for drug development,and demonstrate its application to our group's recent tau interactome dataset as an example.展开更多
Traditional tumor models do not tend to accurately simulate tumor growth in vitro or enable personalized treatment and are particularly unable to discover more beneficial targeted drugs.To address this,this study desc...Traditional tumor models do not tend to accurately simulate tumor growth in vitro or enable personalized treatment and are particularly unable to discover more beneficial targeted drugs.To address this,this study describes the use of threedimensional(3D)bioprinting technology to construct a 3D model with human hepatocarcinoma SMMC-7721 cells(3DP-7721)by combining gelatin methacrylate(GelMA)and poly(ethylene oxide)(PEO)as two immiscible aqueous phases to form a bioink and innovatively applying fluorescent carbon quantum dots for long-term tracking of cells.The GelMA(10%,mass fraction)and PEO(1.6%,mass fraction)hydrogel with 3:1 volume ratio offered distinct pore-forming characteristics,satisfactorymechanical properties,and biocompatibility for the creation of the 3DP-7721 model.Immunofluorescence analysis and quantitative real-time fluorescence polymerase chain reaction(PCR)were used to evaluate the biological properties of the model.Compared with the two-dimensional culture cell model(2D-7721)and the 3D mixed culture cell model(3DM-7721),3DP-7721 significantly improved the proliferation of cells and expression of tumor-related proteins and genes.Moreover,we evaluated the differences between the three culture models and the effectiveness of antitumor drugs in the three models and discovered that the efficacy of antitumor drugs varied because of significant differences in resistance proteins and genes between the three models.In addition,the comparison of tumor formation in the three models found that the cells cultured by the 3DP-7721 model had strong tumorigenicity in nude mice.Immunohistochemical evaluation of the levels of biochemical indicators related to the formation of solid tumors showed that the 3DP-7721 model group exhibited pathological characteristics of malignant tumors,the generated solid tumors were similar to actual tumors,and the deterioration was higher.This research therefore acts as a foundation for the application of 3DP-7721 models in drug development research.展开更多
In vitro 3D cancer spheroids (tumoroids) exhibit a drug resistance profile similar to that found in solid tumors. 3D spheroid culture methods recreate more physiologically relevant microenvironments for cells. Therefo...In vitro 3D cancer spheroids (tumoroids) exhibit a drug resistance profile similar to that found in solid tumors. 3D spheroid culture methods recreate more physiologically relevant microenvironments for cells. Therefore, these models are more appropriate for cancer drug screening. We have recently developed a protocol for MCF-7 cell spheroid culture, and used this method to test the effects of different types of drugs on this estrogen-dependent breast cancer cell spheroid. Our results demonstrated that MCF-7 cells can grow spheroid in medium using a low attachment plate. We managed to grow one spheroid in each well, and the spheroid can grow over a month, the size of the spheroid can grow over a hundred times in volume. Our targeted drug experimental results suggest that estrogen sulfotransferase, steroid sulfatase, and G protein-coupled estrogen receptor may play critical roles in MCF-7 cell spheroid growth, while estrogen receptors α and β may not play an essential role in MCF-7 spheroid growth. Organoids are the miniatures of in vivo tissues and reiterate the in vivo microenvironment of a specific organ, best fit for the in vitro studies of diseases and drug development. Tumoroid, developed from cancer cell lines or patients’ tumor tissue, is the best in vitro model of in vivo tumors. 3D spheroid technology will be the best future method for drug development of cancers and other diseases. Our reported method can be developed clinically to develop personalized drugs when the patient’s tumor tissues are used to develop a spheroid culture for drug screening.展开更多
Recent advances in the study of human hepatocytes derived from induced pluripotent stem cells(iPSC)represent new promises for liver disease study and drug discovery.Human hepatocytes or hepatocyte-like cells different...Recent advances in the study of human hepatocytes derived from induced pluripotent stem cells(iPSC)represent new promises for liver disease study and drug discovery.Human hepatocytes or hepatocyte-like cells differentiated from iPSC recapitulate many func-tional properties of primary human hepatocytes and have been demonstrated as a powerful and efficient tool to model human liver metabolic diseases and fa-cilitate drug development process.In this review,we summarize the recent progress in this field and discuss the future perspective of the application of human iPSC derived hepatocytes.展开更多
Ninety percent of clinical drug development fails despite implementation of many successful strategies,which raised the question whether certain aspects in target validation and drug optimization are overlooked?Curren...Ninety percent of clinical drug development fails despite implementation of many successful strategies,which raised the question whether certain aspects in target validation and drug optimization are overlooked?Current drug optimization overly emphasizes potency/specificity using structure-activityrelationship(SAR)but overlooks tissue exposure/selectivity in disease/normal tissues using structure-tissue exposure/selectivity—relationship(STR),which may mislead the drug candidate selection and impact the balance of clinical dose/efficacy/toxicity.We propose structure-tissue exposure/selectivity—activity relationship(STAR)to improve drug optimization,which classifies drug candidates based on drug’s potency/selectivity,tissue exposure/selectivity,and required dose for balancing clinical efficacy/toxicity.ClassⅠdrugs have high specificity/potency and high tissue exposure/selectivity,which needs low dose to achieve superior clinical efficacy/safety with high success rate.ClassⅡdrugs have high specificity/potency and low tissue exposure/selectivity,which requires high dose to achieve clinical efficacy with high toxicity and needs to be cautiously evaluated.ClassⅢdrugs have relatively low(adequate)specificity/potency but high tissue exposure/selectivity,which requires low dose to achieve clinical efficacy with manageable toxicity but are often overlooked.ClassⅣdrugs have low specificity/potency and low tissue exposure/selectivity,which achieves inadequate efficacy/safety,and should be terminated early.STAR may improve drug optimization and clinical studies for the success of clinical drug development.展开更多
The 2016 Lasker-DeBakey Clinical Medical Research Award was given to three scientists working on different stages of the translational sciences on bringing a high efficacious therapy against hepatitis C virus(HCV)infe...The 2016 Lasker-DeBakey Clinical Medical Research Award was given to three scientists working on different stages of the translational sciences on bringing a high efficacious therapy against hepatitis C virus(HCV)infection to a reality.An effective treatment of HCV chronic infection was developed,by a team led by Michael Sofia,using展开更多
There is little or no research initiated on enlightening Nigerians about the pathogenesis,targets for drug development and repositioning for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.Coronav...There is little or no research initiated on enlightening Nigerians about the pathogenesis,targets for drug development and repositioning for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.Coronavirus disease 2019(COVID-19)is a viral infection causing symptoms like dry cough,sore throat,nasal congestion,tiredness,fever,loss of taste,and smell etc.The disease was first reported in Wuhan,China,in December 2019.The infection is caused by SARS-CoV-2,which is the third introduction of a highly pathogenic coronavirus into the human population.Coronaviruses are viruses with a positive RNA envelope assigned toα,β,γ,andδgenera.Moreover,SARS-CoV-2 belongs to theβgenus.The four structural proteins ofβcoronavirus are membrane(M),envelope(E),spike(S),and nucleocapsid(N)protein,mediation of coronavirus host infection is established by spike(S)protein.Therefore,the search for drug development targets and repositioning of existing therapeutics is essential for fighting the present pandemic.It was reviewed that therapeutics targeting SARS-CoV-2 binding to ACE2 receptor,viral RNA synthesis and replication,3CLpro,RdRp,and helicase will play a crucial role in the development of treatment for SARS-CoV-2 infection.Furthermore,the RdRp and spike protein of SARS-CoV-2 are the most promising targets for drug development and repositioning and vaccine development.Remdesivir combination with chloroquine/hydroxychloroquine are promising drug repositioning for the treatment of COVID-19,and mRNA-1273 targeting spike protein is the promising vaccine.However,as patient management and drug repositioning are taking place,it is imperative to identify other promising targets used by SARS-CoV-2 to establish infection,to develop novel therapeutics.展开更多
Cancer drug development is a time and resources consuming process.Around 90%of drugs entering clinical trials fail due to lack of efficacy and/or safety issues,more often after conspicuous research and economic effort...Cancer drug development is a time and resources consuming process.Around 90%of drugs entering clinical trials fail due to lack of efficacy and/or safety issues,more often after conspicuous research and economic efforts.Part of the discarded drugs might be beneficial only in a subgroup of the study patients,and some adverse events might be prevented by identifying those patients more vulnerable to toxicities.The implementation of pharmacogenomic biomarkers allows the categorization of patients,to predict efficacy and toxicity and to optimize the drug development process.Around seventy FDA approved drugs currently present one or more genetic biomarker to keep in consideration,and with the progress of Precision Medicine tailoring therapies on individuals’genomic landscape promises to become a new standard of cancer care.In the current article we review the role of pharmacogenomics in cancer drug development,underlying the advantages and challenges of their implementation.展开更多
Repolarization-related lethal arrhythmias have led to the concept of“repolarization reserve”,which may help elucidate the relationship between K^(+) currents and other components of repolarization.Pharmacological ma...Repolarization-related lethal arrhythmias have led to the concept of“repolarization reserve”,which may help elucidate the relationship between K^(+) currents and other components of repolarization.Pharmacological manipulation as well as congenital and cardiac disease may affect repolarization and alter the repolarization reserve,leading to the development of arrhythmias.Pharmacological enhancement of outward currents or suppression of inward currents has been shown to be of therapeutic value.A number of newly found selective ion channel inhibitors or agonists have been investigated for their ability to enhance repolarization reserve and decrease the incidence of arrhythmia.In this paper we review the development,potential mechanisms,clinical application,and pharmacological significance of repolarization reserve in order to better understand,predict and prevent unexplained adverse cardiac events.展开更多
Developments of drugs or natural products from plants are possibly made, simple to use and lower cost than modern drugs.The development processes can be started with studying local wisdom and literature reviews to cho...Developments of drugs or natural products from plants are possibly made, simple to use and lower cost than modern drugs.The development processes can be started with studying local wisdom and literature reviews to choose the plants which have long been used in diverse areas, such as foods, traditional medicine, fragrances and seasonings.Then those data will be associated with scientific researches, namely plant collection and identification, phytochemical screening by gas chromatography-mass spectrometry,pharmacological study/review for their functions, and finally safety and efficiency tests in human.For safety testing, in vitro cell toxicity by cell viability assessment and in vitro testing of DNA breaks by the comet assay in human peripheral blood mononuclear cells can be performed.When active chemicals and functions containing plants were chosen with safety and efficacy for human uses, then, the potential medicinal natural products will be produced.Based on these procedures, the producing cost will be cheaper and the products can be evaluated for their clinical properties.Thus, the best and lowest-priced medicines and natural products can be distributed worldwide.展开更多
Coastal medicine is a promising field for research and drug development,because several natural products isolated from marine organisms have been found to be therapeutically useful in a clinical setting.In comparison ...Coastal medicine is a promising field for research and drug development,because several natural products isolated from marine organisms have been found to be therapeutically useful in a clinical setting.In comparison to terrestrial products,the merit of marine compounds arises from the diversity in their chemical structure and unique bioactivity.A recently discovered marine compound,xyloketal B,displays neuroprotective and antioxidative effects in in-vitro and in-vivo experimental models.It elicits these beneficial effects through mitochondrial protection,free radical scavenging,reducing reactive oxygen species production and suppressing apoptotic signaling.In addition,unpublished data from our lab revealed that transient receptor potential melastatin 7 channel activity,implicated in a myriad of neurodegenerative diseases,was inhibited following xyloketal B administration.In this review,the therapeutic effect of xyloketal B will be evaluated based on existing evidence and its potential for drug development will be also discussed.展开更多
With the improvements in computer computing ability,data accumulation and rapid algorithm development,the integration of artificial intelligence(AI)and drug synthesis has been accelerated,significantly improving the d...With the improvements in computer computing ability,data accumulation and rapid algorithm development,the integration of artificial intelligence(AI)and drug synthesis has been accelerated,significantly improving the design and synthesis of drug molecules.Recently,data-driven computer-aided synthesis tools have been quickly and widely applied in retrosynthetic analysis,reaction prediction and automated synthesis,which can effectively accelerate the process of drug discovery and development and improve the quality of designed and synthesized drug molecules.Here,we review the development and applications of computer-aided synthesis technology and introduce recent advances in computer-aided drug development from three aspects:computer-aided drug design,computer-aided drug synthesis route design and computer-aided intelligent drug synthesis machines.Furthermore,the challenges and opportunities of computer-aided drug synthesis technology are discussed.展开更多
Pharmaceutical technology is an indispensable and important link in drug research and development,which plays a key role in drug research and development quality.In the background of science and technology development...Pharmaceutical technology is an indispensable and important link in drug research and development,which plays a key role in drug research and development quality.In the background of science and technology development,pharmaceutical technology has been greatly developed,but also to promote the quality of drug research and development,to provide more guarantee for people’s health.In the new era,how to achieve pharmaceutical technology innovation,so as to further improve the quality of drug research and development,is an important research topic in the current related industries.This paper mainly revolves around quality of pharmaceutical technology development of a series of exploration,in the traditional drug development based on a better control of drug quality,the future of smart pharmaceutical green pharmaceutical development direction,aims to further enhance the pharmaceutical technology,promote the quality of research and development to promote the comprehensive,promote the steady development of the pharmaceutical industry as a whole.展开更多
Objective To help investors assess and control the costs of new drug development and reduce the risks of new drug development projects.Methods Cost analysis and financial forecasting were carried out with the integrat...Objective To help investors assess and control the costs of new drug development and reduce the risks of new drug development projects.Methods Cost analysis and financial forecasting were carried out with the integrated approach of earned value management.According to the principle of earned value management deviation analysis,the basic process of the new drug research and development project was combined with the hypothesis method from the research of Tufts Drug Development Research Center.Results and Conclusion If the project progress check was carried out in the clinical trial,the project costs were found overspent,the efficiency was low,the project progress was faster,and the resource investment was ahead.It is recommended that the adjustment should be made to reduce the input of resources,and increase the efficient key personnel to take the place of some less efficient staff.展开更多
Basic research features its indelible contribution to and energetic promotion of scientific cause and advancing social progress. This article explores its vital position and rewarding role in creating socio-economic b...Basic research features its indelible contribution to and energetic promotion of scientific cause and advancing social progress. This article explores its vital position and rewarding role in creating socio-economic benefits by reviewing the development and marketing success of a new drug, "Di’ aoxinxuekang".展开更多
1.The Current Situation
Facing China's accession to the WTO,our pharmaceutical industries must prepare to meet extremely strong competition,because 97% of the synthetic medicines and antibiotics marketed in the co...1.The Current Situation
Facing China's accession to the WTO,our pharmaceutical industries must prepare to meet extremely strong competition,because 97% of the synthetic medicines and antibiotics marketed in the country are copies of foreign products.展开更多
Diabetic eye disease refers to a group of eye complications that occur in diabetic patients and include diabetic retinopathy, diabetic macular edema, diabetic cataracts, and diabetic glaucoma. However, the global epid...Diabetic eye disease refers to a group of eye complications that occur in diabetic patients and include diabetic retinopathy, diabetic macular edema, diabetic cataracts, and diabetic glaucoma. However, the global epidemiology of these conditions has not been well characterized. In this study, we collected information on diabetic eye disease-related research grants from seven representative countries––the United States, China, Japan, the United Kingdom, Spain, Germany, and France––by searching for all global diabetic eye disease journal articles in the Web of Science and Pub Med databases, all global registered clinical trials in the Clinical Trials database, and new drugs approved by the United States, China, Japan, and EU agencies from 2012 to 2021. During this time period, diabetic retinopathy accounted for the vast majority(89.53%) of the 2288 government research grants that were funded to investigate diabetic eye disease, followed by diabetic macular edema(9.27%). The United States granted the most research funding for diabetic eye disease out of the seven countries assessed. The research objectives of grants focusing on diabetic retinopathy and diabetic macular edema differed by country. Additionally, the United States was dominant in terms of research output, publishing 17.53% of global papers about diabetic eye disease and receiving 22.58% of total citations. The United States and the United Kingdom led international collaborations in research into diabetic eye disease. Of the 415 clinical trials that we identified, diabetic macular edema was the major disease that was targeted for drug development(58.19%). Approximately half of the trials(49.13%) pertained to angiogenesis. However, few drugs were approved for ophthalmic(40 out of 1830;2.19%) and diabetic eye disease(3 out of 1830;0.02%) applications. Our findings show that basic and translational research related to diabetic eye disease in the past decade has not been highly active, and has yielded few new treatment methods and newly approved drugs.展开更多
文摘Objective To identify the critical risks in the process of innovative drug research and development,and to provide reference for improving the efficiency of innovative drug development and risk control in China.Methods Expert investigation and analytic hierarchy process were used to determine the weights of different risks.Results and Conclusion The research and analysis results showed that the risks at different stages of development had different effects on the success rate of drug development,among which the risk at the drug discovery stage influenced the most.In the drug discovery stage,inappropriate target selection had the greatest impact on the success rate of drug development.The lack of appropriate cell tissue or animal models had the greatest impact on the success rate of drug development from the discovery of a compound to the application for clinical trials.The difference in changes between nonclinical and clinical studies had the greatest impact on the success rate of drug development from early clinical studies to pivotal clinical studies.Incorrect dose selection had the greatest impact on the success rate of drug development from pivotal clinical studies to marketing authorization applications.The biggest impact from the marketing authorization application to the approval stage was inadequate communication with regulators.After investigating the weight of risk factors in the process of innovative drug development based on scientific methods,a new perspective for the risk control of new drug development and improving the research and development efficiency is provided.
文摘Model-informed drug develop⁃ment(MIDD)is the application of a various math⁃ematical,statistical,and biological models to facilitate drug development,decision making and regulatory review.As a quantitative tool,MIDD approaches allow an integration of information obtained from non-clinical studies and clinical trials in a drug development program.General understandings of the underlying biology,patho⁃physiology,and pharmacology can also be incor⁃porated into the model.MIDD is centered on knowledge and inferences generated from inte⁃grated models of the physicochemical character⁃istics of a molecule,its disposition in the body,and its mechanism of action,and how the drug might affect a disease from both an efficacy and a safety perspective.MIDD approaches have the potential to significantly streamline drug develop⁃ment,by improving clinical trial efficiency,opti⁃mizing dose and regimen and waive unneces⁃sary clinical studies.This presentation will use cases studies to demonstrate how to apply MIDD in early phase of clinical trials.
文摘Since President Obama announced the Precision Medicine Initiative from a national strategy perspective in his State of the Union address,precision medicine has rapidly become a world-wide hotspot and drawn global attention in the medical field.Precision medicine aims at applying genetic information of individual diseases to guide his or her diagnosis and treatment.
基金supported by funding from the Bluesand Foundation,Alzheimer's Association(AARG-21-852072 and Bias Frangione Early Career Achievement Award)to EDan Australian Government Research Training Program scholarship and the University of Sydney's Brain and Mind Centre fellowship to AH。
文摘Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia cases.Although there have been recent developments in tauopathy biomarkers and disease-modifying treatments,ongoing progress is required to ensure these are effective,economical,and accessible for the globally ageing population.As such,continued identification of new potential drug targets and biomarkers is critical."Big data"studies,such as proteomics,can generate information on thousands of possible new targets for dementia diagnostics and therapeutics,but currently remain underutilized due to the lack of a clear process by which targets are selected for future drug development.In this review,we discuss current tauopathy biomarkers and therapeutics,and highlight areas in need of improvement,particularly when addressing the needs of frail,comorbid and cognitively impaired populations.We highlight biomarkers which have been developed from proteomic data,and outline possible future directions in this field.We propose new criteria by which potential targets in proteomics studies can be objectively ranked as favorable for drug development,and demonstrate its application to our group's recent tau interactome dataset as an example.
基金supported by the National Natural Science Foundation of China(Nos.51975400 and 62031022)Shanxi Provincial Key Medical Scientific Research Project(Nos.2020XM06 and 2021XM12)+3 种基金Fundamental Research Program of Shanxi Province(No.202103021224081)Shanxi Provincial Basic Research Project(Nos.202103021221006 and 202103021223040)Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi(No.2021L044)Shanxi-Zheda Institute of Advanced Materials and Chemical Engineering(No.2022SX-TD026).
文摘Traditional tumor models do not tend to accurately simulate tumor growth in vitro or enable personalized treatment and are particularly unable to discover more beneficial targeted drugs.To address this,this study describes the use of threedimensional(3D)bioprinting technology to construct a 3D model with human hepatocarcinoma SMMC-7721 cells(3DP-7721)by combining gelatin methacrylate(GelMA)and poly(ethylene oxide)(PEO)as two immiscible aqueous phases to form a bioink and innovatively applying fluorescent carbon quantum dots for long-term tracking of cells.The GelMA(10%,mass fraction)and PEO(1.6%,mass fraction)hydrogel with 3:1 volume ratio offered distinct pore-forming characteristics,satisfactorymechanical properties,and biocompatibility for the creation of the 3DP-7721 model.Immunofluorescence analysis and quantitative real-time fluorescence polymerase chain reaction(PCR)were used to evaluate the biological properties of the model.Compared with the two-dimensional culture cell model(2D-7721)and the 3D mixed culture cell model(3DM-7721),3DP-7721 significantly improved the proliferation of cells and expression of tumor-related proteins and genes.Moreover,we evaluated the differences between the three culture models and the effectiveness of antitumor drugs in the three models and discovered that the efficacy of antitumor drugs varied because of significant differences in resistance proteins and genes between the three models.In addition,the comparison of tumor formation in the three models found that the cells cultured by the 3DP-7721 model had strong tumorigenicity in nude mice.Immunohistochemical evaluation of the levels of biochemical indicators related to the formation of solid tumors showed that the 3DP-7721 model group exhibited pathological characteristics of malignant tumors,the generated solid tumors were similar to actual tumors,and the deterioration was higher.This research therefore acts as a foundation for the application of 3DP-7721 models in drug development research.
文摘In vitro 3D cancer spheroids (tumoroids) exhibit a drug resistance profile similar to that found in solid tumors. 3D spheroid culture methods recreate more physiologically relevant microenvironments for cells. Therefore, these models are more appropriate for cancer drug screening. We have recently developed a protocol for MCF-7 cell spheroid culture, and used this method to test the effects of different types of drugs on this estrogen-dependent breast cancer cell spheroid. Our results demonstrated that MCF-7 cells can grow spheroid in medium using a low attachment plate. We managed to grow one spheroid in each well, and the spheroid can grow over a month, the size of the spheroid can grow over a hundred times in volume. Our targeted drug experimental results suggest that estrogen sulfotransferase, steroid sulfatase, and G protein-coupled estrogen receptor may play critical roles in MCF-7 cell spheroid growth, while estrogen receptors α and β may not play an essential role in MCF-7 spheroid growth. Organoids are the miniatures of in vivo tissues and reiterate the in vivo microenvironment of a specific organ, best fit for the in vitro studies of diseases and drug development. Tumoroid, developed from cancer cell lines or patients’ tumor tissue, is the best in vitro model of in vivo tumors. 3D spheroid technology will be the best future method for drug development of cancers and other diseases. Our reported method can be developed clinically to develop personalized drugs when the patient’s tumor tissues are used to develop a spheroid culture for drug screening.
基金supported by Sanofi-Aventis,The Helmsley Charitable Trust and The Ellison Medical Foundation.GHL was supported by 100 Talents Program of the Chinese Academy of Sciences.
文摘Recent advances in the study of human hepatocytes derived from induced pluripotent stem cells(iPSC)represent new promises for liver disease study and drug discovery.Human hepatocytes or hepatocyte-like cells differentiated from iPSC recapitulate many func-tional properties of primary human hepatocytes and have been demonstrated as a powerful and efficient tool to model human liver metabolic diseases and fa-cilitate drug development process.In this review,we summarize the recent progress in this field and discuss the future perspective of the application of human iPSC derived hepatocytes.
文摘Ninety percent of clinical drug development fails despite implementation of many successful strategies,which raised the question whether certain aspects in target validation and drug optimization are overlooked?Current drug optimization overly emphasizes potency/specificity using structure-activityrelationship(SAR)but overlooks tissue exposure/selectivity in disease/normal tissues using structure-tissue exposure/selectivity—relationship(STR),which may mislead the drug candidate selection and impact the balance of clinical dose/efficacy/toxicity.We propose structure-tissue exposure/selectivity—activity relationship(STAR)to improve drug optimization,which classifies drug candidates based on drug’s potency/selectivity,tissue exposure/selectivity,and required dose for balancing clinical efficacy/toxicity.ClassⅠdrugs have high specificity/potency and high tissue exposure/selectivity,which needs low dose to achieve superior clinical efficacy/safety with high success rate.ClassⅡdrugs have high specificity/potency and low tissue exposure/selectivity,which requires high dose to achieve clinical efficacy with high toxicity and needs to be cautiously evaluated.ClassⅢdrugs have relatively low(adequate)specificity/potency but high tissue exposure/selectivity,which requires low dose to achieve clinical efficacy with manageable toxicity but are often overlooked.ClassⅣdrugs have low specificity/potency and low tissue exposure/selectivity,which achieves inadequate efficacy/safety,and should be terminated early.STAR may improve drug optimization and clinical studies for the success of clinical drug development.
文摘The 2016 Lasker-DeBakey Clinical Medical Research Award was given to three scientists working on different stages of the translational sciences on bringing a high efficacious therapy against hepatitis C virus(HCV)infection to a reality.An effective treatment of HCV chronic infection was developed,by a team led by Michael Sofia,using
文摘There is little or no research initiated on enlightening Nigerians about the pathogenesis,targets for drug development and repositioning for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.Coronavirus disease 2019(COVID-19)is a viral infection causing symptoms like dry cough,sore throat,nasal congestion,tiredness,fever,loss of taste,and smell etc.The disease was first reported in Wuhan,China,in December 2019.The infection is caused by SARS-CoV-2,which is the third introduction of a highly pathogenic coronavirus into the human population.Coronaviruses are viruses with a positive RNA envelope assigned toα,β,γ,andδgenera.Moreover,SARS-CoV-2 belongs to theβgenus.The four structural proteins ofβcoronavirus are membrane(M),envelope(E),spike(S),and nucleocapsid(N)protein,mediation of coronavirus host infection is established by spike(S)protein.Therefore,the search for drug development targets and repositioning of existing therapeutics is essential for fighting the present pandemic.It was reviewed that therapeutics targeting SARS-CoV-2 binding to ACE2 receptor,viral RNA synthesis and replication,3CLpro,RdRp,and helicase will play a crucial role in the development of treatment for SARS-CoV-2 infection.Furthermore,the RdRp and spike protein of SARS-CoV-2 are the most promising targets for drug development and repositioning and vaccine development.Remdesivir combination with chloroquine/hydroxychloroquine are promising drug repositioning for the treatment of COVID-19,and mRNA-1273 targeting spike protein is the promising vaccine.However,as patient management and drug repositioning are taking place,it is imperative to identify other promising targets used by SARS-CoV-2 to establish infection,to develop novel therapeutics.
文摘Cancer drug development is a time and resources consuming process.Around 90%of drugs entering clinical trials fail due to lack of efficacy and/or safety issues,more often after conspicuous research and economic efforts.Part of the discarded drugs might be beneficial only in a subgroup of the study patients,and some adverse events might be prevented by identifying those patients more vulnerable to toxicities.The implementation of pharmacogenomic biomarkers allows the categorization of patients,to predict efficacy and toxicity and to optimize the drug development process.Around seventy FDA approved drugs currently present one or more genetic biomarker to keep in consideration,and with the progress of Precision Medicine tailoring therapies on individuals’genomic landscape promises to become a new standard of cancer care.In the current article we review the role of pharmacogenomics in cancer drug development,underlying the advantages and challenges of their implementation.
基金supported by the National Natural Science Foundation of China(No.81170177).
文摘Repolarization-related lethal arrhythmias have led to the concept of“repolarization reserve”,which may help elucidate the relationship between K^(+) currents and other components of repolarization.Pharmacological manipulation as well as congenital and cardiac disease may affect repolarization and alter the repolarization reserve,leading to the development of arrhythmias.Pharmacological enhancement of outward currents or suppression of inward currents has been shown to be of therapeutic value.A number of newly found selective ion channel inhibitors or agonists have been investigated for their ability to enhance repolarization reserve and decrease the incidence of arrhythmia.In this paper we review the development,potential mechanisms,clinical application,and pharmacological significance of repolarization reserve in order to better understand,predict and prevent unexplained adverse cardiac events.
文摘Developments of drugs or natural products from plants are possibly made, simple to use and lower cost than modern drugs.The development processes can be started with studying local wisdom and literature reviews to choose the plants which have long been used in diverse areas, such as foods, traditional medicine, fragrances and seasonings.Then those data will be associated with scientific researches, namely plant collection and identification, phytochemical screening by gas chromatography-mass spectrometry,pharmacological study/review for their functions, and finally safety and efficiency tests in human.For safety testing, in vitro cell toxicity by cell viability assessment and in vitro testing of DNA breaks by the comet assay in human peripheral blood mononuclear cells can be performed.When active chemicals and functions containing plants were chosen with safety and efficacy for human uses, then, the potential medicinal natural products will be produced.Based on these procedures, the producing cost will be cheaper and the products can be evaluated for their clinical properties.Thus, the best and lowest-priced medicines and natural products can be distributed worldwide.
基金Supported by Canadian Institutes of Health Research(CIHR)China-Canada Joint Health Research Initiative to HSS(CIHR,FRN#132571).
文摘Coastal medicine is a promising field for research and drug development,because several natural products isolated from marine organisms have been found to be therapeutically useful in a clinical setting.In comparison to terrestrial products,the merit of marine compounds arises from the diversity in their chemical structure and unique bioactivity.A recently discovered marine compound,xyloketal B,displays neuroprotective and antioxidative effects in in-vitro and in-vivo experimental models.It elicits these beneficial effects through mitochondrial protection,free radical scavenging,reducing reactive oxygen species production and suppressing apoptotic signaling.In addition,unpublished data from our lab revealed that transient receptor potential melastatin 7 channel activity,implicated in a myriad of neurodegenerative diseases,was inhibited following xyloketal B administration.In this review,the therapeutic effect of xyloketal B will be evaluated based on existing evidence and its potential for drug development will be also discussed.
基金This work was supported by grants from the National Natural Science Foundation of China(Nos.81922064,22177083,81874290,81803755)Sichuan University Postdoctoral Interdisciplinary Innovation Fund,and West China Nursing Discipline Development Special Fund Project,Sichuan University(No.HXHL21011).
文摘With the improvements in computer computing ability,data accumulation and rapid algorithm development,the integration of artificial intelligence(AI)and drug synthesis has been accelerated,significantly improving the design and synthesis of drug molecules.Recently,data-driven computer-aided synthesis tools have been quickly and widely applied in retrosynthetic analysis,reaction prediction and automated synthesis,which can effectively accelerate the process of drug discovery and development and improve the quality of designed and synthesized drug molecules.Here,we review the development and applications of computer-aided synthesis technology and introduce recent advances in computer-aided drug development from three aspects:computer-aided drug design,computer-aided drug synthesis route design and computer-aided intelligent drug synthesis machines.Furthermore,the challenges and opportunities of computer-aided drug synthesis technology are discussed.
文摘Pharmaceutical technology is an indispensable and important link in drug research and development,which plays a key role in drug research and development quality.In the background of science and technology development,pharmaceutical technology has been greatly developed,but also to promote the quality of drug research and development,to provide more guarantee for people’s health.In the new era,how to achieve pharmaceutical technology innovation,so as to further improve the quality of drug research and development,is an important research topic in the current related industries.This paper mainly revolves around quality of pharmaceutical technology development of a series of exploration,in the traditional drug development based on a better control of drug quality,the future of smart pharmaceutical green pharmaceutical development direction,aims to further enhance the pharmaceutical technology,promote the quality of research and development to promote the comprehensive,promote the steady development of the pharmaceutical industry as a whole.
文摘Objective To help investors assess and control the costs of new drug development and reduce the risks of new drug development projects.Methods Cost analysis and financial forecasting were carried out with the integrated approach of earned value management.According to the principle of earned value management deviation analysis,the basic process of the new drug research and development project was combined with the hypothesis method from the research of Tufts Drug Development Research Center.Results and Conclusion If the project progress check was carried out in the clinical trial,the project costs were found overspent,the efficiency was low,the project progress was faster,and the resource investment was ahead.It is recommended that the adjustment should be made to reduce the input of resources,and increase the efficient key personnel to take the place of some less efficient staff.
文摘Basic research features its indelible contribution to and energetic promotion of scientific cause and advancing social progress. This article explores its vital position and rewarding role in creating socio-economic benefits by reviewing the development and marketing success of a new drug, "Di’ aoxinxuekang".
文摘1.The Current Situation
Facing China's accession to the WTO,our pharmaceutical industries must prepare to meet extremely strong competition,because 97% of the synthetic medicines and antibiotics marketed in the country are copies of foreign products.
基金supported by the National Natural Science Foundation of China,No.82122009 (to JX)Science Research Foundation ofAier Eye Hospital Group,No.AM2001D1 (to JX)the Natural Science Foundation of Hunan Province,No.2020JJ5002 (to SJ)。
文摘Diabetic eye disease refers to a group of eye complications that occur in diabetic patients and include diabetic retinopathy, diabetic macular edema, diabetic cataracts, and diabetic glaucoma. However, the global epidemiology of these conditions has not been well characterized. In this study, we collected information on diabetic eye disease-related research grants from seven representative countries––the United States, China, Japan, the United Kingdom, Spain, Germany, and France––by searching for all global diabetic eye disease journal articles in the Web of Science and Pub Med databases, all global registered clinical trials in the Clinical Trials database, and new drugs approved by the United States, China, Japan, and EU agencies from 2012 to 2021. During this time period, diabetic retinopathy accounted for the vast majority(89.53%) of the 2288 government research grants that were funded to investigate diabetic eye disease, followed by diabetic macular edema(9.27%). The United States granted the most research funding for diabetic eye disease out of the seven countries assessed. The research objectives of grants focusing on diabetic retinopathy and diabetic macular edema differed by country. Additionally, the United States was dominant in terms of research output, publishing 17.53% of global papers about diabetic eye disease and receiving 22.58% of total citations. The United States and the United Kingdom led international collaborations in research into diabetic eye disease. Of the 415 clinical trials that we identified, diabetic macular edema was the major disease that was targeted for drug development(58.19%). Approximately half of the trials(49.13%) pertained to angiogenesis. However, few drugs were approved for ophthalmic(40 out of 1830;2.19%) and diabetic eye disease(3 out of 1830;0.02%) applications. Our findings show that basic and translational research related to diabetic eye disease in the past decade has not been highly active, and has yielded few new treatment methods and newly approved drugs.
