Modern drugs have changed epilepsy,which affects people of all ages.However,for young people with epilepsy,the framework of drug development has stalled.In the wake of the thalidomide catastrophe,the misconception eme...Modern drugs have changed epilepsy,which affects people of all ages.However,for young people with epilepsy,the framework of drug development has stalled.In the wake of the thalidomide catastrophe,the misconception emerged that for people<18 years of age drugs,including antiseizure medications(ASMs),need separate proof of efficacy and safety,overall called"pediatric drug development".For ASMs,this has changed to some degree.Authorities now accept that ASMs are effective in<18 years as well,but they still require"extrapolation of efficacy,"as if minors were another species.As a result,some of the pediatric clinical epilepsy research over the past decades was unnecessary.Even more importantly,this has hampered research on meaningful research goals.We do not need to confirm that ASMs work before as they do after the 18th birthday.Instead,we need to learn how to prevent brain damage in young patients by preventing seizures and optimize ASMs’uses.Herein we discuss how to proceed in this endeavor.展开更多
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
With the rapid development of modern science and technology, traditional randomized controlled trials have become insufficient to meet current scientific research needs, particularly in the field of clinical research....With the rapid development of modern science and technology, traditional randomized controlled trials have become insufficient to meet current scientific research needs, particularly in the field of clinical research. The emergence of real-world data studies, which align more closely with actual clinical evidence, has garnered significant attention in recent years. The following is a brief overview of the specific utilization of real-world data in drug development, which often involves large sample sizes and analyses covering a relatively diverse population without strict inclusion and exclusion criteria. Real-world data often reflects real clinical practice: treatment options are chosen according to the actual conditions and willingness of patients rather than through random assignment. Analysis based on real-world data also focuses on endpoints highly relevant to clinical benefits and the quality of life of patients. The booming big data technology supports the utilization of real-world data to accelerate new drug development, serving as an important supplement to traditional clinical trials.展开更多
Objective To identify technical risks in the process of innovative drug development,and to provide reference for technical risk management so as to reduce the uncertainties and improve the efficiency of research and d...Objective To identify technical risks in the process of innovative drug development,and to provide reference for technical risk management so as to reduce the uncertainties and improve the efficiency of research and development.Methods The initial risk index was investigated by literature research.Then,the Likert scale was used to design a questionnaire,and the experts’opinion was used to analyze the risk factors affecting the different stages of the development of innovative drugs in China.Results and Conclusion Based on the analysis of questionnaire,31 risk indicators of five key stages in the development of innovative drugs from drug discovery to marketing authorization were established.The key risk indicators constructed in this study can provide reference for technology-related risk management in the process of innovative drug development.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
Zinc(Zn) is an essential mineral element for plant growth and development. Zn deficiency in crops frequently occurs in many types of soils. It is therefore crucial to identify genetic resources linking Zn acquisition ...Zinc(Zn) is an essential mineral element for plant growth and development. Zn deficiency in crops frequently occurs in many types of soils. It is therefore crucial to identify genetic resources linking Zn acquisition traits and development of crops with improved Zn-use efficiency for sustainable crop production. In this study, we functionally identified a rice uncharacterized ABCG(ATP-binding cassette G-subfamily) gene encoding a PDR20(pleiotropic drug resistance 20) metal transporter for mediation of rice growth, seed development and Zn accumulation. OsPDR20 was localized to the plasma membrane, but it was not transcriptionally induced under Zn deficiency, rather was sufficiently up-regulated under high level of Zn stress. Yeast(Saccharomyces cerevisiae) transformed with OsPDR20 displayed a relatively lower Zn accumulation with attenuated cellular growth, suggesting that OsPDR20 had an activity for Zn transport. Knocking-down OsPDR20 by RNA interference(RNAi) compromised rice growth with shorter plant height and decreased biomass in rice plantlets grown under hydroponic media. Zn concentration in the roots of OsPDR20 knocked-down rice lines declined under Zn deficiency, while they remained unchanged compared with the wild type under normal Zn supply. A rice lifelong field trial demonstrated that OsPDR20 mutation impaired the capacity of seed development, with shortened panicle and seed length, compromised spikelet fertility, and reduced grain number per plant or grain weight per unit area. Interestingly, OsPDR20 mutation elevated the accumulation of Zn in husk and brown rice over the wild type. Overall, this study pointed out that OsPDR20 is fundamentally required for rice growth and seed development through Zn transport and homeostasis.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
SARS-CoV-2 has been marked as a highly pathogenic coronavirus of COVID-19 disease into the human population,causing over 5.5 million confirmed cases worldwide.As COVID-19 has posed a global threat with significant hum...SARS-CoV-2 has been marked as a highly pathogenic coronavirus of COVID-19 disease into the human population,causing over 5.5 million confirmed cases worldwide.As COVID-19 has posed a global threat with significant human casualties and severe economic losses,there is a pressing demand to further understand the current situation and develop rational strategies to contain the drastic spread of the virus.Although there are no specific antiviral therapies that have proven effective in randomized clinical trials,currently,the rapid detection technology along with several promising therapeutics for COVID-19 have mitigated its drastic transmission.Besides,global institutions and corporations have commenced to parse out effective vaccines for the prevention of COVID-19.Herein,the present review will give exhaustive details of extensive researches concerning the drug discovery and therapeutic options for COVID-19 as well as some insightful discussions of the status of COVID-19.展开更多
Cancer is one of the leading causes of death worldwide. Recent advances in cellular therapy have demonstrated that this platform has the potential to give patients with certain cancers a second chance at life. Unlike ...Cancer is one of the leading causes of death worldwide. Recent advances in cellular therapy have demonstrated that this platform has the potential to give patients with certain cancers a second chance at life. Unlike chemical compounds and proteins, cells are living, self-replicating drugs that can be engineered to possess exquisite specificity. For example, T cells can be genetically modified to express chimeric antigen receptors (CARs), endowing them with the capacity to recognize and kill tumor cells and form a memory pool that is ready to strike back against persisting malignant cells. Anti-CD19 chimeric antigen receptor T cells (CART19s) have demonstrated a remarkable degree of clinical efficacy for certain malignancies. The process of developing CART19 essentially follows the conventional “one gene, one drug, one disease” paradigm derived from Paul Ehrlich’s “magic bullet” concept. With major players within the pharmaceutical industry joining forces to commercialize this new category of “living drugs,” it is useful to use CART19 as an example to examine the similarities and differences in its development, compared with that of a conventional drug. In this way, we can assimilate existing knowledge and identify the most effective approach for advancing similar strategies. This article reviews the use of biomarker-based assays to guide the optimization of CAR constructs, preclinical studies, and the evaluation of clinical efficacy;adverse effects (AEs);and CART19 cellular kinetics. Advanced technologies and computational tools that enable the discovery of optimal targets, novel CAR binding domains, and biomarkers predicting clinical response and AEs are also discussed. We believe that the success of CART19 will lead to the development of other engineered T cell therapies in the same manner that the discovery of arsphenamine initiated the era of synthetic pharmaceuticals.展开更多
Gordon Life Science Institute is the first Internet Research Institute ever established in the world. It is a non-profit institute. Those scientists who really dedicate themselves to science and loving science more th...Gordon Life Science Institute is the first Internet Research Institute ever established in the world. It is a non-profit institute. Those scientists who really dedicate themselves to science and loving science more than anything else can become its member. In the friendly door-opened Institute, they can maximize their time and energy to engage in their scientific creativity. They have also believed that science would be more truthful and wonderful if scientists do not have to spend a lot of time on funding application, and that great scientific findings and creations in history were often made by those who were least supported or funded but driven by interesting imagination and curiosity. Recollected in this review article is its establishing and developing processes, as well as its philosophy and accomplishments. Particularly, its productive and by-productive outcomes have covered the following five very hot topics in bioinformatics and drug development: 1) PseAAC and PseKNC;2) Disported key theory;3) Wenxiang diagram;4) Multi-label system prediction;5) 5-steps rule. Their impacts on the proteomics and genomics as well as drug development are substantially and awesome.展开更多
Detection of drugs in hair has become popular in recent years. The significantly long drug detection window (months) in hair has allowed the retrospective investigation and measurement of past consumption of drug. As ...Detection of drugs in hair has become popular in recent years. The significantly long drug detection window (months) in hair has allowed the retrospective investigation and measurement of past consumption of drug. As the majority of drugs are basic, an extraction method was developed based on a methanolic solution for detection of basic/weak basic drugs in hair. It was compared with alkaline digestion (NaOH) followed by LLE. A filtration step with filtration vials was added and their materials were compared. After filtration, extracts were injected directly onto a C18 column coupled to Sciex ABI 2000 MSMS. The mobile phase was 50% methanol, 0.1% formic acid and 2 mM ammonium acetate (isocratic). Both methods were compared by applying them to real samples. Results showed that calibration was linear with r2 of 0.991-0.999 for 20 tested analytes. The matrix effect was assessed to be between 91.4%- 110.2% for 18 analytes. PTFE filter material showed better recoveries over the GMF and PVDF based filters. Stability of analytes during extraction in general was better with methanolic incubation rather than alkaline digestion. With regard to real sample recovery, 6 out of 10 analytes recovered better with alkaline digestion. In conclusion, the methanolic method is capable of extracting most basic drugs in hair samples but only part of the total incorporated drug. Therefore, these results suggest that a combination of both methods (methanolic and alkaline extractions) in hair sample processing for general detection of basic and weak basic drugs may produce better results. However, not all basic drugs are stable under alkaline digestion.展开更多
Anticancer drugs research and development have been the largest market area in the pharmaceutical industry in terms of the number of project, clinical trials and spending. In the last 10 - 30 years, targeting therapy ...Anticancer drugs research and development have been the largest market area in the pharmaceutical industry in terms of the number of project, clinical trials and spending. In the last 10 - 30 years, targeting therapy for cancers has been developed and achieved enormous clinical effectiveness by transforming some previously deadly malignancies into chronically manageable conditions, but cure problem still remains. This mini review outlined the current status of anticancer drugs development and hinted the opinions of how to further increase the accuracy and efficacy of discovery for cancer treatment.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
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
Interfaces have always been of concern with respect to the delivery of bioactives.Interfaces within the delivery system that can affect stability are a concern;however,there are other interfaces of importance,such as ...Interfaces have always been of concern with respect to the delivery of bioactives.Interfaces within the delivery system that can affect stability are a concern;however,there are other interfaces of importance,such as the interface with the body tissue,the regulatory interface and the emerging interface when drug delivery is linked to e-health applications.This presentation will address all these interfaces covering basic science aspects as well as discussion of e-health applications.There are interfaces between different phases in formulations such as emulsions,foams,suspensions etc.There are interfaces between actives and excipients within a formulation.The actives as well as excipients may be in different states.展开更多
Recently,generic drug products have played an increasingly important role in the health care system globally,especially in the developing world,as they provide for an effective and more affordable alternative for heal...Recently,generic drug products have played an increasingly important role in the health care system globally,especially in the developing world,as they provide for an effective and more affordable alternative for healthcare professionals.Generic drug products are proven therapeutically equivalent to the corresponding innovator’s product,and hence can be substituted in clinical practice.The objective of generic drug development is to develop a stable and bioequivalent generic drug product with desirable properties in a timely manner.This presentation is intended to summarize three important sequential stages essential for successful generic drug development based on a regulatory experience in reviewing and evaluating the Pharmaceutical Development Section(P2)of the ASEAN Common Technical Dossier(ACTD)of generic drug product applications submitted to the Food and Drug Administration,Thailand[1,2].展开更多
Many therapeutic drugs are racemates;i.e. they are chiral molecules consisting of “left”- and “right-handed” enantiomers (stereoisomers that are mirror images of each other, and are non-superimposable). In some ca...Many therapeutic drugs are racemates;i.e. they are chiral molecules consisting of “left”- and “right-handed” enantiomers (stereoisomers that are mirror images of each other, and are non-superimposable). In some cases, both enantiomers of the drug contribute to some extent (or equally) to the therapeutic effect;in other cases they contribute not at all. The same is true for the adverse effects of racemate drugs: the adverse effects of a racemate drug can be greater-than, less-than, or equal to one or the other enantiomer. An unusual situation arises when a drug consists of “atropisomers”, stereoisomers arising because of hindered rotation about a single chemical bond. We summarize the concept of atropisomerism, and give examples.展开更多
miRNAs are non-coding RNAs that play a regulatory role in expression of genes and are associated with diseases. Quantitatively measuring expression levels of miRNAs can help understanding the mechanisms of human disea...miRNAs are non-coding RNAs that play a regulatory role in expression of genes and are associated with diseases. Quantitatively measuring expression levels of miRNAs can help understanding the mechanisms of human diseases and discovering new drug targets. There are three major methods that have been used to measure the expression levels of miRNAs: real-time reverse transcription PCR (qRT-PCR), microarray, and the newly introduced next-generation sequencing (NGS). NGS is not only suitable for profiling of known miRNAs that qRT-PCR and microarray can do too but also able to detect unknown miRNAs that the other two methods are incapable. Profiling of miRNAs by NGS has been progressed rapidly and is a promising field for applications in drug development. This paper will review the technical advancement of NGS for profiling miRNAs, including comparative analyses between different platforms and software packages for analyzing NGS data. Examples and future perspectives of applications of NGS profiling miRNAs in drug development will be discussed.展开更多
The molecular characterization of various cancers has shown that cancers with the same origins,histopathologic diagnoses,and clinical stages can be highly heterogeneous in their genetic and epigenetic alterations that...The molecular characterization of various cancers has shown that cancers with the same origins,histopathologic diagnoses,and clinical stages can be highly heterogeneous in their genetic and epigenetic alterations that cause tumorigenesis.A number of cancer driver genes with functional abnormalities that trigger malignant transformation and that are required for the survival of cancer cells have been identified.Therapeutic agents targeting some of these cancer drivers have been successfully developed,resulting in substantial improvements in clinical symptom amelioration and outcomes in a subset of cancer patients.However,because such therapeutic drugs often benefit only a limited number of patients,the successes of clinical development and applications rely on the ability to identify those patients who are sensitive to the targeted therapies.Thus,biomarkers that can predict treatment responses are critical for the success of precision therapy for cancer patients and of anticancer drug development.This review discusses the molecular heterogeneity of lung cancer pathogenesis;predictive biomarkers for precision medicine in lung cancer therapy with drugs targeting epidermal growth factor receptor(EGFR),anaplastic lymphoma kinase(ALK),c-ros oncogene 1 receptor tyrosine kinase[ROSl),and immune checkpoints;biomarkers associated with resistance to these therapeutics;and approaches to identify predictive biomarkers in anticancer drug development.The identification of predictive biomarkers during anticancer drug development is expected to greatly facilitate such development because it will increase the chance of success or reduce the attrition rate.Additionally,such identification will accelerate the drug approval process by providing effective patient stratification strategies in clinical trials to reduce the sample size required to demonstrate clinical benefits.展开更多
文摘Modern drugs have changed epilepsy,which affects people of all ages.However,for young people with epilepsy,the framework of drug development has stalled.In the wake of the thalidomide catastrophe,the misconception emerged that for people<18 years of age drugs,including antiseizure medications(ASMs),need separate proof of efficacy and safety,overall called"pediatric drug development".For ASMs,this has changed to some degree.Authorities now accept that ASMs are effective in<18 years as well,but they still require"extrapolation of efficacy,"as if minors were another species.As a result,some of the pediatric clinical epilepsy research over the past decades was unnecessary.Even more importantly,this has hampered research on meaningful research goals.We do not need to confirm that ASMs work before as they do after the 18th birthday.Instead,we need to learn how to prevent brain damage in young patients by preventing seizures and optimize ASMs’uses.Herein we discuss how to proceed in this endeavor.
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With the rapid development of modern science and technology, traditional randomized controlled trials have become insufficient to meet current scientific research needs, particularly in the field of clinical research. The emergence of real-world data studies, which align more closely with actual clinical evidence, has garnered significant attention in recent years. The following is a brief overview of the specific utilization of real-world data in drug development, which often involves large sample sizes and analyses covering a relatively diverse population without strict inclusion and exclusion criteria. Real-world data often reflects real clinical practice: treatment options are chosen according to the actual conditions and willingness of patients rather than through random assignment. Analysis based on real-world data also focuses on endpoints highly relevant to clinical benefits and the quality of life of patients. The booming big data technology supports the utilization of real-world data to accelerate new drug development, serving as an important supplement to traditional clinical trials.
文摘Objective To identify technical risks in the process of innovative drug development,and to provide reference for technical risk management so as to reduce the uncertainties and improve the efficiency of research and development.Methods The initial risk index was investigated by literature research.Then,the Likert scale was used to design a questionnaire,and the experts’opinion was used to analyze the risk factors affecting the different stages of the development of innovative drugs in China.Results and Conclusion Based on the analysis of questionnaire,31 risk indicators of five key stages in the development of innovative drugs from drug discovery to marketing authorization were established.The key risk indicators constructed in this study can provide reference for technology-related risk management in the process of innovative drug development.
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.
基金financially supported by the National Natural Science Foundation of China(Grant No.21777072)。
文摘Zinc(Zn) is an essential mineral element for plant growth and development. Zn deficiency in crops frequently occurs in many types of soils. It is therefore crucial to identify genetic resources linking Zn acquisition traits and development of crops with improved Zn-use efficiency for sustainable crop production. In this study, we functionally identified a rice uncharacterized ABCG(ATP-binding cassette G-subfamily) gene encoding a PDR20(pleiotropic drug resistance 20) metal transporter for mediation of rice growth, seed development and Zn accumulation. OsPDR20 was localized to the plasma membrane, but it was not transcriptionally induced under Zn deficiency, rather was sufficiently up-regulated under high level of Zn stress. Yeast(Saccharomyces cerevisiae) transformed with OsPDR20 displayed a relatively lower Zn accumulation with attenuated cellular growth, suggesting that OsPDR20 had an activity for Zn transport. Knocking-down OsPDR20 by RNA interference(RNAi) compromised rice growth with shorter plant height and decreased biomass in rice plantlets grown under hydroponic media. Zn concentration in the roots of OsPDR20 knocked-down rice lines declined under Zn deficiency, while they remained unchanged compared with the wild type under normal Zn supply. A rice lifelong field trial demonstrated that OsPDR20 mutation impaired the capacity of seed development, with shortened panicle and seed length, compromised spikelet fertility, and reduced grain number per plant or grain weight per unit area. Interestingly, OsPDR20 mutation elevated the accumulation of Zn in husk and brown rice over the wild type. Overall, this study pointed out that OsPDR20 is fundamentally required for rice growth and seed development through Zn transport and homeostasis.
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.
文摘SARS-CoV-2 has been marked as a highly pathogenic coronavirus of COVID-19 disease into the human population,causing over 5.5 million confirmed cases worldwide.As COVID-19 has posed a global threat with significant human casualties and severe economic losses,there is a pressing demand to further understand the current situation and develop rational strategies to contain the drastic spread of the virus.Although there are no specific antiviral therapies that have proven effective in randomized clinical trials,currently,the rapid detection technology along with several promising therapeutics for COVID-19 have mitigated its drastic transmission.Besides,global institutions and corporations have commenced to parse out effective vaccines for the prevention of COVID-19.Herein,the present review will give exhaustive details of extensive researches concerning the drug discovery and therapeutic options for COVID-19 as well as some insightful discussions of the status of COVID-19.
基金support from the Center for Cellular Immunotherapiesthe Abramson Cancer Center at the Perelman School of Medicine,University of Pennsylvania+1 种基金the Parker Institute for Cancer ImmunotherapyPeking University
文摘Cancer is one of the leading causes of death worldwide. Recent advances in cellular therapy have demonstrated that this platform has the potential to give patients with certain cancers a second chance at life. Unlike chemical compounds and proteins, cells are living, self-replicating drugs that can be engineered to possess exquisite specificity. For example, T cells can be genetically modified to express chimeric antigen receptors (CARs), endowing them with the capacity to recognize and kill tumor cells and form a memory pool that is ready to strike back against persisting malignant cells. Anti-CD19 chimeric antigen receptor T cells (CART19s) have demonstrated a remarkable degree of clinical efficacy for certain malignancies. The process of developing CART19 essentially follows the conventional “one gene, one drug, one disease” paradigm derived from Paul Ehrlich’s “magic bullet” concept. With major players within the pharmaceutical industry joining forces to commercialize this new category of “living drugs,” it is useful to use CART19 as an example to examine the similarities and differences in its development, compared with that of a conventional drug. In this way, we can assimilate existing knowledge and identify the most effective approach for advancing similar strategies. This article reviews the use of biomarker-based assays to guide the optimization of CAR constructs, preclinical studies, and the evaluation of clinical efficacy;adverse effects (AEs);and CART19 cellular kinetics. Advanced technologies and computational tools that enable the discovery of optimal targets, novel CAR binding domains, and biomarkers predicting clinical response and AEs are also discussed. We believe that the success of CART19 will lead to the development of other engineered T cell therapies in the same manner that the discovery of arsphenamine initiated the era of synthetic pharmaceuticals.
文摘Gordon Life Science Institute is the first Internet Research Institute ever established in the world. It is a non-profit institute. Those scientists who really dedicate themselves to science and loving science more than anything else can become its member. In the friendly door-opened Institute, they can maximize their time and energy to engage in their scientific creativity. They have also believed that science would be more truthful and wonderful if scientists do not have to spend a lot of time on funding application, and that great scientific findings and creations in history were often made by those who were least supported or funded but driven by interesting imagination and curiosity. Recollected in this review article is its establishing and developing processes, as well as its philosophy and accomplishments. Particularly, its productive and by-productive outcomes have covered the following five very hot topics in bioinformatics and drug development: 1) PseAAC and PseKNC;2) Disported key theory;3) Wenxiang diagram;4) Multi-label system prediction;5) 5-steps rule. Their impacts on the proteomics and genomics as well as drug development are substantially and awesome.
文摘Detection of drugs in hair has become popular in recent years. The significantly long drug detection window (months) in hair has allowed the retrospective investigation and measurement of past consumption of drug. As the majority of drugs are basic, an extraction method was developed based on a methanolic solution for detection of basic/weak basic drugs in hair. It was compared with alkaline digestion (NaOH) followed by LLE. A filtration step with filtration vials was added and their materials were compared. After filtration, extracts were injected directly onto a C18 column coupled to Sciex ABI 2000 MSMS. The mobile phase was 50% methanol, 0.1% formic acid and 2 mM ammonium acetate (isocratic). Both methods were compared by applying them to real samples. Results showed that calibration was linear with r2 of 0.991-0.999 for 20 tested analytes. The matrix effect was assessed to be between 91.4%- 110.2% for 18 analytes. PTFE filter material showed better recoveries over the GMF and PVDF based filters. Stability of analytes during extraction in general was better with methanolic incubation rather than alkaline digestion. With regard to real sample recovery, 6 out of 10 analytes recovered better with alkaline digestion. In conclusion, the methanolic method is capable of extracting most basic drugs in hair samples but only part of the total incorporated drug. Therefore, these results suggest that a combination of both methods (methanolic and alkaline extractions) in hair sample processing for general detection of basic and weak basic drugs may produce better results. However, not all basic drugs are stable under alkaline digestion.
文摘Anticancer drugs research and development have been the largest market area in the pharmaceutical industry in terms of the number of project, clinical trials and spending. In the last 10 - 30 years, targeting therapy for cancers has been developed and achieved enormous clinical effectiveness by transforming some previously deadly malignancies into chronically manageable conditions, but cure problem still remains. This mini review outlined the current status of anticancer drugs development and hinted the opinions of how to further increase the accuracy and efficacy of discovery for cancer treatment.
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.
文摘Interfaces have always been of concern with respect to the delivery of bioactives.Interfaces within the delivery system that can affect stability are a concern;however,there are other interfaces of importance,such as the interface with the body tissue,the regulatory interface and the emerging interface when drug delivery is linked to e-health applications.This presentation will address all these interfaces covering basic science aspects as well as discussion of e-health applications.There are interfaces between different phases in formulations such as emulsions,foams,suspensions etc.There are interfaces between actives and excipients within a formulation.The actives as well as excipients may be in different states.
文摘Recently,generic drug products have played an increasingly important role in the health care system globally,especially in the developing world,as they provide for an effective and more affordable alternative for healthcare professionals.Generic drug products are proven therapeutically equivalent to the corresponding innovator’s product,and hence can be substituted in clinical practice.The objective of generic drug development is to develop a stable and bioequivalent generic drug product with desirable properties in a timely manner.This presentation is intended to summarize three important sequential stages essential for successful generic drug development based on a regulatory experience in reviewing and evaluating the Pharmaceutical Development Section(P2)of the ASEAN Common Technical Dossier(ACTD)of generic drug product applications submitted to the Food and Drug Administration,Thailand[1,2].
文摘Many therapeutic drugs are racemates;i.e. they are chiral molecules consisting of “left”- and “right-handed” enantiomers (stereoisomers that are mirror images of each other, and are non-superimposable). In some cases, both enantiomers of the drug contribute to some extent (or equally) to the therapeutic effect;in other cases they contribute not at all. The same is true for the adverse effects of racemate drugs: the adverse effects of a racemate drug can be greater-than, less-than, or equal to one or the other enantiomer. An unusual situation arises when a drug consists of “atropisomers”, stereoisomers arising because of hindered rotation about a single chemical bond. We summarize the concept of atropisomerism, and give examples.
文摘miRNAs are non-coding RNAs that play a regulatory role in expression of genes and are associated with diseases. Quantitatively measuring expression levels of miRNAs can help understanding the mechanisms of human diseases and discovering new drug targets. There are three major methods that have been used to measure the expression levels of miRNAs: real-time reverse transcription PCR (qRT-PCR), microarray, and the newly introduced next-generation sequencing (NGS). NGS is not only suitable for profiling of known miRNAs that qRT-PCR and microarray can do too but also able to detect unknown miRNAs that the other two methods are incapable. Profiling of miRNAs by NGS has been progressed rapidly and is a promising field for applications in drug development. This paper will review the technical advancement of NGS for profiling miRNAs, including comparative analyses between different platforms and software packages for analyzing NGS data. Examples and future perspectives of applications of NGS profiling miRNAs in drug development will be discussed.
基金supported in part by the National Institutes of Health Specialized Program of Research Excellence(SPORE)Grant CA070907 developmental awardThe University of Texas MD Anderson Cancer Center support Grant CA-016672+3 种基金endowed funds to The University of Texas MD Anderson Cancer Centerthe Moon Shots Programthe Homer Flower Research Fundthe Goldman Sachs Philanthropy Fund
文摘The molecular characterization of various cancers has shown that cancers with the same origins,histopathologic diagnoses,and clinical stages can be highly heterogeneous in their genetic and epigenetic alterations that cause tumorigenesis.A number of cancer driver genes with functional abnormalities that trigger malignant transformation and that are required for the survival of cancer cells have been identified.Therapeutic agents targeting some of these cancer drivers have been successfully developed,resulting in substantial improvements in clinical symptom amelioration and outcomes in a subset of cancer patients.However,because such therapeutic drugs often benefit only a limited number of patients,the successes of clinical development and applications rely on the ability to identify those patients who are sensitive to the targeted therapies.Thus,biomarkers that can predict treatment responses are critical for the success of precision therapy for cancer patients and of anticancer drug development.This review discusses the molecular heterogeneity of lung cancer pathogenesis;predictive biomarkers for precision medicine in lung cancer therapy with drugs targeting epidermal growth factor receptor(EGFR),anaplastic lymphoma kinase(ALK),c-ros oncogene 1 receptor tyrosine kinase[ROSl),and immune checkpoints;biomarkers associated with resistance to these therapeutics;and approaches to identify predictive biomarkers in anticancer drug development.The identification of predictive biomarkers during anticancer drug development is expected to greatly facilitate such development because it will increase the chance of success or reduce the attrition rate.Additionally,such identification will accelerate the drug approval process by providing effective patient stratification strategies in clinical trials to reduce the sample size required to demonstrate clinical benefits.