Did pediatric drug development advance epilepsy treatment in young patients?It is time for new research goals

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.

Utilization of Real-World Data in Drug Development

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.

Analytic Hierarchy Process for Technological Risks in the Process of Innovative Drug Development in China

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.

Cases studies of application of model-informed drug development in early phase clinical trials

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.

Rationally designed treatment for metastatic colorectal cancer:Current drug development strategies

The therapeutic landscape of metastatic colorectal cancer(mCRC)has changed substantially with the emergence of new molecularly targeted agents(MTA)usedas single agents or alongside standard chemotherapy.The use of these MTAs extended the overall survival ofpatients with mCRC to a level that current chemotherapeutics alone could not achieve.In addition,improvement in surgical techniques and ablation modalities offer cure to a limited subset of patients with mCRC andMTAs have been found to have a significant role heretoo,as they aid resectability.However,for the majority of patients,mCRC remains an invariably incurabledisease necessitating continued courses of combinedtreatment modalities.During the course of these treatments,either cytotoxic or biological,cancer cells maintain their ability to acquire mitogenic mutations whichrender them resistant to treatment.Key challengesremain to identify appropriate subsets of patients whowill most likely benefit from these new MTAs and effectively select these based on validated biomarkers.Moreover,better knowledge of the biology of colorectal cancer and the mechanisms via which it bypasses blockade of known signalling pathways will help us design better and more rational sequencing of these treatments,so that we can maximise the survivorship of mCRC patients.This review outlines treatment strategies for known molecular alterations with new MTAs and highlights some promising strategies.

Is it time to rethink the Alzheimer's disease drug development strategy by targeting its silent phase?

Alzheimer＇s disease （AD） is the most frequent cause of dementia in the western world. In clinical terms, AD is characterized by progres- sive cognitive decline that usually begins with memory impairment. As the disease progresses, AD inevitably affects all intellectual functions including executive functions, leading to complete dependence for basic activities of daily life and premature death.

The changing world of drug development

Drug development in oncology is undergoing a substantial shift nowadays. The drivers for this are multi-factorial. On the one side, drug development is performed more rationally than ever, profiting from the scientific advances in molecular biology in general and the elucidation of the various ＂omes＂ from genome to metabolome in particular.

Opinion on pharmacology research and new drug development from precision medicine

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.

Current status and trends in small nucleic acid drug development:Leading the future

Small nucleic acid drugs,composed of nucleotides,represent a novel class of pharmaceuticals that differ significantly from conventional small molecule and antibody-based therapeutics.These agents function by selectively targeting specific genes or their corresponding messenger RNAs(mRNAs),further modulating gene expression and regulating translation-related processes.Prominent examples within this category include antisense oligonucleotides(ASO),small interfering RNAs(siRNAs),micro-RNAs(miRNAs),and aptamers.The emergence of small nucleic acid drugs as a focal point in contemporary biopharmaceutical research is attributed to their remarkable specificity,facile design,abbreviated development cycles,expansive target spectrum,and prolonged activity.Overcoming challenges such as poor stability,immunogenicity,and permeability issues have been addressed through the integration of chemical modifications and the development of drug delivery systems.This review provides an overview of the current status and prospective trends in small nucleic acid drug development.Commencing with a historical context,we introduce the primary classifications and mechanisms of small nucleic acid drugs.Subsequently,we delve into the advantages of the U.S.Food and Drug Administration(FDA)approved drugs and mainly discuss the challenges encountered during their development.Apart from researching chemical modification and delivery system that efficiently deliver and enrich small nucleic acid drugs to target tissues,promoting endosomal escape is a critical scientific question and important research direction in siRNA drug development.Future directions in this field will prioritize addressing these challenges to facilitate the clinical transformation of small nucleic acid drugs.

Artificial intelligence as a tool in drug discovery and development

The rapidly advancing field of artificial intelligence(AI)has garnered substantial attention for its potential application in drug discovery and development.This opinion review critically examined the feasibility and prospects of integrating AI as a transformative tool in the pharmaceutical industry.AI,encompassing machine learning algorithms,deep learning,and data analytics,offers unprecedented opportunities to streamline and enhance various stages of drug development.This opinion review delved into the current landscape of AI-driven approaches,discussing their utilization in target identification,lead optimization,and predictive modeling of pharmacokinetics and toxicity.We aimed to scrutinize the integration of large-scale omics data,electronic health records,and chemical informatics,highlighting the power of AI in uncovering novel therapeutic targets and accelerating drug repurposing strategies.Despite the considerable potential of AI,the review also addressed inherent challenges,including data privacy concerns,interpretability of AI models,and the need for robust validation in realworld clinical settings.Additionally,we explored ethical considerations surrounding AI-driven decision-making in drug development.This opinion review provided a nuanced perspective on the transformative role of AI in drug discovery by discussing the existing literature and emerging trends,presenting critical insights and addressing potential hurdles.In conclusion,this study aimed to stimulate discourse within the scientific community and guide future endeavors to harness the full potential of AI in drug development.

Identifying and Managing Technical Risks in the Process of Innovative Drugs Development in China

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.

Breast Cancer MCF-7 Cell Spheroid Culture for Drug Discovery and Development

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.

Why 90%of clinical drug development fails and how to improve it?

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.

Human induced pluripotent stem cells derived hepatocytes:rising promise for disease modeling,drug development and cell therapy

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.

The 2016 Lasker-DeBakey Clinical Medical Research Award: Innovative hepatitis C virus(HCV) replicons leading to drug development for hepatitis C cure

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 a prodrug approach and the drug PSI-7977 or Sofosbuvir was approved in 2013 less than 28 years after the initial discovery of HCV.

Molecular targets for COVID-19 drug development:Enlightening Nigerians about the pandemic and future treatment

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.

Strategies for translating proteomics discoveries into drug discovery for dementia

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.

Opportunities and challenges of implementing Pharmacogenomics in cancer drug development

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.

Repolarization reserve, arrhythmia and new drug development

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.

Interdisciplinary researches for potential developments of drugs and natural products

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.