Non clinical evaluation strategy based on extracellular vesicle therapy / 中国生物制品学杂志

@#The concept of extracellular vesicles(EV) was proposed in 2011 by the International Society for Extracellular Vesicles(ISEV),and EV can be widely used in various fields of disease treatment as therapeutic drugs and drug delivery carriers.The therapy based on EV may become a new model of disease treatment in addition to traditional drug therapy and cell therapy-EV cell-free therapy.As a vector,compared with viral vector and synthetic non viral vector,EV have unique advantages and great potential.However,EV have some challenges in clinical transformation because of their unique biological properties.Moreover,this field is relatively new,and there are no relevant policies and regulations specifically for EV therapy.By collecting information from ClinicalTrials.gov platform,this paper summarized the research progress based on EV therapy,put forward suggestions for the existing regulatory system,discussed the general principles of EV non clinical research,pharmaceutical research,pharmacodynamics and pharmacokinetics research,safety evaluation and other non clinical evaluation strategies,so as to provide reference for the formulation of non clinical evaluation research scheme based on EV therapy.

Exploration of hapten-induced atopic dermatitis murine models for non-clinical pharmacodynamics study of drugs / 药学学报

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory dermatosis with a variety of clinical manifestations and difficult to cure. Currently, many AD drug candidates have entered the research and development pipeline. In order to provide technical specifications for the clinical development of AD drugs, the Center for Drug Evaluation of National Medical Products Administration released the "Technical Guidelines for Clinical Trials of Drugs for AD Treatment" (Draft for Comments) in November 2022. Non-clinical pharmacodynamics evaluation is an important research before the drug enters clinical trials. Oxazolone (OXA)- and 2,4-dinitro-fluorobenzene (DNFB)-induced models are the most popular classical hapten-induced AD murine models, but variations of modeling are existing in the methods from different studies, including sensitization sites, haptens' dosages, the period of challenges, and the skin lesions severity evaluation as well. In this study, the investigation of OXA- and DNFB-induced AD murine models with various conditions of modeling was performed to compare the characteristics of hapten-induced AD murine models in the pathological process and severity according to the appearance of AD patients, and the guidance of pharmacodynamics evaluation of AD-therapeutic drugs in clinical trials as well, which may provide a proposal for AD treatment drug candidates in the non-clinical pharmacodynamics evaluation. All animal experiments were approved by the Animal Care & Welfare Committee of Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College (approval No.: 00007782 and 00007784).

Research progress and considerations on non-clinical studies of the drugs administered through the ocular vitreous body / 药学学报

In recent years, with the development of ophthalmic therapeutic drugs, the vitreous body, as a channel for the treatment of ophthalmic diseases, especially fundus diseases, has opened up a new therapeutic approach for various choroidal neovascular diseases, macular edema, uveitis and other diseases associated with fundus diseases, which is represented by wet age-related macular degeneration (wAMD). The drugs administered through the vitreous body mainly include ocular anti-vascular endothelial growth factor (VEGF) injections, microplasmin and hormones. For this kind of ophthalmic products, there are no clear technical guidelines and norms for non-clinical research at home and abroad. This article combines review practices and cases of marketed products to sort out the research progress and considerations on non-clinical studies of ophthalmic drugs dosing through the ocular vitreous body, in order to provide references for the research and evaluation of such drugs.

Interpretation of guidance on non-clinical safety evaluation for nanomedicines / 药学学报

With the rapid development of nanotechnology, the research and development of nanomedicines have become one of the development directions of drug innovation. Nanomedicines have special physical and chemical properties, such as nanoscale effects and nanostructure effects, so they have special biological properties, which may change the pharmacokinetic profiles such as absorption and tissue distribution of drug molecules, and thus affect their safety and effectiveness. There are many special concerns on the non-clinical safety evaluation of nanomedicines at the basis of ordinary drug because of the particularity of nanomedicines. On August 25, 2021, China issued Guidance on Non-clinical Safety Evaluation for Nanomedicines(interim). This article interprets comprehensively the guidance, focuses on the key points of non-clinical safety evaluation for nanomedicines, and expounds combined with some cases, aiming to provide reference for drug researchers.

Non clinical pharmacodynamic evaluation system of high-altitude hypoxic brain injury / 药学学报

The air at high altitude is thin and belongs to the environment of low temperature, low oxygen and low pressure. The human brain is the most sensitive to hypoxia. Hypoxia will cause dysfunction of the central nervous system, resulting in high-altitude hypoxic brain injury, including mild high altitude headache and more destructive high altitude cerebral edema (HACE). Recently, with more and more people work and live in high altitude areas, the development of high-altitude hypoxic brain injury drugs would produce great economic value and social significance. Non clinical pharmacodynamic evaluation is the basic of drug development, which plays a key role in improving the success rate of clinical transformation and reducing the risk of clinical research. This review summarizes the cell models and animal models, and the evaluation indicators usually used to explore the candidates of high-altitude hypoxic brain injury. We aim at establishing a standardized non clinical efficacy evaluation system for high altitude hypoxic encephalopathy, and provide a standardized reference for drug development in hypoxic encephalopathy at high altitude at nonclinical stage.

Attitude and perception of post-graduate residents toward thesis: A cross-sectional study

Background: To increase research productivity among post-graduate (PG) students, there is inclusion of research dissertation or thesis in their academic curriculum. However, thesis or research project during the residency remains is the last priorities due to high demands on the PG student’s energy and time in terms of patient care. There are a very few such studies conducted in our nation pertaining to perception of PG students toward thesis. Aim and Objectives: This study is to assess the attitude and perception of medical PG residents toward research dissertation or thesis during residency training. Materials and Methods: This was an observational, cross-sectional study with the 2nd and 3rd year MS/MD PG students as participants. Study tool was pre-validated questionnaire consisting 40 questions under following domains: University regulations (5), attitude toward thesis (4), perception toward benefits of thesis (15), perception toward obstacles of thesis (13), and practice in regard to thesis (3). A study was initiated after approval of Institutional Ethics Committee. After obtaining written informed consent, a questionnaire was given to each student and was collected after 25–30 min. Confidentiality of responses was ensured by maintaining anonymity of responders. Data were entered into Excel and a descriptive analysis was done. Results: Of these 55 pre/paraclinical and 70 clinical PG students (n = 125) returned completely filled questionnaire. The mean age of the students was 27.40 ± 2.20 and was in the 2nd or 3rd year of the residency. 256% participants were from clinical whereas 44% were from pre/paraclinical branches. The majority of postgraduate students preferred observational studies (80%) over interventional study for thesis (19.2%). 61.6% PG students felt that thesis should be mandatory. Majority of students agreed to benefit of thesis which helps them to develop skills such as literature search (92.8%), data processing (84%), statistical analysis (73.6%), interpretation of results, and discussion (80.8%). PG students felt that there are few obstacles in their thesis such as inadequate lab facilities (66.4%), inadequate study tools (62.4%), and incompetent technical staff (55.2%). Conclusion: A number of barriers such as lack time, funding, and poor availability of research facilities for conduct of research need to be addressed to further enhance PG student’s positive attitude toward thesis.

Advances in risk assessment systems from non-clinical to clinical arrhythmia stages / 中国临床药理学与治疗学

The withdrawal of drugs from the market due to serious adverse reactions arising from the risk of cardiac arrhythmia has been a major concern for regulatory authorities in recent years. In 2005, the International Council for the Harmonisation of Registration of Medicinal Products for Human Use (ICH) issued preclinical S7B and clinical E14 guidelines for the evaluation of arrhythmia risk. The former includes in vitro hERG experiments and in vivo animal-based QT studies, while the latter is the TQT study (thorough QT study, TQT study). The high cost and conservative results of TQT studies have led to the introduction of new alternative methods, and the E14 guidelines were revised in 2015 and introduced concentration-QT analysis (C-QTc), based on the PK/PD (pharmacokinetics/pharmacodynamics) concept, by making full use of high-quality double-negative data from the non-clinical phase (double-negative, low risk of hERG tests at high clinical exposure, and low risk of QTc prolongation in vivo QTc study) makes it possible to substitute TQT studies based on specific situations. This article reviews the history of the development of E14 and its latest developments, analyses the specific situations in which C-QT can replace TQT studies through case studies, introduces the preclinical-clinical arrhythmia risk stage assessment system and compares the drug assessment process and decision making under different versions of E14 guidelines, with a view to providing a reference for the arrhythmia risk assessment system in China.

Research strategies and considerations on non-clinical pharmacokinetics of nanomedicine / 中国临床药理学与治疗学

With the rapid development of nanotechnology, the research and development of nanomedicine has become one of the current development directions of drug innovation. The pharmacokinetic characteristics of nanomedicine are significantly different from general drugs because of the scale effect based on nanostructures, and pharmacokinetics studies of nanomedicine may be different from the general drugs. This article focuses on the research strategies and considerations on non-clinical pharmacokinetics of nanomedicine, including test agents, in vivo/in vitro assays, biological sample analysis, data evaluation and analysis etc., providing references for developers.

Evaluation of non-clinical anxiety disorder models / 药学学报

Anxiety disorders are one of the most common mental disorders in adults, the cause of which derives from a combination of genetics and environmental factors. A series of animal models have been established according to their pathogenesis to measure the level of anxiety or induce anxiety only, and these models have been widely applied in the non-clinical evaluation of anxiolytics. In this review, we present the current trends in the study of anxiety disorders and summarize typical non-clinical anxiety animal models, including models that both measure anxiety levels and induce anxiety, and models that induce anxiety only. This review summarizes the important issues in standardized non-clinical research of anxiety disorders and proposes criteria for the selection of an appropriate R&D model.

Interventions to reduce caesarean section rates at government medical college and hospital Aurangabad, India

Background: Caesarean sections are effective in saving maternal and infant lives, but only when they are performed for medically indicated reasons, The Objective of this study was to reduce caesarean Section rate at GMCH, Aurangabad and to improve overall birthing experience with respectful maternity care.Methods: The caesarean sections done at GMCH Aurangabad were audited using Robson`s Ten Group classification system to identify the major contributors to the overall CS rate. The following clinical and non-clinical interventions were applied dynamically to control the caesarean section rates. Clinical Interventions were changes in protocols regarding induction of labour, Intermittent auscultation as opposed to continuous electronic foetal monitoring in low risk cases, use of a partogram, encouragement of different birthing positions, promoting TOLAC to reduce the secondary CS rate. Nonclinical interventions include encouragement of DOULA (birth companion), ante-natal counselling of the expectant mothers, training of healthcare staff for respectful maternity care and use of evidence based clinical practice guidelines with mandatory second opinion for every non recurrent indication of CS. Auditing of caesarean section using Robson classification.Results: In this study there has been steady decline in LSCS rates from 33% to 26.9%. On analysis with Robson classification, group 5 (previous LSCS) made largest contribution of 36.9% followed by Group 1, 2, 10 each contributed 18.01%,13.2% and 11.2% respectively. Group 6 to 10 account for 23%. Various birthing positions lowered use of oxytocics from 33 % to 19% as well lowered episiotomy rates with greater success in vaginal delivery.Conclusions: Modification of induction protocols have reduced the primary LSCS rates and successful VBAC using FLAMM score was helpful in reducing the repeat caesarean Sections. Various birthing positions, DOULA gave greater success in vaginal delivery. LSCS rates in mothers with breech, multiple or oblique/transverse lies were largely unmodifiable. Limiting the CS rate in low-risk pregnancies by individualizing every labour and not to set a time limit as long as mother and baby are closely monitored.

Towards optimizing caesarean section: a five-year review of caesarean sections at a Southern Nigeria hospital

Background: Monitoring caesarean sections at hospital level is essential to reduce unnecessary caesarean sections while still ensuring adequate access to caesarean section. This study was conducted to determine the caesarean section rate and indications for caesarean section at the study centre and provide objective data for institutional interventions towards reducing unnecessary caesarean sections in the centre.Methods: A retrospective descriptive study of patients that had caesarean sections between 1st January 2013 and 31st December 2017 at the Federal Medical Centre, Yenagoa, Nigeria. Data were analyzed using Statistical Package for Social Sciences version 22.Results: There were 5,793 deliveries and 1,654 were by caesarean section. The average caesarean section rate was 28.6%. The leading indications for caesarean section were cephalopelvic disproportion (26.6%), previous cesarean section (18.2%), suspected fetal distress (11.2%), severe preeclampsia/eclampsia (7.9%), obstructed labour (6%), and breech presentation (5.9%).Conclusions: The 28.6% caesarean section rate in this study falls within a widely varied rate across Nigeria at hospital level but is comparable to rates within the south-south geopolitical zone of Nigeria. The leading indications for caesarean section are modifiable, thus there is room for institutional intervention to reduce unnecessary caesarean sections. Collaborative research between institutions is required to assess peculiar regional determinants of caesarean section towards developing suitable interventions to reduce unnecessary caesarean sections regionally.

Exploration of nonclinical pharmacodynamics evaluation system of Alzheimer's disease / 药学学报

Alzheimer's disease (AD) is the most common neurodegenerative disease that causes dementia among elderly people. The pathogenesis of AD is still unclear, and currently approved drugs only provide symptomatic benefits and do not prevent or delay progressive neurodegeneration. Meanwhile, potential drugs in development are facing great challenges in clinical translation. Therefore, finding effective treatment for the unmet clinical needs of AD is of great economic value and social significance. In this review, we will summarize the current models and pharmacodynamics evaluation methods of anti-AD drug based on the recent studies at home and abroad, and provide reference for drug development in AD at nonclinical stage.

Study on non-verbal communication knowledge among doctors of non-clinical and para clinical departments of Government Vellore medical college hospital, Vellore, Tamil Nadu, India

Background: Many Studies and Research Articles in our medical field focuses on Verbal Communication component. The Non-Verbal Component has been neglected in many circumstances. But Medical science endorses that Non-Verbal component plays a major role in the communication process in all set ups whether it is in the classrooms, Examination Hall, Outpatient Room or Wards or Intensive Care Units. The objective of this study is to access the knowledge and Awareness of NVC Component among Doctors of Non-Clinical and Para Clinical Departments of GVMCH - Vellore, Tamil Nadu, India.Methods: This Cross-Sectional Study was conducted among 45 Doctors across 7 Departments of Government Medical College Vellore. Mean, Median, Mode and Standard Deviation were used for quantitative Data and Pearson Chi Square Test and Logistic regression was used for qualitative Data using Trial Version of SPSS 22.Results: The mean Score was 7.2±2.8 with Mean scoring percentile of 28.8 ±11.5. There was Pearson’s Chi Square significance for Variables like External Resources related to NVC, Books related to NVC, UG and PG pursued at, Exposure to Workshops or CME s related to NVC, and age Group < 35. But on running Logistic Regression we got statistical significance for variables like External resources related to NVC, UG studied at same state, Age Group >35 years.Conclusions: Variables like External resources, UG studied at same state, Age Group >35 years Showed Statistical significance in knowledge on Non-Verbal communication in this Study set up.

Exploration of non-clinical pharmacodynamics evaluation system of amyotrophic lateral sclerosis / 药学学报

Amyotrophic lateral sclerosis (ALS) is among the most common type of motor neuron diseases, and its pathogenesis remains unclear. In recent years, our understanding of the genetic basis of ALS has led to the development of various ALS disease models, which allow for screening of ALS-related drugs and treatment methods. This review focuses on the research progress of ALS, summarizes the systems of commonly used experimental animal models, including transgenic animals, gene knockout approaches and autonomous animal models, points to the problems needing attention in standardized ALS non-clinical research, and proposes the criteria for selection of standardized R&D model.

Non-clinical factors and predictors of self-rating of oral health among young adolescents in a rural Nigerian population

Aim: The aim of the study was to assess the non-clinical determinants and predictors of self-ratings of oral health among young adolescents in a Nigerian rural population. Methods: A cross-sectional survey was conducted among adolescents of 11-13 years old in Igboora, Nigeria. Information on self-rating of oral health, self-assessed satisfaction with oral health condition and tooth appearance, pain history, consultation with the dentist and oral hygiene measures were obtained using structured questionnaires translated to the local language. Data were analysed using SPSS version 23; Chi Square and logistic regression were used to establish associations between variables and predictors with p value < 0.05 statistically significant. Results: A total of 400 respondents participated in the study. Most 346 (86.5%) rated their oral health positively. Those who expressed dissatisfaction with the appearance of their teeth, 17 (44.7%) dissatisfaction with their oral health condition, 25 (45.5%) had toothache in the preceding six months, 44 (19.7%) perceived a need for dental treatment, 43 (16.7%) or cleaned their teeth once daily or less frequently, 37 (20.9%), rated their oral health poorly (p < 0.001, p < 0.001, p = 0.001, p = 0.012, p < 0.001, respectively). The significant predictors of self-ratings of oral health were self-assessed satisfaction with oral health condition, toothache in the preceding six months and frequency of tooth cleaning. Conclusion: Satisfaction with oral health condition, toothache in the preceding six months and frequency of tooth cleaning are factors that predict self-rating of oral health in young adolescents in the rural community studied

Non-clinical studies required for new drug development - Part I: early in silico and in vitro studies, new target discovery and validation, proof of principles and robustness of animal studies

This review presents a historical overview of drug discovery and the non-clinical stages of the drug development process, from initial target identification and validation, through in silico assays and high throughput screening (HTS), identification of leader molecules and their optimization, the selection of a candidate substance for clinical development, and the use of animal models during the early studies of proof-of-concept (or principle). This report also discusses the relevance of validated and predictive animal models selection, as well as the correct use of animal tests concerning the experimental design, execution and interpretation, which affect the reproducibility, quality and reliability of non-clinical studies necessary to translate to and support clinical studies. Collectively, improving these aspects will certainly contribute to the robustness of both scientific publications and the translation of new substances to clinical development.

Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies

The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose.

Consideration on non-clinical safety evaluation of traditional Chinese medicine / 中国药理学与毒理学杂志

Safety,efficacy and quality control are the three essential elements for drugs,including traditional Chinese medicine(TCM). Currently,rapid development of life sciences,medicine and phar?macy provides new prospects for TCM. Considering the long history of TCM application,modern phar? macology and toxicology, global standards and expectations on the safety of TCM, how to evaluate the safety of TCM scientifically has become a key to the research and development of TCM. This review aims to discuss current technical requirements of non-clinical safety study of TCM as well as the challenges.

Determination of parameters of developmental toxicity study on pediatric drugs and focus of attention for safety evaluation of traditional Chinese medicine / 中国药理学与毒理学杂志

There is an increasing demand for neonatal and juvenile animal toxicity studies during the research and development of new drugs. In this paper,we discussed general evaluation parameters of pediatric non-clinical safety with pediatric drugs,such as growth and development and food intake,and paramenters of other organs and systems, such as the central nervous system,reproductive system, behavior evaluation in combination with our own experience. In addition,the characteristics of non-clin?ical safety evaluation of new traditional Chinese medicine materia medica used for juvenile animals were analyzed. This paper is intended reference for non-clinical safety evaluation of pediatric drugs and to gain some experience related to formulation of new guidelines.

Technical considerations on non-clinical study and evaluation for biosimilar products / 中国药学杂志

OBJECTIVE: To evaluate biosimilar products focus on the similarities in the quality, safety and eificacy between the candidate and reference products. METHODS: Comparative non-clinical studies should be conducted and stepwise development should be carried out to demonstrate the similarity in non-clinical study for the candidate and reference products. Usually the necessity and content of in vivo study are dependent on the results of previous comparative studies in vitro. RESULTS AND CONCLUSION: Determination of the non-clinical similarity should be based on the statistical analysis of the candidate and reference products. Evaluation for toxicity similarities can focus on toxicity profile in types and extent. The non-clinical similarities will affect the strategy of clinical trial for biosimilars.