First Line Anti-Tuberculosis Drugs Resistance Patterns of <i>Mycobacterium tuberculosis</i>Isolates from Newly Diagnosed Cases of Tuberculosis

Introduction: Tuberculosis is a major cause of mortality and morbidity world-wide. Anti-tuberculosis drugs have been used for many decades but resistance to them is now widespread. Globally 5% of tuberculosis cases and in India 3% among new TB cases. This study was planned to know the pattern of first line anti-tuberculosis drug resistance in south Gujarat, Surat region in newly diagnosed patients of tuberculosis. Material and Methods: 350 samples were processed for homogenisation and concentration using 4% NAOH-2.9% trisodium citrate. Processed samples were inoculated in liquid medium that is MGIT (Mycobacterial growth indicator tube). Positive samples for M. tbwere processed further for first line anti-tuberculosis drugs sensitivity testing (DST). Reading was taken by using MicroMGIT system. Result: Out of 350 samples 59 (17%) were positive samples, of which 48 (13%) were M. tb and 11 (3%) were non tuberculous mycobacteria. Out of 48 samples 2% (1 isolate) was resistant to isoniazid and Rifampicin while 2% were monoresistant to isoniazide, 2% monoresistant to streptomycin. No rifampicin monoresistant was detected. Conclusion: Such study may help in control of tuberculosis at regional and national level which would in turn help in planning of measures to control Multi-drug resistance tuberculosis. Continuous surveillance should be applied to know the periodic changing patterns and trend in Drug resistant tuberculosis.

NAT2＊6A, a haplotype of the N-acetyltransferase 2 gene, is an important biomarker for risk of anti-tuberculosis drug-induced hepatotoxicity in Japanese patients with tuberculosis

AIM: To investigate an association between N -acetyltransferase 2 (NAT2 )-haplotypes/diplotypes and adverse effects in Japanese pulmonary tuberculosis patients. METHODS: We studied 100 patients with pulmonary TB treated with anti-TB drugs including INH. The frequencies and distributions of single nucleotide polymorphisms, haplotypes, and diplotypes of NAT2 were determined by the PCR-restriction fragment length polymorphism method, and the results were compared between TB patients with and without adverse effect, using multivariate logistic regression analysis.RESULTS: Statistical analysis revealed that the frequency of a variant haplotype, NAT2*6A , was signifi cantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity [P = 0.001, odds ratio (OR) = 3.535]. By contrast, the frequency of a wild-type (major) haplotype, "NAT2*4", was signif icantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P < 0.001, OR = 0.265). There was no association between NAT2-haplotypes and skin rash or eosinophilia. CONCLUSION: The present study shows that NAT2 is one of the determinants of anti-TB drug-induced hepatotoxicity. Moreover, the haplotypes, NAT2*4 and NAT2*6A, are useful new biomarkers for predicting anti- TB drug-induced hepatotoxicity.

Pyrrolidine dithiocarbamate alleviates the anti-tuberculosis drug-induced liver injury through JAK2/STAT3 signaling pathway:An experimental study

Objective:To study the effect of pyrrolidine dithiocarbamate(PDTC) on the anti-tuberculosis drug-induced liver injury and the molecular mechanism. Methods:Clean male SD rats were selected as experimental animals and randomly divided into normal group,model group,PDTC group and AG490 group. Animal model of anti-tuberculosis drug-induced liver injury was established by intragastric administration isoniazid + rifampicin. PDTC group received intraperitoneal injection of PDTC,and AG490 group received intraperitoneal injection of AG490. Twenty-eight days after intervention,the rats were executed,and the liver injury indexes,inflammation indexes and oxidative stress indexes in serum as well as JAK2/STAT3 expression,liver injury indexes,inflammation indexes and oxidative stress indexes in liver tissue were determined. Results:p-JAK2,p-STAT3,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA expression in liver tissue as well as TBIL,ALT,AST,γ-GT,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA levels in serum of model group were significantly higher than those of normal group while p-JAK2,p-STAT3,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA expression in liver tissu as well as TBIL,ALT,AST,γ-GT,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA levels in serum of PDTC group and AG490 group were significantly lower than those of model group. Conclusions:PDTC can inhibit the inflammation and oxidative stress mediated by JAK2/STAT3 signaling pathway to alleviate the anti-tuberculosis drug-induced liver injury.

An Update on the Clinical Pipelines of New Antibacterial Drugs Developed in China

Antibacterial resistance is a global health threat that requires further concrete action on the part of all countries.In this context,one of the biggest concerns is whether enough new antibacterial drugs are being discovered and developed.Although several high-quality reviews on clinical antibacterial drug pipelines from a global perspective were published recently,none provides comprehensive information on original antibacterial drugs at clinical stages in China.In this review,we summarize the latest progress of novel antibacterial drugs approved for marketing and under clinical evaluation in China since 2019.Information was obtained by consulting official websites,searching commercial databases,retrieving literature,asking personnel from institutions or companies,and other means,and a considerable part of the data covered here has not been included in other reviews.As of June 30,2023,a total of 20 antibacterial projects from 17 Chinese pharmaceutical companies or developers were identified and updated.Among them,two new antibacterial drugs that belong to traditional antibiotic classes were approved by the National Medical Products Administration(NMPA)in China in 2019 and 2021,respectively,and 18 antibacterial agents are in clinical development,with one under regulatory evaluation,five in phase-3,six in phase-2,and six in phase-1.Most of the clinical candidates are new analogs or monocomponents of traditional antibacterial pharmacophore types,including two dual-acting hybrid antibiotics and a recombinant antibacterial protein.Overall,despite there being 17 antibacterial clinical candidates,our analysis indicates that there are still relatively few clinically differentiated antibacterial agents in stages of clinical development in China.Hopefully,Chinese pharmaceutical companies and institutions will develop more innovative and clinically differentiated candidates with good market potential in the future research and development(R&D)of original antibacterial drugs.

Use of Cost Effective Semi-Automated (Mannual/Micro) MGIT System over BACTEC 960 to Perform First Line Anti-Tuberculosis Drugs Sensitivity Testing

Introduction: Multi-drug resistant tuberculosis (MDR-TB) that is the tuberculosis that is resistant to at least 2 of the first line anti-tuberculosis drugs is fatal infectious disease. Cases of MDR-TB are now increasing with 30,000 cases of MDR-TB reported in 2013 by national TB programme. Rapid diagnosis of MDR-TB is extremely important for rapid treatment of patient and to prevent spread of MDR-TB to other. BACTEC 960 system helps in rapid diagnosis but purchase of expensive instrument for the same is the limitation. However, the same purpose can be solved by use of semi-automated MGIT system. Aims and Objectives: Aim of this study is to do drug sensitivity testing of the first line anti-tuberculosis drugs with the use of semi-automated MGIT systems. 350 newly registered and suspected cases of tuberculosis in tertiary care hospital were included. Samples were processed for digestion and decontamination and inoculated in MGIT tubes and also on LJ medium. Reading was taken using semi-automated MGIT system. Positive tubes were confirmed by rapid test for M. tuberculosis and then drug sensitivity was performed. Result: Out of 350 samples, 62% were sputum;33% were pleural fluid and rest 5% were lymph node, Ascetic fluid, CSF, pus. Average day of positivity by MGIT was 13 - 20 days as compared to 25 - 37 days by solid medium, which was statistically significant with p value Conclusion: Manual MGIT System is a simple, efficient, safe to use diagnostic system. It does not require any expensive/special instrumentation other than the UV lamp for detection of fluorescence. The rapidity by which mycobacteria are detected is the most important advantage of the Manual MGIT. In areas with limited resources where purchase of expensive instruments such as the MGIT960 is out of scope, the use of manual MGIT for rapid susceptibility testing for MDR-TB could be a possibility.

New strategies against drug resistance to herpes simplex virus

Herpes simplex virus （HSV）, a member of the Herpesviridae family, is a significant human pathogen that results in mucocutaneous lesions in the oral cavity or genital infections. Acyclovir （ACV） and related nucleoside analogues can successfully treat HSV infections, but the emergence of drug resistance to ACV has created a barrier for the treatment of HSV infections, especially in immunocompromised patients. There is an urgent need to explore new and effective tactics to circumvent drug resistance to HSV. This review summarises the current strategies in the development of new targets （the DNA helicase/primase （H/P） complex）, new types of molecules （nature products） and new antiviral mechanisms （lethal mutagenesis of Janus-type nucleosides） to fight the drug resistance of HSV.

The brain-derived neurotrophic factor in neuronal plasticity and neuroregeneration: new pharmacological concepts for old and new drugs

Neurotrophins：Neurotrophins are peptides or proteins that are known to regulate neuronal viability,development,and function Beyond synaptic plasticity,neurotrophins protect neurons from apoptosis and also promote neurogenesis to recover neuronal defici even in adulthood.

New drugs for the treatment of metastatic colorectal cancer

Colorectal cancer(CRC)represents one of the most frequent malignancies in terms of incidence and mortality,thus representing the third leading cause of cancer death worldwide.In the last decade,few drugs have enriched the treatment landscape of metastatic CRC and have significantly affected prognosis.Unlike other neoplasms,metastatic CRC patients who have exhausted treatment options often still maintain a good performance status.There are many challenges to increasing potential treatment options,notably a better understanding of disease biology and the mechanisms of resistance underlying cancer treatment failure.The development of new drugs for metastatic CRC certainly represents one of the most important challenges in medical oncology.This article discusses the main limitations in the development of new drugs and potential future scenarios.In particular,we addressed three questions:(1)The main limitations of targeted therapy in the treatment of metastatic CRC(mCRC);(2)New target armamentarium that could escape primary and secondary resistance and lead to more personalized mCRC therapy;and(3)Future directions.

Literature Review on the Development of New Drugs Based on TRIZ

Objective To promote the application of TRIZ theory in the new drug R&D and the innovative development of medical devices.Methods TRIZ can be literally translated as“theory of inventive problem resolving”,focusing on clarifying and solving contradictions in the system.This article introduces the TRIZ theory and the general process of new drug development.It collects literature in the field of new drug development and medical devices and refers to ideas for solving problems in some successful cases of applying TRIZ theory in other fields.Results and Conclusion After summarizing the general ideas of TRIZ to solve the problems,it is concluded that attention should be paid to applying TRIZ theory in the development of new drug and medical devices.

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.

PREDICTION OF THE THERAPEUTIC EFFECTIVENESS OF NEW DRUGS FROM CLINICAL PHARMACOLOGY STUDIES

The development of new drugs for therapeutic purposes has become very expensive and time-consuming in American and European countries.It is estimated that on the average 50 to 100 million dollars and 10 or more years from the time of patenting are required to make a new drug available for general prescription. Every new drug needs to be charac-

Reference of New Zealand’s Drug Shortage Management Measures

Objective To provide a scientific reference for China’s drug shortage and supply mechanism by conducting a specific study on New Zealand’s management measures for dealing with the shortage of drugs.Methods Through reviewing the official website of the New Zealand Pharmaceutical Management Agency(PHARMAC)and relevant literature,the specific measures to deal with drug supply and shortage in New Zealand were sorted out,and then some countermeasures were put forward for our domestic drug supply.Results and Conclusion PHARMAC worked closely with the pharmaceutical suppliers and signed contracts to maintain their relationship.A sound drug supply mechanism has been established to respond to various supply issues.At present,there are some problems in drug supply in China,such as the lack of timely publicity of shortage information,the lack of management team for supply,and the lack of alternative drug supply mechanism.China should learn from the PHARMAC to establish a supply contract management team to promote the transparency of drug shortage information and seek alternative drug supply actively.

Regulation of “Checkpoint Molecule” Sheds New Light on Anti-Cancer Drug Development

The rivalry between T cells and tumor cells somewhat mimics the scene of 'Tom and Jerry,' an animated series in which Tom (a house cat) rarely succeeds in catching Jerry (a mouse), mainly because of Jerry’s cleverness and cunning abilities. In a way, tumor cells are like Jerry, in terms of their crafty and sneaky features.

New Developments in Drug Therapy and Research of Cerebral Vasospasm

In this manuscript a comprehensive coverage of recent developments in the drug therapy of vasospasm while providing the background information that neuroscientists need to understand its rationale. The range of new agents available for treatment of cerebral vasospasm is expanding rapidly along with rapid advances in pharmacology and physiology that are uncovering the mechanisms of this disease. Although there are many publications for treatment of cerebral vaso-spasm, most are focusing on different aspects of vasospasm treatment and many have limited value due to insufficient quality. Moreover, the complexity of this, in many cases deleterious condition, is enormous and the information needed to understand drug effects is accordingly often not readily available in a single source. A number of pharmacological and medical therapies are currently in use or being investigated in an attempt to reverse cerebral vasospasm, but only a few have proven to be useful. Current research efforts promise the eventual production of new medical therapies. At last, recommendations for the use of different treatment stages based on currently available clinical data are provided.

Real-World Evidence Supporting New Drug Review and Approval in European Union and Its Enlightenment to China

Objective To analyze the application of real-world evidence(RWE)in the field of medicine in European Union,and provide suggestions for RWE supporting the review and approval of new drugs in China.Methods The European Medicines Agency(EMA)and other databases were used to search relevant documents for analyzing the European Union’s new drug review and approval process with the support of RWE.Results and Conclusion The European Union carrying out new drug review and approval with the support of RWE has just begun.The decision-making process includes three stages such as new drug research and development,review,and approval.However,there are some challenges in data quality,research methods,evidence sufficiency,and research process of RWE supporting the European Union in reviewing and approving new drugs.At present,RWE can accurately grasp the clinical effects of drugs and improve the safety and effectiveness in the process of assisting the review and approval of new drugs.At the same time,RWE also can promote the development and application of Traditional Chinese Medicine(TCM)and help find out the potential value of TCM such as new indications.

A New Anticancer Drug

After some six years of hard work, a research team headed by Prof. Liu Zhivu (Z.Y. Liu) at the Shanghai Institute of Organic Chemistry, CAS, has scored major progress in independently generating a novel cancer killer called epothilone. Their findings have been granted three patents, and their research paper Total Synthesis of Epothilone: A Thorough Stereospecific Expoxidation of the 3-0-(4-methoxy) Benzyl Ether of Epothilone C has been accepted for publication in the Chemistry - European Journal.

Application Research of Earned Value Management in New Drug Research and Development Projects

Objective To help investors assess and control the costs of new drug development and reduce the risks of new drug development projects.Methods Cost analysis and financial forecasting were carried out with the integrated approach of earned value management.According to the principle of earned value management deviation analysis,the basic process of the new drug research and development project was combined with the hypothesis method from the research of Tufts Drug Development Research Center.Results and Conclusion If the project progress check was carried out in the clinical trial,the project costs were found overspent,the efficiency was low,the project progress was faster,and the resource investment was ahead.It is recommended that the adjustment should be made to reduce the input of resources,and increase the efficient key personnel to take the place of some less efficient staff.

The CAS System of New Drug Research and Its Key Results

The Chinese Academy of Science (CAS), the top national research hub for natural sciences, has always been committed itself to the national target of research and development (R&D) of new medicines. During the past several decades, a great number of R&D achievements have been attained. During the period from 1986 to 1999, for example, 135 pharmacutical projects won prizes of the CAS awards for natural sciences, inventions and S&T progress (roughly ac-

Research Progress of Transdermal Patches in Veterinary Drug Preparations

With the development of pharmaceutics and other disciplines theories and advanced technologies, the application of many new drug delivery systems has gradually increased in clinical veterinary. Among the many drug delivery systems, transdermal patch can maintain stable and effective plasma concentration and therapeutic effect in vivo for a long time after skin dressing delivery, which provides a safe and effective drug-delivery way for the therapy and prevention of some chronic diseases and partial analgesia in a simple and convenient way. Veterinary drug transdermal preparations have been developed both at home and abroad, and satisfactory results have been achieved in the experimental application. Based on the study of veterinary transdermal patches at home and abroad, this paper systematically describes the development and characteristics of transdermal patches, the factors affecting skin permeation and the evaluation this type of preparations in veterinary drugs.