新药研发医学知识培训课件

1、New words and expressionacute: acute infection（急性感染）, acute leukemia（急性白血病） chronic: chronic gastritis（慢性胃炎）agonist: stimulator antagonist: blocker adverse reaction（不良反应）: any bad effect or undesirable effect caused by drug use at normal dose（正常剂量）New words and expressionacute: new chemical entity(新

2、化学实体): new compound shows pharmacological activity against certain disease, which is also called lead compound(先导化合物) or drug candidate(候选药物) in-vitro（体外）: outside of organisms in vivo（体内）: within a whole living organism new chemical entity(新化学实体): n1.What is a new drug?Chemical structure（化学成分） Dosa

3、ge form(剂型）Route of administration（给药途径）Indication（适应症）New drug1.What is a new drug?Chemical 2.Why do we need new drugs? many incurable diseases still await conquest to produce new drugs that are superior than existing medications the ultimate goal: to provide effective, accessible and affordable me

4、dicines for all 2.Why do we need new drugs? ma In the past, drugs were extracted from plant and animal sources, but the purity of drugs was very limited. quinine（奎宁）: extracted from the bark of cinchona（金鸡纳树皮）, its antimalarial（抗疟疾） function was discovered by the Indians in North America 3. Evolutio

5、n of new drug In the past, drugs were extr From 1900 chemically synthesized drugs became available, the purity of drugs were remarkably promoted which increased the specificity of action . e.g. quinine can be artificially synthesized in 1945 Nowadays most western medicines are totally synthesized or

6、 semi-synthesized From 1900 chemically synthes With the development of genetic engineering（基因工程） more drugs will be produced artificially. e.g. the first genetically engineered drug is rh-insulin (for the treatment of diabetes ) and was first marketed in America in 1982 . With the development of gen

7、e4. Regulation of drug development The range of novel chemical entities developed has occasionally led to unexpected toxicity. In order to ensure the safety and efficacy of new drugs, their development must follow statutory procedures（法定程序）.4. Regulation of drug developm Thalidomide -a big tragedy !

8、 Thalidomide was developed by a German pharmaceutical company. It was sold from 1957 to 1961 in almost 50 countries under at least 40 brand names. Thalidomide was chiefly sold and prescribed to pregnant women, as an antiemetic(止吐药) to combat morning sickness and as an aid to help them sleep。In 1961

9、when thalidomide was withdrawn from the market, more than ten thousand deformed babies were born. They suffered from phocomelia(海豹肢). Thalidomide -a big t Developing a new drug is a highly complex, time-consuming, risky and costly process.5.An overview of new drug development Developing a new drug i

10、s a complex and time-consuming New drug development requires multidisciplinary efforts for many years, involving numerous steps and many sophisticated techniques 0.5-1year 3-4years 6-8years 2-3years complex and time-consuming0.5 risky: Only a very small portion of NCEs can be finally marketed as dru

11、g product risky: costly: One billion costly:One billion6. Development of new drugs6.1 Strategies for discovering new chemical entities Serendipity : The new therapeutic agent is discovered by chance. e.g. the discovery of penicillin Alexander Fleming penicillum6. Development of new drugs Al Molecula

12、r roulette（分子的轮盘赌） A great many of new chemical structures were synthesized randomly and screened by animal or in-vitro models of human disease to see if any of the newly obtained structures prove certain effect. Disadvantage: wasteful, dependent on sensitive models for screening Molecular roulette（

13、分子的轮盘 Minor structure changes in existing agents Penicillin，青霉素Penicillin Oxacillin，苯唑西林Ampicillin，氨苄西林 Minor structure changes in eDisadvantages of penicillin: unstable to acid unstable to -lactamase(内酰胺酶) little effect on Gram negative bacteria（革兰氏阴性菌） Disadvantages of penicillin: Programmed basic

14、 research with synthesis of specific chemicals e.g.1 Histamie(H2) receptor antagonist (such as Cimetidine西米替丁) for peptic ulcer Histamine receptors can be classified in to three classes , H1,H2 and H3, they distribute in different tissues, and cause different effects when agitated. H2 receptor exist

15、s in gastric wall cells, when agitated by histamine the secretion of gastric acid is enhanced , causing peptic ulcer . H2 receptor antagonist can specifically bind with H2 receptor but without agitation. Programmed basic research e.g. 2 angiotensin-converting enzyme inhibitor(血管紧张素转化酶抑制剂) for hypert

16、ension angiotensin is converted to angiotensin by angiotensin-converting enzyme. angiotensin can bind with angiotensin receptor (AT, existing in vascular smooth muscle ) , leading to vasoconstriction and rise of blood pressure. angiotensin-converting enzyme inhibitor such as Captopril（卡托普利） can bind

17、 with the converting enzymes, thus angiotensin couldnt bind to the converting enzymes and wont be converted to angiotensin . e.g. 2 angiotensin-convert Clinical observation of drug action in practice New pharmacological action which is not detected in animal models may be discovered in clinical appl

18、ication. thiazide diuretics(噻嗪类利尿剂) are used for the treatment of edema(水肿), their antihypertensive effects was not predicted from animal screening test, but identified after the drugs were marketed and being used in practice. Clinical observation of drug6.2 Pre-clinical studies medicinal chemistry

19、studies: technology for production, chemical and physical properties, stability, dosage form, standards for quality control 新药研发医学知识培训课件 pharmacological and toxicological studies include: pharmacodynamic（药物效应动力学） studies : drug action( therapeutic effect and adverse effect) dose-effect relationship

20、( minimal effective dose, maximal effect, median effective dose , median lethal dose) mechanism of action（作用机制）: interaction with its target pharmacokinetic（药物代谢动力学） studies: absorption, distribution, metabolism and excretion of the drug toxicity in animals：acute toxicity, chronic toxicity special t

21、oxicity pharmacological and toxicoSome important definitions in toxicologicalassessmentAcute toxicity testing: acute toxic reactions within 24 hours after single dosingChronic toxicity testing: toxic reactions which result from repeated doses, usually for three monthsLD50(median lethal dose): the do

22、se that kills 50% of animalsED50(median effective dose): the dose causing therapeutic effects in 50% of experimental animals therapeutic index =LD50/ ED50 Some important definitions in 新药研发医学知识培训课件Significance of preclinical studydetermine the possibility of conducting clinical trials predict possib

23、le toxicity and safety range in man provide reference for selection of initial dose in clinical trials Significance of preclinical st 6.3 Clinical trails: Phase : small scale studies on 20-30 volunteers to prove the safety in man as well as the tolerability, the whole process last 6 to 9 months. dos

24、e-ranging study(剂量递增试验)：to determine appropriate doses for therapeutic use and tolerability (maximum tolerated dose 最大耐受剂量 ) in man. informed consent(知情同意书)：information about a particular treatment or test for subjects to decide whether or not to undergo such treatment or test. 6.3 Clinical trails:

25、Phase : randomized, controlled and blind study are used to determine the therapeutic effect, indication and adverse reaction of the new therapeutic agent on patients, the test subjects should be no less than 100 pairs. Phase : large scale study( usually in multi-center study worldwide ) to further e

26、valuate efficacy and safety of the new drug. the test subjects should be no less than 300. After phase 3 studies, a new drug application(新药申请) is submitted to the regulatory authorities with a request for product license. Phase : randomized, contro Phase : post-marketing study under wide application

27、 of the new drug to examine the therapeutic effects and adverse reactions of the new drug as well as to discover new indications and adverse reactions that were not uncovered before. The test subjects should be no less than 2000. Phase : post-marketing stu Withdrawal of cerivastatin(西立伐他汀) form the

28、market: Cerivastatin is a synthetic member of the class of statins used to lower cholesterol and prevent cardiovascular disease. It was marketed in the late 1990s. During post-marketing surveillance, 52 deaths were reported in patients using cerivastatin, mainly from rhabdomyolysis (横纹肌溶解)and its resultant renal failure(肾衰竭). Ceri