新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)培訓(xùn)課件

1、新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)New words and expressionacute: acute infection（急性感染）, acute leukemia（急性白血?。?chronic: chronic gastritis（慢性胃炎）agonist: stimulator antagonist: blocker adverse reaction（不良反應(yīng)）: any bad effect or undesirable effect caused by drug use at normal dose（正常劑量）新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)2New words and express

2、ionacute: new chemical entity(新化學(xué)實(shí)體): new compound shows pharmacological activity against certain disease, which is also called lead compound(先導(dǎo)化合物) or drug candidate(候選藥物) in-vitro（體外）: outside of organisms in vivo（體內(nèi)）: within a whole living organism新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)3 new chemical entity(新化學(xué)實(shí)體): n1.What i

3、s a new drug?Chemical structure（化學(xué)成分） Dosage form(劑型）Route of administration（給藥途徑）Indication（適應(yīng)癥）New drug新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)41.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 goa

4、l: to provide effective, accessible and affordable medicines for all 新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)52.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（奎寧）: extracted from the bark of cinchona（金雞納樹皮）, its antimalarial（抗瘧疾） fun

5、ction was discovered by the Indians in North America 3. Evolution of new drug新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)6 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 syn

6、thesized in 1945 Nowadays most western medicines are totally synthesized or semi-synthesized新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)7 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

7、 of diabetes ) and was first marketed in America in 1982 .新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)8 With the development of gene4. 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 m

8、ust follow statutory procedures（法定程序）.新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)94. Regulation of drug developm Thalidomide -a big tragedy ! 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 t

9、o pregnant women, as an antiemetic(止吐藥) to combat morning sickness and as an aid to help them sleep。In 1961 when thalidomide was withdrawn from the market, more than ten thousand deformed babies were born. They suffered from phocomelia(海豹肢). 新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)10 Thalidomide -a big t Developing a new drug is

10、 a highly complex, time-consuming, risky and costly process.5.An overview of new drug development新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)11 Developing a new drug is a complex and time-consuming New drug development requires multidisciplinary efforts for many years, involving numerous steps and many sophisticated techniques 0.5-1

11、year 3-4years 6-8years 2-3years新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)12 complex and time-consuming0.5 risky: Only a very small portion of NCEs can be finally marketed as drug product新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)13 risky: 新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)13 costly: One billion新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)14 costly:One billion新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)16. Development of new drugs6.1 Strategies for discov

12、ering new chemical entities Serendipity : The new therapeutic agent is discovered by chance. e.g. the discovery of penicillin Alexander Fleming penicillum新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)156. Development of new drugs Al Molecular roulette（分子的輪盤賭） A great many of new chemical structures were synthesized randomly and screen

13、ed 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新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)16 Molecular roulette（分子的輪盤新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)培訓(xùn)課件Disadvantages of penicillin: unstable to acid unstable to -lacta

14、mase(內(nèi)酰胺酶) little effect on Gram negative bacteria（革蘭氏陰性菌） 新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)18Disadvantages of penicillin:新藥 Programmed basic 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 clas

15、ses , H1,H2 and H3, they distribute in different tissues, and cause different effects when agitated. H2 receptor exists 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 b

16、ut without agitation. 新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)19 Programmed basic research e.g. 2 angiotensin-converting enzyme inhibitor(血管緊張素轉(zhuǎn)化酶抑制劑) for hypertension angiotensin is converted to angiotensin by angiotensin-converting enzyme. angiotensin can bind with angiotensin receptor (AT, existing in vascular smooth muscle )

17、 , leading to vasoconstriction and rise of blood pressure. angiotensin-converting enzyme inhibitor such as Captopril（卡托普利） can bind with the converting enzymes, thus angiotensin couldnt bind to the converting enzymes and wont be converted to angiotensin .新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)20 e.g. 2 angiotensin-convert Clini

18、cal observation of drug action in practice New pharmacological action which is not detected in animal models may be discovered in clinical application. thiazide diuretics(噻嗪類利尿劑) are used for the treatment of edema(水腫), their antihypertensive effects was not predicted from animal screening test, but

19、 identified after the drugs were marketed and being used in practice. 新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)21 Clinical observation of drug6.2 Pre-clinical studies medicinal chemistry studies: technology for production, chemical and physical properties, stability, dosage form, standards for quality control 新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)22新藥研發(fā)醫(yī)學(xué)知識(shí)

20、培訓(xùn)22 pharmacological and toxicological studies include: pharmacodynamic（藥物效應(yīng)動(dòng)力學(xué)） studies : drug action( therapeutic effect and adverse effect) dose-effect relationship ( minimal effective dose, maximal effect, median effective dose , median lethal dose) mechanism of action（作用機(jī)制）: interaction with it

21、s target pharmacokinetic（藥物代謝動(dòng)力學(xué)） studies: absorption, distribution, metabolism and excretion of the drug toxicity in animals：acute toxicity, chronic toxicity special toxicity 新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)23 pharmacological and toxicoSome important definitions in toxicologicalassessmentAcute toxicity testing: acute to

22、xic reactions within 24 hours after single dosingChronic toxicity testing: toxic reactions which result from repeated doses, usually for three monthsLD50(median lethal dose): the dose that kills 50% of animalsED50(median effective dose): the dose causing therapeutic effects in 50% of experimental an

23、imals therapeutic index =LD50/ ED50 新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)24Some important definitions in 新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)25新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)25Significance of preclinical studydetermine the possibility of conducting clinical trials predict possible toxicity and safety range in man provide reference for selection of initial dose in clinical

24、 trials 新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)26Significance 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. dose-ranging study(劑量遞增試驗(yàn))：to determine appropriate doses for therapeutic use and tole

25、rability (maximum tolerated dose 最大耐受劑量 ) in man. informed consent(知情同意書)：information about a particular treatment or test for subjects to decide whether or not to undergo such treatment or test. 新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)27 6.3 Clinical trails:新藥研發(fā)醫(yī)學(xué) Phase : randomized, controlled and blind study are used to deter

26、mine 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 evaluate efficacy and safety of the new drug. the test subjects s

27、hould be no less than 300. After phase 3 studies, a new drug application(新藥申請(qǐng)) is submitted to the regulatory authorities with a request for product license. 新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)28 Phase : randomized, contro Phase : post-marketing study under wide application of the new drug to examine the therapeutic effects

28、 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. 新藥研發(fā)醫(yī)學(xué)知識(shí)培訓(xùn)29 Phase : post-marketing stu Withdrawal of cerivastatin(西立伐他汀) form the market: Cerivastatin is a synthetic me

29、mber 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 (橫紋肌溶解)and its resultant renal failure(腎衰竭). Cerivastati