1、,Unit 8 Development of new drugs,2.Evolution of a new drug In ancient time drugs were extracted from plant and animal sources, but the purity of drugs was very limited.digitalis: extracted from Digitalis purpurea and Digitalis lanata , including digitoxin and digoxin etc. Be used for the treatment o
2、f chronic cardiac insufficiency.opium : extracted from the opium poppy . Opium contains more than twenty alkaloids such as morphine and Codeine. Some of them are important painkillers (narcotic analgesics)quinine: extracted from the bark of cinchona, its antimalarial function was discovered by the I
3、ndians in North America, 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 1945Nowadays most western medicines are totally synthesized or semi-synthesized Wi
4、th the development of genetic engineering more drugs will be produced artificially. Most genetically engineered drugs are proteins. Foreign DNA fragment encoding certain protein is cloned in an appropriate host cell through vector (usually plasmid ). The foreign protein can be,expressed in the host
5、cell . If the protein is secreted outside the cell it can be purified from the fermentation broth. If the protein remains in the cell it can be purified after crushing the cells. e.g. the first genetically engineered drug is rh-insulin (for the treatment of diabetes ) and was first marketed in Ameri
6、ca in 1982 . The gene that encoding human insulin is cloned in E.coli then the bacteria obtain the ability to produce human insulin . After cultivation of the engineered bacteria, human insulin is accumulated during the bacterias life process.,2. Development of new drugs 2.1 Strategies for discoveri
7、ng new chemical entities Serendipity : The new therapeutic agent is discovered by chance. E.g. the discovery of penicillin,Alexander Fleming,penicillum,Molecular rouletteA great many of new chemical structures were synthesized randomly and screened by animal or in-vitro models of human disease to se
8、e if any of the newly obtained structures prove certain effect. Minor structure changes in existing agents,penicillin,Penicillin ,oxacillin,ampicillin, Programmed basic research with synthesis of specific chemicals e.g. 1 angiotensin-converting enzyme inhibitorangiotensin is converted to angiotensin
9、 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 can bind with the converting enzymes, thus angiotensin could
10、nt bind to the converting enzymes and wont be converted to angiotensin . e.g.2 H2 receptor antagonist (such as Cimetidine) Histamine receptors can be classified in to three classes , H1,H2 and H 3, they distribute in different tissues, and cause different effects when agitated. H2 receptor exists in
11、 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., clinical observation of drug action in practiceNew pharmacological action which is not detected in
12、animal models may be discovered after clinical application. e.g. thiazide diuretics are used for the treatment of edema, their antihypertensive effects was discovered in its clinical application 2.2 pre-clinical studies of the new therapeutic agent objectives: support for human pharmacology support
13、for human toxicology prediction of pharmacokinetics screening new dosage forms and formulation,Content: medicinal chemistry studies: technology for production, chemical and physical properties, stability, dosage form, standards for quality control pharmacological and toxicological studies include:ph
14、armacodynamic 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: interaction with its targetpharmacokinetic studies: absorption, distribution, metabolism and e
15、xcretion of the drugtoxicity in animal models,2.3 clinical trails: Phase : small scale studies on 20-30 volunteers to prove the desired pharmacological effect and the safety in man as well as the tolerability, the whole process last 6 to 9 months. Phase : randomized, controlled and blind study are u
16、sed to determine the therapeutic effect, indication and adverse reaction of the new therapeutic agent , the test subjects should be no less than 100 pairs. Phase : large scale study to further evaluate efficacy and safety of the new drug. the test subjects should be no less than 300. Phase : post-marketing study under wide application 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.,
