Development of New Drugs.docx

1、Development of New DrugsDevelopment of New DrugsAim Drug development aims to produce a novel therapeutic agent which is superior in efficacy to existing remedies and which causes less frequent or less severe adverse effects.1. Evolution of a new drugThe development of a new therapeutic agent involve

2、s a multidisciplinary group in many years of work. Formerly, drugs were extracted from natural plant and animal sources. Therapeutic use was empirical and based on traditional experience. Over the last 80 years an impressive number of drugs have been synthesized chemically. With the development of g

3、enetic engineering and the production of monoclonal antibodies it is likely that even more agents will be produced artificially.Synthetic techniques have produced pure substances. This has led to increased specificity of action and, in some cases, greater efficacy and reduced toxicity. Unfortunately

4、 new drug development is expensive, and only a few substances (less than 1%) of those developed are actually marketed and used in practice.The range of novel chemical entities developed has occasionally led to unexpected toxicity. As a consequence, most governments have established bodies to regulat

5、e drug marketing, e.g. the committee on Safety of Medicines in Britain, and the Food and Drug Administration in the USA. These agencies supervise clinical research on new drugs and license new products. Although they serve to protect the public and are seen to do so, the statutory procedures that mu

6、st be followed in applying for a license for a new drug add greatly to the costs and time of development.There is some evidence that the rate of introduction of entirely novel agents is slowing down. Whether this reflects economic pressures or diminished novel synthetic capacity or ability is not cl

7、ear.2 Drug development strategiesSeveral strategies have been used in the development of new drugs. Over the years all have had success but no single approach has been consistently successful.Serendipity, luck an intuitionThis approach has been applied less frequently in recent years. The discovery

8、of penicillin by Fleming was in this category.Molecular rouletteRandom chemical synthesis of new structures and pharmacological screening, this approach is wasteful and depends on the availability of sensitive animal or in-vitro models of human disease, which often do not exist.Minor structural chan

9、ges in existing agentsOccasionally this leads to compounds of greater efficacy and rarely to drugs with novel actions detected in pharmacological screening or clinical practice.Programmed basic research with synthesis of specific chemical Intellectually this approach is the most satisfying. There ha

10、ve been spectacular results, e.g. levodopa and dopamine agonists in the treatment of Parkinsonism; beta-receptor blockers for angina; histamine (H2) antagonists in peptic ulcer disease; converting enzyme inhibitors in hypertension. However, this approach is expensive and this is no guarantee of succ

11、ess.Clinical observation of drug action in practiceThis is the traditional means of drug assessment. New applications arise from measurement of drug action in man in disease states. The antihypertensive effects of thiazide diuretics and beta-blockers were not predicted from animal screening tests. T

12、hey were only identified after the drugs were available and were being used in practice.3. Experimental pharmacologyThese studies determine whether the drug has the desired profile of action in model systems. The models are selected to provide as reliable an index of efficacy in man as possible.Seve

13、ral models are usually employed. The models may be simple or complex and include:1) cell cultures or bacteria2) partially purified enzymes or sub-cellular particles3) isolated tissues4) perfused organs5) intact animals from mice to primates4. Toxicological assessmentIn parallel with pharmacological

14、experiments on efficacy, the toxic effects of acute and chronic dosing are determined. Acute toxicity is less important as long as LD50 (the dose that kills 50% of animals) is not close to the ED50 (the dose causing 50% of maximal pharmacological response).Chronic toxicity testing is more relevant t

15、o clinical applications and should take place along the following lines:1) the route of administration, dose range, dose frequency and plasma levels should be appropriate to likely clinical indications. If possible, methods should be available to measure plasma concentrations and to determine patter

16、ns of metabolism.2) At least two species should be studied, usually dog and rat or mouse. If possible, a species should be selected with a similar profile of metabolism to man.3) The duration of treatment should be consistent with the likely duration of use in man and the relative life expectancy of the animal species. Usually toxicity studies are undertaken over a period of 4 weeks to at least 1 year.4) Haematological and bio