Clinical pharmacology. Drug development.

Currently between 15 and 20 new medicines (as opposed to new formulations of old drugs) are marketed in an average year. Before the introduction of any drug to man, many months and usually several years of research and development have taken place. The starting point for discovery of a new drug may be reached in several different ways. Firstly, chemical entities that have been synthesised by the same or another company are subjected to a battery of tests designed to detect different types of biological activity. These include studies of the effects on animal behaviour and work on isolated tissues. In addition animal models of disease states are sometimes used. In general this is not an efficient form of research since at best only one in every four to five thousand chemical entities screened is marketed as a medicine. Indeed, recent evidence suggests the ratio may be closer to one in ten thousand: it is for this reason that this "random" approach is losing favour. A second approach entails the synthesis and testing of chemical analogues of existing medicines for biological activity. Although in general this leads to minor advantages such as better absorption, greater potency, and a more selective action, surprises may occur. On occasions these are disadvantageous and may limit the subsequent use of the drug. Additional properties, however, may become evident when the compound is tried in man. This serendipitous approach led to the introduction of the thiazide diuretics and oral hypoglycaemic agents (both of which represent slight modifications of the early antimicrobial sulphanilamide) and of clonidine for hypertension. The newest and most rational form of research and development has been to design a substance to fulfil a particular biological role. At its simplest this may entail the synthesis of a naturally occurring substance-for example, a hormone or vitamin. A good example is the introduction of levodopa, a precursor of the neurotransmitter dopamine, which is deficient in patients with Parkinson's disease. Alternatively, chemical analogues of naturally occurring substances have been developed with the intent of modifying the effects of the endogenous substances. Drugs of this type include the 3-adrenoceptor antagonists (initially pronethalol and propranolol) to block the effects of circulating catecholamines and thereby reduce myocardial oxygen consumption to relieve angina pectoris. More recent examples include cimetidine to block the action of histamine on H2 receptors, thus reducing acid output from the stomach to allow healing of peptic ulcers. Captopril is another substance introduced recently to inhibit the action of the converting enzyme responsible for generating angiotensin II, thereby lowering blood pressure. Although this approach has been successful in recent years, the main problem limiting the rate of introduction of new drugs