Another innovative approach to predicting harmful effects is the computer graphic technique COMPACT (for computer optimised parametric analysis for chemical toxicity). It is based on an understanding of chemicals, known as P450 enzymes, that are naturally present in the body and which are responsible for metabolising drugs and foreign substances. Some of these enzymes interact with drugs to create toxicity whilst others have a detoxifying effect. A drug can only react with a P450 enzyme if it has the correct shape and electronic distribution, that is, if it fits into the enzyme like a key into a lock. This is determined by the computer which then announces whether a new chemical will be potentially toxic or carcinogenic, or safe under ordinary conditions of use.(20)
Ultimately, whatever preliminary tests are carried out, it is human trials that represent the most valid method since only they can reveal how a drug is processed by the human body. This view is reflected by Professor Dennis Parke, former member of the British government's Committee on Safety of Medicines, the body responsible for approving the introduction of new drugs. Parke explains that '... there are indeed more appropriate alternatives to experimental animal studies and for the safety evaluation of new drugs, these comprise short-term in vitro tests with micro-organisms, cells and tissues, followed by sophisticated ... studies in human volunteers and patients'.(21)
Laboratory tests are not the only way to discover useful therapies. Clinical investigation of existing medicines often leads to important advances as physicians discover new uses for these drugs. One example is the early beta-blocking drug, propranolol, which was first introduced for heart problems but then unexpectedly found to lower blood pressure in patients.(22) As a result beta-blockers are now a major treatment for high blood pressure. The discovery of phenobarbitone's anti-epileptic effects in 1912 has been described as the most important advances in medical treatment of the disease. During clinical investigation of phenobarbitone's sedative properties, Hauptmann noticed that the drug also reduced epileptic attacks. He then carried out further tests with epileptic patients to confirm his observation.(23) Today, phenobarbitone is still an important treatment for epilepsy.
In cancer research, the first effective anti-tumour agents originated with the discovery that one of the long-term effects of the mustard gases used in World War I was damage to the bone marrow.(24) Doctors noticed that exposed soldiers and workers experienced a dramatic lowering of their white blood cell count and suggested the chemicals as a possible treatment for leukemia and lymphoma - cancers characterised by an over production of white blood cells. The nitrogen mustards are now used in combination with other anti-cancer drugs to treat conditions like Hodgkin's disease.
This approach - the careful analysis of drug and chemical side effects - has enormous scope since all substances have multiple actions, and whilst many are obviously harmful, others can be harnessed for the patient's benefit.
Human clinical studies must necessarily be used if, for some reason, drug researchers are not able to experiment on animals. In the case of Alzheimer's Disease there are no close 'animal models' on which to test treatments but drug development has still proceeded: researchers have been guided by human tissue studies instead. An example is the development of tacrine, the first drug specifically for controlling Alzheimer's Disease. Analysis of tissue from Alzheimer patients revealed a defect in brain chemistry which leads to decreased production of the nerve chemical acetylcholine. Tacrine was suggested as a way of combating this and although it is not a cure, it has been found to improve symptoms.(25)
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