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Medicine and Health

New drugs - made to measure

   
 
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drugs that can be designed from the start to avoid the secondary effects that vary from one individual to another.
Why do effective drugs sometimes have serious secondary effects? Because each individual metabolises them differently. By coordinating European research under the COST programme (coordinated action in the field of science and technology) it has been possible to make considerable progress in our knowledge of variations in the human enzyme systems responsible for metabolism. Through this work, the pharmaceuticals industry is now in a position to devise new and much safer products.

 

We are all different where drugs are concerned. Some of these drugs are being withdrawn from sale despite having been on the market for years. Deemed to pose no danger, they have been found to cause serious secondary effects for some people that only become apparent after a very long period of use. Why is this? At the end of the 1970s various scientific reports gave rise to suspicions that the enzymes responsible for the assimilation of drugs vary from one person to another.

Greater knowledge in this area would make it possible to take account of this variation when developing new drugs. Under the COST B1 action, a research project involving 15 European countries - the complexity of the problem being such as to require cooperation on this scale - will help us to achieve a better understanding of such phenomena and to take more effective action in preventing them.

Variations on a theme
For a dozen years or so, work has focused on the P450s, a particularly important family of enzymes responsible for the metabolism of drugs. There are nearly 40 different P450s in the human body, about half of which control reactions involving substances which have remained the same throughout our evolution - so much so that we all possess virtually identical enzymes. It is probable that the other half have evolved in such a way as to metabolise substances which our bodies no longer secrete, and this is the category of enzymes that interact with numerous drugs.

With the passage of time, these enzymes - now deprived of specific functions - have undergone modifications through genetic mutations in their DNA. Today 10% of the population possesses variants of some of these enzymes, and these are the people who may encounter serious problems when given a drug which is normally innocuous.

During the first four years of the research, considerable progress was made in identifying variations in the different enzyme systems. "Standardisation of the techniques employed in the classification of the different human variants and in the study of the enzymes concerned has marked a decisive stage," explains Alan Boobis, the UK delegate on the COST B1 Management Committee. "Harmonisation of our efforts and methods was imperative, if we were to avoid unnecessary duplication in our work, while at the same time guaranteeing the complementarity of our findings."

The danger of
interaction On the basis of these particularly positive results, the action was extended twice, once in 1991 and again in 1995. The work was broadened to take in basic research covering mathematical approaches aimed at defining variability in the consumption of drugs among European populations. Different groups, working in parallel, have focused their research on specific aspects: interactions between drugs or with other substances such as those found in cigarette smoke, alcohol and chemical compounds in convenience foods; behaviour of drugs in persons affected by renal insufficiency or heart disease; reasons why the effects of drugs vary from one individual to another.

The scientists observed, for instance, that the simultaneous administration of terfenadine, a common antihistamine for the treatment of hay fever, along with other drugs (notably certain anti-fungal agents and the antibiotic erythromycin) could lead to very serious, even lethal, heart disorders in certain patients. They also came up with an explanation of the working of the mechanisms likely to lead this kind of accident.

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The interaction (very rare but highly dangerous) of terfenadine with certain other drugs can now be avoided. This antihistamine is currently used in the treatment of hay fever.

And what about the
pharmaceuticals industry? The project has had a significant impact on pharmacology and on the development of new drugs. Twenty years ago, before being administered to humans, a product was tested on animals as thoroughly as possible, but often complications were detected only after its introduction in the treatment of patients. Nowadays, drugs are devised from the outset in such a way as to avoid conflicts with enzyme variants. New drugs are tested not only in vitro but also using complex computer modelling techniques, in an attempt to eliminate any risk of unexpected secondary effects, even among that part of the population considered to be "at risk". Possible interactions between drugs can be described during the design of the new products. Doctors are now much better informed of the variations likely to occur from one patient to the next and of the probable interactions with, for example, alcohol or coffee. It is already possible to predict which subgroup of the population is at risk of reacting unfavourably to a given drug by virtue of its state of health.

In the near future it will be possible to carry out routine examinations to detect unusual forms of enzymes affecting the metabolism of drugs; it will be sufficient to analyse the DNA contained in a small cell sample (from blood or cheek tissue) and to compare it with the data base compiled mainly as a result of the COST B1 action. Using computer models, it will be possible to simulate with some accuracy what would happen if a given individual were to take a particular new drug - thereby reducing the frequency of secondary effects and of other potentially lethal reactions.

"Because of the large number of countries involved, this project has had a considerable impact on the pharmaceuticals industry throughout Europe," Alan Boobis points out. "Almost all the major companies working on the development of drugs are using our discoveries as a model. Prior to the COST B1 action, the United States was unquestionably ahead in most areas relating to drug metabolism research. Now, Europe has assumed the role of leading player in numerous key areas."

 

 

Project Title:  
Criteria for the choice and definition of healthy volunteers and/or patients for phase I and studies in drug development



Contract Reference: Medical Research - B1
Action COST (European Cooperation in the field of Scientific and Technical Research)

CORDIS databaseFor more information on this project,
go to the Cordis database Record

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