Rus Articles Journal

Ideal target of

Modern knowledge of failures in work of an organism allows to develop drugs for fight against this or that illness purposefully. Just as the engineer can design the car for performance of strictly certain operation, designing of the drugs capable to influence an organism in a set way became possible today.

it seems to

At a view of pharmaceutical booths that in the world there is a huge number of drugs which only increases every day. And advertizing often convinces us that practically any illness can be cured thanks to emergence of new medicine. Very few people know that the different companies let out the same active agent, changing only a trade name and appearance of packing. Aspirin with taste of a water-melon or carrots, for example, can be available for sale. But, unfortunately, such novelties on a step do not bring closer mankind to a victory over this or that illness. At the same time rather new drugs (that is containing earlier unknown active substances) appears in the world not so much - several ten a year.

of “Bullet“ of Paul Ehrlich

had to cost doctors drugs Just a century ago, many of which were not specific, and their action only weakened unpleasant displays of an illness, or they just strengthened an organism which also gradually coped with an illness. High-quality break in this question was made at the beginning of the XX century. Paul Ehrlich who got in 1908 the Nobel Prize for opening in immunology became the founder of modern pharmacology. Being engaged in methods of coloring of histologic and microbiological preparations, he differently looked at the known fact that the same chemical molecule well contacts cages of one type and ignores all others. It led the scientist to understanding of the principle of specific interaction (the principle “a key - the lock“) - one of whales on whom there is a modern biology. Continuing analogy, he assumed that it is possible to find a molecule which will influence a certain biological object (for example, to kill an infecting agent or cancer cells) and will not influence any other objects. The author of the theory called such, then hypothetical, molecules “magic bullets“. Being guided by this principle, in Ehrlich`s laboratory for the first time in the history of steel purposefully to look for medicinal substances against a concrete illness. Means against syphilis which was widely applied within several decades was the most effective in influence. Besides, specific drugs against a sleepy illness and malaria which also affected the reasons of these diseases were found, killing monocelled parasites - a trypanosome and a malarial plasmodium.

the Choice of the purpose

the General public holds the opinion that drugs are created at scientific institutes and universities. However it is fair only partly. The large pharmaceutical companies usually are engaged in development of concrete drugs. Of course, knowledge of the reasons of diseases which is got in scientific centers serves as the base for creation of drugs. They can be published in opened scientifically - medical editions. Similar works are often conducted in parallel by several groups of scientists, but the one who was ahead of others in the press is considered the pioneer. And here publication of intermediate results during development of medicine is not accepted. It is like to transfer to the opponent the classified information. Development of new medicine from beginning to end and its legal release on the market can appear it is too expensive even for the richest universities. Considering the cost of all tests (which the legislation in the West demands), and also expenses on studying of substances which were then unsuitable, release on the market of essentially new medicine costs the developer, by different estimates, in 1 - 1,7 one billion dollars. And financial difficulties can remove opening for many years.

to interest sponsors, many biological scientific articles come to an end with optimistic phrases:“ Our results concern etiologies such - that and can be used when developing drugs against it“. However, the description of molecular bases of any pathology does not guarantee a possibility of creation of medicine at all. To depart on the Moon, the nobility as her phases change is not enough. And basic researches, as a rule, do not yield results which can be patented and sold at once (therefore - that them is financed by the state and non-profit organizations). For firms - developers results of basic researches are necessary mainly to choose a target - a biomolecule or other structure in an organism guilty or at least involved in development of a certain pathology. In other words, medicine is developed not against an abstract illness, and against a concrete molecule - a target.

the Chemical lottery and molecular design

Not always scientific knowledge are enough

to assume what molecule has to influence this biological target. In such situation there was Paul Ehrlich. He could know nothing about molecular characteristics of the factors causing diseases. In its time only “responsible“ for infectious diseases absolutely precisely was known. And Ehrlich undertook a pale spirokheta - the causative agent of syphilis, almost incurable in those days. It was necessary - to touch one at random molecules with different structure in hope that some it will be effective: the guaranteed way to pull out the happy lottery ticket is to buy them all. Its laboratory began to synthesize a set of various organic compounds and to methodically check how they influence on the causative agent of a disease. It was lucky rather quickly: effective was a connection with serial number 606. It was called salvarsan. It became the first effective remedy against syphilis which was widely applied for several decades. Presently screening, that is search of connections at random, any more not such hard labor as was in recent times. The modern automated methods allow to test per day as tens of thousands of connections influence this target. The special robot with a speed of a machine gun drips the tested substances in hundreds of holes of tablets, and the automatic measuring device, the reader, detects a signal (there is no interaction with a target) and writes down results in computer databases. The few connections which will show some effect (them “hits“ call), select for further researches.

other approach is Sometimes possible

. In the last decades thanks to efforts of “fundamental“ scientists there are known three-dimensional structures of an increasing number of biological molecules, including that which can serve as targets for drugs. On the basis of the saved-up data it is possible to predict structure of a molecule which has to interact with this biological target specifically. Using the principle of biological interaction “a key - the lock“, scientists project “a molecule - a master key“. This approach is called rational design. It was effective, in particular, during creation of a number of chemotherapeutic drugs against HIV. They were created so: in large-scale basic researches the structure of HIV - protease - protein which is absolutely necessary for formation of the correct structure of other proteins of the AIDS virus was thoroughly studied. HIV - protease is not similar to own proteins of a human body, so, is a suitable target. Then scientists “designed“ and synthesized molecules which thanks to the specific structure interact with HIV - protease and interfere with biological activity. As a result the “correct“ proteins are not synthesized, and the virus cannot breed. “Antiproteazny“ drugs allow to constrain reproduction of HIV in an organism of the patient with AIDS, being one of two components of so-called highly active anti-retrovirus therapy.

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After by screening and rational design or their combination identified a number of molecules - candidates for drugs which influence a target, there comes the turn of their detailed studying in laboratory. It is necessary because, in - the first, the automated testing could yield false positive result. In - the second, future medicine has to have a number of “additional“ properties: to be dissolved in water, to get, as a rule, in living cell (where there is a majority of targets), not to be very toxic, not to cause the strong immune answer, not too quickly to collapse in intestines and the blood course... Besides, if connection influences a biomolecule in a test tube, it does not mean at all that it will work also in living cell. On cells of the person which grow up in special incubators it is possible to test some properties of future drugs, for example the general toxicity. But without experiences on the whole organism it is impossible to find out how substance is soaked up in intestines as it is brought out of an organism through kidneys or collapses in a liver whether it is transferred by blood, whether causes anomalies of development, whether destroys certain bodies and fabrics. All this is checked by series of animal experiments. Finally medicine has to treat an organism, but not a separate cage.

In an apple

the Example of ideally calculated choice of a target - enzyme which splits fats in a digestive tract. It is affected by one of anti-obesity drugs. To a meeting with a target it should not be soaked up in intestines that in itself excludes a vital issue of achievement by medicine of the target. Besides, the risk of side effects is minimized - the molecule of medicine cannot just reach physiologically important structures of an organism. Any loads of kidneys and liver, any problems of removal from an organism. Well and the choice of the illness - in an apple: in the rich countries tens of percent of adults have excess weight, drugs are released without recipe, and the diagnosis puts everyone to itself, looking at scales.

Grounds of clinical tests

Even if the therapeutic effect is observed by

at laboratory animals, it is not a guarantee of the same positive result for the person yet. Therefore clinical tests are absolutely necessary. In civilized countries all examinees without fail have to express in writing the consent to participation in experiment. The World medical association formulated these principles in 1964 in the so-called Helsinki declaration. According to the rules accepted in the West, clinical tests consist of three stages, and everyone the subsequent includes an increasing number of patients - volunteers.

In the first phase make sure that substance X does not cause any too heavy side effect. Concerning their gravity, of course, requirements differ: to drugs against cancer or AIDS write off a lot of things therefore in this case some negative effects are the smaller evil, than progressing of a killing illness. Further study characteristics of biochemical transformations and removal from an organism (so-called pharmacokinetics and a farmakodinamika). The first phase is necessary for confirmation of the data obtained at experiments on animals, for definition of the most transferable doses (they are several times lower, than obviously harmful to animals). Tests of this phase are carried out on healthy volunteers whose risk is well paid.

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At the second stage estimates efficiency of medicine: whether it helps? Here, naturally, it is necessary to involve not healthy, but sick volunteers with a certain disease. To prove efficiency of medicine, compare at least two groups of patients: one - accepts “the candidate for drugs“, and another - receives placebo or standard therapy. That subjective factors did not influence results of researches, such tests do by “blind people“: the patient does not know what group he treats. Moreover, and the medical staff, except scientists - observers, should not know to what patients that is given (“double blind tests“). In favor of preservation of privacy when carrying out experiment there are at least two arguments. First of all personal interest can interfere with business and cause a perversion of results, or compassion of medics to the patients receiving placebo will push to create them the best conditions also leaving that can also distort a true picture.

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After will clinically prove the existing efficiency of medicine, the third phase of researches - selection of a dosage of new medicine and the scheme of its application, and also detailed studying of side effects begins. Such researches are conducted on big groups of patients and for a long time.

The more patients participates in tests, the received conclusions are more reliable. At a small amount of participants the difference between control and skilled groups can be erased absolutely from - for casual individual differences. The main difficulty of clinical tests of the second and third stages consists in that during a reasonable period to find enough suitable patients and to receive their consent to participation in researches. In the last decades less residents of civilized countries are ready to sacrifice themselves to science. Therefore the tendency to movement of clinical tests from the rich countries (the USA, Japan, Western Europe) in poor is more and more clearly observed: here and work of medics is cheaper, and it is easier to receive a consent of patients and the legislation which regulates carrying out clinical tests is softer (if at all exists). Today already about 40% of such experiments are made outside the countries - the chief developers of new medicines.

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At each stage of creation of a certain medicine rejects a considerable share of the studied substances. Most of the “candidates“ found by means of screening and chosen from tens or hundreds of thousands of connections are unsuitable as medicine for one reason or another. The chance to become new medicine drops out to about one “candidate“ of one thousand. But we will assume that the pharmacological company nevertheless managed to find the necessary substance: heavy side effects were not found, and the powerful bureaucratic structure grants permission for sale of new medicine (in the USA, for example, Food and Drug Administration, in Europe - European Medicines Agency is engaged in it). Time to reap the fruits. Development of medicine is similar to creation of the computer program: at first expensive and laborious work, and then it is possible to duplicate a valuable product almost without expenses.

However and after a medicine entry into the market the producer cannot relax completely: messages on side effects which arose at application of medicine, for example, for certain age groups, for the patients having the accompanying diseases and so on gather and analyzed. Whatever large-scale were clinical tests, something always remains passed: if the negative effect arises with a frequency of one on 5000, then it, most likely, will not be shown at tests on 300 patients. For example, gradual accumulation of messages on serious consequences of overdoses of some preparations “for cold“ for children of the first years of life was led to what at the end of 2007 some leading pharmaceutical companies voluntarily withdrew from the detskiye market of the version of a number of preparations.

Chernobyl in tablets

Despite all tests and checks of safety which are demanded by the legislation of the European countries sometimes permission to sale is got by not so harmless substances. The most terrible example - talidomid. This medicine was developed in 1950 - e years the German pharmaceutical company GR ü nenthal, it passed the put tests and was widely applied in 1950 - 1960 - e years as snotvornoe and as means against nausea at pregnant women until it became clear that application of a preparation during pregnancy leads to appearance of children with congenital uglinesses, such as strong shortening or total absence of extremities. Before doctors and scientists bethought, about 10 000 children - cripples managed to be born. The United States were lucky: the expert of FDA Frances Oldkhem of Kelsey did not allow sale of a talidomid in America, having counted the carried-out tests insufficient what then received a special award from hands of the president Kennedy for.

Who orders opening?

Main, though, fortunately, not always only, the purpose for the sake of which all pharmaceutical companies undertake development of this or that medicine - receiving profit. Certainly, at the choice of targets the advantage for mankind is considered. And still development of new medicine - business therefore the decision is made on the basis of careful forecasts, the analysis of the potential market of buyers. From - for it developers of drugs often ignore, in - the first, rare diseases, in - the second, those which are widespread in the poor countries. For example, infectious diseases remain one of the main reasons for death on Earth: more than one million people a year die only of malaria. At the same time at developers of drugs “in great demand“ not the most dangerous, but widespread diseases in the rich countries. In the list of world leaders of sales of 2006 1 - e the place (more than 14 billion dollars) is taken by Lipitor - means for decrease in level of cholesterol (certainly, it is useful, but it is possible just to watch a diet). On 4 - m the place - cure for disorders of digestion (diarrhea), on 6 - m and 7 - m - from rheumatoid arthritis, on 13 - m - from a depression. The only means among 50 leaders of sales which is related to infectious diseases (a vaccine against a pneumococcus) borrows only 46 - e the place. According to recently carried out analysis of the global market, the most great pent-up demand - on new drugs against diabetes. Also in the first lines of the most demanded - drugs against Alzheimer and Parkinson`s syndromes, a hypertension and other diseases.

Other important factor which defines the decision “to undertake - not to undertake“ development of medicine - it is existence of well characterized and “proved“ target: that is it has to be precisely known that this protein, the cage, a microbe play a key role at a certain illness and if to influence him, it will improve a state. Besides, the target has to be “convenient“ for creation of medicine. It is desirable that it was readily available for interactions with medicine and unlike other structures in an organism which carry out useful functions, otherwise medicine will influence for certain and them. But the road to the real opening is incredibly long. And so far most of developers of drugs “look for them under a lamp“ - where it is easier to find something.

“The initiative of drugs against the ignored diseases“ - non-profit organization which in cooperation with WHO, UNICEF and the pharmaceutical companies is engaged in development “unpromising“ from the point of view of profit, but the vital drugs tries to Correct a situation, for example. So, in 2007 they offered a new cheap drug against malaria. And in this case business of rescue of people was not comparable with benefit.