08 December 2015

To victory over troubles

How to overcome the diseases of the century

Natalia Bulgakova, "Search" No. 49-2015

"Scientific foundations of the effectiveness and safety of medicines" – this is the topic of the regular session of the General Meeting of the Russian Academy of Sciences. Our materials tell about the problems that are planned to be discussed at this forum.

According to a scientific forecast published in the journal Nature, by 2040 the average human life expectancy will be 120 years. But is it possible to live to such an age without medication? Without vaccines, insulin, immunomodulatory drugs? The answer is unequivocal: it is impossible. 

What are they, medicines of the XXI century? How to resist the "diseases of the century"? On the eve of the General Meeting of the Russian Academy of Sciences, the readers of "Search" were told about this by the chief therapist of Russia, director of the Research Institute of Pulmonology, organizer and scientific director of the National Forum "Man and Medicines", Academician Alexander CHUCHALIN.

 – Before talking about medicines, it should be noted that the medicine of the future involves a new approach to healthcare. The concept of "4P medicine" is gaining popularity in the world. What does 4P mean? Firstly, the prognosis (that is, the prediction of the disease based on the individual characteristics of the organism and genome), secondly, prevention (prevention of the occurrence of the disease), thirdly, personalization (individual approach to each person) and, fourthly, participativeness (from the English participate – to participate) – active participation the person himself to take care of his health, as well as attracting specialists of various profiles to treatment. The complexity of the approach will contribute to an increase in life expectancy. The second and third "P" suggest the use of modern medicines.

The diseases of the century that we have to deal with first of all are the so–called chronic non-communicable diseases. According to official WHO data, about 59 million people die every year in the world. Among the causes of death, coronary heart disease occupies a leading position. In second place is a cerebral infarction. The third, fourth and fifth lines are associated with respiratory diseases: chronic obstructive pulmonary disease (COPD), respiratory diseases, lung cancer, trachea and bronchi plus tuberculosis. The sixth line is diabetes. Therefore, if we want to change the situation with mortality, we need to understand, first of all, what can be done in the treatment of four groups of diseases: diseases associated with changes in blood vessels (heart attacks and strokes), COPD, cancer, diabetes. The task is more than relevant! After all, it is a real misfortune that Russia today is a country of super–mortality: more than 2 million people die in our country every year, and among the causes of death, according to calculations, chronic non-communicable diseases account for 86%.

It is pleasant to note that the scientist who identified the relevance of this topic was the President of the USSR Academy of Medical Sciences Nikolai Nikolaevich Blokhin. He was the first in the world to introduce the concept of "epidemiology of chronic non-communicable diseases". 

Today, 207,600 studies are being conducted on the approbation of medicines. Scientists from 180 countries participate in them. 

The design of new drugs goes in three directions: low-molecular compounds, biological drugs, gene therapy. It is important to note that scientific theory always precedes the creation of new drugs. The role of fundamental sciences – chemistry, physics, biology – in the creation of medicines is extremely high. 

Low–molecular compounds - the so-called "small molecules" - occupy a prominent place among medicines. Here is just one example. At one time, the chemist Rimma Evstigneeva set out to create a remedy for allergies. Over time, it transformed and proved to be very effective for the treatment of patients with influenza and other respiratory viral diseases. Rimma Parfenovna did not find out this, she passed away earlier. Her students, developing her brilliant ideas, showed that the histidine salt molecule is able to control the function of interferon receptors. This is the greatest discovery. 

Big changes are taking place in the field of biological medicines. Monoclonal antibodies (MCAS) play a leading role in the treatment of many "diseases of the century". Their era was discovered by the Argentine biochemist Caesar Milstein and his colleague Georg Koehler: together with biologist Niels Jerne, in 1984 they were awarded the Nobel Prize in Medicine for their work "The theory of specificity in the development and control of immune systems and the discovery of the principles of creating monoclonal antibodies." Today, MCAS are widely used in clinical practice – in oncology, cardiology, dermatology, rheumatology, allergology, pulmonology, ophthalmology. And they are potentially applicable in all therapeutic areas.

Recently, Bobby Gasper, a pediatrician and immunologist working at Imperial College in the USA, presented the final data on the treatment of 30 children with congenital combined immunodeficiency with gene therapy methods. These are doomed children: they die early either from infections or from tumors. Thanks to new medical technologies developed at Imperial College, 18 babies were cured. Gene therapy is also successful in the treatment of skin diseases, hemophilia and some other severe congenital diseases. I do not know any examples of gene therapy in Russia yet. 

It should be noted that the creation of a drug is a complex multi–stage process. Schematically, the chain of stages is as follows: scientific theory – molecule – clinical studies – systematic review – meta-analysis – level of evidence – clinical recommendations. Years pass from the first stage to the use of the drug in medical practice. 

Cardiology. Currently, 17,789 clinical trials are being conducted in the field of treatment of heart diseases. The root of many problems is atherosclerosis. Coronary vessels altered by cholesterol plaques are prone to thrombosis. The theory of the pathogenesis of atherosclerosis was developed by the Russian scientist N.Anichkov, who showed that the basis of atherosclerotic lesions of the arteries is the penetration of lipids – mainly cholesterol – into the vessel wall. He studied in detail the stages of development, progress and regression of atherosclerotic plaques, for the first time presented atherosclerosis as a systemic disease caused by various risk factors: lipid metabolism disorders, increased blood pressure (hypertension), etc. Moreover, N. Anichkov predicted the further stages of the study of atherosclerosis. 

In the last two or three decades, statin therapy has been the main one in the treatment of atherosclerosis; they belong to the group of reductase inhibitors, at one time their discovery was a great achievement. However, it turned out that statins also have undesirable effects: they negatively affect the muscular apparatus, causing weakness and inflammation of the muscles, are a risk factor for the development of type II diabetes. The molecular mechanisms of these complications have been studied. A new generation of statins, as shown by a study completed last year, also carry the risk of diabetes.

A breakthrough in the treatment of atherosclerosis was the creation of monoclonal antibodies that prevent the degradation of receptors to low-density lipoproteins. The use of MCA can increase the effectiveness of statins and significantly reduce the risk of atherosclerosis in people with a family predisposition to it. Monoclonal antibodies are targeted drugs, unlike statins. 

Another topic related to cardiology is the formation of blood clots in coronary vessels. This process, called the coagulation cascade, takes place in several stages. The first drugs to appear were those acting at the last stage – they contribute to the dissolution of blood clots. Young Evgeny Chazov injected himself intravenously with fibrolysin to show its safety. The era of the use of fibrolysin, streptokinase, and then other drugs began. 

When the mechanism of the coagulation cascade was studied, drugs began to appear that regulate this process at other stages. So, three years ago, a new generation of medicines that prevent the formation of a blood clot and a blood clot – direct inhibitors of thrombin and blood clotting factor (Xa factor) - entered clinical practice. Treatment with anticoagulants can cause a dangerous complication – bleeding, which can lead to death. A meta-analysis based on 12 studies of new-generation drugs did not establish that these drugs lead to fatal bleeding. But, it turned out, this does not mean that they do not lead at all. Even if the risk of a fatal complication is low, say, in one out of 10 thousand patients – it's still a problem! Some direct anticoagulants circulate in the blood for three days. This means that antidote medications are needed, which could quickly "turn off" their effect on the body in case of complications. This task was solved very quickly. Already in 2015, clinical trials of monoclonal antibodies that block the direct thrombin inhibitor (dabigartan) ended. The second phase of clinical trials of the low molecular weight compound PER977, a universal antidote (for thrombin inhibitor, X factor, heparin), is currently underway. Targeted drugs have been developed that act on the tissue factor (this is the reaction that the collagen matrix responds to endothelial damage and which can cause shock due to disruption of the coagulation cascade), and a number of others. 

Very big changes are taking place in this field today. So, the success of the fight against cardiovascular diseases today is determined by two areas of research. The first is related to understanding the mechanism of atherosclerosis and the creation of a new generation of anti–lipid drugs - targeted, acting mainly on the receptor apparatus through which cholesterol metabolism is ultimately carried out at the intracellular level. The second is homeostasis management. Having learned how to manage homeostasis, we will learn how to effectively treat stroke, myocardial infarction and a number of other diseases.

Oncology. According to the forecast, humanity will defeat cancer by 2020-2030. Two types of drugs are considered promising in the treatment of cancer patients: monoclonal antibodies and kinase inhibitor. Currently, 7899 clinical trials are being conducted on the topic of "Oncology". 

Today, there is a big breakdown in the consciousness of both society and doctors: the use of a palliative approach to cancer patients should be reduced in favor of active treatment. The hope for its success is given by a huge variety of monoclonal antibodies – plus personalized therapy. For example, in breast cancer, depending on its morphology, stage, tumor size, etc., a different palette of MCA is used. Preventive drugs are being developed. For example, tamoxifen: it is recommended to take it for women if genotyping (a method that allows you to make an individual genetic passport of a person) showed a high risk of disease. A study conducted for 16 years revealed a significant decrease in new cases of breast cancer in a group of women who took this drug daily. 

Colossal funds are spent on the treatment of lung cancer. In many countries, powerful scientific centers are engaged in the search for a cure, but progress is still slow: it is possible to win only a few months of life. Here the roll is made in the creation of vaccines (antigen-specific immunotherapy). Immunomodulation is also used – with the help of monoclonal antibodies that stimulate the immune system. 

In the treatment of other types of cancer, the role of MCA is extremely high. I think if we do not establish the MKA industry in Russia, we will have very poor demographic indicators. 

Diabetes. In the very near future, we are expecting big changes in the treatment of endocrinological diseases. In endocrinology itself, a small number of drug studies are conducted (995), with the exception of insulin therapy (7889 clinical studies). Insulin is used to treat patients suffering from various forms of diabetes mellitus. "Smart" insulins are being created: they include hexamers and, if necessary, send a monomer (low molecular weight insulin) into the bloodstream. Super-prolonged (up to 42 hours) action insulins have already been introduced into clinical practice. Several companies have developed inhaled insulins, one of them is now at the stage of clinical development. Biosimilar insulin should be available by 2020.

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