Clinical Pharmacology

Zdorovye - - NEWS - Professor Yosef Karako

Professor Yosef Karako cooperates in the Department of Internal Medicine of the University Hospital "Hadassah" in Jerusalem and Tel Aviv. He heads the clinical pharmacology unit, acts as chairman of the commission acting on the basis of the Helsinki Declaration, and heads the world's only Information and Consulting Center for the Use of Drugs and Medications, Hadassah-Eshel. The main achievements of "Hadassah" in the field of pharmacogenetics, Professor Karako considers studies of anticoagulants, antiplatelet agents against antiepileptic drugs and their practical application. He considers the revision of medical treatment to be an equally important achievement. In an exclusive interview with Health magazine, Professor Karako spoke about the history of Israeli pharmacogenetics, its present and future. He also told how the rational use of drugs saves lives.

Professor Karako says: "The concept of clinical pharmacology means - the art of using medicines or competent, reasonable use of drugs. This is an independent discipline that studies the effects of drugs on the body. There was clinical pharmacology more than 50 years ago, when in many countries the requirements for medicines sharply increased. Suddenly they realized that you can not just produce drugs without more in-depth study of matter. This served as the basis for creating a new discipline. Clinical pharmacology is a very narrow specialization, which includes many sub-disciplines. Among others, we pay special attention to personalized medicine. The essence of this sub-sector boils down to the following: there is a clear observation that people do not react in an identical way, and even similar to the same dosage of the same drug. And then the experts try to understand why this is happening. If they can understand the essence and mechanism of this phenomenon, they will be able to bring the method of treatment or the drug to a specific patient in advance and achieve an optimal response. This will allow you to choose another drug or to prescribe a different dosage, etc.

Some differences in the reaction are associated with genetic factors and are part of the study of pharmacogenetics. "

Tell us, please, about the history of the development of Israeli pharmacogenetics.

- This industry has started to develop worldwide, has become a world trend. In Israel, the impetus was the repatriation of Jews from all over the world. In particular, many years ago, our scientists found among the immigrants from Kurdistan a sensitivity to boiled beans. Eating them, they decompose the red blood cells. It turned out that this ethnic group is also sensitive to certain medications because of the lack of a certain enzyme. These observations, which we have been conducting for many years, fell on an era in which it was very difficult to fully understand the meaning of this anomaly. These people knew that you can not even touch beans. Over time, scientists found a correlation with certain drugs that they could not take. At first there were 7 drugs, then this list was reduced to 5. Then the scientists only found connections, but could not explain them. Today we know the explanation. In principle, a heterogeneous population - Jews from different ethnic groups and other non-Jewish ethnoses living in Israel - served as

the impetus for the development of Israeli pharmacogenetics.

Then in the world, a number of studies were conducted, most of which fell to the share of Israeli scientists on the topic of "acetylation." This is a kind of reaction, the role of which is neutralization of drugs. When the "awakening" happened all over the world, Israel did not stand aside. So we developed our genetic and other research methods in order to take the world's leading positions in science and in its practical application in the hospital. "Hadassah" was one of the pioneers in Israeli pharmacogenetics in the study of anticoagulants and other drugs. And he is in the lead today. We make unique discoveries.

As far as I understand, one of your "chips" is anticoagulants.

- Today in many countries, particularly in Eastern Europe, old anticoagulants are quite actively used, and they avoid this problem. I'm sure that there is still using Coumadin. There, this is the main question - how to treat a patient with Coumadin. This problem is so important that many doctors are afraid to treat the patient with this drug, since the patient can show a weak or, on the contrary, an excessive reaction. And this is a serious "headache" of local doctors. This is a fairly common phenomenon in the world. With the development of genetic research, laboratories, training in the leading medical centers of the world, research and practical application of anticoagulants has quite stepped forward. Today we occupy the leading positions in the world.

- What is the mission of pharmacogenetics?

Pharmacogenetics is trying to detect genetic factors that modify a person's reaction to drug treatment. When a patient comes into my office, he does not have any external sign, on the basis of which I could argue that this will react in this way, and the other patient will be different. But the prognosis, which is a promising vision of pharmacogenetics, boils down to the fact that in the foreseeable future each patient will have an individual genetic characteristic, and when he enters the doctor's office, the doctor will be able to offer him personalized treatment in advance. In which areas of medicine is pharmacogenetics particularly applicable?

- In oncology it is impossible to treat patients without using genetic markers of the tumor. For this, a puncture is taken from the tumor, its type is determined, its mutations are genetic changes in the tumor itself and on this basis a decision is made about a method or preparation for treating each particular patient. This is the personalized treatment of the tumor.

And besides oncology?

- With respect to non-cancer patients, we are talking about individual selection of treatment in accordance with the genetic properties of the patient himself, and not a cancerous tumor. This area appeared 20 years ago, it is developing rapidly and trying to open new horizons in the proper use of medicines.

Can you give some examples?

- There is a category of drugs that suppress bone marrow. They reduce the number of white blood cells and cause the patient to be particularly sensitive and prone to infections. We know how to find people who are particularly sensitive to the effects of such drugs and, and know how to prescribe the appropriate dosage. A certain enzyme in these people, instead of decomposing the drug, because of genetic modification (in Israel, 1 out of 300 people absolutely lacks such an enzyme, 10% of it is partially absent), it can not resist it. In each of these categories of patients, it is necessary to apply such drugs in an individual way.

And how did this work before?

- Previously, people were given medicine, performed on a regular basis a clinical blood test. If, suddenly, it turned out that the patient reacted extremely sharply, then the dosage of the drug was adjusted. It's like running after ...

Trial and error method?

- Exactly. Today, as I have already noted, the approach is different: we choose the appropriate dosage or preparation in advance. I can give one more example - the use of anticoagulants - drugs that prevent the formation of blood clots. For example, coumadin or warfarin. In accordance with the properties of this drug, the required dosage is unknown. It differs individually - from one patient to another. The range can be 1:20. What to do? - Use the trial and error method: give the usual dosage, check the level of dilution of blood. All need to be brought to one level without knowing in advance the dosage for each of the patients.

And you found a solution?

- We are particularly active in studying the use of

coagulants. To date, we have learned to typify markers, which almost 70% establish a difference. This is essential.

- In biology this is a very high indicator. This allows us to predict the dosage required by a particular patient. This "game" - giving the patient a drug, analyzing his tests - tires the patient himself, and, in the process, can be accompanied by extremely high blood thinning, which creates the risk of hemorrhage. With the help of genetic markers, the entire process can be made much more accurate, quick and effective and with minimal side effects. And there are many such examples.

This is called personalized medicine, associated with pharmacogenetics - the typing of genetic markers in humans, which significantly affect its response to drug treatment. In some cases, we use this knowledge on a daily basis. This is an innovative approach. There are not many medical institutions around the world that use it. We use it within the framework of clinical research, inside Hadassah - we are interested in this. In other countries, some hospitals use this approach on an ongoing basis, in others - in extreme cases, if, suddenly, a patient arrives who is unclear about the drug. Then the doctors try to understand whether its excessive reaction or, sometimes, the lack of response, is the result of a genetic modification that makes it either extremely sensitive or causes resistance to drug treatment. This is in a nutshell about what we do.

The key concept is the word "reasonable" [use of drugs]. What can lead to irrational?

- Reasonable application is important for drugs that are subject to two conditions: first - there is a significant difference between the reactions of different people - we know, the second - the importance of lack of response or excessive reaction can be fraught with danger, lead to extremely abrupt side effects with lethal outcome in extreme cases. In those cases when both conditions are met, we should use our approach.

How, in your opinion, is the rational use of drugs expressed in public medicine?

- Everything depends on the society. And the degree of progress. I will give you a fairly radical example. In Africa, this approach is not practiced, due to the lack of resources. In the US and other countries where I passed specialization, when a patient comes to the hospital, he leaves a sample of his DNA, and biopolymers (proteins and nucleic acids - DNA and RNA) are sequenced in advance. Regardless of the reason for visiting the hospital. And today in the patient's medical card contains his genetic map. On the next visit, he will not be offered conventional treatment. The doctor will tell the patient: "So you have pneumonia. You need this drug. Let's check how effective it will be in accordance with your genetic profile, whether the chances of your reaction to treatment with this drug are high. " This is the ultimate goal of modern medicine. And this approach is used today in some US states, in some hospitals. This is the direction in which to move. Israel is a developed state, but we have limited resources, so we can talk about the rational use of drugs in those medical institutions that are interested in it, who have the necessary capabilities and understanding of the importance of the issue. For example, there is a drug that is used against recurrence of breast cancer. Tamoxifen. Its effectiveness depends on the activity of a certain enzyme, which is sometimes absent in women. It is 5% -10%. It is necessary to recognize these women and offer them an alternative to tamoxifen.

In some situations, people who have suffered a heart attack are implanted with stents that dilate the blood vessels and prevent repeated vascular thrombosis, give drugs for blood thinning - against platelets. This drug must undergo activation with an enzyme. Some people do not have this enzyme. Therefore, the chance of a recurrent myocardial infarction in a person who does not have this enzyme is very high. This drug is not active in its case. Finding such a patient and offering him an alternative drug is part of our job.

I will give you one more example. There are inactive drugs, various opiate derivatives. Take codeine for example. It is prescribed for cough and pain. His or his derivatives. It is inactive in the fight against pain and must undergo activation in the body. 5% -7% of people lack an activating enzyme. This is a genetic defect. When this happens in American hospitals, which I mentioned, such a person will not be prescribed codeine, knowing in advance that it will be ineffective in this case. He will be given another drug that does not require activation. And there are many such examples. Today, pharmacogenetics is looking for ever new situations in which it is possible to offer an alternative that will be effective, avoid side effects, increase safety, etc.

You have already mentioned the desire of modern medicine to its personalized stage. How close is Hadassah to it today?

- There are islands of personalized medicine in Hadassah: it is undoubtedly hematology and oncology. In other branches, directions is a matter of personal initiative. As, for example, in our division. Where there is personalized medicine, it does not necessarily cross all branches. I receive treatment from all over Israel and sometimes from abroad with questions about a patient who reacts or does not respond to treatment. Perhaps the reason is genetic? "And I'm checking."

It is important to note that there are other reasons that someone has side effects, and someone else does not respond to treatment at all. And these reasons are many. Therefore, it is not always important to first look for genetic factors. I'm talking about those extreme, special cases, and not about an integrated approach. It is important to understand that if, for example, all those who have not reacted at all, or those who have had an excessive reaction, turn to Hadassah, there will be many cases among them, not caused by genetic factors. These cases may be due to how they prescribed the drug, whether the diagnosis was correctly diagnosed. There may be 1000 and 1 reason. But there is in this group a subgroup in which there are people who could be recognized and explained why they do not react, or why their reaction is excessive. This is a point approach, not a general one. This is a little in touch with another issue of clinical pharmacology, not related to personalized medicine. This is due to the art of drug treatment: if you prescribe a drug to a patient that needs to be taken a certain number of times a day, and you prescribe it once a day and are surprised at the lack of reaction ... This is due to the area we are dealing with today, in an era when all databases exist in the public domain, therefore such cases should not occur, and we, as specialists, are no longer needed in these cases. Previously, our help was used in cases that today seem trivial - there were many mistakes of this kind: how to take, how much, with what you can combine, with what - no, etc. Etc.

In addition to the achievements in the field of pharmacogenetics, what else does Hadassah offer to Israeli and foreign patients?

- We have the Information and Consultation Center for the use of medicines and medicines "Hadassah-Eshel".

What is this center? How was the idea of its creation born?

- When people grow up, they accumulate diseases, and they are treated by numerous doctors. Practically, each doctor looks at the patient "at his own angle" and heals the body, on whose treatment he specializes. There is not always an all-seeing and omnidirectional eye that sees the full picture of what is happening. More than once, especially with elderly people, it happens that a patient comes to you, who is treated by a urologist, an oncologist, a hematologist, a neurologist - each within his discipline - and prescribes his medications. And the patient comes to you with a heap of medicines, while no one, never looked, did not check whether there is a logic in this or that treatment. Perhaps the drug prescribed for the disease A specialist A in general leads to the appearance of symptoms or their worsening in case of B. Our center is engaged in the revision of drugs. In the professional literature it is recommended to revise the drugs once a year. But in most cases this does not happen.

Are you talking about people who take the same drug on a continuous basis?

- That's right. This does not happen, since not only in Israel, but also in other countries, the patient's stay in the doctor's office in the clinic is 6-7 minutes. During these six minutes the doctor talks to you, checks you, "talks" with the computer ... He does not have time to start checking all the drugs prescribed by various narrow specialists. The doctor in the clinic does not revise the drugs - because of time constraints.

People come to us with various questions. The team of the center is responsible for reviewing all medications taken by the patient, and gives an opinion. Regardless of the patient's questions, the employees of the center specify general information: the medications should be taken this way, as many times a day, before or after meals, etc. A table is prepared for all the medications the patient takes, which is the first part of the answer. The patient is then provided with information on all the issues and problems found with regard to the drugs being taken. For example, the patient is informed: "The dosage of such a drug is too high. Perhaps, it is worth weighing the dose reduction. " Or: "The dosage is too low. There is a relationship between drug A and drug B that you are taking. Perhaps it is worth adjusting the dosage or choosing another drug ", etc. etc. We provide feedback to every patient who applies to us - both by phone and in writing. The patient receives a very detailed letter, we send a copy of the letter to the patient's family doctor. We have no right to change

the prescriptions and testimonies, but we inform the patient, we express our opinion. With this, the patient goes to his doctor, and as a result, almost 50% of the cases occur changes. I think this is a very important achievement. Israelis we provide the center's services absolutely free of charge.

And foreign patients can also apply to you?

- We are ready to provide our services to citizens of other countries. This, of course, is not hi-tech - it is impossible to compare pharmacogenetics with an information and consulting center. Nevertheless, this service may be in demand. Moreover, there is no need for a person to come to Israel for consultations. You can pay for it remotely and receive it remotely. This is the practice adopted in Hadassah.

It is important to note that the uniqueness of our center, which has been operating for 10 years now, is that it serves patients, not doctors. In the world there are many centers that provide information and advice to doctors, our center only helps patients.

Over the years, the Hadassah-Eshel Center, its professional team responded to 30,000 appeals. We have a colossal experience. We will gladly provide our experience and competence to citizens of other countries.

How many similar centers are there in the world?

- As I have already noted, in the world there are many centers that advise doctors and medical personnel. Our center is the first of its kind. We focus our knowledge, efforts on the patient and believe that he is a partner, an accomplice in the treatment process. The more he understands, the higher the chance that the treatment will be more effective. To date, the most important task is the patient's cooperation. Usually, the patient decides: "Since I started taking this drug, my ear hurts. So, you need to stop taking it. And, since I'm balding, I need to stop taking that drug. " Choosing for yourself what to take, and that you do not need to take, a person does damage to himself. The same applies to changing the dosage, time and number of doses per day. This is due to a misunderstanding. When a patient understands what's what, when he was given an expert opinion, with a seal, the chance of constant correct intake of the drug he needs is much higher. In Israel, such a center is only in Hadassah. There are specialists who consult privately, but in Israel not everyone can "pull" such costs.

How did it happen that only now can you turn to a Russian-speaking audience?

"We have never advertised our services before. Foreigners simply contacted us through the official Hadassah websites in Russian, English and other languages. Yes, and the center existed mainly due to donations, there was no budget for advertising. I rarely touch on the topic of the center in the media. Nevertheless, the day of my speech, we get 1000 hits. Therefore, I did not say much about it, the capacities were not the same - we would simply not have coped with the heap of calls from around the world, because the need for revision of medicines is great. Where else can the patient turn? - He will open the brochure of the manufacturer of the drug? If he reads what's written there, he will not take this medicine in his life! It's written there that he is dying or something like that ... What is he to do? - Google to help? There he will find a lot of unreliable information, which only will confuse him.

Now that the situation has changed, and the experience accumulated over 10 years has no price, we can offer our services not only to the Israelis. Our center has great potential, because there is information "hunger" in everything that concerns the revision of drug treatment.

As I have already noted, the patient does not need to come to Hadassah to get the service. Moreover, the processes of information delivery are automated. We have templates for letters that allow us to use existing knowledge.

You are right, in the era of telemedicine, you can get advice without leaving home.

- Telemedicine - allows you to give advice without checking the patient. I have many comments on this technology. But in our case we are talking about giving information. There is a process called "intejk" - obtaining primary data about the patient. As soon as this process is over, it is caused by the transfer by the patient of reliable information about medication and its diseases. This information enters the database, resulting in a fairly extensive review. By the way, we can translate and send the patient a final letter in Russian. Since more than 1 million Russian-speaking citizens live in Israel, which also need our services, the center is open to operators who speak Russian. By the way, we have collected a solid array of data on Russian-speaking Israelis, which provides us with great opportunities for research work.

How would you describe your achievements and achievements of your colleagues in the field of pharmacogenetics for the last year?

- We actively promoted the practical application of the results of our research. In many cases, we have proved that there are differences in people's reactions to medication. The biggest challenge is to apply the results of research in practice.

Why is this challenge so important?

- Because none of the factors affect one-on-one. After all, this is not only genetics, but also other components, and this is not one single gene, but also other genes. The main thing is to learn how to correctly apply our findings, the results of research in practice. It is equally important to convince end users, including doctors, that the trial and error method is already unacceptable, is inappropriate. We need to move forward, because the yard is already 21st century.

How much do you manage to persuade doctors?

"Thanks to experience and accumulated knowledge, over time we manage to convince doctors to stop useless, and often harmful," experiments on people. "Today, basically, we are engaged in applying our achievements in practice - we are introducing new methods, but we are also opening new methods that have a deterministic effect on the response to drug treatment - in various fields. For example, we conduct numerous studies of the use of coumadin and coagulants. Today, we are trying to find differences between Ethiopian Jews and Jews from other countries. And these undeniable differences allow us to create a model, explain how to apply our methods of treatment more correctly to different ethnic groups.

Now that the situation has changed, and the experience accumulated over 10 years has no price, we can offer our services not only to the Israelis. Our center has great potential, because there is information "hunger" in everything that concerns the revision of drug treatment.

As I have already noted, the patient does not need to come to Hadassah to get the service. Moreover, the processes of information delivery are automated. We have templates for letters that allow us to use existing knowledge.

You are right, in the era of telemedicine, you can get advice without leaving home.

- Telemedicine - allows you to give advice without checking the patient. I have many comments on this technology. But in our case we are talking about giving information. There is a process called "intejk" - obtaining primary data about the patient. As soon as this process is over, it is caused by the transfer by the patient of reliable information about medication and its diseases. This information enters the database, resulting in a fairly extensive review. By the way, we can translate and send the patient a final letter in Russian. Since more than 1 million Russian-speaking citizens live in Israel, which also need our services, the center is open to operators who speak Russian. By the way, we have collected a solid array of data on Russian-speaking Israelis, which provides us with great opportunities for research work.

How would you describe your achievements and achievements of your colleagues in the field of pharmacogenetics for the last year?

- We actively promoted the practical application of the results of our research. In many cases, we have proved that there are differences in people's reactions to medication. The biggest challenge is to apply the results of research in practice.

Why is this challenge so important?

- Because none of the factors affect one-on-one. After all, this is not only genetics, but also other components, and this is not one single gene, but also other genes. The main thing is to learn how to correctly apply our findings, the results of research in practice. It is equally important to convince end users, including doctors, that the trial and error method is already unacceptable, is inappropriate. We need to move forward, because the yard is already 21st century.

How much do you manage to persuade doctors?

"Thanks to experience and accumulated knowledge, over time we manage to convince doctors to stop useless, and often harmful," experiments on people. "Today, basically, we are engaged in applying our achievements in practice - we are introducing new methods, but we are also opening new methods that have a deterministic effect on the response to drug treatment - in various fields. For example, we conduct numerous studies of the use of coumadin and coagulants. Today, we are trying to find differences between Ethiopian Jews and Jews from other countries. And these undeniable differences allow us to create a model, explain how to apply our methods of treatment more correctly to different ethnic groups.

And this model can be applied to other ethnic groups, outside of Israel?

Similar problems are dealt with in the US, because there is also a very heterogeneous population. We are quite actively cooperating with American colleagues in these matters.

How much does genetics "interfere" in the effects of drugs, on the response to their use?

- In general terms, genetics can affect the drug in two ways: first, it affects the rate of decomposition of the drug - the faster it decomposes, the less effective it is. The faster the drug goes out of the body. In some patients, there is a tendency to rapid decomposition of drugs due to genetic changes in the body. Or, on the contrary: slow decomposition leads to the accumulation of the drug in the body, thereby creating toxicity. The second mechanism of genetics influences the target organ. Each drug should work in some area. To work is to enter into an interaction with some protein, and this protein has a gene, and if the gene has been modified right up to the change in the target organ, and there are many such examples, the drug will be more effective or less effective. Thus, the genetic changes in the target organ affect the patient's sensitivity to the drug. It is these two parameters that we are constantly guided by.

You mentioned oncological diseases, treatment with coumadin and other anticoagulants. What additional diseases are treated with products of

pharmacogenetics?

- These are heart diseases - various anticoagulants used against thromboses. There are drugs in the field of neurology - antiepileptic drugs. Almost in all areas you will find a "trace" of pharmacogenetics. We are trying to work in those areas in which the genetic factor is dominant, not "one of". These are the main areas.

What is the contribution of Hadassah to world pharmacogenetics?

- Mainly in the field of studying and applying anticoagulants. The relationship between genetics and anticoagulants. We take part in transnational research. Academic consortia create information for the benefit of patients in the framework of international cooperation, trying to combine all this information, create directives on the correct use of drugs. We are involved in the creation of similar documents in the field of coagulants.

Does Hadassah share its knowledge?

- This is a very dynamic industry. We constantly receive appeals from abroad and offer cooperation. Those who want to study in Hadassah, we accept with open arms. But, I'll tell you, cooperation and training today is happening with the help of this little thing (points to your computer). We are constantly in contact with our colleagues, we exchange information.

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