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"Anti rejection drugs" are not far away from us

Date:2020-03-03

Anti rejection drugs can only be used for a long time


Looking back on the development of medicine in the 20th century, organ transplantation is definitely one of the most important progress. Now in the treatment of some end-stage diseases, organ transplantation has become the last "trump card" in the hands of clinicians. Thanks to this technology, many critically ill patients are lucky to get rid of persistent diseases, achieve long-term survival, and finally return to society as normal people.


According to statistics, the 10-year survival rate of kidney transplant patients in China has exceeded 60%, and the 5-year survival rate of liver transplant patients has reached 50%. Recently, the author interviewed Beijing Friendship Hospital kidney transplantation center, the earliest center of kidney transplantation in China, which is also one of the largest kidney transplantation centers in China. The director of the center is the discipline leader of Beijing Institute of Urology and the field professor of Urology director of friendship hospital. Professor Tian pointed out that at present, the level of organ transplantation technology has become increasingly mature, which is the embodiment of the comprehensive development of medical basis and clinical level, in which the development of immunosuppression technology plays a crucial role.


Rejection is fast and slow


Just as a country must have its army and police, our body also has a set of developed immune system. Only when it operates normally, can we resist the invasion of external bacteria and viruses, and remove the aging or malignant cells in the body. However, because the working principle of the immune system is to "eliminate the dissident", it becomes a "stumbling block" for the survival of transplanted organs - unless it comes from the siblings of the same egg twin, once other organs are implanted into our body, it will become the target of "rejection" of immune cells. However, how quickly the rejection starts and how serious the injury is depends on the distance between the transplanted organ and us.


Among them, the most urgent and violent reaction is called "hyperacute rejection", which usually occurs within 24 hours after transplantation. It is generally believed that this rejection is mainly due to the serious incompatibility between ABO blood group and HLA. As there is no effective treatment at present, once the super acute rejection occurs, it will eventually lead to the failure of transplantation.


If the donor of the organ and the recipient of the organ match the ABO blood group, the HLA match degree is also high, and the super acute rejection usually does not occur, but within days to months after transplantation, some patients will still face another kind of rejection, that is, acute rejection, when a large number of immune cells will still attack the transplanted organ in groups. "The good thing is that by increasing the dosage of immunosuppressants, or adding more powerful drugs, the vast majority of acute rejection will be relieved, and the normal operation of the transplanted organ will not be affected in the future." Said the field professor.


Professor Ye Ye further pointed out that there is also a kind of chronic rejection, which usually occurs months to years after organ transplantation. There are still many doubts about this kind of rejection in the transplantation community, and the corresponding prevention and treatment methods are still mainly immunosuppressants. So, how to use immunosuppressive drugs and how to use them?


Three arrows in a row inhibit immune response


"The so-called immunosuppressant is a drug that has an inhibitory effect on the immune response. It can inhibit the proliferation and function of immune cells (such as T cells and B cells)." "In order to achieve the overall inhibition of rejection, we need to combine the existing immunosuppressive drugs. At present, the most commonly used combination includes three types of drugs, which we call" three arrows in one shot "


The oldest of the three arrows is glucocorticoid. As a non-specific immunosuppressant, glucocorticoids can inhibit many aspects of immune response.


The second arrow is calmodulin inhibitors, represented by cyclosporine A and tacrolimus, which play an important role in the inhibition of rejection. Cyclosporine A can be regarded as a milestone in the history of organ transplantation. After its appearance, it has increased the survival rate of liver transplantation from 30% to 70%. Its function is to inhibit the synthesis of cytokine IL-2, which is the key link of immune cell activation.


The third arrow has only been used in clinic for more than ten years. It is called mycophenolic acid. Because of its less hepatorenal toxicity and relative safety, it plays an increasingly important role in anti rejection. They have synergistic effect with cyclosporine A and other drugs, and further strengthen the anti immune effect on the premise of sufficient dose.


"The combination of the above three drugs can greatly reduce the risk of immune rejection and make the transplanted organ and the recipient's immune system safe for a long time. It can be said that after nearly half a century's development, the effectiveness of anti rejection drugs has been very good. "


Help patients stick to medication


Nevertheless, clinicians still have some "new problems" to solve. In the late 1970s, it was remarkable that the one-year survival rate of kidney transplantation reached 50%. Now some patients have survived 40 years after transplantation. How to suppress rejection for a long time is still a serious challenge. In fact, it's a problem just to make sure the patients keep taking it. In 2006, the first face changing operation was carried out in China. Media reports that the patient died at the end of last year have a lot to do with his failure to adhere to immunosuppressive drugs.


Clinically, the degree to which patients receive treatment according to their doctor's orders is called "compliance". However, there are many factors that affect the compliance of patients who take anti rejection drugs for a long time. In addition to cost and inconvenience, side effects are the most important factors.


People often say "it's three poisons of medicine". Professor Ye Ye pointed out that despite years of development, anti rejection drugs have not only been quite mature in terms of effectiveness, but also significantly reduced side effects, but the latter will still become a major incentive for patients to discontinue treatment, for example, glucocorticoids may cause metabolic disorders, hyperglycemia, hyperlipidemia and hypertension.


Even in the anti rejection drugs, the relatively safe mycophenolic acid drugs also have "defects". For example, some patients will have abdominal pain, diarrhea and other gastrointestinal symptoms after taking medicine, and a few patients even have serious infection during taking medicine. Once the above situation occurs, it will affect the compliance of the patients, resulting in the reduction or discontinuation of mycophenolic acid drugs, and the loss of such drugs The protection of transplanted organs ultimately affects the efficacy of drugs.


To this end, the pharmaceutical industry is trying to develop new immunosuppressive drugs to minimize the side effects. According to Professor Ye Ye, at present, a new type of "mycophenolate sodium enteric coated tablet" (trade name: MIFF / myfortic) has been approved by FDA of the United States and Europe and officially launched. The drug does not dissolve in the acid condition of the stomach, and the active ingredient mycophenolic acid (MPa) is released after reaching the small intestine. The unique advantages of dosage form reduce the adverse reactions of the gastrointestinal tract, improve the tolerance and compliance of the drug, Compared with the traditional mycophenolic acid (mycophenolate mofetil), the reduction and discontinuation of mycophenolate mofetil significantly reduced, which ensured that the transplanted organ had sufficient mycophenolic acid protection. In addition, clinical data also showed that the incidence of severe infection was significantly reduced during the treatment period.


Field professor pointed out that after transplantation, only long-term regular medication can inhibit their own rejection, which is the so-called long "eat" to long-term safety. With the mature surgical technology and the positive effect of anti rejection drugs, how to improve the compliance of patients is becoming a key factor for the long-term survival of patients.


How to make patients take drugs, how to help them form the habit of taking drugs regularly, and how to reduce the side effects of drugs through the development or improvement of drugs are still the focus of the future transplant industry. Meconol sodium, with its unique intestinal solvent type, improves the compliance and tolerance of the drug, ensures the sufficient organ protection dose of mycophenolic acid, and is of great benefit to their long-term survival.

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