What Are Immunosuppressants?

Immunosuppressants are drugs that have an inhibitory effect on the body's immune response. They can inhibit the proliferation and function of immune response-related cells (T cells, B cells and other macrophages), and can reduce antibody immune responses. Immunosuppressants are mainly used in organ transplantation for rejection and autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, dermatomycosis, membrane glomerulonephritis, inflammatory bowel disease, and autoimmune hemolytic anemia.

Drug Name: Immunosuppressant
Foreign name: Immunosuppressant
Whether prescription drugs: prescription

Main indications: Autoimmune diseases, allergic diseases
Adverse reactions: Application of cyclophosphamide in early pregnancy may cause fetal malformations
Drug type: Chemical drugs and biological agents
Including: Cyclosporine, Rapamycin, Tacrolimus

Immunosuppressant

n. immunosuppressive agent; overview of immunosuppressor

Classification of immunosuppressants

There are five main types of commonly used immunosuppressants: (1) glucocorticoids, such as cortisone and prednisone; (2) microbial metabolites, such as cyclosporin and rattanycin; (3) anti-metabolism Substances, such as azathioprine and 6-mercaptopurine; (4) polyclonal and monoclonal anti-lymphocyte antibodies, such as anti-lymphocyte globulin and OKT3; and (5) alkylating agents, such as cyclophosphamide.

According to synthetic methods, immunosuppressants can be roughly divided into:

(1) microbial fermentation products: cyclosporin CsA, tacrolimus (FK506), rapamycin Rapamycin (RPM) and its derivatives SDZ RAD, Mizoribine (MZ), etc .; (2) completely organic Synthesis: Most of them are derived from antineoplastics, mainly including alkylating agents and antimetabolites. Including hormones (adrenocortical hormones, glucocorticoids), azathioprine (Aza), methotrexate, Leflunomide, breqinar (BQR), etc .; (3) semi-synthetic compounds: RS61443 (mycophenolate mofetil, MMF), SDZIMMl25, DeoxysPergualin (DSG, deoxyspergualin), etc .; (4) biological agents: antithymocyte globulin (ATG), antilymphocyte globulin (ALG), etc.

According to their development status, immunosuppressants can be roughly divided into:

Immunosuppressant first generation

Adrenal corticosteroids (including adrenal cortex hormones and glucocorticoids, etc., medicines include prednisone and methylprednisolone Methyprednisolone, triptolide tablets, azathioprine, anti-lymphocyte globulin, that is, anti-lymphocyte immunoglobulin The protein ALG) is representative, and its main role is to lyse immune-active cells and block cell differentiation. It is characterized by non-specificity and is a wide range of immunosuppressants. ALG has no inhibitory effect on bone marrow. The main side effects are metabolic disorders, hyperglycemia, hyperlipidemia, and hypertension. At present, the general tendency is to reduce its use or discontinuation as much as possible, but there is still controversy in the transplant community;

Immunosuppressant second generation

Cyclosporine (Cyclosporin, Cyclosporin A, Shan Diming, Cyspin, Cyclosporine Polypeptide A, Cyclosporine (Cy-A, Cs-A), Neoaldi (Neoral) and other It is represented by cromos, a cytokine synthesis inhibitor, whose main role is to block the effect of interleukin 2 (IL-2) on immune-active cells and interfere with cell activation. It is mainly lymphocytes and has relatively specificity. .CsA and FK506 have been approved by the FDA for clinical use, and the remaining drugs are still in clinical trials. Their main side effect is nephrotoxicity;

Immunosuppressant third generation

Rapamycin and Mycophenolate Mofetil (MMF) are used to inhibit PI3K-related signaling pathways, thereby suppressing the proliferation and expansion of immune cells, and have synergistic effects with second-generation preparations;

Immunosuppressant fourth generation

Represented by anti-IL-2 receptor monoclonal antibodies, FTYZO, etc., the main role is to change Cytokine earthworms, such as inhibiting TH1, enhancing TH2.

According to its clinical application, immunosuppressants are classified as: (1) preventive medication: CsA, FK506, MMF, Aza, Prednisone; (2) treatment / reverse acute rejection (rescue medication): MP (methylprednisolone) Dragon), ALG or ATG, Murononab-CD3 or CD4, MMF, FK506, etc. (3) Induced medication (delayed renal function due to acute tubular necrosis, high-risk patients, secondary transplantation, cyclosporine nephrotoxicity patients): ATG or ALG, OKT3 or OKT4, Simulect or Zenapax, etc.

Major immunosuppressant

Cyclosporin

Borel, Switzerland, in the late 1970s, discovered a circular peptide containing only 11 amino acids extracted from the fungal fermentation product, named cyclosporine (CsA), which can effectively inhibit the lymphocyte response and Hyperplasia. It has a good selective inhibitory effect on T cells, especially TH cells, while the inhibitory effect on other immune cells is relatively weak, so it has achieved good results in anti-organ transplant rejection; it is also used for autoimmunity The treatment of disease is therefore an immunosuppressant with high clinical value. After 10 years of clinical trial application research, its anti-rejection effect is stronger than other drugs and its side effects are much smaller. Therefore, it was officially registered for market application in the late 1980s. The clinical application of CsA in the past 20 years has shown amazing results. In addition to small intestine transplantation, the one-year survival rate of patients / grafts for liver, kidney, heart, heart / lung, and pancreas transplantation is 70-85%. Before that, Only 30-50%. The incidence of CsA-related neurotoxic symptoms is about 10-28%, which is a more important factor affecting the prognosis of patients. Mild to headache, limb tremor, sensory disturbance are more common, moderate to visual impairment. The incidence of severe manifestations of CsA-related neurotoxicity is extremely low. ^[1-2]

Tacrolimus

(Tacrolimus, FK506)

Tacrolimus (FK506) is a macrolide antibiotic extracted from soil fungi with strong immunosuppressive properties. Its drug strength is 10-100 times that of cyclosporine A. The effect of rejection in organ transplantation is better than cyclosporin.

In 1984, Fujisawa of Japan isolated Streptomyces spp. In Tsukuba, Osaka, Japan, and Tacrolimus was isolated by fermentation and purification. In 1989, the Starzl Organ Transplantation Center at the University of Pittsburgh put Proctor into clinical trials for the first time. In 1993, it was listed in Japan as Prograf. After being approved by the FDA in 1995, it was officially used in many countries. At present, Proxox has been widely used in the transplantation of liver, pancreas, kidney, heart, lung and other solid organs. According to the University of Pittsburgh report, in the rescue therapy ineffective with cyclosporine, the success rate of FK506 in liver transplant patients is 87%, and the success rate of kidney transplant patients is 74%. Since its launch in China in 1999, so far, the cumulative number of transplant patients who have used this product has exceeded 5,000. Basically, every transplant center and unit has applied Proclopeptide products. In 2002, the total amount of drugs used in hospitals nationwide was 340 million yuan, accounting for 5.44% of the entire immunosuppressive agent; in 2003, it was 540 million yuan, accounting for 8.17% of the entire immunosuppressive agent. This variety ranks 70th among the nation's best-selling drugs and ranks 4th in immunosuppressants. But because of its high cost, most patients are financially unaffordable, limiting their use. It is worth noting that Huachansu, which is exclusively produced by Anhui Jinchan Pharmaceutical, of this type of product. It is a pure traditional Chinese medicine preparation for treating hepatitis B and antitumor. It has been widely used in major hospitals in Beijing, Shanghai, Guangzhou and other places.

Globally, the number of transplant patients who use Proclopeptide has increased rapidly year by year, approximately 22,000 in March 1997,> 50k in December 1998,> 68,000 in December 1999> 93,000 in December 2000, and 93,000 in December 2001. > 12 million. Low in 2002. In many countries such as the United States and Europe, more than 90% of liver transplant patients are taking Proclopux, more than 60% of kidney transplant patients are taking Proclopux, and more than 90% of patients undergoing pancreas-kidney transplantation Taking Procloplast. By the end of last year, more than 150,000 transplant patients worldwide were using Procloplast products.

FK506 has only a history of more than ten years in clinical application, and its time is short. Therefore, some aspects (pharmacology and toxicology) are not fully studied. The main side effects of FK506 are nephrotoxicity, neurotoxicity, and effects on the function of the circulatory system, digestive system, respiratory system and cardiovascular system. Tacrolimus can induce diabetes (probability of about 10% to 30%), and in severe cases can cause ketoacidosis. The incidence of FK506-related hypertension was significantly lower than that of CsA. Rapamycin Compared with FK506 and CsA, rapamycin is a new immunosuppressant that does not interact with calmodulin and is considered to have no effect on blood pressure.

Macrolipid immunosuppressants (including FK506 and rapamycin) can be taken not only internally but also externally, mainly for some skin diseases such as atopic dermatitis, psoriasis, lichen planus, contact dermatitis, and baldness Spots and the like have a certain effect. In addition, the December issue of Arthritis Rheum 2003; 48: 3328-3337 published a report that the immunosuppressive agent tacrolimus alone treats active rheumatoids at a dose of 2 or 3 mg / day Arthritis (RA) appears to be safe and effective, but usually the larger the dose, the greater the improvement. ^[3-4]

Rapamycin

(Rapamycin, Sirolimus, Rapamycin, Rapamune, RAPA, RPM, Sirolimus)

Rapamycin is a lipophilic triene nitrogen-containing macrolide antibiotic immunosuppressive drug produced by Streptomyces hygroscopicus isolated from soil samples of Pacific Easler Island by the Canadian Ayerst Laboratory in 1975. An immunosuppressant for rejection of solid organ transplants. Rapamycin has a similar structure to tacrolimus, but its mechanism of action is different. The interaction between rapamycin and tacrolimus has not been thoroughly studied.

In 1989, Morris et al. Used it for anti-graft rejection for the first time and found that the effective anti-proliferative effect of peripheral blood mononuclear cells was 50 to 500 times stronger than cyclosporine (C17A), and the renal toxicity was stronger than that of cyclosporine and tacrolimus. Divisions are low. In 1999 it was used clinically. From the current clinical application, RAPA has a good anti-rejection effect, and has good synergistic effects with immunosuppressants such as cyclosporine A (CsA) and FK506. It is a good curative effect, low toxicity, and no renal toxicity New immunosuppressant.

CsA and FK506 are related to drug-induced renal dysfunction, especially in the process of delayed recovery of transplanted kidney function, the drug with renal toxicity should be avoided as far as possible in treatment. So far, no significant renal toxicity has been found in RAPA.

The combined application of RAPA and CsA, FK506, MMF, etc. have good synergistic effects. The benefits are reducing the amount of various immunosuppressive agents in the treatment plan, reducing the side effects of immunosuppressive agents, enhancing the effect of immunosuppressive .

RAPA has similar side effects as FK506. In a large number of clinical trials, the side effects were found to be dose-dependent and reversible. The therapeutic dose of RAPA has not been found to have significant renal toxicity and no gingival hyperplasia. The main toxic side effects include: headache, nausea, dizziness, nosebleeds, and joint pain.

SDZ RAD is a derivative of rapamycin. SDZ RAD has a hydroxyethyl chain at position 40, which can increase the polarity of the molecule, thereby improving oral bioavailability, and SDZ RAD can be administered at the same time as CsA, because its half-life is shorter than that of sirolimus Phase III trials have compared it with a standard protocol consisting of CsA, hormones and Snapsil, and some progress has been made.

Mycophenolate mofetil

(Mycophenolate Mofetil, MMF, RS-61443)

Mycophenolate is a semi-synthetic mycophenolate with anti-metabolism produced by a fungus belonging to the genus Penicillin. It was synthesized by Nelson, a US company Syntex, under the trade name Cellcept. The active ingredient in this medicine is mycophenolic acid (MPA). Mycophenolate is a 2-ethyl ester derivative of mycophenolate and has a strong immunosuppressive effect. ^[5-6]

Mizoribine

(Mizoribine, MZ, bredinin, bredinin)

Imidazolipin is an imidazole antibiotic obtained from the culture filtrate of soil mold Eupenicil-liumbrefeldianum by Asahi Kasei Japan. As an immunosuppressant, it has been used in clinical kidney transplantation in Japan since December 1991. Many clinical transplant centers in Japan have adopted mizoribine as a conventional immunosuppressive drug after kidney transplantation. In recent years, it has also been used as an anti-rejection drug in kidney transplantation in China. Compared with similar drugs, azathioprine, mizoribine has less hepatotoxicity and bone marrow suppression. Its main adverse reactions are gastrointestinal reactions, hematological disorders and allergic symptoms, and occasionally bone marrow suppression and acute renal failure. ^[7-8]

Cyclophosphamide Immunosuppressant Cyclophosphamide

Cyclophosphamide is also known as "cancer"; "cancer"; Andersen; cyclophosphine mustard, because it has no effect before being activated, so unlike nitrogen mustard, there is no local blistering and irritation that does not cause local necrosis or phlebitis . The gastrointestinal response is lighter than that of nitrogen mustard, which manifests as anorexia and nausea. Large doses can also cause vomiting, but it is not very serious. Hair loss is more common, and usually occurs 3 to 4 weeks after treatment, and can be regenerated after stopping treatment. Myelosuppression: Leukocyte decline is much more significant than platelet decline. Although the bone marrow suppression caused by this product is more common, it is generally easier to recover. Toxic cystitis: It is a unique toxic reaction, which can be seen in high-dose injections. Mainly due to the concentration of its hydrolysate in the bladder, causing bladder irritation and oliguria, hematuria, proteinuria and so on. Liver damage is more common and should be used with caution in patients with preexisting liver disease. A few patients may still have adverse reactions such as dizziness, restlessness, and hallucinations. Long-term application can cause testicular atrophy in men, lack of sperm, amenorrhea in women, ovarian fibrosis, and teratogens. Disable pregnant women. Occasionally, gastric ulcer, bleeding, etc. ^[9] .

Cytokine inhibitor

Everoli (Afinitor)

Everolimus is a mammalian rapamycin target protein inhibitor first developed by Novartis. It is mainly used to prevent rejection after kidney transplantation and heart transplantation. Everolimus in 2003 Approved in Europe for the treatment of rejection after organ transplantation and marketed. Everolimus is a sirolimus derivative that is effective in preventing organ transplant rejection. Its antiproliferative and immunosuppressive effects are through the formation of complexes with immune binding proteins, which interfere with the formation of regulatory proteins that control cell metabolism and proliferation. Everolimus is rapidly absorbed in local tissues, has a long residual time in cells, and has intracellular activity, which can significantly reduce neointimal hyperplasia. Everolimus has a wide range of applications and can be used to treat renal and cardiac rejection in adults, advanced renal cancer, subventricular giant cell astrocytoma with nodular sclerosis and treatment of surgically unresectable Or a progressive pancreatic neuroendocrine tumor that has spread to other parts of the body. The most common adverse reactions include upper respiratory tract infections, sinus and ear infections, mouth ulcers, and so on. ^[10]

DNA synthesis inhibitor

Azathioprine (AZA)

In 1960, 6-mercaptopurine was found to delay the rejection of skin grafts. In the following years, azathioprine was found to delay organ transplant rejection, including human kidney transplant rejection. AZA is metabolized into the active product 6-mercaptopurine, which can inhibit purine biosynthesis, inhibit DNA, RNA and protein synthesis, and inhibit lymphocyte proliferation response. AZA is classified as the first-generation immunosuppressant because it non-selectively inhibits the synthesis of purine nucleotides in the body's cells. It is well absorbed orally and completely metabolized in the body. Purine nucleotide synthesis is inhibited to a considerable extent in a variety of cells. Adverse reactions to AZA include bone marrow suppression, liver toxicity, gastrointestinal toxicity, and the risk of inducing tumors, causing agranulocytosis and decreased platelet counts. ^[11]

Active ingredients of Chinese herbal medicine for immunosuppression

Tripterygium wilfordii

Tripterygium wilfordii is a perennial vine of the genus Tripterygium spp., Which has the functions of clearing heat and detoxifying, reducing swelling, de-accumulating, killing insects, and stopping bleeding. It is by far one of the most reliable traditional Chinese medicines for immunosuppression. Most of its active ingredients are diterpenes and triterpenes, such as triptolide, triptolide, and triptolide. Due to its remarkable immunosuppressive activity and special chemical structure, scholars at home and abroad have synthesized hundreds of derivatives in order to develop new high-efficiency, low-toxic immunosuppressants. Currently, triptolide has been used in clinical practice in China, which is a relatively effective Chinese medicine immunosuppressant, which can significantly inhibit the cellular and humoral immune functions of mice without significant adverse reactions ^[12] .

other

fingolimod Immunosuppressant fingolimod

Fingolimod was a newly synthesized compound successfully developed by Japanese scholars in 1994 after the structural modification of the active ingredients of Cordyceps sinensis [7]. Its chemical structure and mechanism of action are different from the currently used immunosuppressive agents. It can reduce the number of T and B lymphocytes in peripheral blood, thereby reducing the attack on the graft, and does not affect natural killer cells, granulocytes and single cells. Nuclear cell function. Both animal experiments and clinical phase III experiments of organ transplantation have shown its powerful immunosuppressive activity and unique pharmacological effects, which can not only prevent the occurrence of rejection, but also reverse the rejection that has occurred. In addition to its own immunosuppressive activity, it is used in combination with other immunosuppressive agents (such as cyclosporine A, sirolimus, and tacrolimus) to have good synergistic effects, small adverse reactions and high bioavailability ^[13] .