Cyclophosphamide Azathioprine

Azathioprine, cyclophosphamide, nicotinic acid, tetracycline, and vitamin A... 

Azathioprine, cyclophosphamide, methotrexate, leflunomide Lymphocyte-specific cytotoxic agents Mycophenolate mofetil... 

The treatment of collagen disease is based on immunosuppressive therapies. Immunosuppressive agents, such as corticosteroids, are widely used. In addition, cytotoxic agents (azathioprine, cyclophosphamide, and methotrexate) have also been administered. 

As indicated earlier, most cases of type 1 diabetes are caused by an autoimmune response that selectively attacks and destroys pancreatic beta cells in susceptible individuals. Therefore, drugs that suppress this autoimmune response may be helpful in limiting beta cell destruction, thereby decreasing the severity of this disease.4,41 Several immunosuppressants have been investigated as a way to potentially minimize beta cell loss from the autoimmune reactions underlying type 1 diabetes some immunosuppressants that have been considered for this situation include cyclosporine, azathioprine, cyclophosphamide, methotrexate, and glucocorticoids.11 The pharmacology of these immunosuppressants is discussed in more detail in Chapter 37. 

Mechanism of Action. Cyclosporine and tacrolimus (see below) are known as calcineurin inhibitors because they inhibit a specific protein (calcineurin) in lymphoid tissues. This inhibition ultimately suppresses the production of IL-2, a cytokine that plays a critical role in immune response by promoting the growth and proliferation of activated T lymphocytes and other immune cells, such as NK. cells (see Fig. 37—1).5,52 Thus, cyclosporine is one of the premier immunosuppressants because of its relative selectivity for T cells and its inhibition of a key mediator of the immune response (IL-2).41 This relatively specific inhibition is often advantageous when compared with other nonse-lective drugs such as azathioprine, cyclophosphamide, and glucocorticoids that inhibit virtually all the cells and chemical mediators involved in the immune response. 

Anticancer chemotherapies Azathioprine, cyclophosphamide, methotrexate etc. The cytotoxic substances affect proliferating cells and hematopoiesis as well as lymphocyte proliferation are especially sensitive. Association with risk of clinical infections clearly established. 1 % of chemotherapy patients develop an independent cancer within 10 years, 3 % within 20. Noteworthy, some anticancer drugs are now used also as immunosuppressant for autoimmune diseases... 

Cytotoxic drugs Azathioprine, cyclophosphamide Mercaptopurine Cytarabine, dactinomycin, methotrexate... 

A number of case reports describe an increase in the effects of warfarin, accompanied by bleeding in some cases, caused by an-tineoplastic regimens containing carboplatin, chlormethine, cyclophosphamide, doxorubicin, etoposide, gefitinib, gemcitabine, ifosfamide with mesna, methotrexate, procarbazine, trastuzum-ab, vincristine or vindesine. A decrease in the effects of warfarin has been seen with azathioprine, cyclophosphamide, mercaptop-urine and mitotane, a decrease in the effects of acenocoumarol has been seen with mercaptopurine, and a decrease in the effects of phenprocoumon have l n seen with azathioprine. 

Azathioprine, chloramphenicol, colchicine, cyclophosphamide, cytarabine, 5-fluorodeoxyuridine, 5-fluorouracil, hydroxyurea, mercaptopurine, metformin, methotrexate, phenobarbital, phenytoin, primidone, proton pump inhibitors, pyrimethamine, sulfasalazine, and vinblastine... 

HI. Disruption of cell metabolism with inhibition of proliferation. At dosages below those needed to treat malignancies, some cytostatics are also employed for immunosuppression, e.g., azathioprine, methotrexate, and cyclophosphamide (p. 298). The antiproliferative effect is not specific for lymphocytes and involves both T- and B-cells. 

Outcome measurements used in the evaluation of the outcome of treatment of RA with sulfasalazine, parenteral gold salts, D-penicillamine, hydroxychloroquine, prednisolone, MTX, cyclophosphamide (CyC), and azathioprine in single drug therapy cannot be compared with endpoints used in SBC-5-lMNs and biological-DMARDs combined with MTX. 

The ability of certain anticancer agents to suppress both humoral and cellular immunity has been exploited in the field of organ transplantation and in diseases thought to be caused by an abnormal or heightened immune response. In particular, the alkylating agents cyclophosphamide and chlorambucil have been used in this context, as have several of the antimetabolites, including methotrexate, mercaptopurine, azathioprine. 

Cyclophosphamide is a component of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) and other drug combinations used in the treatment of breast cancer. Cyclophosphamide in combination may produce complete remissions in some patients with ovarian cancer and oat cell (small cell) lung cancer. Other tumors in which benehcial results have been reported include non-oat cell lung cancers, various sarcomas, neuroblastoma, and carcinomas of the testes, cervix, and bladder. Cyclophosphamide also can be employed as an alternative to azathioprine in suppressing immunological rejection of transplant organs. 

Azathioprine also has applications in certain disorders with autoimmune components, most commonly rheumatoid arthritis. It is as effective as cyclophosphamide in the treatment of Wegener s granulomatosis. It has largely been replaced by cyclosporine in immunosuppressive therapy. Relative to other cytotoxic agents, the better oral absorption of azathioprine is the reason for its more widespread clinical use. 

When chemotherapeutic mercaptopurines (eg, azathioprine) are given concomitantly with allopurinol, their dosage must be reduced by about 75%. Allopurinol may also increase the effect of cyclophosphamide. Allopurinol inhibits the metabolism of probenecid and oral anticoagulants... 

Idiopathic thrombocytopenic purpura (ITP) Prednisone,1 vincristine, occasionally cyclophosphamide, mercaptopurine, or azathioprine commonly high-dose gamma globulin, plasma immunoadsorption or plasma exchange Usually good... 

Autoimmune hemolytic anemia Prednisone,1 cyclophosphamide, chlorambucil, mercaptopurine, azathioprine, high-dose gamma globulin Usually good... 

Autoreactive tissue disorders (autoimmune diseases)2 Prednisone, cyclophosphamide, methotrexate, interferon-a and -3, azathioprine, cyclosporine, infliximab, etanercept, adalimumab Often good, variable... 

Cyclophosphamide is given in patients with contraindications to azathioprine. The dose is nsuaily half of the azathio-... 

Initially, the immunosuppressive agents, such as cyclophosphamide (32), azathioprine, and methotrexate, were developed to inhibit malignant cell proliferation. The immunosuppressant activity was discovered later and these agents were then applied to treat autoimmune diseases, where patients did not respond to high doses of steroids (51). The potential side effects associated with these agents have encouraged the search for unique immunosuppressants having more acceptable safety and efficacy profiles (62). Future approaches need to incorporate early treatment with immunotherapy... 

When injected, azathioprine (Imuran) is rapidly converted to 6-mercaptopurine. The half-life of azathioprine after intravenous injection is 10 to 20 min, and that of 6-mercaptopurine is somewhat longer. The cytotoxic activity of these thiopurines is due to the conversion of mercaptopurine to 6-thiouric acid, a noncarcinostatic metabolite. This action is thought to block the excess synthesis of inosinic acid from its precursors, glutamine and phosphoribosylpyrophosphate. In addition, unlike cyclophosphamide, azathioprine is a potent anti-inflammatory substance that can cause a reduction in the number of monocytes and neutrophils at inflammatory sites. Antibody responses are also inhibited by azathioprine. Studies in humans have shown that azathioprine decreases the y-globulin and antibody levels, thus influencing IgG rather than IgM production. This makes azathioprine an effective immunosuppressant in the early phases of immune responses. It is less effective or completely ineffective in altering either the effector phase or already established reactivities. 

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