Cyclophosphamide immunosuppressive effects

Cyclophosphamide disturbs the mechanisms associated with DNA synthesis and cell proliferation by alkylating DNA in proliferating and nonproliferating cells. Its mechanisms of immunosuppressive effects are similar to its antineoplastic actions. Cyclophosphamide affects both B and T cells, but it produces more toxicity to B cells because they recover slowly. It has some unpredictable effects on T-cell-mediated immunity where it actually augments some T-cell-mediated responses however, the overall response is inhibitory. 

Cyclophosphamide is a prodrug which is converted into active metabolites in the liver. Urotoxic side effects must be anticipated they can be suppressed by the additional administration of sodium-2 mercaptoethanesulphonate. This alkylating substance has a strong immunosuppressive effect therefore, it is occasionally used to prevent graft rejection or (at a low dosage) in autoimmune hepatitis, (s. p. 686)... 

The immunosuppressive effect of cytotoxic agents, with or without the concurrent use of steroids, can result in serious infections, which are the primary cause of death in patients with minimal-change nephropathy. Other toxicities associated with cyclophosphamide include gonadal fibrosis, which results in sterility, hemorrhagic cystitis, alopecia, and a potential to develop malignancy in those on long-term treatment. Patients on chronic steroid therapy often develop growth retardation, osteoporosis, obesity, and cataracts. ... 

Cyclophosphamide itself is inaetive, but after administration it is metabolised to aetive alkylating metabolites. A study in animals found that pretreatment with chloramphenieol redueed the effects of cyclophosphamide and redueed the produetion of its aetive metabolites. Although another animal study also found a reduetion in lethality of cyclophosphamide with ehloramphenicol, the immunosuppressive effect of cyclophosphamide was unehanged. A study in 4 patients found that chloramphenicol 1 g twice daily for 12 days prolonged the mean serum half-life of a single intravenous dose of cyclophosphamide from 7.5 to 11.5 hours, but did not signifieantly affect the AUC of the metabolites. ... 

A clinical study that was started to find out if pentostatin would improve the immunosuppressive effects of cyclophosphamide, carmustine and etoposide in bone marrow transplant patients was stopped when acute and fatal cardiovascular collapse developed in the first 2 patients. Both patients had been given cyclophosphamide 800mg/m and etoposide 200 mg/m, both every 12 hours for 8 doses, and carmustine 112 mg/m daily for 4 doses. On day 3 pentostatin 4 mg/m, given over 4 hours, was added. Within 8 to 18 hours after completion of chemotherapy both patients developed confusion, hypothermia, hypotension, respiratory distress, pulmonary oedema, and eventually fatal ventricular fibrillation within 45 to 120 minutes of the first symptoms. A later study in rats similarly found that pentostatin markedly increased the acute toxicity of cyclophosphamide. The reasons for this cardiotoxicity are not understood. Neither of the 2 patients had previously shown any evidence of cardiac abnormalities. ... 

Activities of 748 (FIAC), 758 (FMAU), and related compounds against several viruses were compared, " and the combined effects of 748 (FIAC) and 758 (FMAU) with other antiviral drugs, or with cyclophosphamide (for FMAU), an immunosuppressive agent, were examined. 

For instance, the chemotherapeutic drug cyclophosphamide is in most cases immunosuppressive however, it can also induce autoimmunity (Hutchings et al., 1985). Likewise, dimethylnitrosamine, a nitrosamine detected in some foods, has been shown to have both suppressing and enhancing effects on the immune system (Yoshida et al., 1989). 

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. 

Astragalus Astragalus membranaceus) Uses Rx of resp infxns, enhancement of immune system, HF Action Root saponins t diuresis, -1- BP anti-inflammatory action related to the stimulation of macrophages, t antibody formation t T-lymphocyte proliferation Available forms Caps/tabs 1-4 g tid, PO Liq ext 4-8 mL/d (1 2 ratio) dry ext 250 mg (1 8 ratio) tid, PO Notes E Immunosuppression w/ doses >28 g Interactions t Effect OF acyclovir, anticoagulants, antihypertensives, antithrombotics, antipits, intCTleukin 2, intCTferon X effect OF cyclophosphamide EMS t Risk of bleeding... 

With chlorambucil and melphalan, although administered orally complaints of nausea and vomiting are minimal. The other toxic effects are comparable to those of cyclophosphamide. Chlorambucil has marked immunosuppressant activity. 

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. 

El-Abasy, M., M. Motobu, K. Nakamura, K. Koge, T. Onodera, O. Vainio, P. Toivanen, and Y. Hirota. Preventive and therapeutic effects of sugar cane extract on cyclophosphamide-induced immunosuppression in chickens. Int Immunopharmacol 2004 4(8) 983-990. 

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... 

Adverse Effects. Cyclophosphamide is used very cautiously as an immunosuppressant because of the possibility of severe side effects, including carcinogenic effects during long-term use. Other side effects include hematologic disorders (leukopenia, thrombocytopenia), cardiotoxicity, nephrotoxicity, and pulmonary toxicity. 

Cyclophosphamide (Cytoxan and Endoxan) is used in the treatment of Hodgkin s disease, lymphosarcoma, and other lymphomas. It is employed as a secondary drug in patients with acute leukemia and in combination with doxorubicin in women with breast cancer. A drug combination effective in the treatment of breast cancer is cyclophosphamide, methotrexate, fluorouracil, and prednisone (CMFP). Cyclophosphamide is also an immunosuppressive agent. The toxicity of cyclophosphamide causes alopecia, bone marrow depression, nausea and vomiting, and hemorrhagic cystitis. 

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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