Cyclophosphamide immunosuppressive action

Whitehouse MW, Beck FW, Droege MM, et al. 1974. Lymphocyte deactivation by (potential immunosuppressant) alkylating metabolites of cyclophosphamide. Agents Actions 4 117-124. 

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... 

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. 

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. 

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. 

The calcium channel blocker mibefradil (Posicor ) was removed from the market in 1998. The headline for the Pink Sheets article describing this action was "Posicor Withdrawal Reflects Complexity of Interaction Profile" (59). Products identified as potentially dangerous in combination with mibefradil included cardiac drugs, such as amiodarone, flecainide, and propafenone oncologic products, such as tamoxifen, cyclophosphamide, etoposide, ifosfamide, and vinblastine and the immunosuppressant medications cyclosporine and tacrolimus. The sponsor s decision to withdraw mibefradil was based on the complexity of the drug interaction information that would have to be communicated to ensure safe usage. 

A number of chemicals with demonstrable suppression of immune function produce this action via indirect effects. By and large, the approach that has been most frequently used to support an indirect mechanism of action is to show immune suppression after in vivo exposure but no immune suppression after in vitro exposure to relevant concentrations. One of the most often cited mechanisms for an indirect action is centered around the limited metabolic capabilities of immunocompetent cells and tissues. A number of chemicals have caused immune suppression when administered to animals but were essentially devoid of any potency when added directly to suspensions of lymphocytes and macrophages. Many of these chemicals are capable of being metabolized to reactive metabolites, including dime-thylnitrosamine, aflatoxin Bi, and carbon tetrachloride. Interestingly, a similar profile of activity (i.e., suppression after in vivo exposure but no activity after in vitro exposure) has been demonstrated with the potent immunosuppressive drug cyclophosphamide. With the exception of the PAHs, few chemicals have been demonstrated to be metabolized when added directly to immunocompetent cells in culture. A primary role for a reactive intermediate in the immune suppression by dimethylnitrosamine, aflatoxin Bi, carbon tetrachloride, and cyclophosphamide has been confirmed in studies in which these xenobiotics were incubated with suspensions of immunocompetent cells in the presence of metabolic activation systems (MASs). Examples of MASs include primary hepatocytes, liver microsomes, and liver homogenates. In most cases, confirmation of a primary role for a reactive metabolite has been provided by in vivo studies in which the metabolic capability was either enhanced or suppressed by the administration of an enzyme inducer or a metabolic inhibitor, respectively. 

Of particular significance to toxicology is that a chemical with a mechanism of action that requires interaction with an active metabohc process may only exert toxicity when hair growth is in an active growth phase. Exposure at other times may not elicit any response. Many cytotoxic chemicals (e.g., cancCT chemotherapeutic drugs and immunosuppressants such as cyclophosphamide) with a mechanism of action that is to kill dividing cells will produce hair loss (alopecia) as an imwanted side effect of nonselective activity. 

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