Immunosuppressive agents toxicity

Immunosuppression induced by sirolimus (36) appears to be mediated by a mechanism distincdy different from that of either cyclosporin or FK-506. Sirolimus markedly suppresses IL-2 or IL-4-driven T-ceU proliferation. The preclinical studies suggest that sirolimus is a potent immunosuppressive agent in transplantation and autoimmune disease models. The clinical potential of this agent depends on its toxicity profile (80). 

The immunosuppressive agents (azathioprine and mercaptopurine) are generally limited to use in patients not achieving adequate response to standard medical therapy, or to reduce steroid doses when toxic doses are required. The usual dose of azathioprine is 2 to 3 mg/kg/day and 1 to 1.5 mg/kg/day for mercaptopurine. Up to 3 to 4 months may be required to observe a response. Starting doses are typically 50 mg/day and increased at 2-week intervals while monitoring complete blood count with differential. 

Toxicities are numerous and include nephrotoxicity, hypertension, hyperglycemia, liver dysfunction, hyperkalemia, altered mental status, seizures, and hirsutism. Cyclosporine causes very little bone marrow toxicity. While an increased incidence of lymphoma and other cancers (Kaposi s sarcoma, skin cancer) have been observed in transplant recipients receiving cyclosporine, other immunosuppressive agents may also predispose recipients to cancer. Some evidence suggests that tumors may arise after cyclosporine treatment because the drug induces TGF-B, which promotes tumor invasion and metastasis. 

Originally developed for chemotherapy, azathioprine is used today mainly as an immunosuppressive agent and rarely as an antineoplastic drug. It was introduced as an immunosuppressive agent by a British pioneer of tissue transplantation, Roy Caine. Azathioprine was used to prevent rejection after tissue transplantation as a replacement for 6-mercaptopurine because it was less toxic. In addition to tissue transplantation, it is also used for rheumatoid arthritis and Crohn s disease. Azathioprine is a prodrug which in the body is converted to its active metabolites 6-mercaptopurine and 6-thioinosinic acid. Until the discovery of cyclosporine, azathioprine in combination with steroids was the standard treatment to prevent rejection after tissue transplantation. 

This chapter addresses immunosuppressive drugs, or immunosuppressants, that are currently available to prevent the rejection of transplants or to treat specific diseases caused by an autoimmune response. Clearly, these drugs must be used very cautiously because too much suppression of the immune system will increase a patient s susceptibility to infection from foreign pathogens. Likewise, these drugs are rather toxic and often cause a number of adverse effects to the kidneys, lungs, musculoskeletal system, and other tissues. Nonetheless, immunosuppressive agents are often life-... 

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. 

IMPDH) is an enzyme involved in guanosine nucleotide synthesis required for organisms to divide and replicate. Although tiazofurin, ribavirin, and mizoribine inhibit IMPDH, they exhibit broad cellular toxicity, lack of IMPDH enzyme specificity, and sustained response in monotherapy. Immunosuppressive agents with high IMPDH enzyme specificity have been prepared to address these concerns. 

Cyclosporine is a macrolide antibiotic and has been used as an immunosuppressive agent. Cyclosporine can cause both renal and nonrenal toxicity. Clinically renal toxicity consists of four discrete syndromes which include acute reversible renal functional impairment, delayed renal allograft function, acute vasculopathy, and chronic nephropathy with interstitial fibrosis. Proximal tubular epithelium is uniquely sensitive to the toxic effect. The toxic effect is characterized by isometric cytoplasmic vacuolations (several small equally sized vacuoles in cytoplasm), necrosis with or without subsequent mineralization, inclusion bodies (giant mitochondria), and giant lysosomes. Acute vasculopathy consists of vacuolization of the arteriolar smooth muscles and endothelial cells leading to necrosis. In some cases, thrombotic microangiopathy develops, characterized by thrombosis of the renal micro vasculature. Long-term treatment with cyclosporine results in chronic nephropathy with interstitial fibrosis (Chamey et al., 2004). 

A feature of the pharmacologic action of azathioprine is its delayed onset, which may take 8-12 weeks to become apparent, possibly due to the slow accumulation of 6-TGN within the cells. The same is not necessarily true for the toxic effects of azathioprine, some of which may occur at any time during treatment (e.g., bone marrow suppression). Azathioprine appears to be a more potent immunosuppressive agent than does 6-MP itself, which may reflect differences in the pharmacodynamics and pharmacokinetics of the two compounds, as well as the relative abundance of different metabolites which are formed after their administration. Studies with hepatocytes have found that azathioprine toxicity involves depletion of reduced glutathione leading to mitochondrial injury with profound depletion of ATP and cell death by necrosis. Cell death was... 

Miller LW (2002) Cardiovascular toxicities of immunosuppressive agents. American Journal of Transplantation 2 807-818. 

NSC 109724 Asta 4942 Ifex Mitoxana and many other names) is related to cyclophosphamide, and also is an (alkylating) cytotoxic ANTICANCER and immunosuppressant AGENT. It works by interfering with cellular DNA and so inhibits cell replication. It is particularly used for testicular cancer, and is routinely used simultaneously with mesna (which reduces the urothelial toxicity), i-inositol myo-inositol. 

Monitor patients for acute toxicities secondary to conditioning regimen immunosuppressive agents. In addition, offer advice on preventive therapies for toxicities and treatment options for toxicities. 

Pain management. Chronic pain secondary to chronic GVHD needs close monitoring and drug adjustments to attain near complete pain control within 24-48 hours. Monitor patients for chronic toxicities secondary to conditioning regimen immunosuppressive agents. In addition, offer advice on preventive therapies for toxicities and treatment options for toxicities. 

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