Immunosuppressive therapy azathioprine

The aminosalicylates, azathioprine, 6-MP, and infliximab are all viable options for treatment and maintenance of IBD in pediatric patients. Use of immunosuppressive therapy or infliximab may help reduce overall corticosteroid exposure. 

Azathioprine was originally approved by the FDA in 1968 as an adjunct immunosuppressant for use in renal transplant recipients. It is available in oral and IV dosage forms.11 Prior to the advent of cyclosporine, the combination of azathioprine and corticosteroids was the mainstay of immunosuppressive therapy. Over the past 10 years, the use of azathioprine has declined markedly due in large part to the success of the MPA derivatives, which are more specific inhibitors of T cell proliferation. 

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

When immunosuppressive therapy is administered for long periods, the patient must be monitored closely for chronic toxicity. Blood counts should be monitored routinely in patients on azathioprine because hematologic toxicity resulting in infection and bleeding may occur. Cushingoid effects, aseptic... 

The major types of drug therapy used in IBD include aminosalicylates, glucocorticoids, immunosuppressive agents (azathioprine, mercaptopu-rine, cyclosporine, and methotrexate), antimicrobials (metronidazole and ciprofloxacin), and agents to inhibit tumor necrosis factor-a (TNF-a) (anti-TNF-a antibodies). 

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. 

Echinacea (Echinacea purpurea) Uses immune system stimulant prevention/Rx of colds, flu as supportive th apy for colds chronic infxns of the resp tract lower urinary tract Action Stimulates phagocytosis cytokine production T resp cellular activity topically exerts anesthetic, antimicrobial, anti-inflammatory effects Efficacy Not established may X severity duration of URI Available forms Caps w/ powdered herb equivalent to 300-500 mg, PO, tid pressed juice 6-9 mL, PO, once/d tine 2-4 mL, PO, tid (1 5 dilution) tea 2 tsp (4 g) of powdered herb in 1 cup of boiling water Noles/SE Fever, taste p -version, urticaria, angioedema Contra w/ autoimmune Dz, collagen Dz, progressive systemic Dz (TB, MS, collagen-vascular disorders), HIV, leukemia, may interfere w/ immunosuppressive therapy Interactions t Risk of disulfiram-like reaction W/ disulfiram, metronidazole T risk of exacerbation of HIV or AIDS W/ chinacea amprenavir, other protease inhibitors X effects OF azathioprine, basiliximab, corticosteroids, cyclosporine, daclizumab, econazole vag cream, muromonab-CD3, mycophenolate, prednisone, tacrolimus EMS Possible immunosuppression... 

Azathioprine, in combination with corticosteroids, has historically been used more widely than any other drug in immunosuppressive therapy. It is classified as a... 

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. 

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. 

Nonspecific immunosuppressive therapy in an adult patient is usually through cyclosporin (35), started intravenously at the time of transplantation, and given orally once feeding is tolerated. Typically, methylprednisone is started also at the time of transplantation, then reduced to a maintenance dose. Azathioprine (31) may also be used in conjunction with the prednisone to achieve adequate immunosuppression. Whereas the objective of immunosuppression is to protect the transplant, general or excessive immunosuppression may lead to undesirable complications, eg, opportunistic infections and potential malignancies. These adverse effects could be avoided if selective immunosuppression could be achieved. Suspected rejection episodes are treated with intravenous corticosteroids. Steroid-resistant rejection may be treated with monoclonal antibodies (78,79) such as Muromonab-CD3, specific for the T3-receptor on human T-cells. Alternatively, antithymocyte globulin (ATG) may be used against both B- and T-cells. 

A 33-year-old woman took immunosuppressive therapy after renal transplantation ciclosporin (dosage adjusted to achieve blood concentrations of 120-160 ng/ml), azathioprine 1 mg/kg (frequency of administration not stated), and methylprednisolone 40 mg/ day from day 1 after transplantation, tapered weekly by 4—8 mg/day. Because of rejection symptoms at weeks 1, 4, and 7, she received three cycles of intravenous methylprednisolone 250 mg/day, each cycle lasting 5-7 days she also received a bolus dose of methylprednisolone 500 mg on day 0. Pregnancy was diagnosed on day 12 after transplantation (9 weeks after conception). At week 6 after transplantation she had a missed abortion. Curettage was performed and a partial hydatidiform mole was detected. She was discharged at week 10 and immunosuppressive therapy was tapered. 

A patient developed atorvastatin-induced severe autoimmune hepatitis and a lupus-like syndrome. Although the drug was immediately withdrawn, the disease persisted and deteriorated to a fulminant form with acute hepatic failure. There was no response to conventional immunosuppression with glucocorticoids and azathioprine. Only the introduction of intense immunosuppressive therapy, as used in solid organ transplantation, led to a complete and sustained recovery. The patient had the HLA haplotypcs DR3 and DR4, which are well-known genetic factors associated with autoimmune diseases. 

Azathioprine [a zah THIO preen] has been the cornerstone of immunosuppressive therapy over the last several decades. It has a nitroimidazoloyl side chain attached to the sulfur of 6-mercap-topurine, which is removed by non-enzymatic reduction in the body by glutathione to yield 6-mercaptopurine (6-MP). The latter is then converted to the corresponding nucleotide, thioinosinic acid (TIMP), by the salvage pathway enzyme, hypoxanthine-gua-nine phosphoribosyl transferase. The immunosuppressant effects of azathioprine are due to this fraudulent nucleotide. (See pp. 380-381 for a discussion of 6-MP s mechanism of action, resistance, pharmacokinetics, and adverse effects.) Because of their rapid proliferation in the immune response, and their dependence on de novo synthesis of purines required for cell division, lymphocytes are predominantly affected by the cytotoxic effects of azathioprine. The drug has little effect on suppressing a secondary immune response. 

Randomized controlled trials of azathioprine, methotrexate, cladribine, intravenous immunoglobulin and cyclophosphamide have not shovm definite modification to the aggressive course of PP MS (Leary and Thompson, 2005). However, these immunosuppressant therapies continue to be evaluated in patients with active aggressive MS. 

Of the toxic side effects, a major concern among clinicians is for dose-dependent bone marrow suppression (myelotoxicity), which occurs in 2. 6% of patients and can be fatal if not addressed properly. Study data suggest that a high incidence of secondary acute myeloid leukemia or brain cancer is correlated with low TPMT activity and high 6-TGN levels in children under immunosuppressive therapy. TPMT activity is subject to wide interindividual and interethnic variability due to TPMT gene polymorphism. In the Caucasian population, 0.3% of all individuals have no TPMT activity and 11% have intermediate activity, leading some to advocate additional monitoring of this activity in patients to help prevent unnecessary bone marrow toxicity from azathioprine treatment. 

Patients unresponsive to steroids are given immunosuppressive agents (azathioprine and methotrexate). These drugs have had limited success, and unfortunately, they also have a high incidence of side effects. Nonspecific therapies include oxygen supplementation, bronchodilator therapy (e.g., theophylline) if there is concomitant chronic obstructive lung disease, and prompt antibiotic therapy if an infection is associated with the disease. 

Few studies have compared splenectomy with PSE in a randomized, prospective fashion. In a series by Mozes et al. [118], 53 patients who were to later undergo renal transplant with azathioprine immunosuppressive therapy (which causes leukopenia and thrombocytopenia) were randomly assigned to a splenectomy group (25 patients) or a PSE group (28 patients). For patients in the PSE group, a mean of... 

Clinically, the most common symptoms include dyspnea and pleuritic chest pain (38). Chest radiography reveals elevated hemidiaphragms. Some improvement has been noted using inhaled p agonists and theophylUine. A more global evaluation of SLE disease activity usually leads to an increase in immunosuppressive therapy using corticosteroids, methotrexate, cyclosporine, mycophenalate, cyclophosphamide, or azathioprine, with subsequoit improvement in symptoms (38). 

Immunosuppression is the mainstay of treatment for many manifestations of BD. Glucocorticoids are the foundation of therapy but may not be sufficient for long-term immunosuppression or for severe disease involvement. Other immunosuppressive therapies, such as azathioprine (31), methotrexate (32), chlorambucil (33,34), cyclophosphamide, and penicillamine (35), have been studied in limited fashion. 

Immunosuppressants such as azathioprine or 6-mercaptopurine can be used for unresponsive patients or those who develop corticosteroid dependency. Remission may be maintained in up to 58% of patients after 5 years of treatment.1,25 Intermittent infliximab dosing (5 mg/kg IV every 8 weeks) may be used to maintain disease remission and reduce the need for corticosteroids in patients with moderate to severe UC. Colectomy is an option for patients with progressive disease who cannot be maintained on drug therapy alone. 

Patients with CD are at high risk for disease relapse after induction of remission. Within 2 years, up to 80% of patients suffer a relapse therefore, most patients should be evaluated for indefinite maintenance therapy. Maintenance of remission of CD may be achieved with oral or topical aminosalicylate derivatives, immunosuppressants (such as azathioprine, 6-mercaptopurine, and methotrexate), or infliximab. 

For immunosuppressive effects methotrexate is most frequently used in RA but also azathioprine and cyclosporin are employed. Methotrexate doses for this indication can be lower than those used for cancer chemotherapy but significant toxicity such as nausea, cytopenias and mucosal lesions, and with longterm therapy slowly progressive hepatotoxicity may still be seen. 

The present primary mode of therapy for these diseases involves the use 5-amino-salicylate (5-ASA) products. Often patients require additional medications, including corticosteroids, to help induce remission and various immune modulators, such as azathioprine, 6-mercaptopurine or methotrexate, to maintain remission. In Crohn s disease certain antibiotics, such as metronidazole and ciprofloxacin, and infliximab Remi-cade), an anti-tumor necrosis factor-a(TNFa) antibody, also have been used. The pharmacology of antibiotics, immunosuppressive drugs, and corticosteroids is discussed in Chapters 43,57, and 60, respectively. 

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