Mycophenolate Azathioprine

MPA derivatives have replaced azathioprine as the antiproliferative agent of choice in most organ transplant centers. The MPA derivatives generally are considered to provide a more specific immunosuppressive effect compared with azathioprine. Mycophenolate mofetil and enteric-coated mycophe-nolic acid have similar safety and efficacy data in renal transplant recipients. 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

Basiliximab is a mouse/human chimeric monoclonal antibody with specificity and high affinity for the a-subunit of the IL-2 receptor. The antibody acts as an lL-2Ra antagonist and inhibits lL-2-mediated activation and proliferation of T l)unphocytes. It is indicated for the prevention of acute organ rejection in adult and paediatric renal transplant recipients in combination with other immunosuppressive agents like cyclosporin, azathioprine, mycophenolate mofetU... 

Thervet E, Morelon E, Ducloux D, Bererhi L, Noel LEI, Janin A, Bedrossian J, Puget S, Chalopin JM, Mihatsch M, Legendre C, Kreis FI. Cyclosporine withdrawal in stable renal transplant recipients after azathioprine-mycophenolate mofetil conversion. Clin Transplant 2000 14 561-566. 

Immunosuppressive drugs can be divided into five basic categories. Corticosteroids such as methylprednisolone and prednisone are a part of virtually all immunosuppressive drug regimens. Corticosteroids block the production of IL-1 and have potent anti-inflammatory effects. Calcineurin inhibitors such as cyclosporine and tacrolimus are also used in a majority of immunosuppressive drug regimens. Calcineurin inhibitors inhibit the production and secretion of IL-2. IL-2 is involved with T-lymphocyte activation and proliferation. Antiproliferative agents such as azathioprine, mycophenolate mofetil, and sirolimus block T-lymphocyte... 

Drug Methotrexate Leflunomide Azathioprine Mycophenolate Cyclophosphamide... 

These agents generally are considered to be adjuvant to the calcineurin inhibitors or possibly sirolimus. The antiproliferatives azathioprine and the mycophenolic acid (MPA) derivatives inhibit 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... 

Systemic therapies are seldom used for mild to moderate psoriasis, and are generally reserved for patients with moderate to severe psoriasis.17 29 Oral agents include sulfasalazine, acitretin, methotrexate, cyclosporine, mycophenolate mofetil, azathioprine, tacrolimus, and hydroxyurea. Parenteral agents include the biologic response modifiers alefacept, efalizumab, etanercept, infliximab, and many others, currently at various stages of research or approval for psoriasis. 

Knight SR, Russell NK, Barcena L, Morris PJ. (2009) Mycophenolate mofetil decreases acute rejection and may improve graft survival in renal transplant recipients when compared with azathioprine A systematic review. Transplantation 87 785-794. 

Drugs that may affect mycophenolate include acyclovir, antacids, azathioprine, cholestyramine, ganciclovir, iron, probenecid, and salicylates. 

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... 

Cytotoxic agents which are exclusively used to achieve immunosuppression are azathioprine and mycophenolate mofetil, although their over all mechanism of action is similar to that of the antitumor dmgs, i.e. inhibition of lymphocyte proliferation after antigen exposure. 

Mycophenolate mofetil is used together with cyclosporine and corticosteroids for the prophylaxis of acute organ rejection in patients undergoing allogeneic renal, or hepatic transplants. Compared with azathioprine it is more lymphocyte-specific and is associated with less bone marrow suppression, fewer opportunistic infections and lower incidence of acute rejection. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolate mofetil is rapidly hydrolyzed to mycopheno-lic acid, its active metabolite. Mycophenolic acid is a reversible noncompetitive inhibitor of inosine monophosphate dehydrogenase, an important enzyme for the de novo synthesis of purines. As lymphocytes have little or no salvage pathway for purine... 

Early clinical trials indicate that mycophenolate mofetil in conjunction with cyclosporine and corticosteroids is a more effective regimen than azathioprine in preventing the acute rejection of transplanted organs. GI side effects are most common. 

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

Drug interactions In a randomized, double-blind study, Zenapax or placebo was added to an immunosuppressive regimen of cyclosporine, mycophenolate mofetil, and steroids to assess tolerability, pharmacokinetics, and drug interactions. The addition of Zenapax did not result in an increased incidence of adverse events or a change in the types of adverse events reported. The following medications have been administered in clinical trials with Zenapax with no incremental increase in adverse reactions cyclosporine, mycophenolate mofetil, ganciclovir, acyclovir, azathioprine, and corticosteroids. 

Drug interactions No formal drug-drug interaction studies have been conducted. The following medications have been administered in clinical trials with Simulect with no incremental increase in adverse reactions azathioprine, corticosteroids, cyclosporine, mycophenolate mofetil, and muromonab-CD3. 

Combined administration of azathioprine and allopurinol may result in severe pancytopenia. The dose of Azathioprine should be reduced by two-thirds when given with allopurinol. Azathioprine rarely causes liver dysfunction, frequently manifested by an isolated rise in ALT and bilirubin. With the introduction of mycophenolate mofetil, azathioprine may be relegated to a second-line anti metabolite for the prevention of graft rejection. 

Mycophenolate mofetil reduces the risk of first acute rejection by 50%. Toxicity is minor, but includes bone marrow suppression and gastrointestinal complaints. A higher incidence of CMV disease compared to azathioprine control wxs observed in the clinical trials. Recent registry studies appear to indicate that renal transplant recipients receiving mycophenolate have improved long-term outcomes. 

Azathioprine is administered to patients who do not respond to calcineurin inhibitors, sirolimus and glucocorticoids. Daily doses of 3-10 mg/kg of azathioprine are administered 1 or 2 days before renal transplantation or on the day of surgery for prophylactic therapy. Mycophenolate mofetil is increasingly used in place of azathioprine for tissue transplantation since it is less myelotoxic and causes few opportunistic infections. 

Rippin SJ, Serra AL, Marti HP, Wuthrich RP. 2007. Six year followup of azathioprine and mycophenolate mofetil use during the first six months of renal transplantation. Clin Nephrol. 67 374-380. 

Cyclosporine is an important drug in preventing rejection after kidney, hver, heart and other organ transplantation (Haberal et al., 2004). Cyclosporine usually is combined with other immunosuppressives especially glucocorticoids and either azathioprine or mycophenolate mofedl and sirolimus (Krensky et al., 2005). In renal alio transplants it has improved graft acceptance in most clinics to 95 percent. In addition to its use in transplantation cyclosporine is used for the treatment of a number of autoimmune diseases. In autoimmune diseases, as might be anticipated, cyclosporine is most effective in those which are T cell mediated. These include several forms of psoriasis, rheumatoid arthritis refractive to all other therapy, uveitis, nephrotic syndrome and type I diabetes mellitus. 

Mycophenolate mofetil has replaced azathioprine as the major antiproliferative agent used to prevent transplant rejection. It is usually used in combination with glucocorticoids and a calcineurin inhibitor (Mele and Halloran, 2000). 

Mycophenolate selectively blocks the proliferation of T and B lymphocytes and acts like azathioprine it is being evaluated in combination immrmo-suppressive regimens for organ transplantation. 

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