Mofetil mycophenolate

FK-506 (37) interferes with IL-2 synthesis and release and has a cyclosporin-like profile, but is considerably more potent in vitro. IC q values are approximately 100-fold lower. This neutral macroHde suppresses the mixed lymphocyte reaction T-ceU proliferation generation of cytotoxic T-ceUs production of T-ceU derived soluble mediators, such as IL-2, IL-3, and y-IFN and IL-2 receptor expression (83). StmcturaHy, FK-506 is similar to sirolimus. Mycophenolate mofetil (33), brequinar (34), and deoxyspergualin are in various phases of clinical evaluation. Identification of therapeutic efficacy and safety are important factors in the deterrnination of their utiUty as immunosuppressive agents. 

Mycophenolate mofetil 0.5-1.5 g by mouth twice Myelosuppression, gastrointestinal 250 mg = 3.11... 

APCs, antigen-producing cells MMF, mycophenolate mofetil OKT-3, muronomab-CD3. (Adapted from Mueller XM. Drug immunosuppressive therapy for adult heart transplantation I. Immune response to allograft and mechanism of action of immunosuppressants. Ann Thorac Surg 2004 77 354-362, with permission.)... 

FIGURE 52-2. Center-specific protocols may use RATG, an IL-2RA, or no induction therapy. In any situation, patients receive IV methylprednisolone prior to, during, or immediately following the transplant operation. The patient then will begin the maintenance immunosuppressive regimen. The center-specific protocol will specify which calcineurin inhibitor (cyclosporine or tacrolimus) is used in combination with mycophenolate mofetil or sirolimus with or without steroids. Patients then are monitored for signs and symptoms of rejection. 

BUN, blood urea nitrogen Cl, calcineurin inhibitor CSA, cyclosporine IL-2RA, interleukin 2 receptor antagonist LFTs, liver function tests MMF, mycophenolate mofetil OKT-3, muronomab-CD3 RATG, rabbit antithymocyte immunoglobulin ... 

Mycophenolate mofetil was approved by the FDA in 1995, and enteric-coated mycophenolic acid was approved in 2004. Both agents are considered to be adjunctive immunosuppressants. Mycophenolic acid acts by inhibiting inosine monophosphate deydrogenase, a vital enzyme in the de novo pathway of purine synthesis. Inhibition of this enzyme prevents the proliferation of most cells that are dependent on the de novo pathway for purine synthesis, including T cells.7,11,26-28... 

Mycophenolate mofetil is available in 250 mg capsules and 500 mg tablets, an oral suspension (100 mg/mlL, in cherry syrup), and an injectable.11 Usual doses of mycophenolate mofetil range from 1000 to 3000 mg/day in two to four divided doses. The conversion between oral and IV mycophenolate mofetil is 1 1. Enteric-coated mycophenolic acid is available in 180 and 360 mg tablets. For conversion between mycophenolate mofetil and enteric-coated MPA, 1000 mg mycophenolate mofetil is equivalent to 720 mg enteric-coated MPA.26,29 The recommended starting dose of enteric-coated mycophenolic acid is 720 mg given twice daily.11 It appears that conversion of mycophenolate mofetil to enteric-coated mycophenolic acid is safe, but more studies are needed to determine the exact role of enteric-coated MPA in the immunosuppressive armamentarium. Mycophenolic acid trough concentrations can be monitored, but they are not recommended routinely. 

The most common adverse events associated with these agents are GI (18% to 54%, namely, diarrhea, nausea, vomiting, and gastritis) and myelosuppression (20% to 40%).7,11,26-28 Despite its enteric coating, to date, mycophenolic acid has shown no significant benefit in terms of reduction in GI adverse events compared with mycophenolate mofetil in renal transplant recipients.26... 

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. 

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... 

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... 

Most of the interactions with mycophenolate mofetil and enteric-coated MPA are due to reductions in intestinal absorption. Aluminum-, magnesium-, or calcium-containing antacids decrease the peak level and overall exposure of MPA from either of the preparations.11 If a patient requires liquid antacids, they should be administered at least 4 hours before... 

Tacrolimus 3 mg by mouth twice a day Mycophenolate mofetil 1000 mg by mouth twice a day Prednisone 10 mg by mouth once a day Bactrim SS 1 tablet daily... 

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. 

Mycophenolate mofetil in doses of 1 to 1.5 g twice daily (maximum dose 3 g/day) is effective as adjunctive therapy in patients with resistant psoriasis on cyclosporine.29,38 As monotherapy, there may be some benefit in patients with moderate psoriasis and psoriatic arthritis, but not in severe psoriasis.29... 

Prophylaxis of acute GVHD for nonmyeloablative preparative regimens is varied, but a calcineurin inhibitor with either methotrexate or mycophenolate mofetil is used.6 To date, trials evaluating the optimal acute GVHD prophylaxis regimen have not been conducted. 

Mycophenolate mofetil (CellCept) inhibits DNA and RNA synthesis and has been shown to have a specific lymphocyte antiproliferative effect. Although not FDA approved for this indication, oral mycophenolate mofetil appears effective in the treatment of moderate to severe plaque psoriasis. The usual dose is 500 mg orally four times a day, up to a maximum of 4 g/day. Common adverse effects include GI toxicity (diarrhea, nausea, vomiting), hematologic effects (anemia, neutropenia, thrombocytopenia), and viral and bacterial infections. Lymphoproliferative disease or lymphoma has been reported. 

A phase II clinical study of FTY720 in de novo renal transplant patients showed superior efficacy of FTY720 compared to mycophenolate mofetil, if combined with cyclosporine A and steroids [57], In a 1 year, multicentre,... 

Shipkova, M., Armstrong, V.M., Wieland, E., Niedmann, P.D., Schiitz, E., Brenner-WeiC, G., Voihsel, M., Braun, E. and Oellerich, M., Identification of glucoside and carboxyl-linked glucuronide conjugates of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil. Brit. J. Pharmacol., 1999,126, 1075. 

Bardsley-Elhot A, Noble S, Foster RH. (1999) Mycophenolate mofetil A review of its use in the management of solid organ transplantation. Bio Drugs 12 363 10. 

Moore RA, Derry S. (2006) Systematic review and meta-analysis of randomised trials and cohort studies of mycophenolate mofetil in lupus nephritis. Arthritis Res Ther 8 R182. 

Walsh M, James M, Jayne D, Tonelli M, Manns BJ, Hemmelgam BR. (2007) Mycophenolate mofetil for induction therapy of lupus nephritis A systematic review and meta-analysis. Clin J Am Soc Nephrol 2 968-975. 

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. 

Mimouni D, Anhalt GJ, Cummins DL, Kouba DJ, Thome JE, Nousari HC. (2003) Treatment of pemphigus vulgaris and pemphigus foliaceus with mycophenolate mofetil. Arch Dermatol 139 739-742. 

Ransom JT. (1995) Mechanism of action of mycophenolate mofetil. Therap Drug Monitor 17 681-684. 

Salvador M, Holzer H, de Mattos A, Solhnger H, Ams W, Oppenheimer E, Maca J, Hall M. (2004) Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 4 231-236. 

Behrend M, Braun F. (2005) Enteric-coated mycophenolate sodium Tolerability profile compared with mycophenolate mofetil. Drugs 65 1037-1050. 

Hale MD, Nicholls AJ, Bullingham RES, Hene R, Hoitsma A, Squifflet J-P, Weimar W, Vanrenterghem Y, Van de Woude FJ, Verpooten GA. (1998) The pharmacokinetic-pharmacodynamic relationship for mycophenolate mofetil in renal transplantation. Clin Pharmacol Ther 64 672-683. 

Perez-Aytes A, Ledo A, Boso V, Carey JC, Castell M, Vento M. (2010) Immunosuppressive drugs and pregnancy Mycophenolate mofetil embryopathy. NeoReviews 11 578-589. 

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