|(what is this?)|
|(what is this?)|
黴酚酸原本是由義大利醫學家巴托羅密歐‧高西歐在1893年發現的抗生素，也是第一個人工合成與純化到結晶型態的抗生素；但是它卻被世人所遺忘，直到1912年美國科學家阿爾斯柏格與布萊克重新合成並將之命名為黴酚酸，才又得到注意。它是一個廣效性的藥物，可用於抗病毒、抗真菌、抗癌以及抗銀屑病。山喜多是由南美洲遺傳學家安東尼‧艾力森與他的妻子艾爾西‧悠桂（Elsie M. Eugui）開發出來，並於1995年5月3日通過美國食品藥品監督管理局許可用於腎臟移植。
Mycophenolate mofetil is beginning to be used in the management of auto-immune disorders such as idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), scleroderma (systemic sclerosis or SSc), and pemphigus vulgaris (PV) with success for some patients.
It is also currently being used as a long-term therapy for maintaining remission of granulomatosis with polyangiitis, though thus far, studies have found it inferior to azathioprine.[來源請求] A combination of mycophenolate and ribavirin has been found to stop infection by and replication of dengue virus in vitro.
Takayasu arteritis, ANCA-associated vasculitides and all medium vessel vasculitic conditions do respond to it. However, due to its slow onset of action, initial aggressive disease may be managed with high dose steroids and other immunosuppressants. Maintenance of remission is much better with mycophenolate, especially due to lower infection rate with this agent. After persistent remission, dose can be reduced to 1000 mg per day, but not lower as relapses more common in doses lower than this.[來源請求]
Common adverse drug reactions (≥1% of patients) associated with mycophenolate therapy include diarrhea, nausea, vomiting, joint pain; infections, leukopenia, and/or anemia reflect the immunosuppressive and myelosuppressive nature of the drug. Mycophenolate sodium is also commonly associated with fatigue, headache, cough and/or breathing issues. Intravenous (IV) administration of mycophenolate mofetil is also commonly associated with thrombophlebitis and thrombosis. Infrequent adverse effects (0.1–1% of patients) include esophagitis, gastritis, gastrointestinal tract hemorrhage, and/or invasive cytomegalovirus (CMV) infection. More rarely, pulmonary fibrosis or various neoplasia occur: melanoma, lymphoma, other malignancies having an occurrences of 1 in 20 to 1 in 200, depending on the type, with neoplasia in the skin being the most common site. Several cases of pure red cell aplasia (PRCA) have also been reported.
The U.S. Food and Drug Administration (FDA) has issued an alert that patients on mycophenolate mofetil and mycophenolic acid are at increased risk of opportunistic infections, such as activation of latent viral infections, including shingles, other herpes infections, cytomegalovirus, and BK virus associated nephropathy. In addition the FDA is investigating 16 patients that developed a rare neurological disease while taking the drug. This is a viral infection known as progressive multifocal leukoencephalopathy; it attacks the brain and is usually fatal.
GI intolerance in about 10% of patients taking mycophenolate mofetil can be overcome largely by replacing it with mycophenolate sodium or azathioprine.[來源請求]
Among the most common effects of this drug is increased blood cholesterol levels. Other changes in blood chemistry such as hypomagnesemia, hypocalcemia, hyperkalemia, and an increase in blood urea nitrogen (BUN) can occur.
Mycophenolate is derived from the fungus Penicillium stoloniferum or in P. echinulatum. Mycophenolate mofetil is metabolised in the liver to the active moiety mycophenolic acid. It reversibly inhibits inosine monophosphate dehydrogenase, the enzyme that controls the rate of synthesis of guanine monophosphate in the de novo pathway of purine synthesis used in the proliferation of B and T lymphocytes. Other cells are able to recover purines via a separate salvage pathway and are thus able to escape the effect.
Mycophenolate is potent and can, in many contexts, be used in place of the older anti-proliferative azathioprine. It is usually used as part of a three-compound regimen of immunosuppressants, also including a calcineurin inhibitor (ciclosporin or tacrolimus) and prednisolone.
Mycophenolate mofetil is the morpholinoethyl ester of mycophenolic acid; the ester masks the carboxyl group. Mycophenolate mofetil is reported to have a pKa values of 5.6 for the morpholino moiety and 8.5 for the phenolic group.
Mycophenolic acid was discovered by Italian medical scientist Bartolomeo Gosio. Gosio collected a fungus from spoiled corn and named it Penicillium glaucum. (The species is now called P. brevicompactum.) In 1893 he found that the fungus had antibacterial activity. In 1896 he could isolate the crystals of the compound, which he successfully demonstrated as the active antibacterial compound against the anthrax bacterium. This was the first antibiotic that was isolated in pure and crystalline form. But the discovery was forgotten. It was rediscovered by two American scientists C.L. Alsberg and O.M. Black in 1912, and gave the name mycophenolic acid. The compound was eventually demonstrated to have antiviral, antifungal, antibacterial, anticancer, and antipsoriasis activities. Although it is not commercialised as antibiotic due to its adverse effects, its modified compound (ester derivative) is an approved immunosuppressant drug in kidney, heart, and liver transplantations, and is marketed under the brands CellCept (mycophenolate mofetil by Roche) and Myfortic (mycophenolate sodium by Novartis).
Cellcept was developed by a South African geneticist Anthony Allison and his wife Elsie M. Eugui. In the 1970s while working at the Medical Research Council, Allison investigated the biochemical causes of immunune deficiency in children. He discovered the metabolic pathway involving an enzyme, inosine monophosphate dehydrogenase, which is responsible for undersirable immune response in autoimmune diseases, as well as for immune rejection in organ transplantation. He conceived an idea that if a molecule that could block the enzyme is discovered, then, it would become an immunosuppressive drug that could be used for autoimmune diseases and in organ transplantation. In 1981 he decided to go for drug discovery and approached several pharmaceutical companies, which turned him down one by one as he had no primary knowledge on drug research. However, Syntex liked his plans and asked him to join the company with his wife. He became Vice President for the research. In one of their experiments the Allisons used an antibacterial compound, mycophenolate mofetil, which was abandoned in clinical use due to its adverse effects. They discovered that the compound had immunosuppressive activity. They synthesised a chemical variant for increased activity and reduced adverse effects. They subsequently demonstrated that it was useful in organ transplantation in experimental rats. After successful clinical trials, the compound was approved for use in kidney transplant by the US Food and Drug Administration on 3 May 1995, and was commercialised under the brand name CellCept.
- Jasek, W (编). Austria-Codex 62nd. Vienna: Österreichischer Apothekerverlag. 2007: 1484–95. ISBN 978-3-85200-181-4 （German）.
- CellCept (PDF). TGA eBusiness Services. Roche Products Pty Limited. 13 December 2012 [25 February 2014].
- B023737100 | 藥品資訊 | 就醫指南 | 天主教耕莘醫療財團法人耕莘醫院. www.cth.org.tw. [2017-05-13] （中文（台灣））.
- CellCept®山喜多®. www.roche.com.tw. [2017-05-13] （中文（台灣））.
- Silverman Kitchin, Jennifer E.; Pomeranz, Miriam Keltz; Pak, Grace; Washenik, Ken; Shupack, Jerome L. Rediscovering mycophenolic acid: A review of its mechanism, side effects, and potential uses. Journal of the American Academy of Dermatology. 1997, 37 (3): 445–449. doi:10.1016/S0190-9622(97)70147-6.
- Risk Evaluation and Mitigation Strategy (REMS) Under Review for CellCept and Myfortic. U.S. Food and Drug Administration. [23 July 2014].
- Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3[页码请求]
- editor, Mark Harber,. Practical nephrology. 2014: 449. ISBN 9781447155478.
- Moore RA, Derry S. Systematic review and meta-analysis of randomised trials and cohort studies of mycophenolate mofetil in lupus nephritis. Arthritis Research & Therapy. 2006, 8 (6): R182. doi:10.1186/ar2093. PMC 1794528. PMID 17163990.
- Boehm I et al. Chilblain lupus erythematosus Hutchinson: successful treatment with mycophenolate mofetil. Arch Dermatol 2001;137:235 – 236 http://archderm.jamanetwork.com/article.aspx?articleid=478189
- D'Cruz DP, Khamashta MA, Hughes GR. Systemic lupus erythematosus. Lancet. February 2007, 369 (9561): 587–96. doi:10.1016/S0140-6736(07)60279-7. PMID 17307106.
- Walsh M, James M, Jayne D, Tonelli M, Manns BJ, Hemmelgarn BR. Mycophenolate mofetil for induction therapy of lupus nephritis: a systematic review and meta-analysis. Clinical Journal of the American Society of Nephrology. September 2007, 2 (5): 968–75. doi:10.2215/CJN.01200307. PMID 17702723.
- Knight SR, Russell NK, Barcena L, Morris PJ. Mycophenolate mofetil decreases acute rejection and may improve graft survival in renal transplant recipients when compared with azathioprine: a systematic review. Transplantation. March 2009, 87 (6): 785–94. doi:10.1097/TP.0b013e3181952623. PMID 19300178.
- Remuzzi G, Lesti M, Gotti E, 等. Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial. Lancet. 2004, 364 (9433): 503–12. doi:10.1016/S0140-6736(04)16808-6. PMID 15302193.
- Mimouni D, Anhalt GJ, Cummins DL, Kouba DJ, Thorne JE, Nousari HC. Treatment of pemphigus vulgaris and pemphigus foliaceus with mycophenolate mofetil. Archives of Dermatology. June 2003, 139 (6): 739–42. doi:10.1001/archderm.139.6.739. PMID 12810504.
- Diamond MS, Zachariah M, Harris E. Mycophenolic acid inhibits dengue virus infection by preventing replication of viral RNA. Virology. 2002, 304 (2): 211–21. doi:10.1006/viro.2002.1685. PMID 12504563.
- Takhampunya R, Ubol S, Houng HS, Cameron CE, Padmanabhan R. Inhibition of dengue virus replication by mycophenolic acid and ribavirin. The Journal of General Virology. July 2006, 87 (Pt 7): 1947–52. doi:10.1099/vir.0.81655-0. PMID 16760396.
- CellCept (mycophenolate mofetil) August 2009. U.S. Food and Drug Administration. August 14, 2009 [2009-08-21].
- CellCept (mycophenolate mofetil) August 2009. U.S. Food and Drug Administration. August 14, 2009 [2009-08-21].
- FDA Issues Second CellCept Warning. newsinferno.com. 2008-05-18 [2010-10-26].
- MedWatch Safety Alerts for Human Medical Products. fda.gov. May 2008 [2010-10-26].
- Drugs.com: Mycophenolic acid 副作用
- Anderson, HA; Bracewell, JM; Fraser, AR; Jones, D; Robertson, GW; Russell, JD. 5-Hydroxymaltol and mycophenolic acid, secondary metabolites from Penicillium echinulatum (PDF). Transactions of the British Mycological Society. December 1988, 91 (4): 649–651. doi:10.1016/S0007-1536(88)80040-8.
- Fulton B, Markham A. "Mycophenolate mofetil : a review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in renal transplantation." Drugs. 1996, 51(2):278-98.
- Ransom JT. Mechanism of action of mycophenolate mofetil. Therapeutic Drug Monitoring. December 1995, 17 (6): 681–4. doi:10.1097/00007691-199512000-00023. PMID 8588241.
- Dooley, MA; Jayne, D; Ginzler, EM; Isenberg, D; Olsen, NJ; Wofsy, D; Eitner, F; Appel, GB; Contreras, G; Lisk, L; Solomons, N; ALMS Group. Mycophenolate versus Azathioprine as Maintenance Therapy for Lupus Nephritis. New England Journal of Medicine. 17 November 2011, 365 (20): 1886-95. doi:10.1056/NEJMoa1014460.
- Zhang, Lixin; Demain, Arnold L. Natural Products: Drug Discovery and Therapeutic Medicine. Totowa, N.J.: Humana Press. 2005: 14. ISBN 9781592599769.
- Regueira, T. B.; Kildegaard, K. R.; Hansen, B. G.; Mortensen, U. H.; Hertweck, C.; Nielsen, J. Molecular Basis for Mycophenolic Acid Biosynthesis in Penicillium brevicompactum. Applied and Environmental Microbiology. 2011, 77 (9): 3035–3043. doi:10.1128/AEM.03015-10. PMC 3126426. PMID 21398490.
- Bentley, Ronald. Mycophenolic Acid: A One Hundred Year Odyssey from Antibiotic to Immunosuppressant. Chemical Reviews. 2000, 100 (10): 3801–3826. doi:10.1021/cr990097b. PMID 11749328.
- Watts, Geoff. Anthony Clifford Allison. The Lancet. 2014, 383 (9925): 1290. doi:10.1016/S0140-6736(14)60635-8.
- Allison, Anthony C. Immunosuppressive drugs: the first 50 years and a glance forward. Immunopharmacology. 2000, 47 (2-3): 63–83. doi:10.1016/S0162-3109(00)00186-7. PMID 10878284.
- Allison, AC; Kowalski, WJ; Muller, CD; Eugui, EM. Mechanisms of action of mycophenolic acid.. Annals of the New York Academy of Sciences. 1993, 696 (1): 63–87. doi:10.1111/j.1749-6632.1993.tb17143.x. PMID 7906496.
- Nelson, PH; Eugui, E; Wang, CC; Allison, AC. Synthesis and immunosuppressive activity of some side-chain variants of mycophenolic acid.. Journal of Medicinal Chemistry. 1990, 33 (2): 833–838. doi:10.1021/jm00164a057. PMID 1967654.
- Eugui, Elsie M.; Allison, Anthony C. Immunosuppressive Activity of Mycophenolate Mofetil. Annals of the New York Academy of Sciences. 1993, 685 (1): 309–329. doi:10.1111/j.1749-6632.1993.tb35881.x. PMID 8363235.
- Allison, AC; Eugui, EM. Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF).. Clinical Transplantation. 1996, 10 (1 Pt 2): 77–84. PMID 8680053.
- Allison, AC; Eugui, EM. The design and development of an immunosuppressive drug, mycophenolate mofetil.. Springer Seminars in Immunopathology. 1993, 14 (4): 353–80. doi:10.1007/bf00192309. PMID 8322167.
- Allison, AC; Eugui, EM. Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil. Immunological Reviews. 1993, 136 (1): 5–28. doi:10.1111/j.1600-065x.1993.tb00652.x. PMID 7907572.
- Bechstein, WO; Suzuki, Y; Kawamura, T; Jaffee, B; Allison, A; Hullett, DA; Sollinger, HW. Low-dose combination therapy of DUP-785 and RS-61443 prolongs cardiac allograft survival in rats. Transplant International. 1992, 5 (Suppl 1): S482–3. PMID 14621853.
- Kawamura, T; Hullett, DA; Suzuki, Y; Bechstein, WO; Allison, AM; Sollinger, HW. Enhancement of allograft survival by combination RS-61443 and DUP-785 therapy. Transplantation. 1993, 55 (4): 691–4; discussion 694–5. doi:10.1097/00007890-199304000-00001. PMID 8475537.
- Taylor, DO; Ensley, RD; Olsen, SL; Dunn, D; Renlund, DG. Mycophenolate mofetil (RS-61443): preclinical, clinical, and three-year experience in heart transplantation. The Journal of Heart and Lung Transplantation. 1994, 13 (4): 571–82. PMID 7947873.
- Donlon, Diane M. New Agent to Prevent Kidney Transplant Rejection Now Available. Stanford University. 15 June 1995 [23 July 2014].
- CellCept registry data demonstrated superior long-term organ transplant outcomes. Roche.com. F. Hoffmann-La Roche Ltd. [23 July 2014].