Mycophenolic acid was initially discovered by ItalianBartolomeo Gosio in 1893.[15][16] It was rediscovered in 1945 and 1968.[16] It was approved for medical use in the United States in 1995 following the discovery of its immunosuppressive properties in the 1990s.[14][15] It is available as ageneric medication.[17] In 2022, it was the 227th most commonly prescribed medication in the United States, with more than 1million prescriptions.[18][19]
Mycophenolate is used for the prevention oforgan transplantrejection. Mycophenolate mofetil is indicated for the prevention of organ transplant rejection in adults andkidney transplantation rejection in children over 2 years; whereas mycophenolate sodium is indicated for the prevention of kidney transplant rejection in adults. Mycophenolate sodium has also been used for the prevention of rejection inliver,heart, orlung transplants in children older than two years.[20]
Its increasing application in treatinglupus nephritis has demonstrated more frequent complete response and less frequent complications[21] compared tocyclophosphamide bolus therapy, a regimen with risk of bone marrow suppression, infertility, and malignancy.[13] Further work addressing maintenance therapy demonstrated mycophenolate superior to cyclophosphamide, again in terms of response and side-effects.[13][24] Walsh proposed that mycophenolate should be considered as a first-line induction therapy for treatment of lupus nephritis in people without kidney dysfunction.[25]
Compared withazathioprine it has higher incidence of diarrhea, and no difference in risk of any of the other side effects in transplant patients.[26] Mycophenolic acid is 15 times more expensive than azathioprine.[27]
Mycophenolic acid is associated with miscarriage and congenital malformations when used during pregnancy, and should be avoided whenever possible by women trying to get pregnant.[32][33]
Purines (including the nucleosidesguanosine andadenosine) can either be synthesizedde novo usingribose 5-phosphate or they can besalvaged from free nucleotides. Mycophenolic acid is a potent, reversible, non-competitive inhibitor ofinosine-5′-monophosphate dehydrogenase (IMPDH), an enzyme essential to thede novo synthesis ofguanosine-5'-monophosphate (GMP) frominosine-5'-monophosphate (IMP).[35] IMPDH inhibition particularly affectslymphocytes since they rely almost exclusively onde novo purine synthesis.[36] In contrast, many other cell types use both pathways, and some cells, such as terminally differentiated neurons, depend completely on purine nucleotide salvage.[37] Thus, use of mycophenolic acid leads to a relatively selective inhibition ofDNA replication inT cells andB cells.
Mycophenolate is potent and can, in many contexts, be used in place of the older anti-proliferativeazathioprine.[41] It is usually used as part of a three-compound regimen of immunosuppressants, also including acalcineurin inhibitor (ciclosporin ortacrolimus) and a glucocorticoid (e.g.dexamethasone orprednisone).[42]
Mycophenolate mofetil, aprodrug form of mycophenolic acid used in medicine
Mycophenolate mofetil is themorpholinoethylester of mycophenolic acid; the ester masks thecarboxyl group.[43] Mycophenolate mofetil is reported to have apKa values of 5.6 for the morpholino moiety and 8.5 for the phenolic group.
Mycophenolic acid was discovered by Italian medical scientistBartolomeo Gosio. Gosio collected a fungus from spoiled corn and named itPenicillium glaucum. (The species is now calledP. brevicompactum.[citation needed]) In 1893 he found that the fungus had antibacterial activity. In 1896 he isolated crystals of the compound, which he successfully demonstrated as the active antibacterial compound against theanthrax bacterium.[23] This was the first antibiotic that was isolated in pure and crystalline form. But the discovery was forgotten.[44] It was rediscovered by two American scientists C.L. Alsberg and O.M. Black in 1912, and given the name mycophenolic acid. The compound was eventually demonstrated to have antiviral, antifungal, antibacterial, anticancer, and antipsoriasis activities.[45] Although it is not commercialised as antibiotic due to its adverse effects, its modified compound (ester derivative) is an approvedimmunosuppressant drug in kidney, heart, and liver transplantations, and is marketed under the brands Cellcept (mycophenolate mofetil byRoche) and Myfortic (mycophenolate sodium byNovartis).[46]
Cellcept was developed by a South African geneticistAnthony Allison and his wife Elsie M. Eugui. In the 1970s while working at theMedical Research Council, Allison investigated the biochemical causes of immune deficiency in children. He discovered the metabolic pathway involving an enzyme,inosine monophosphate dehydrogenase, which is responsible for undesirable immune response inautoimmune diseases, as well as forimmune rejection inorgan 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 of drug research. However,Syntex liked his plans and asked him to join the company with his wife.[47] 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.[48][49] They synthesised a chemical variant for increased activity and reduced adverse effects.[50][51][52][53][54] They subsequently demonstrated that it was useful in organ transplantation in experimental rats.[55][56] After successful clinical trials,[57] the compound was approved for use inkidney transplant by theU.S. Food and Drug Administration on 3 May 1995,[58] and was sold under the brand name Cellcept.[59][60] It was approved for use in the European Union in February 1996.[11]
It was initially introduced as theprodrug mycophenolate mofetil (MMF, brand name Cellcept) to improve oralbioavailability. The salt mycophenolate sodium has also been introduced. Enteric-coated mycophenolate sodium (EC-MPS) is an alternative MPA formulation.
MMF and EC-MPS appear to be equal in benefits and safety.[61]
Preliminary data suggest thatmycophenolate mofetil might have benefits in people with multiple sclerosis. However the evidence is insufficient to determine the effects as an add‐on therapy for interferon beta-1a in people with RRMS.[66]
^abcde"Cellcept"(PDF).TGA eBusiness Services. Roche Products Pty Limited. 13 December 2012.Archived from the original on 8 July 2020. Retrieved25 February 2014.
^Remuzzi G, Lesti M, Gotti E, Ganeva M, Dimitrov BD, Ene-Iordache B, et al. (2004). "Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial".Lancet.364 (9433):503–12.doi:10.1016/S0140-6736(04)16808-6.PMID15302193.S2CID22033113.
^Anderson HA, Bracewell JM, Fraser AR, Jones D, Robertson GW, Russell JD (December 1988). "5-Hydroxymaltol and mycophenolic acid, secondary metabolites from Penicillium echinulatum".Transactions of the British Mycological Society.91 (4):649–651.doi:10.1016/S0007-1536(88)80040-8.
^Fulton B, Markham A (February 1996). "Mycophenolate mofetil. A review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in renal transplantation".Drugs.51 (2):278–98.doi:10.2165/00003495-199651020-00007.PMID8808168.S2CID46954073.
^Bentley R (October 2000). "Mycophenolic Acid: a one hundred year odyssey from antibiotic to immunosuppressant".Chemical Reviews.100 (10):3801–26.doi:10.1021/cr990097b.PMID11749328.
^Nelson PH, Eugui E, Wang CC, Allison AC (February 1990). "Synthesis and immunosuppressive activity of some side-chain variants of mycophenolic acid".Journal of Medicinal Chemistry.33 (2):833–8.doi:10.1021/jm00164a057.PMID1967654.
^Allison AC, Eugui EM (February 1996). "Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF)".Clinical Transplantation.10 (1 Pt 2):77–84.doi:10.1111/j.1399-0012.1996.tb00651.x.PMID8680053.
^Allison AC, Eugui EM (1993). "The design and development of an immunosuppressive drug, mycophenolate mofetil".Springer Seminars in Immunopathology.14 (4):353–80.doi:10.1007/bf00192309.PMID8322167.S2CID26433174.
^Allison AC, Eugui EM (December 1993). "Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil".Immunological Reviews.136 (1):5–28.doi:10.1111/j.1600-065x.1993.tb00652.x.PMID7907572.S2CID711727.
^Bechstein WO, Suzuki Y, Kawamura T, Jaffee B, Allison A, Hullett DA, et al. (1992). "Low-dose combination therapy of DUP-785 and RS-61443 prolongs cardiac allograft survival in rats".Transplant International.5 (Suppl 1): S482-3.doi:10.1111/tri.1992.5.s1.482.PMID14621853.S2CID222199749.
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