| 词条 | Mycophenolic acid |
| 释义 |
| Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 476995047 | drug_name = | IUPAC_name = (4E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoic acid | image = Mycophenolicacid.svg | width = 200 | image2 = Mycophenolic acid ball-and-stick.png | pronounce = {{IPAc-en|ˌ|m|aɪ|k|oʊ|f|ᵻ|ˈ|n|ɒ|l|ɪ|k}} | tradename = CellCept, Myfortic | Drugs.com = {{drugs.com|MTM|mycophenolic-acid}} | MedlinePlus = a601081 | licence_EU = | licence_US = mycophenol | pregnancy_AU = D | pregnancy_US = D | legal_AU = S4 | legal_CA = Rx-only | legal_UK = POM | legal_US = Rx-only | routes_of_administration = By mouth, intravenous[1] | bioavailability = 72% (sodium), 94% (mofetil)[1] | protein_bound = 82–97%[1] | metabolism = Hepatic[1] | elimination_half-life = 17.9±6.5 hours[1] | excretion = Urine (93%), faeces (6%)[1] | IUPHAR_ligand = 6832 | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 24280-93-1 | ATC_prefix = L04 | ATC_suffix = AA06 | PubChem = 446541 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB01024 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 393865 | UNII_Ref = {{fdacite|changed|FDA}} | UNII = HU9DX48N0T | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D05096 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 168396 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 866 | C=17 | H=20 | O=6 | molecular_weight = 320.34 g/mol | smiles = O=C1OCc2c1c(O)c(c(OC)c2C)C\\C=C(/C)CCC(=O)O | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C17H20O6/c1-9(5-7-13(18)19)4-6-11-15(20)14-12(8-23-17(14)21)10(2)16(11)22-3/h4,20H,5-8H2,1-3H3,(H,18,19)/b9-4+ | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = HPNSFSBZBAHARI-RUDMXATFSA-N }}{{Infobox drug | drug_name= Mycophenolate mofetil | Verifiedfields = changed | verifiedrevid = 476999346 | image = Mycophenolate mofetil2DACS.svg | width = 250px | image2=Mycophenolate mofetil ball-and-stick.png | IUPAC_name = 2-Morpholin-4-ylethyl (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoate | tradename = CellCept | Drugs.com = {{drugs.com|monograph|mycophenolate-mofetil}} | licence_EU = yes | licence_US = Mycophenolate_mofetil | legal_status = | CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 128794-94-5 | ATC_prefix = L04 | ATC_suffix = AA06 | ChEBI_Ref = {{ebicite|changed|EBI}} | ChEBI = 8764 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = C07908 | PubChem=5281078 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 1456 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00688 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 4444535 | C=23 | H=31 | N=1 | O=7 | molecular_weight=433.49474 g/mol | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C23H31NO7/c1-15(5-7-19(25)30-13-10-24-8-11-29-12-9-24)4-6-17-21(26)20-18(14-31-23(20)27)16(2)22(17)28-3/h4,26H,5-14H2,1-3H3/b15-4+ | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = RTGDFNSFWBGLEC-SYZQJQIISA-N | smiles=CC1=C(C(=C(C2=C1COC2=O)O)CC=C(C)CCC(=O)OCCN3CCOCC3)OC }} Mycophenolic acid, also called mycophenolate[2], is an immunosuppressant drug used to prevent rejection in organ transplantation. It was initially introduced as the prodrug mycophenolate mofetil (MMF, trade name CellCept) to improve oral bioavailability. More recently, the salt mycophenolate sodium (trade name Myfortic) has also been introduced. Discovered by Italian medical scientist Bartolomeo Gosio in 1893, mycophenolic acid was the first antibiotic to be synthesised in pure and crystalline form. But its medical application was forgotten until two American scientists C.L. Alsberg and O.M. Black resynthesised it in 1912, and gave its chemical name. It was eventually found to be a broad-spectrum acting drug having antiviral, antifungal, antibacterial, anticancer, and antipsoriasis properties.[3] The clinically usable drug Cellcept was developed by South African geneticist Anthony Allison and his wife Elsie M. Eugui. It was first approved in the United States in 1995 for use in kidney transplantation.[4] Medical usesMycophenolate is used for the prevention of organ transplant rejection. Mycophenolate mofetil is indicated for the prevention of organ transplant rejection in adults and renal transplant rejection in children over 2 years; whereas mycophenolate sodium is indicated for the prevention of renal transplant rejection in adults. Mycophenolate sodium has also been used for the prevention of rejection in liver, heart, or lung transplants in children older than two years.[5] It is also used for retroperitoneal fibrosis along with a number of other medications.[6] An immunosuppressant that has decreased the incidence of acute rejection in solid transplant recipients, mycophenolate is increasingly utilized as a steroid sparing treatment in autoimmune diseases and similar immune-mediated disorders including Behçet's disease, pemphigus vulgaris, refractory incomplete systemic lupus erythematosus,[7] immunoglobulin A nephropathy, small vessel vasculitides, and psoriasis.[8] Its increasing application in treating lupus nephritis has demonstrated more frequent complete response and less frequent complications[8] compared to cyclophosphamide bolus therapy, a regimen with risk of bone marrow suppression, infertility, and malignancy.[9] Further work addressing maintenance therapy demonstrated mycophenolate superior to cyclophosphamide, again in terms of response and side-effects.[9] Walsh proposed that mycophenolate should be considered as a first-line induction therapy for treatment of lupus nephritis in people without kidney dysfunction.[10] Comparison to other agentsCompared with azathioprine it has higher incidence of diarrhea, and no difference in risk of any of the other side effects.[11] Mycophenolic acid is 15 times more expensive than azathioprine.[12] The exact role of mycophenolate vs azathioprine has yet to be conclusively established. Adverse effectsCommon 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.[5] 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.[13][14]{{Nonspecific|date=March 2018}} Several cases of pure red cell aplasia (PRCA) have also been reported.[15] 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.[16] Mycophenolic acid is associated with miscarriage and congenital malformations when used during pregnancy, and should be avoided whenever possible by women trying to conceive.[17][18] GI intolerance in about 10% of patients taking mycophenolate mofetil can be overcome largely by replacing it with mycophenolate sodium or azathioprine.{{Citation needed|date= November 2014}} Blood testsAmong 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.[19][20] Mechanism of actionPurines can either be synthesized de novo using ribose 5-phosphate or they can be salvaged from free nucleotides. Mycophenolic acid is potent, reversible, non-competitive inhibitor of inosine-5′-monophosphate dehydrogenase (IMPDH), an enzyme essential to the de novo synthesis of guanosine-5'-monophosphate (GMP) from inosine-5'-monophosphate (IMP).[21] IMPDH inhibition particularly affects lymphocytes since they rely almost exclusively on de novo purine synthesis.[22] In contrast, many other cell types use both pathways, and some cells, such as terminally differentiated neurons, depend completely on purine nucleotide salvage.[23] Thus, use of mycophenolic acid leads to a relatively selective inhibition of DNA replication in T cells and B cells. PharmacologyMycophenolate can be derived from the fungi Penicillium stoloniferum, P. brevicompactum and P. echinulatum.[24] Mycophenolate mofetil is metabolised in the liver to the active moiety mycophenolic acid. It reversibly inhibits inosine monophosphate dehydrogenase,[25] 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.[26] Other cells recover purines via a separate salvage pathway and are thus able to escape the effect.[19] Mycophenolate is potent and can, in many contexts, be used in place of the older anti-proliferative azathioprine.[27] It is usually used as part of a three-compound regimen of immunosuppressants, also including a calcineurin inhibitor (ciclosporin or tacrolimus) and a glucocorticoid (prednisolone or prednisone). ChemistryMycophenolate mofetil is the morpholino{{zwnj}}ethyl 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.[28] HistoryMycophenolic 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 isolated crystals of the compound, which he successfully demonstrated as the active antibacterial compound against the anthrax bacterium.[3] This was the first antibiotic that was isolated in pure and crystalline form. But the discovery was forgotten.[29] 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.[30] 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).[31] 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 undesirable 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.[32] 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.[33][34] They synthesised a chemical variant for increased activity and reduced adverse effects.[35][36][37][38][39] They subsequently demonstrated that it was useful in organ transplantation in experimental rats.[40][41] After successful clinical trials,[42] the compound was approved for use in kidney transplant by the U.S. Food and Drug Administration on 3 May 1995,[4] and was commercialised under the brand name CellCept.[43][44] ResearchMycophenolate 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.[45] 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.{{citation needed|date=September 2012}} A combination of mycophenolate and ribavirin has been found to stop infection by and replication of dengue virus in vitro.[46][47] References1. ^1 2 3 4 {{cite web|title=CellCept|work=TGA eBusiness Services|publisher=Roche Products Pty Limited|date=13 December 2012|accessdate=25 February 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03448-3|format=PDF}} {{Immunosuppressants}}{{DEFAULTSORT:Mycophenolic Acid}}Mikofenolát-mofetil2. ^https://www.uptodate.com/contents/mycophenolate-overview-of-use-and-adverse-effects-in-the-treatment-of-rheumatic-diseases?search=mycophenolate&source=search_result&selectedTitle=2~148&usage_type=default&display_rank=5 3. ^1 {{cite journal|last1=Silverman Kitchin|first1=Jennifer E.|last2=Pomeranz|first2=Miriam Keltz|last3=Pak|first3=Grace|last4=Washenik|first4=Ken|last5=Shupack|first5=Jerome L.|title=Rediscovering mycophenolic acid: A review of its mechanism, side effects, and potential uses|journal=Journal of the American Academy of Dermatology|year=1997|volume=37|issue=3|pages=445–449|doi=10.1016/S0190-9622(97)70147-6}} 4. ^1 {{cite web|title=Risk Evaluation and Mitigation Strategy (REMS) Under Review for CellCept and Myfortic|url=http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm148735.htm|publisher=U.S. Food and Drug Administration|accessdate=23 July 2014}} 5. ^1 Rossi S, editor. 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