草稿:黴酚酸

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黴酚酸
Mycophenolicacid.svg
Mycophenolic acid ball-and-stick.png
系统(IUPAC)命名名称
(4E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoic acid
临床数据
读音 /ˌmkfˈnɒlɪk/
商品名 CellCept, Myfortic
Drugs.com Multum消费者信息
MedlinePlus a601081
医疗法规
妊娠分级
  • AU: D
  • US: D (证据表明有风险)
给药途径 Oral,
intravenous[1]
合法狀態
合法状态
药代动力学数据
生物利用度 72% (sodium),
94% (mofetil)[2]
蛋白结合度 82–97%[2]
代谢 Hepatic[2]
生物半衰期 17.9±6.5 hours[2]
排泄 Urine (93%),
faeces (6%)[2]
识别信息
CAS注册号 24280-93-1 ✓
ATC代码 L04AA06
PubChem CID 446541
IUPHAR/BPS英语IUPHAR/BPS 6832
DrugBank DB01024 ✓
ChemSpider 393865 ✓
UNII HU9DX48N0T ✗
KEGG D05096 ✓
ChEBI CHEBI:168396 ✓
ChEMBL英语ChEMBL CHEMBL866 ✓
化学信息
化学式 C17H20O6
摩尔质量 320.34 g/mol
 ✗✓ (what is this?)英语Wikipedia:WikiProject_Chemicals/Chembox_validation  (verify)
Mycophenolate mofetil
Mycophenolate mofetil2DACS.svg
Mycophenolate mofetil ball-and-stick.png
系统(IUPAC)命名名称
2-Morpholin-4-ylethyl (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoate
临床数据
商品名 CellCept
Drugs.com Monograph
医疗法规
识别信息
CAS注册号 128794-94-5 ✓
ATC代码 L04AA06
PubChem CID 5281078
DrugBank DB00688 ✓
ChemSpider 4444535 ✓
KEGG C07908 ✓
ChEBI CHEBI:8764 ✗
ChEMBL英语ChEMBL CHEMBL1456 ✓
化学信息
化学式 C23H31NO7
摩尔质量 433.49474 g/mol
 ✗✓ (what is this?)英语Wikipedia:WikiProject_Chemicals/Chembox_validation  (verify)

黴酚酸(英文:Mycophenolic acid 或 mycophenolate),為器官移植手術使用來預防排斥作用的免疫抑制藥物。它抑制T細胞B細胞生長所需的酵素。早期黴酚酸是以黴酚酸酯的前體藥物之型態來販售,以提升它的生物利用度。 近年來,它也以黴酚酸鈉(睦體康[3])的形式販售,而黴酚酸酯在市面上也可以買到(山喜多[4])。

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[5]。山喜多是由南美洲遺傳學家安東尼‧艾力森英语Anthony Clifford Allison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[6]

醫療用途[编辑]

黴酚酸主要用於預防器官移植排斥。對於預防成人器官移植排斥與預防兩歲以上兒童腎臟移植排斥,可用黴酚酸酯;而黴酚酸鈉則可用於預防成人與兩歲以上腎臟、肝臟心臟、心肺、肺臟移植排斥[7],也可以與其他藥物並用來治療腹膜後纖維化[8]

除了用來預防器官移植受贈者發生急性排斥作用以外,近年來黴酚酸酯用來治療如貝賽特氏症、尋常型天皰瘡、頑固性不全系統性紅斑狼瘡、免疫球蛋白A腎病、小血管炎、銀屑病自體免疫疾病的案例也愈來愈多[9][10]

在狼瘡性腎炎的治療上,因為相比於環磷酰胺丸劑,黴酚酸少了副作用(骨髓抑制、不育、惡性化)[11][9]且病人反應較佳,因此採用黴酚酸治療狼瘡性腎炎有增加的趨勢。在持續的治療上,黴酚酸的表現也較環磷酰胺為佳[11]。 沃爾什等人甚至認為在病人的沒有喪失腎功能的情況下,應該先使用黴酚酸來治療狼瘡性腎炎[12]

與其他藥物比較[编辑]

硫唑嘌呤相比,黴酚酸比較容易造成腹瀉[13],而且價格是硫唑嘌呤的十五倍[14];因此到底要不要使用黴酚酸來取代硫唑嘌呤尚無結論。

未來可能的用途[编辑]

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英语pemphigus vulgaris (PV) with success for some patients.[15]

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英语viral replication of dengue virus in vitro.[16][17]

Takayasu arteritis, ANCA-associated vasculitides英语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]

副作用[编辑]

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英语thrombophlebitis and thrombosis. Infrequent adverse effects (0.1–1% of patients) include esophagitis英语esophagitis, gastritis, gastrointestinal tract hemorrhage, and/or invasive cytomegalovirus (CMV) infection.[7] More rarely, pulmonary fibrosis英语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.[18][19] Several cases of pure red cell aplasia英语pure red cell aplasia (PRCA) have also been reported.[20]

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英语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.[21]

Mycophenolic acid is associated with miscarriage and congenital malformations when used during pregnancy, and should be avoided whenever possible by women trying to conceive.[22][23]

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]

血液試驗[编辑]

Among the most common effects of this drug is increased blood cholesterol levels. Other changes in blood chemistry such as hypomagnesemia, hypocalcemia英语hypocalcemia, hyperkalemia, and an increase in blood urea nitrogen (BUN) can occur.[1][24]

藥理學[编辑]

Mycophenolate is derived from the fungus Penicillium stoloniferum英语Penicillium stoloniferum or in P. echinulatum英语Penicillium echinulatum.[25] Mycophenolate mofetil is metabolised in the liver to the active moiety mycophenolic acid. It reversibly inhibits inosine monophosphate dehydrogenase英语inosine monophosphate dehydrogenase,[26] 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.[27] Other cells are able to recover purines via a separate salvage pathway and are thus able to escape the effect.[1]

Mycophenolate is potent and can, in many contexts, be used in place of the older anti-proliferative azathioprine.[28] It is usually used as part of a three-compound regimen of immunosuppressants, also including a calcineurin inhibitor (ciclosporin or tacrolimus英语tacrolimus) and prednisolone.

化學[编辑]

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.[29]

歷史[编辑]

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英语Penicillium 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.[5] This was the first antibiotic that was isolated in pure and crystalline form. But the discovery was forgotten.[30] 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.[31] 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英语Novartis Foundation).[32]

Cellcept was developed by a South African geneticist Anthony Allison英语Anthony Clifford Allison and his wife Elsie M. Eugui. In the 1970s while working at the Medical Research Council英语Medical Research Council (United Kingdom), Allison investigated the biochemical causes of immunune deficiency in children. He discovered the metabolic pathway involving an enzyme, inosine monophosphate dehydrogenase英语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英语Syntex liked his plans and asked him to join the company with his wife.[33] 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.[34][35] They synthesised a chemical variant for increased activity and reduced adverse effects.[36][37][38][39][40] They subsequently demonstrated that it was useful in organ transplantation in experimental rats.[41][42] After successful clinical trials,[43] the compound was approved for use in kidney transplant英语Kidney transplantation by the US Food and Drug Administration on 3 May 1995,[6] and was commercialised under the brand name CellCept.[44][45]

參考文獻[编辑]

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  18. ^ http://reference.medscape.com/drug/cellcept-myfortic-mycophenolate-343209#4
  19. ^ http://www.bnf.org
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  28. ^ 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. 
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  35. ^ 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. 
  36. ^ 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. 
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  38. ^ Allison, AC; Eugui, EM. Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF).. Clinical Transplantation. 1996, 10 (1 Pt 2): 77–84. PMID 8680053. 
  39. ^ 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. 
  40. ^ 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. 
  41. ^ 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. 
  42. ^ 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. 
  43. ^ 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. 
  44. ^ Donlon, Diane M. New Agent to Prevent Kidney Transplant Rejection Now Available. Stanford University. 15 June 1995 [23 July 2014]. 
  45. ^ CellCept registry data demonstrated superior long-term organ transplant outcomes. Roche.com. F. Hoffmann-La Roche Ltd. [23 July 2014].