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Jsjsjs1111/沙盒4
臨床資料
懷孕分級
  • D
给药途径口服
ATC碼
法律規範狀態
法律規範
  • 处方药（℞-only）
藥物動力學數據
生物利用度Well absorbed
药物代谢通过黄嘌呤氧化酶
生物半衰期3小时
排泄途徑极少量的肾脏排泄
识别信息
  • 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)sulfanyl]-7H-purine
CAS号446-86-6  checkY
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
化学信息
化学式C9H7N7O2S
摩尔质量277.263 g/mol
3D模型（JSmol（英语：JSmol））
  • [O-][N+](=O)c3ncn(c3Sc1ncnc2ncnc12)C
  • InChI=1S/C9H7N7O2S/c1-15-4-14-7(16(17)18)9(15)19-8-5-6(11-2-10-5)12-3-13-8/h2-4H,1H3,(H,10,11,12,13) checkY
  • Key:LMEKQMALGUDUQG-UHFFFAOYSA-N checkY

硫唑嘌呤（英語：Azathioprine，音/ˌæzəˈθaɪɵpriːn/）是一种嘌呤类似物的免疫抑制剂。It is produced by a number of generic manufacturers and as branded names (Azasan by Salix in the U.S., Imuran by GlaxoSmithKline in Canada,the U.S., Australia, Ireland and Great Britain, Azamun in Finland and Imurel in Scandinavia and France).

历史

Azathioprine was first introduced into clinical practice by Sir Roy Calne, the British pioneer in transplantation. Following the work done by Sir Peter Medawar and Gertrude Elion in discovering the immunological basis of rejection of transplanted tissues and organs, Calne introduced 6-mercaptopurine as an experimental immunosuppressant for kidney and cardiac transplants.

When azathioprine was discovered, he then introduced it as a less-toxic replacement for 6-mercaptopurine. For many years, dual therapy with azathioprine and steroids was the standard antirejection regimen, until cyclosporine was introduced into clinical practice (also by Calne) in 1978.

用途

它与其它药物联合用于预防器官移植中的排斥，以及单独使用治疗一系列的自身免疫性疾病，包括类风湿性关节炎、Template:Link-en old、炎症性肠病（如克罗恩病和溃疡性结肠炎） multiple sclerosis, autoimmune hepatitis, atopic dermatitis, Myasthenia Gravis, Neuromyelitis optica / NMO / Devic, restrictive lung disease, and others.

作用机理

Azathioprine is a pro-drug; following oral ingestion, it is metabolized into the active 6-mercaptopurine (6-MP), itself a purine synthesis inhibitor. 6-Mercaptopurine impedes DNA synthesis and thus inhibits the proliferation of cells, especially the fast-growing lymphocytes. T-cells and B-cells are particularly affected by the inhibition of purine synthesis. Moreover, azathioprine blocks the downstream effects of CD28 costimulation, and 6-MP interacts directly with GTP-binding protein Rac1, thus blocking upregulation of BCL-xl mRNA and protein. In vivo data indicate inflammatory bowel disease patients treated with azathioprine have more apoptotic mononuclear cells than untreated controls, indicating this mechanism may be responsible for the in vivo response to the drug in this disease.[1]

短期副作用

Azathioprine 50-mg oral tablet

Side effects include nausea, fatigue, hair loss, and rash. Because azathioprine suppresses the bone marrow, patients will be more susceptible to infection. Acute pancreatitis can also occur, especially in patients with Crohn's disease.[2]

Caution should be exercised when it is used in conjunction with purine analogues such as allopurinol. The enzyme thiopurine S-methyltransferase (TPMT) deactivates 6-mercaptopurine. Genetic polymorphisms of TPMT can lead to excessive drug toxicity, thus assay of serum TPMT may be useful to avoid this complication.[3]

Cyclosporine has now replaced some of the azathioprine use due to fewer side effects, especially in heart-related transplantations.[4][5][6] Moreover, despite being 15 times more expensive,[7] mycophenolate mofetil is also increasingly being used in place of azathioprine in organ transplantation, as it is associated with less bone marrow suppression, fewer opportunistic infections, and a lower incidence of acute rejection.[8]

长期副作用（癌症）

Metabolic pathway for azathioprine.

Azathioprine is listed as a human carcinogen in the 11th Report on Carcinogens of the U.S. Department of Health and Human Services, although they note the International Agency for Research on Cancer considered some of the animal studies to be inconclusive because of limitations in the study design and inadequate reporting.[9] In the 12th and current report, it is asserted that azathioprine is "known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans."[10]

Furthermore, as is detailed below, additional postmarketing experience has meant the U.S. Food and Drug Administration has required warnings to be placed on packaging with respect to increased risks of certain cancers.

The risks involved seem to be related both to the duration and to the dosage used. People who have previously been treated with an alkylating agent may have an excessive risk of cancers if treated with azathioprine. Epidemiological studies have provided "sufficient" evidence of azathioprine carcinogenicity in humans,[11] although the methodology of past studies and the possible underlying mechanisms are questioned.[12]

The various diseases requiring transplantation, and thus azathioprine, may in themselves increase the risks of non-Hodgkin's lymphoma, squamous cell carcinomas of the skin, hepatobiliary carcinomas, and mesenchymal tumours to which azathioprine may add additional risks. Those receiving azathioprine for rheumatoid arthritis may have a lesser risk than those undergoing transplantation.[13]

Cases of hepatosplenic T-cell lymphoma - a rare type of T-cell lymphoma - have been reported in patients treated with azathioprine. The majority occurred in patients with inflammatory bowel disease. Adolescents and young adult males were the major cohort of cases. They presented with a very aggressive disease course and, with one exception, died of the lymphoma. The FDA has required changes to the labeling to inform users and clinicians of the issue.[14]

皮肤癌

In transplant patients, skin cancer is 50 to 250 times more common than the general population, and between 60% and 90% of patients are affected 20 years after transplantations. The use of the immunosuppressive medication (including azathioprine) in organ transplantation has been linked to increased rates of developing skin cancer.[15] Azathioprine causes the accumulation of 6-thioguanine (6-TG) in patients' DNA, which can trigger cancer when the patient is later exposed to ultraviolet light. Patients taking azathioprine were found to be abnormally sensitive to UVA light.[16]

怀孕及哺乳时的使用

While azathioprine had not been thought to cause fetal malformation (teratogenesis), and the risk to the offspring of treated women is small, a more recent product monograph produced by Glaxo Smith Kline and dated June 2005 does note that Imuran can cause fetal harm when given to a pregnant woman. Their document also states the drug should not be given during pregnancy or in patients of reproductive potential without careful weighing of benefit versus the risks, and should be avoided whenever possible in pregnant women. It goes on to state, when used in pregnancy, the patient should be apprised of the potential hazard to the fetus. While stating no adequate and well-controlled studies have taken place in humans, when given to animals in doses equivalent to human dosages, teratogenesis was observed. Transplant patients already on this drug should not discontinue or becoming pregnant. This contrasts to the later-developed drugs tacrolimus and mycophenolate, which are contraindicated by the manufacturers during pregnancy.[17]

As for all cytotoxic drugs, the manufacturer advises not to breastfeed whilst taking azathioprine. The Lactation Risk Category (LAC) reported by Thomas Hale in "Medications and Mothers' Milk" lists azathioprine as "L3", termed "moderately safe".

参考资料

  1. ^ Maltzman, J. S.; Koretzky, G. A. Azathioprine: Old drug, new actions. Journal of Clinical Investigation. 2003, 111 (8): 1122–1124. PMC 152947 可免费查阅. PMID 12697731. doi:10.1172/JCI18384. 
  2. ^ Weersma, R. K., Peters, F. T. M., Oostenbrug, L. E., van den Berg, A. P., van Haastert, M., Ploeg, R. J., Posthumus, M. D., Homan van der Heide, J. J., Jansen, P. L. M. and van Dullemen, H. M. Increased incidence of azathioprine-induced pancreatitis in Crohn's disease compared with other diseases. Alimentary Pharmacology & Therapeutics. 2004, 20 (8): 843–850. PMID 15479355. doi:10.1111/j.1365-2036.2004.02197.x.  已忽略未知参数|month=（建议使用|date=） (帮助)
  3. ^ Konstantopoulou M, Belgi A, Griffiths KD, Seale JR, Macfarlane AW. Azathioprine-induced pancytopenia in a patient with pompholyx and deficiency of erythrocyte thiopurine methyltransferase. 英国医学杂志. 2005, 330 (7487): 350–1. PMC 548735 可免费查阅. PMID 15705694. doi:10.1136/bmj.330.7487.350.  已忽略未知参数|month=（建议使用|date=） (帮助)
  4. ^ Bakker, R. C.; Hollander, A. A. M. J.; Mallat, M. J. K.; Bruijn, J. A.; Paul, L. C.; De Fijter, J. W. Conversion from cyclosporine to azathioprine at three months reduces the incidence of chronic allograft nephropathy. Kidney International. 2003, 64 (3): 1027–1034. PMID 12911553. doi:10.1046/j.1523-1755.2003.00175.x. 
  5. ^ Henry, M. L.; Sommer, B. G.; Ferguson, R. M. Beneficial effects of cyclosporine compared with azathioprine in cadaveric renal transplantation. The American Journal of Surgery. 1985, 150 (5): 533. doi:10.1016/0002-9610(85)90431-3. 
  6. ^ Modry, D. L.; Oyer, P. E.; Jamieson, S. W.; Stinson, E. B.; Baldwin, J. C.; Reitz, B. A.; Dawkins, K. D.; McGregor, C. G.; Hunt, S. A. Cyclosporine in heart and heart-lung transplantation. Canadian journal of surgery. Journal canadien de chirurgie. 1985, 28 (3): 274–280, 282. PMID 3922606. 
  7. ^ Remuzzi, G.; Lesti, M.; Gotti, E.; Ganeva, M.; Dimitrov, B.; Ene-Iordache, B.; Gherardi, G.; Donati, D.; Salvadori, M. Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial. The Lancet. 2004, 364 (9433): 503–12. PMID 15302193. doi:10.1016/S0140-6736(04)16808-6.  已忽略未知参数|month=（建议使用|date=） (帮助)
  8. ^ Woodroffe R, Yao G, Meads C, Bayliss S, Ready A, Raftery J, Taylor R. Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study. Health Technol Assess. 2005, 9 (21): 1–194. PMID 15899149. 
  9. ^ Sittig's Handbook of Toxic and Hazardous Chemicals and Carcinogens
  10. ^ The 12th Report on Carcinogens of the US Department of Health and Human Services. http://ntp.niehs.nih.gov/?objectid=03C9AF75-E1BF-FF40-DBA9EC0928DF8B15
  11. ^ International Agency for Research on Cancer (IARC). Azathioprine - 5. Summary of Data Reported and Evaluation. Summaries & Evaluations. 世界卫生组织: VOL.: 26 (1981) (p. 47). 1987. 
  12. ^ Gombar V, Enslein K, Blake B, Einstein K. Carcinogenicity of azathioprine: an S-AR investigation. Mutat Res. 1993, 302 (1): 7–12. PMID 7683109. doi:10.1016/0165-7992(93)90083-8. 
  13. ^ International Agency for Research on Cancer (IARC). Azathioprine - Evidence for carcinogenicity to humans (sufficient). Summaries & Evaluations. 世界卫生组织: Supplement 7: (1987) (p. 119). 1987. 
  14. ^ FDA Warning with respect to cancer/lymphoma risks with azathioprine http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm258794.htm
  15. ^ Skin cancer alert for organ drug. BBC在线. BBC. September 15, 2005 [June 10, 2012]. 
  16. ^ O'Donovan, P.; Perrett, C. M.; Zhang, X.; Montaner, B.; Xu, Y. Z.; Harwood, C. A.; McGregor, J. M.; Walker, S. L.; Hanaoka, F. Azathioprine and UVA Light Generate Mutagenic Oxidative DNA Damage. Science. 2005, 309 (5742): 1871–1874. PMC 2426755 可免费查阅. PMID 16166520. doi:10.1126/science.1114233. 
  17. ^ 英国国家处方集 45 March 2003

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