Azathioprine
|
|
| Systematic (IUPAC) name |
| 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)sulfanyl]-7H-purine |
| Clinical data |
| Trade names |
Azasan, Imuran |
| AHFS/Drugs.com |
monograph |
| MedlinePlus |
a682167 |
| Licence data |
US FDA:link |
| Pregnancy cat. |
D (AU) D (US) |
| Legal status |
℞ Prescription only |
| Routes |
Mainly oral (maybe initially intravenous) |
| Pharmacokinetic data |
| Bioavailability |
60±31% |
| Protein binding |
20–30% |
| Metabolism |
Activated non-enzymatically, deactivated mainly by xanthine oxidase |
| Half-life |
26 to 80 minutes |
| Excretion |
Renal, 98% as metabolites |
| Identifiers |
| CAS number |
446-86-6 Y
55774-33-9 (sodium salt) |
| ATC code |
L04AX01 |
| PubChem |
CID 2265 |
| DrugBank |
DB00993 |
| ChemSpider |
2178 Y |
| UNII |
MRK240IY2L Y |
| KEGG |
D00238 Y |
| ChEBI |
CHEBI:2948 Y |
| ChEMBL |
CHEMBL1542 Y |
| Chemical data |
| Formula |
C9H7N7O2S |
| Mol. mass |
277.263 g/mol |
SMILES
- [O-][N+](=O)c3ncn(c3Sc1ncnc2ncnc12)C
|
InChI
-
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) Y
Key:LMEKQMALGUDUQG-UHFFFAOYSA-N Y
|
| Physical data |
| Melt. point |
238–245 °C (460–473 °F) |
Y (what is this?) (verify)
|
Azathioprine (INN, /ˌæzəˈθaɪɵpriːn/, abbreviated AZA) is an immunosuppressive drug used in organ transplantation and autoimmune diseases and belongs to the chemical class of purine analogues.[1] It inhibits an enzyme that is required for the synthesis of DNA, thus most strongly affects proliferating cells, such as the T cells and B cells of the immune system.[2] It is produced by a number of manufacturers under different brand 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).
|
Contents
- 1 Medical uses
- 1.1 Kidney transplantations
- 1.2 Rheumatoid arthritis
- 1.3 Crohn's disease
- 2 Adverse effects
- 3 Overdose
- 4 Drug interactions
- 5 Pregnancy and breastfeeding
- 6 Pharmacokinetics
- 7 Mechanism of action
- 8 Physical and chemical properties
- 9 History
- 10 References
- 11 External links
|
Medical uses
Azathioprine is used alone or in combination with other immunosuppressive therapy to prevent rejection following organ transplantation, and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), multiple sclerosis, autoimmune hepatitis, atopic dermatitis, myasthenia gravis, neuromyelitis optica (Devic's disease), restrictive lung disease, and others.[3]
In the United States it is currently approved by the Food and Drug Administration (FDA) for use in kidney transplantation from human donors, and for rheumatoid arthritis.[1] Other uses are off-label.
Kidney transplantations
Azathioprine is used to prevent rejections of kidney allografts, usually in conjunction with other therapies including corticosteroids, other immunosuppressants, and local radiation therapy.[4][5] The administration starts either at the time of transplantation or within the following two days.[1]
Rheumatoid arthritis
Being a disease-modifying antirheumatic drug (DMARD), azathioprine is used for the management of the signs and symptoms of adult rheumatoid arthritis.[6] Nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids may be combined or continued (if they were already in use) with azathioprine, but the combination with other DMARDs is not recommended.[1]
Crohn's disease
Azathioprine has been used in the management of moderately to severely or chronically active Crohn's disease,[7] to maintain clinical remission (absence of disease activity) in corticosteroid-dependent patients,[8] and to provide benefit in patients with fistulizing Crohn's disease.[9] The onset of action is slow and it may require several months to achieve clinical response.[7]
Lower doses of azathioprine are used as a therapy in children with refractory or corticosteroid-dependent Crohn's disease, without causing many side effects;[10] however the long-term risks may still outweigh benefits.[11]
Adverse effects
An example of azathioprine 50 mg oral tablets
Nausea and vomiting are common adverse effects, especially at the beginning of a treatment. Such cases are met with taking azathioprine after meals or transient intravenous administration. Side effects that are probably hypersensitivity reactions include dizziness, diarrhoea, fatigue, and skin rashes. Hair loss is often seen in transplant patients receiving the drug, but rarely occurs under other indications. Because azathioprine suppresses the bone marrow, patients can develop anaemia and will be more susceptible to infection; regular monitoring of the blood count is recommended during treatment.[1][12] Acute pancreatitis can also occur, especially in patients with Crohn's disease.[13]
The enzyme thiopurine S-methyltransferase (TPMT) deactivates thioinosinic acid, the active metabolite of azathioprine. Genetic polymorphisms of TPMT, which occurs with a frequency of about 0.3%,[14] can lead to dangerous bone marrow suppression, and assay of serum TPMT or TPMT gene tests may be useful to avoid this complication.[15][16][17]
Ciclosporin has now replaced some of the azathioprine use due to a longer survival time, especially in heart transplantations.[18][19][20] Moreover, despite being 15 times more expensive, 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.[5][21]
Under FDA rules, like many other immunosuppressants, the use of this drug excludes eligibility for blood donation.[22]
Cancers
Azathioprine is listed as a human carcinogen in the 12th Report on Carcinogens by the National Toxicology Program of U.S. Department of Health and Human Services, asserting that it is "known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans."[23] Since August 2009, the U.S. Food and Drug Administration has required warnings to be placed on packaging with respect to increased risks of certain cancers.[24]
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 by International Agency for Research on Cancer (IARC) have provided "sufficient" evidence of azathioprine carcinogenicity in humans (Group 1),[25] although the methodology of past studies and the possible underlying mechanisms are questioned.[26]
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 lower risk than those undergoing transplantation.[27]
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 majority of cases.[11] 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.[28]
Skin cancer
In transplant patients, skin cancer is 50 to 250 times more common than in the general population, and between 60% and 90% of patients are affected 20 years after transplantation. The use of immunosuppressive medication including azathioprine in organ transplantation has been linked to increased rates of developing skin cancer.[29] Azathioprine causes the accumulation of 6-thioguanine (6-TG) in patients' DNA, which might trigger cancer when the patient is later exposed to ultraviolet light. Patients taking azathioprine were found to be abnormally sensitive to UVA light.[30]
Overdose
Large single doses are generally well tolerated; a patient who took 7.5 g azathioprine (150 tablets) at once showed no relevant symptoms apart from vomiting, slightly decreased white blood cell count and marginal changes in liver function parameters. Main symptoms of long-term overdosing are infections of unclear origin, mouth ulcers and spontaneous bleeding, all of which are consequences of the bone marrow suppression.[12]
Drug interactions
Other purine analogues such as allopurinol inhibit xanthine oxidase, the enzyme that breaks down azathioprine, thus increasing the toxicity of azathioprine.[31] On the other hand, low doses of allopurinol have been shown to safely enhance the efficacy of azathioprine, especially in inflammatory bowel disease non-responders.[32][33][34] This may still lead to lower lymphocyte counts and higher rates of infection, therefore the combination requires careful monitoring.[35]
Azathioprine decreases the effects of the anticoagulant warfarin and of non-depolarizing muscle relaxants, but increases the effect of depolarizing muscle relaxants.[12] It can also interfere with niacin (vitamin B3), resulting in at least one case to pellagra and fatal medullary aplasia.[36] It has also been reported to cause vitamin B12 deficiency.[37]
Pregnancy and breastfeeding
While azathioprine had been thought not to cause fetal malformation (teratogenesis), and the risk to the offspring of treated women was thought to be small,[38] it is now known that this drug can cause fetal harm when given to a pregnant woman.[39][40] A 2003 population-based study in Denmark showed that the use of azathioprine and related mercaptopurine resulted in a seven-fold incidence of fetal abnormalities as well as a 20-fold increase in miscarriage.[41] Birth defects in a child whose father was taking azathioprine have also been reported.[42] Although no adequate and well-controlled studies have taken place in humans, when given to animals in doses equivalent to human dosages, teratogenesis was observed.[43] Transplant patients already on this drug should not discontinue on becoming pregnant. This contrasts with the later-developed drugs tacrolimus and mycophenolate, which are contraindicated during pregnancy.[38]
Traditionally, as for all cytotoxic drugs, the manufacturer advises not to breastfeed whilst taking azathioprine. However, the "Lactation Risk Category" reported by Thomas Hale in his book "Medications and Mothers' Milk" lists azathioprine as "L3", termed "moderately safe";[44] some recent studies also indicate that breastfeeding does not need to be withheld as the immediate benefits may outweigh the risks.[45]
Pharmacokinetics
Metabolic pathway for azathioprine (AZA).
[46] * XO: xanthine oxidase * 6-MP: 6-mercaptopurine * TPMT: thiopurine methyltransferase * 6-MMP: 6-methylmercaptopurine * HPRT: hypoxanthine-guanine phosphoribosyltransferase * TIMP: thioinosine monophosphate, thioinosinic acid * 6-TG: 6-thioguanine
Azathioprine is absorbed from the gut to about 88%. Bioavailability varies greatly between individual patients, between 30 and 90%. Highest blood plasma concentrations are reached after one to two hours, and the average plasma half-life is 26 to 80 minutes.[47][48]
Azathioprine is a prodrug that is slowly and almost completely converted to 6-mercaptopurine (6-MP) by reductive cleavage of the thioether. This step is mediated by glutathione and similar compounds in the intestinal wall, the liver and on red blood cells. 6-MP is then activated to thioinosinic acid (thioinosine monophosphate, TIMP). These compounds are metabolized analogously to natural purines, the end products being thiouric acid (38%) and various methylated and hydroxylated purines, which are excreted via the urine. All of these products are inactive.[14][47][48]
Mechanism of action
The active metabolite thioinosinic acid is a purine synthesis inhibitor that works by blocking the enzyme amidophosphoribosyltransferase, among others. It also impedes later steps of DNA synthesis via enzymes such as adenylosuccinate synthase and IMP dehydrogenase, and thus inhibits the proliferation of cells, especially the fast-growing lymphocytes.[48] T-cells and B-cells are particularly affected by the inhibition of purine synthesis.[31] 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.[49] 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.[2]
Physical and chemical properties
Azathioprine is a thiopurine and a pale yellow solid with a slightly bitter taste and a melting point of about 238–245 °C. It is practically unsoluble in water and only slightly soluble in lipophilic solvents such as chloroform, ehanol and diethylether. It dissolves in alkaline aqueous solutions, where it hydrolyzes to 6-mercaptopurine.[47]
Synthesis
Azathioprine is synthesized from 5-chloro-1-methyl-4-nitro-1H-imidazole and 6-mercaptopurine in dimethyl sulfoxide (DMSO).[50] The synthesis of the former starts with an amide from methylamine and diethyl oxalate, which is then cyclizised and chlorinated with phosphorus pentachloride;[51] the nitro group is introduced with nitric acid and sulfuric acid.
History
Azathioprine was synthesized by George Herbert Hitchings and Gertrude Elion in 1957 (named BW 57-322) to produce 6-mercaptopurine (6-MP) in a metabolically active but masked form, and at first used as a chemotherapy drug.[52][53]
Robert Schwartz investigated the effect of 6-MP on the immune response in 1958 and discovered that it profoundly suppresses the formation of antibody when given with antigen in rabbits.[54] Following the work done by Sir Peter Medawar and Gertrude Elion in discovering the immunological basis of rejection of transplanted tissues and organs, and Schwartz's researches on 6-MP, Sir Roy Calne, the British pioneer in transplantation, introduced 6-MP as an experimental immunosuppressant for kidney and cardiac transplants.[55] When Calne asked Elion for related compounds to investigate, Elion suggested azathioprine, which was subsequently found out to be superior by Calne.[56] In 1962, with regimens consisting of azathioprine and prednisone, the transplantation of kidneys to unrelated recipients (allotransplantation) has become successful for the first time.[57] For many years, this kind of dual therapy with azathioprine and glucocorticoids was the standard antirejection regimen, until ciclosporin was introduced into clinical practice (by Calne as well) in 1978.
References
- ^ a b c d e American Society of Health-System Pharmacists (January 2012). "Azathioprine, Azathioprine Sodium". Ahfs Drug Information 2012. Amer Soc of Health System. ISBN 978-1-58528-267-8.
- ^ a b Maltzman, J. S.; Koretzky, G. A. (2003). "Azathioprine: Old drug, new actions". Journal of Clinical Investigation 111 (8): 1122–1124. DOI:10.1172/JCI18384. PMC 152947. PMID 12697731. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=152947. edit
- ^ Patel, A. A.; Swerlick, R. A.; McCall, C. O. (2006). "Azathioprine in dermatology: The past, the present, and the future". Journal of the American Academy of Dermatology 55 (3): 369–389. DOI:10.1016/j.jaad.2005.07.059. PMID 16908341.
- ^ Nuyttens, J. J.; Harper, J.; Jenrette, J. M.; Turrisi, A. T. (2005). "Outcome of radiation therapy for renal transplant rejection refractory to chemical immunosuppression". Radiotherapy and Oncology 74 (1): 17–19. DOI:10.1016/j.radonc.2004.08.011. PMID 15683663.
- ^ a b Remuzzi, G.; Lesti, M.; Gotti, E.; Ganeva, M.; Dimitrov, B.; Ene-Iordache, B.; Gherardi, G.; Donati, D. et al. (August 2004). "Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial". The Lancet 364 (9433): 503–12. DOI:10.1016/S0140-6736(04)16808-6. PMID 15302193.
- ^ Suarez-Almazor, M. E.; Spooner, C.; Belseck, E. (2000). "Azathioprine for treating rheumatoid arthritis". In Suarez-Almazor, Maria E. Cochrane Database of Systematic Reviews. DOI:10.1002/14651858.CD001461.
- ^ a b Sandborn, W. J. (1998). "Azathioprine: State of the art in inflammatory bowel disease". Scandinavian journal of gastroenterology. Supplement 225: 92–99. PMID 9515759.
- ^ Biancone, L.; Tosti, C.; Fina, D.; Fantini, M.; De Nigris, F.; Geremia, A.; Pallone, F. (2003). "Maintenance treatment of Crohn's disease". Alimentary Pharmacology and Therapeutics 17: 31–37. DOI:10.1046/j.1365-2036.17.s2.20.x. PMID 12786610.
- ^ Rutgeerts, P. (2004). "Treatment of perianal fistulizing Crohn's disease". Alimentary Pharmacology and Therapeutics 20: 106–110. DOI:10.1111/j.1365-2036.2004.02060.x. PMID 15352905.
- ^ Kirschner, B. S. (1998). "Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease". Gastroenterology 115 (4): 813–821. DOI:10.1016/S0016-5085(98)70251-3. PMID 9753482.
- ^ a b McGovern, D. P. B.; Jewell, D. P. (2005). "Risks and benefits of azathioprine therapy". Gut 54 (8): 1055–1059. DOI:10.1136/gut.2004.053231. PMC 1774869. PMID 16009676. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1774869.
- ^ a b c Jasek, W, ed. (2007) (in German). Austria-Codex (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 4103–9. ISBN 978-3-85200-181-4.
- ^ 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. (October 2004). "Increased incidence of azathioprine-induced pancreatitis in Crohn's disease compared with other diseases". Alimentary Pharmacology & Therapeutics 20 (8): 843–850. DOI:10.1111/j.1365-2036.2004.02197.x. PMID 15479355.
- ^ a b Mutschler, Ernst; Schäfer-Korting, Monika (2001) (in German). Arzneimittelwirkungen (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. pp. 107, 936. ISBN 3-8047-1763-2.
- ^ Konstantopoulou M, Belgi A, Griffiths KD, Seale JR, Macfarlane AW (February 2005). "Azathioprine-induced pancytopenia in a patient with pompholyx and deficiency of erythrocyte thiopurine methyltransferase". BMJ 330 (7487): 350–1. DOI:10.1136/bmj.330.7487.350. PMC 548735. PMID 15705694. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=548735.
- ^ Yates, C. R.; Krynetski, E. Y.; Loennechen, T.; Fessing, M. Y.; Tai, H. L.; Pui, C. H.; Relling, M. V.; Evans, W. E. (1997). "Molecular diagnosis of thiopurine S-methyltransferase deficiency: Genetic basis for azathioprine and mercaptopurine intolerance". Annals of internal medicine 126 (8): 608–614. PMID 9103127.
- ^ Payne, K.; Newman, W.; Fargher, E.; Tricker, K.; Bruce, I. N.; Ollier, W. E. R. (2007). "TPMT testing in rheumatology: Any better than routine monitoring?". Rheumatology 46 (5): 727–729. DOI:10.1093/rheumatology/kel427. PMID 17255139.
- ^ Bakker, R. C.; Hollander, A. A. M. J.; Mallat, M. J. K.; Bruijn, J. A.; Paul, L. C.; De Fijter, J. W. (2003). "Conversion from cyclosporine to azathioprine at three months reduces the incidence of chronic allograft nephropathy". Kidney International 64 (3): 1027–1034. DOI:10.1046/j.1523-1755.2003.00175.x. PMID 12911553. edit
- ^ Henry, M. L.; Sommer, B. G.; Ferguson, R. M. (1985). "Beneficial effects of cyclosporine compared with azathioprine in cadaveric renal transplantation". The American Journal of Surgery 150 (5): 533. DOI:10.1016/0002-9610(85)90431-3. edit
- ^ Modry, D. L.; Oyer, P. E.; Jamieson, S. W.; Stinson, E. B.; Baldwin, J. C.; Reitz, B. A.; Dawkins, K. D.; McGregor, C. G. et al. (1985). "Cyclosporine in heart and heart-lung transplantation". Canadian journal of surgery. Journal canadien de chirurgie 28 (3): 274–280, 282. PMID 3922606. edit
- ^ Woodroffe R, Yao G, Meads C, Bayliss S, Ready A, Raftery J, Taylor R (2005). "Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study". Health Technol Assess 9 (21): 1–194. PMID 15899149.
- ^ Carol Eustice (October 23, 2005). "Blood Donation - Are rheumatoid arthritis patients able to donate blood?". About.com. http://arthritis.about.com/od/arthqa/f/blooddonation.htm. Retrieved November 29, 2011.
- ^ National Toxicology Program (10 June 2011). "Report On Carcinogens – Twelfth Edition – 2011" (PDF). National Toxicology Program. http://ntp.niehs.nih.gov/ntp/roc/twelfth/roc12.pdf. Retrieved June 20, 2012.
- ^ "FDA: Cancer Warnings Required for TNF Blockers". FDA. August 4, 2009. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm175803.htm. Retrieved June 20, 2012.
- ^ International Agency for Research on Cancer (IARC) (1987). "Azathioprine - 5. Summary of Data Reported and Evaluation". Summaries & Evaluations. World Health Organization. pp. VOL.: 26 (1981) (p. 47). http://www.inchem.org/documents/iarc/vol26/azathioprine.html.
- ^ Gombar V, Enslein K, Blake B, Einstein K (1993). "Carcinogenicity of azathioprine: an S-AR investigation". Mutat Res 302 (1): 7–12. DOI:10.1016/0165-7992(93)90083-8. PMID 7683109.
- ^ International Agency for Research on Cancer (IARC) (1987). "Azathioprine - Evidence for carcinogenicity to humans (sufficient)". Summaries & Evaluations. World Health Organization. pp. Supplement 7: (1987) (p. 119). http://www.inchem.org/documents/iarc/suppl7/azathioprine.html.
- ^ "Imuran (azathioprine) Tablets and Injection". FDA. May 2011. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm258794.htm. Retrieved June 20, 2012.
- ^ "Skin cancer alert for organ drug". BBC Online. BBC news. September 15, 2005. http://news.bbc.co.uk/2/hi/health/4248356.stm. Retrieved June 10, 2012.
- ^ O'Donovan, P.; Perrett, C. M.; Zhang, X.; Montaner, B.; Xu, Y. Z.; Harwood, C. A.; McGregor, J. M.; Walker, S. L. et al. (2005). "Azathioprine and UVA Light Generate Mutagenic Oxidative DNA Damage". Science 309 (5742): 1871–1874. DOI:10.1126/science.1114233. PMC 2426755. PMID 16166520. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2426755.
- ^ a b Sahasranaman, S.; Howard, D.; Roy, S. (2008). "Clinical pharmacology and pharmacogenetics of thiopurines". European Journal of Clinical Pharmacology 64 (8): 753–767. DOI:10.1007/s00228-008-0478-6. PMID 18506437.
- ^ Chocair P, Duley J, Simmonds HA, et al. (1993). "Low-dose allopurinol plus azathioprine/cyclosporin/prednisolone, a novel immunosuppressive regimen.". Lancet 342: 83–84. PMID 8100914.
- ^ Sparrow MP, Hande SA, Friedman S, et al. (2005). "Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine". Aliment Pharmacol Ther 22: 441–6. PMID 16128682.
- ^ Sparrow, M. P.; Hande, S. A.; Friedman, S.; Cao, D.; Hanauer, S. B. (2007). "Effect of Allopurinol on Clinical Outcomes in Inflammatory Bowel Disease Nonresponders to Azathioprine or 6-Mercaptopurine". Clinical Gastroenterology and Hepatology 5 (2): 209–214. DOI:10.1016/j.cgh.2006.11.020. PMID 17296529.
- ^ Govani SM, Higgins PD (2010). "Combination of thiopurines and allopurinol: adverse events and clinical benefit in IBD". J Crohns Colitis 4: 444–9. PMID 21122542.
- ^ Oliveria A, Sanches M, Selores M (2011). "Azathioprine-induced pellagra". J Dermatol 38: 1035–7. PMID 21658113.
- ^ Kim CJ, Park K, Inoue H, et al. (1998). "Azathioprine-lnduced megaloblastic anemia with pancytopenia 22 years after living-related renal transplantation". Int J Urol 5: 100–102. PMID 9535611.
- ^ a b Dinesh K. Mehta (March 2003). British National Formulary, Issue 45. Pharmaceutical Society of Great Britain. London: British Medical Association. ISBN 0-85369-555-5.
- ^ Cleary, B. J.; Källén, B. (2009). "Early pregnancy azathioprine use and pregnancy outcomes". Birth Defects Research Part A: Clinical and Molecular Teratology 85 (7): 647–654. DOI:10.1002/bdra.20583. PMID 19343728.
- ^ Tagatz, G. E.; Simmons, R. L. (1975). "Pregnancy after renal transplantation". Annals of internal medicine 82 (1): 113–114. PMID 799904.
- ^ Nørgård, B.; L. Pedersen, K. Fonager, S. Rasmussen, H. Sørensen (March 2003). "Azathioprine, mercaptopurine and birth outcome: a population-based cohort study". Alimentary pharmacology and therapeutics 17 (6): 827–834. DOI:10.1046/j.1365-2036.2003.01537.x. PMID 12641505.
- ^ Tallent, M. B.; Simmons, R. L.; Najarian, J. S. (1970). "Birth defects in child of male recipient of kidney transplant". JAMA: the journal of the American Medical Association 211 (11): 1854–1855. PMID 4905893.
- ^ Polifka, J. E.; Friedman, J. M. (2002). "Teratogen update: Azathioprine and 6-mercaptopurine". Teratology 65 (5): 240–261. DOI:10.1002/tera.10043. PMID 11967923.
- ^ Thomas W. Hale (April 2010). Medications and Mothers' Milk: A Manual of Lactational Pharmacology. Hale Pub.. ISBN 978-0-9823379-9-8.
- ^ Sau, A.; Clarke, S.; Bass, J.; Kaiser, A.; Marinaki, A.; Nelson-Piercy, C. (2007). "Azathioprine and breastfeeding-is it safe?". BJOG: an International Journal of Obstetrics & Gynaecology 114 (4): 498. DOI:10.1111/j.1471-0528.2006.01232.x.
- ^ Cronstein, B. N. (2004). "Pharmacogenetics in the rheumatic diseases". Annals of the Rheumatic Diseases 63 (Suppl 2): ii25–ii27. DOI:10.1136/ard.2004.028217. PMC 1766779. PMID 15479867. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1766779. edit
- ^ a b c Dinnendahl, V, Fricke, U, ed. (2011) (in German). Arzneistoff-Profile. 2 (25 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
- ^ a b c Steinhilber, D; Schubert-Zsilavecz, M; Roth, HJ (2005) (in German). Medizinische Chemie. Stuttgart: Deutscher Apotheker Verlag. p. 340. ISBN 3-7692-3483-9.
- ^ Cara, C. J.; Pena, A. S.; Sans, M.; Rodrigo, L.; Guerrero-Esteo, M.; Hinojosa, J.; García-Paredes, J.; Guijarro, L. G. (2004). "Reviewing the mechanism of action of thiopurine drugs: Towards a new paradigm in clinical practice". Medical science monitor : international medical journal of experimental and clinical research 10 (11): RA247–RA254. PMID 15507865.
- ^ US Patent 3056785, G. H. Hitchings; Yonkers & G. B. Elion, "Purine Derivatives", issued 1962-10-06
- ^ Blicke, F. F.; Godt, H. C. (1954). "Diuretics. I. 3-Substituted Paraxanthines". Journal of the American Chemical Society 76 (14): 3653. DOI:10.1021/ja01643a015.
- ^ Elion, G. B.; Callahan, S. W.; Hitchings, G. H.; Rundles, R. W. (1960). "The metabolism of 2-amino-6-(1-methyl-4-nitro-5-imidazolyl)thiopurine (B.W. 57-323) in man". Cancer chemotherapy reports. Part 1 8: 47–52. PMID 13849699.
- ^ Thiersch, J. B. (1962). "Effect of 6-(1'-methyl-4'-nitro-5'-imidazolyl)-mercaptopurine and 2-amino-6-(1'-methyl-4'-nitro-5'-imidazolyl)-mercaptopurine on the rat litter in utero". Journal of reproduction and fertility 4: 297–302. PMID 13980986.
- ^ Schwartz, R.; Stack, J.; Dameshek, W. (1958). "Effect of 6-mercaptopurine on antibody production". Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine 99 (1): 164–167. PMID 13601801.
- ^ Calne, R. Y. (1960). "The Rejection of Renal Homografts". The Lancet 275 (7121): 417–418. DOI:10.1016/S0140-6736(60)90343-3.
- ^ Elion, G. (1989). "The purine path to chemotherapy". Science 244 (4900): 41–47. DOI:10.1126/science.2649979. PMID 2649979.
- ^ Murray, J. E.; Merrill, J. P.; Harrison, J. H.; Wilson, R. E.; Dammin, G. J. (1963). "Prolonged Survival of Human-Kidney Homografts by Immunosuppressive Drug Therapy". New England Journal of Medicine 268 (24): 1315–1323. DOI:10.1056/NEJM196306132682401. PMID 13936775.
External links
- Imuran (GlaxoSmithKline Patient Information Leaflet)
- Azasan (manufacturer's website)
- U.S. National Library of Medicine: Drug Information Portal - Azathioprine
|
Immunomodulators: Immunosuppressive drugs / Immunosuppressants (L04)
|
|
Intracellular
(initiation) |
|
Antimetabolites
|
- purine synthesis inhibitors: Azathioprine
- Mycophenolic acid
- pyrimidine synthesis inhibitors: Leflunomide
- Teriflunomide
antifolate: Methotrexate
|
|
|
Macrolides/
other IL-2 inhibitors
|
- FKBP/Cyclophilin/Calcineurin: Tacrolimus
- Ciclosporin
- Pimecrolimus
|
|
|
Other
|
|
|
|
Intracellular
(reception) |
|
IL-1 receptor antagonists
|
|
|
|
mTOR
|
- Sirolimus
- Everolimus
- Ridaforolimus
- Temsirolimus
- Umirolimus
- Zotarolimus
|
|
|
| Extracellular |
|
Antibodies
|
|
Monoclonal
|
|
Serum target
(noncellular)
|
- Complement component 5 (Eculizumab)
- TNF (Adalimumab
- Afelimomab
- Certolizumab pegol
- Golimumab
- Infliximab
- Nerelimomab)
- Interleukin 5 (Mepolizumab)
- Immunoglobulin E (Omalizumab)
- IL-12 and IL-23 (Lebrikizumab
- Ustekinumab)
|
|
|
Cellular target
|
- CD3 (Muromonab-CD3
- Otelixizumab
- Teplizumab
- Visilizumab)
- CD4 (Clenoliximab
- Keliximab
- Zanolimumab)
- CD11a (Efalizumab)
- CD18 (Erlizumab)
- CD20 (Afutuzumab
- Rituximab
- Ocrelizumab
- Pascolizumab)
- CD23 (Gomiliximab
- Lumiliximab)
- CD40 (Teneliximab
- Toralizumab)
- CD62L/L-selectin (Aselizumab)
- CD80 (Galiximab)
- CD147/Basigin (Gavilimomab)
- CD154 (Ruplizumab)
- BLyS (Belimumab)
- CTLA-4 (Ipilimumab
- Tremelimumab)
- CAT (Bertilimumab
- Lerdelimumab
- Metelimumab)
- Integrin (Natalizumab)
- Interleukin-6 receptor (Tocilizumab)
- LFA-1 (Odulimomab)
- IL-2 receptor/CD25 (Basiliximab
- Daclizumab
- Inolimomab)
- T-lymphocyte (Zolimomab aritox)
|
|
|
Unsorted
|
- Atorolimumab
- Cedelizumab
- Fontolizumab
- Maslimomab
- Morolimumab
- Pexelizumab
- Reslizumab
- Rovelizumab
- Siplizumab
- Talizumab
- Telimomab aritox
- Vapaliximab
- Vepalimomab
|
|
|
|
Polyclonal
|
- Anti-thymocyte globulin
- Anti-lymphocyte globulin
|
|
|
|
-cept (Fusion)
|
- CTLA-4 (Abatacept
- Belatacept)
- TNF inhibitor (Etanercept
- Pegsunercept)
- Aflibercept
- Alefacept
- Rilonacept
|
|
|
|
|
cell/phys/auag/auab/comp, igrc
|
|
|
|
|
|
|
Specific antirheumatic products / DMARDs (M01C)
|
|
| Quinolines |
|
|
| Gold preparations |
- Sodium aurothiomalate
- Sodium aurothiosulfate
- Auranofin
- Aurothioglucose
- Aurotioprol
|
|
| Other |
- Penicillamine #/Bucillamine
- Chloroquine #/Hydroxychloroquine
- Leflunomide
- Sulfasalazine #
- antifolate (Methotrexate #)
- thiopurine (Azathioprine) #
|
|
- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
|
|
|
|
|
noco(arth/defr/back/soft)/cong, sysi/epon, injr
|
|
|
|
|
