Azathioprine

Azathioprine
Clinical data
Pronunciation /ˌæzəˈθaɪəˌpriːn/[1]
Trade names Azasan, Imuran and others
AHFS/Drugs.com Monograph
MedlinePlus a682167
License data
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Routes of
administration		 Mainly by mouth (sometimes initially intravenous)
ATC code L04AX01 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 60±31%
Protein binding 20–30%
Metabolism Activated non-enzymatically, deactivated mainly by xanthine oxidase
Biological half-life 26–80 minutes (azathioprine)
3–5 hours (drug plus metabolites)
Excretion Renal, 98% as metabolites
Identifiers
CAS Number 446-86-6 YesY
55774-33-9 (sodium salt)
PubChem (CID) 2265
DrugBank DB00993 YesY
ChemSpider 2178 YesY
UNII MRK240IY2L YesY
KEGG D00238 YesY
ChEBI CHEBI:2948 YesY
ChEMBL CHEMBL1542 YesY
Chemical and physical data
Formula C9H7N7O2S
Molar mass 277.263 g/mol
3D model (Jmol) Interactive image
Melting point 238 to 245 °C (460 to 473 °F)
  (verify)

Azathioprine (AZA), also known by its brand name Imuran, is an immunosuppressive drug used in organ transplantation and autoimmune diseases. It belongs to the chemical class of purine analogues.[2] Synthesized originally as a cancer drug and a prodrug for mercaptopurine in 1957, it has been widely used as an immunosuppressant for more than 50 years.[3]

The main adverse effect of azathioprine is bone marrow suppression, which can be life-threatening, especially in people with a genetic deficiency of the enzyme thiopurine S-methyltransferase. The 6-thioguanine nucleotide metabolites appear to mediate the majority of azathioprine’s immunosuppressive and toxic effects.[4] It is listed by the International Agency for Research on Cancer as a group 1 carcinogen (carcinogenic to humans).[5]

Azathioprine is an imidazolyl derivative and prodrug of mercaptopurine. In vivo, the metabolites of mercaptopurine are incorporated into replicating DNA, halting replication, as well as blocking the pathway for purine synthesis. It thus most strongly affects proliferating cells, such as the T cells and B cells of the immune system.[6][7]

Azathioprine is produced by a number of manufacturers under different brand names. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[8]

Medical uses

Azathioprine is used alone or in combination with other immunosuppressive therapy to prevent rejection following organ transplantation, and to treat an array of autoimmune diseases, including rheumatoid arthritis, pemphigus, systemic lupus erythematosus, Behçet's disease, and other forms of vasculitis, autoimmune hepatitis, atopic dermatitis, myasthenia gravis, neuromyelitis optica (Devic's disease), restrictive lung disease, and others.[7] It is also an important therapy and steroid-sparing agent for inflammatory bowel disease (such as Crohn's disease and ulcerative colitis) and for multiple sclerosis.[4]

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.[2]

Transplantation

Azathioprine is used to prevent rejections of kidney or liver allografts, usually in conjunction with other therapies including corticosteroids, other immunosuppressants, and local radiation therapy.[9][10] The administration protocol starts either at the time of transplantation or within the following two days.[2]

Rheumatoid arthritis

Being a disease-modifying antirheumatic drug (DMARD), azathioprine has been used for the management of the signs and symptoms of adult rheumatoid arthritis.[11] 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.[2]

Crohn's disease

Azathioprine has been used in the management of moderately to severely or chronically active Crohn's disease,[12] to maintain clinical remission (absence of disease activity) in corticosteroid-dependent patients,[13] and to provide benefit in people with fistulizing Crohn's disease.[14] The onset of action is slow and it may require several months to achieve clinical response.[12]

Azathioprine treatment is associated with an increased risk of lymphoma, but it is unclear if this is due to the drug or a predisposition related to Crohn's disease.[15] Lower doses of azathioprine are used as a therapy in children with refractory or corticosteroid-dependent Crohn's disease, without causing many side effects.[16]

In Crohn’s disease, treatment with azathioprine shortly after diagnosis was no more likely to result in corticosteroid-free remission than standard care or placebo.[17]

Others

Azathioprine is sometimes used in systemic lupus erythematosus patients who require a maintenance dose of 15 mg or higher of prednisone and those who experience recurrent flares.[18]

It is used as an add on therapy when steroid therapy is given by mouth for pemphigus and myasthenia gravis, as a "steroid-sparing" agent.[7][19][20]

It was shown to be very effective in eczema and atopic dermatitis in researches, even though it is not commonly used.[7] The British National Eczema Society lists it as a third-line treatment for severe to moderate cases of these skin diseases.[21]

It was widely used for the treatment of multiple sclerosis until the first half of the 1990s. Concerns about increased risk of malignancy has led to a decreased use, yet it is still used in maintenance treatment for patients who frequently relapse.[22]

A widely used therapy for idiopathic pulmonary fibrosis was azathioprine in combination with prednisone and N-acetylcysteine. A 2012 study showed that there were worse outcomes with this combination than with placebo.[23]

Adverse effects

Two generic azathioprine oral tablets, 50 mg each

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, diarrhea, 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.[2][24] Acute pancreatitis can also occur, especially in patients with Crohn's disease.[25]

Under FDA rules, like many other immunosuppressants, the use of this drug excludes eligibility for blood donation.[26]

Pharmacogenetics

The enzyme thiopurine S-methyltransferase (TPMT) is responsible for various activation and deactivation steps in azathioprine's mechanism of action. The first metabolic step that azathioprine undergoes in the body is the conversion to 6-mercaptopurine (6-MP; see Pharmacokinetics), which is itself an immunosuppressant prodrug.[27][28] The TPMT enzyme is responsible, in part, for the methylation of 6-MP into the inactive metabolite 6-methylmercaptopurine - this methylation prevents 6-MP from further conversion into active, cytotoxic thioguanine nucleotide (TGN) metabolites.[27][29] Certain genetic variations within the TPMT gene can lead to decreased or absent TPMT enzyme activity, and individuals who are homozygous or heterozygous for these types of genetic variations may have increased levels of TGN metabolites and an increased risk of severe bone marrow suppression (myelosuppression) when receiving azathioprine.[30] In many ethnicities, TPMT polymorphisms that result in decreased or absent TPMT activity occur with a frequency of approximately 5%, meaning that about 0.25% of patients are homozygous for these variants.[30][31] However, an assay of TPMT activity in red blood cells or a TPMT genetic test can identify patients with reduced TPMT activity, allowing for the adjustment of azathioprine dose or avoidance of the drug entirely.[30][32] The FDA-approved drug label for azathioprine recommends testing for TPMT activity to identify patients at risk for myelotoxicity.[33] Indeed, testing for TPMT activity is currently one of the few examples of pharmacogenetics being translated into routine clinical care.[34]

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."[35] 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.[36]

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),[37] although the methodology of past studies and the possible underlying mechanisms are questioned.[38]

The various diseases requiring transplantation 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.[5]

Cases of hepatosplenic T-cell lymphoma – a rare type of 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.[39] 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.[40]

Skin cancers

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.[41] 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.[42]

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.[24]

Interactions

Other purine analogues such as allopurinol inhibit xanthine oxidase, the enzyme that breaks down azathioprine, thus increasing the toxicity of azathioprine.[43] 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.[44][45][46] This may still lead to lower lymphocyte counts and higher rates of infection, therefore the combination requires careful monitoring.[47][48]

Azathioprine decreases the effects of the anticoagulant warfarin and of non-depolarizing muscle relaxants, but increases the effect of depolarizing muscle relaxants.[24] It can also interfere with niacin (vitamin B3), resulting in at least one case to pellagra and fatal medullary aplasia.[49] It has also been reported to cause vitamin B12 deficiency.[50]

Pregnancy and breastfeeding

Azathioprine can cause birth defects.[51][52][53] 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.[54] Birth defects in a child whose father was taking azathioprine have also been reported.[55] 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.[56] 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.[51]

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".[57]

Pharmacology

Pharmacokinetics

Metabolic pathway for azathioprine (AZA).[58][59] Active metabolites are highlighted.

Azathioprine is absorbed from the gut to about 88%. Bioavailability varies greatly between individual patients, between 30 and 90%, because the drug is partly inactivated in the liver. Highest blood plasma concentrations, counting not only the drug itself but also its metabolites, are reached after one to two hours; and the average plasma half-life is 26 to 80 minutes for azathioprine and three to five hours for drug plus metabolites. 20 to 30% are bound to plasma proteins while circulating in the bloodstream.[7][24][60][61]

Azathioprine is a prodrug, a substance that is not an active drug itself but is activated in the body. This happens in several steps; at first it is slowly and almost completely converted to 6-mercaptopurine (6-MP) by reductive cleavage of the thioether (–S–). This is mediated by glutathione and similar compounds in the intestinal wall, the liver and on red blood cells, without the aid of enzymes. 6-MP is metabolized analogously to natural purines, giving thioguanosine triphosphate (TGTP) and thio-deoxyguanosine triphosphate (TdGTP) via thioinosine monophosphate (TIMP) and several further intermediates. On a second path, the sulfur atom of 6-MP and TIMP is methylated. The end products of azathioprine metabolism are thiouric acid (38%) and various methylated and hydroxylated purines, which are excreted via the urine.[31][60][61]

Mechanism of action

The purine molecule is the framework for two of the four bases that occur in DNA, adenine and guanine. Consequently, blocking the synthesis of purine also hinders DNA synthesis and thus inhibits the proliferation of cells, especially fast-growing cells without a method of nucleotide salvage ("recycling"), such as lymphocytes.[6][61] Two types of lymphocytes, T cells and B cells, are particularly affected by the inhibition of purine synthesis.[43]

Azathioprine's active metabolite methyl-thioinosine monophosphate (MeTIMP) is a purine synthesis inhibitor that works by blocking the enzyme amidophosphoribosyltransferase,[62] possibly among others. Additional mechanisms, mediated by other metabolites, have been discovered several decades after the drug's introduction, mainly in the 1990s and 2000s:[6] Thioguanosine triphosphate (TGTP) is incorporated into RNA, compromising its functionality. It also interacts with the GTP-binding protein Rac1, blocking upregulation of the protein Bcl-xL and thus sending activated T cells into apoptosis (a kind of programmed cell death). The closely related thio-deoxyguanosine triphosphate (TdGTP) is built into DNA.[59][62] Thioinosinic acid impedes later steps of DNA synthesis via enzymes such as adenylosuccinate synthase and IMP dehydrogenase. Moreover, azathioprine blocks the downstream effects of CD28 costimulation, a process required for T cell activation.[63] In vivo data indicate inflammatory bowel disease patients treated with azathioprine have more mononuclear cells that have undergone apoptosis than untreated controls, indicating this mechanism may be responsible for the in vivo response to the drug in this disease.[6]

Chemistry

Azathioprine is a thiopurine linked to a second heterocycle (an imidazole derivative) via a thioether. It is a pale yellow solid with a slightly bitter taste and a melting point of 238–245 °C. It is practically insoluble in water and only slightly soluble in lipophilic solvents such as chloroform, ethanol and diethylether. It dissolves in alkaline aqueous solutions, where it hydrolyzes to 6-mercaptopurine.[60]

Azathioprine is synthesized from 5-chloro-1-methyl-4-nitro-1H-imidazole and 6-mercaptopurine in dimethyl sulfoxide (DMSO).[64] The synthesis of the former starts with an amide from methylamine and diethyl oxalate, which is then cyclizised and chlorinated with phosphorus pentachloride;[65] the nitro group is introduced with nitric 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.[3][66][67]

Robert Schwartz investigated the effect of 6-MP on the immune response in 1958 and discovered that it profoundly suppresses the formation of antibodies when given to rabbits together with antigens.[68] 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 heart transplants.[69] When Calne asked Elion for related compounds to investigate, she suggested azathioprine, which was subsequently found out to be superior (as effective and less toxic to the bone marrow) by Calne.[3][7] On 5 April 1962, with regimens consisting of azathioprine and prednisone, the transplantation of kidneys to unrelated recipients (allotransplantation) was successful for the first time.[7][70] 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.

Ciclosporin has now replaced some of the azathioprine use due to a longer survival time, especially in heart-related transplantations.[71][72][73] Moreover, despite being considerably 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.[10][74]

References

  1. ↑ "Azathioprine". Merriam-Webster Dictionary.
  2. 1 2 3 4 5 American Society of Health-System Pharmacists (January 2012). "Azathioprine, Azathioprine Sodium". AHFS Drug Information 2012. American Society of Health-System Pharmacists. ISBN 978-1-58528-267-8.
  3. 1 2 3 Elion, G. (1989). "The purine path to chemotherapy". Science. 244 (4900): 41–47. doi:10.1126/science.2649979. PMID 2649979.
  4. 1 2 Evans WE. (2004). "Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy.". Ther Drug Monit. 26 (2): 186–91. doi:10.1097/00007691-200404000-00018. PMID 15228163.
  5. 1 2 International Agency for Research on Cancer (IARC) (1987). "Azathioprine". Summaries & Evaluations. World Health Organization. suppl. 7: 119.
  6. 1 2 3 4 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 152947Freely accessible. PMID 12697731.
  7. 1 2 3 4 5 6 7 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.
  8. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  9. ↑ 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.
  10. 1 2 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.
  11. ↑ Suarez-Almazor, M. E.; Spooner, C.; Belseck, E. (2000). Suarez-Almazor, Maria E, ed. "Cochrane Database of Systematic Reviews". Azathioprine for treating rheumatoid arthritis. doi:10.1002/14651858.CD001461.
  12. 1 2 Sandborn, W. J. (1998). "Azathioprine: State of the art in inflammatory bowel disease". Scandinavian journal of gastroenterology. Supplement. 225: 92–99. PMID 9515759.
  13. ↑ Biancone, L.; Tosti, C.; Fina, D.; Fantini, M.; De Nigris, F.; Geremia, A.; Pallone, F. (2003). "Maintenance treatment of Crohn's disease". Alimentary Pharmacology & Therapeutics. 17: 31–37. doi:10.1046/j.1365-2036.17.s2.20.x. PMID 12786610.
  14. ↑ Rutgeerts, P. (2004). "Treatment of perianal fistulizing Crohn's disease". Alimentary Pharmacology & Therapeutics. 20: 106–110. doi:10.1111/j.1365-2036.2004.02060.x. PMID 15352905.
  15. ↑ Kandiel, A; Fraser, AG; Korelitz, BI; Brensinger, C; Lewis, JD (Aug 2005). "Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine.". Gut. 54 (8): 1121–5. doi:10.1136/gut.2004.049460. PMC 1774897Freely accessible. PMID 16009685.
  16. ↑ 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.
  17. ↑ Cosnes, J. (2013). "Early Administration of Azathioprine vs Conventional Management of Crohn's Disease: A Randomized Controlled Trial". Gastroenterology. 145 (4): 758–774. doi:10.1053/j.gastro.2013.04.048.
  18. ↑ Abu-Shakra, M.; Shoenfeld, Y. (2001). "Azathioprine therapy for patients with systemic lupus erythematosus". Lupus. 10 (3): 152–153. doi:10.1191/096120301676669495. PMID 11315344.
  19. ↑ Olszewska, M.; Kolacinska-Strasz, Z.; Sulej, J.; Labecka, H.; Cwikla, J.; Natorska, U.; Blaszczyk, M. (2007). "Efficacy and safety of cyclophosphamide, azathioprine, and cyclosporine (ciclosporin) as adjuvant drugs in pemphigus vulgaris". American journal of clinical dermatology. 8 (2): 85–92. doi:10.2165/00128071-200708020-00004. PMID 17428113.
  20. ↑ Richman, D. P.; Agius, M. A. (2003). "Treatment of autoimmune myasthenia gravis". Neurology. 61 (12): 1652–1661. doi:10.1212/01.wnl.0000098887.24618.a0. PMID 14694025.
  21. ↑ Meggitt, S. J.; Gray, J. C.; Reynolds, N. J. (2006). "Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: A double-blind, randomised controlled trial". The Lancet. 367 (9513): 839–846. doi:10.1016/S0140-6736(06)68340-2. PMID 16530578.
  22. ↑ Casetta, I.; Iuliano, G.; Filippini, G. (2009). "Azathioprine for multiple sclerosis". Journal of Neurology, Neurosurgery & Psychiatry. 80 (2): 131–132; discussion 132. doi:10.1136/jnnp.2008.144972. PMID 19151017.
  23. ↑ The Idiopathic Pulmonary Fibrosis Clinical Research Network (2012). "Prednisone, Azathioprine, and N-Acetylcysteine for Pulmonary Fibrosis". N Engl J Med. 366: 1968–1977. doi:10.1056/NEJMoa1113354. PMC 3422642Freely accessible. PMID 22607134.
  24. 1 2 3 4 Jasek, W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 4103–9. ISBN 978-3-85200-181-4.
  25. ↑ 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. & 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.
  26. ↑ Carol Eustice (October 23, 2005). "Blood Donation - Are rheumatoid arthritis patients able to donate blood?". About.com. Retrieved November 29, 2011.
  27. 1 2 Zaza G, Cheok M, Krynetskaia N, Thorn C, Stocco G, Hebert JM, McLeod H, Weinshilboum RM, Relling MV, Evans WE, Klein TE, Altman RB (September 2010). "Thiopurine pathway". Pharmcogenet Genomics. 20 (9): 573–4. doi:10.1097/FPC.0b013e328334338f. PMID 19952870.
  28. ↑ Stocco G, Pelin M, Franca R, De Iudicibus S, Cuzzoni E, Favretto D, Martelossi S, Ventura A, Decorti G (April 2014). "Pharmacogenetics of azathioprine in inflammatory bowel disease: a role for glutathione-S-transferase?". World J Gastroenterol. 20 (13): 3534–41. doi:10.3748/wjg.v20.i13.3534. PMID 24707136.
  29. ↑ Fujita K, Sasaki Y (August 2007). "Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy". Curr. Drug Metab. 8 (6): 554–62. doi:10.2174/138920007781368890. PMID 17691917.
  30. 1 2 3 Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, Stein CM, Carrillo M, Evans WE, Klein TE (March 2011). Clinical Pharmacogenetics Implementation Consortium. "Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing". Clin Pharmacol Ther. 89 (3): 387–91. doi:10.1038/clpt.2010.320. PMC 3098761Freely accessible. PMID 21270794.
  31. 1 2 Mutschler, Ernst; Schäfer-Korting, Monika (2001). Arzneimittelwirkungen (in German) (8th ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. pp. 107, 936. ISBN 3-8047-1763-2.
  32. ↑ 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.
  33. ↑ "Label: Imuran - azathioprine tablet". Retrieved 19 October 2014.
  34. ↑ Wang L, Pelleymounter L, Weinshilboum R, Johnson JA, Hebert JM, Altman RB, Klein TE (June 2010). "Very important pharmacogene summary: thiopurine S-methyltransferase". Pharmacogenet Genomics. 20 (6): 401–5. doi:10.1097/FPC.0b013e3283352860. PMC 3086840Freely accessible. PMID 20154640.
  35. ↑ National Toxicology Program (10 June 2011). "Report On Carcinogens – Twelfth Edition – 2011" (PDF). National Toxicology Program. Retrieved June 20, 2012.
  36. ↑ "FDA: Cancer Warnings Required for TNF Blockers". FDA. August 4, 2009. Retrieved June 20, 2012.
  37. ↑ International Agency for Research on Cancer (IARC) (1981). "Azathioprine – 5. Summary of Data Reported and Evaluation". Summaries & Evaluations. World Health Organization. 26: 47.
  38. ↑ 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.
  39. ↑ 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 1774869Freely accessible. PMID 16009676.
  40. ↑ "Imuran (azathioprine) Tablets and Injection". FDA. May 2011. Retrieved June 20, 2012.
  41. ↑ "Skin cancer alert for organ drug". BBC Online. BBC news. September 15, 2005. Retrieved June 10, 2012.
  42. ↑ O'Donovan, P.; Perrett, C. M.; Zhang, X.; Montaner, B.; Xu, Y.-Z.; Harwood, C. A.; McGregor, J. M.; Walker, S. L.; Hanaoka, F.; Karran, P. (2005). "Azathioprine and UVA Light Generate Mutagenic Oxidative DNA Damage". Science. 309 (5742): 1871–1874. doi:10.1126/science.1114233. PMC 2426755Freely accessible. PMID 16166520.
  43. 1 2 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.
  44. ↑ Chocair P, Duley J, Simmonds HA, et al. (1993). "Low-dose allopurinol plus azathioprine/cyclosporin/prednisolone, a novel immunosuppressive regimen.". Lancet. 342 (8863): 83–84. doi:10.1016/0140-6736(93)91287-V. PMID 8100914.
  45. ↑ 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 (5): 441–6. doi:10.1111/j.1365-2036.2005.02583.x. PMID 16128682.
  46. ↑ 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.
  47. ↑ Govani SM, Higgins PD (2010). "Combination of thiopurines and allopurinol: adverse events and clinical benefit in IBD". J Crohns Colitis. 4: 444–9. doi:10.1016/j.crohns.2010.02.009. PMC 3157326Freely accessible. PMID 21122542.
  48. ↑ Ansari AR, Patel N, Sanderson J, et al. (2010). "Low dose azathioprine or 6-mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease.". Aliment Pharmacol Ther. 31 (6): 640–647. doi:10.1111/j.1365-2036.2009.04221.x. PMID 20015102.
  49. ↑ Oliveria A, Sanches M, Selores M (2011). "Azathioprine-induced pellagra". J Dermatol. 38 (10): 1035–7. doi:10.1111/j.1346-8138.2010.01189.x. PMID 21658113.
  50. ↑ Kim CJ, Park K, Inoue H, et al. (1998). "Azathioprine-Induced megaloblastic anemia with pancytopenia 22 years after living-related renal transplantation". Int J Urol. 5 (1): 100–102. doi:10.1111/j.1442-2042.1998.tb00250.x. PMID 9535611.
  51. 1 2 Dinesh K. Mehta (March 2003). British National Formulary, Issue 45. Pharmaceutical Society of Great Britain. London: British Medical Association. ISBN 0-85369-555-5.
  52. ↑ 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.
  53. ↑ Tagatz, G. E.; Simmons, R. L. (1975). "Pregnancy after renal transplantation". Annals of Internal Medicine. 82 (1): 113–114. doi:10.7326/0003-4819-82-1-113. PMID 799904.
  54. ↑ Nørgård, B.; L. Pedersen; K. Fonager; S. Rasmussen; H. Sørensen (March 2003). "Azathioprine, mercaptopurine and birth outcome: a population-based cohort study". Alimentary Pharmacology & Therapeutics. 17 (6): 827–834. doi:10.1046/j.1365-2036.2003.01537.x. PMID 12641505.
  55. ↑ 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. doi:10.1001/jama.211.11.1854. PMID 4905893.
  56. ↑ 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.
  57. ↑ Thomas W. Hale (April 2010). Medications and Mothers' Milk: A Manual of Lactational Pharmacology. Hale Pub. ISBN 978-0-9823379-9-8.
  58. ↑ 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 1766779Freely accessible. PMID 15479867.
  59. 1 2 Karran, P.; Attard, N. (2008). "Thiopurines in current medical practice: Molecular mechanisms and contributions to therapy-related cancer". Nature Reviews Cancer. 8 (1): 24–36. doi:10.1038/nrc2292. PMID 18097462.
  60. 1 2 3 Dinnendahl, V; Fricke, U, eds. (2011). Arzneistoff-Profile (in German). 2 (25th ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
  61. 1 2 3 Steinhilber, D; Schubert-Zsilavecz, M; Roth, HJ (2005). Medizinische Chemie (in German). Stuttgart: Deutscher Apotheker Verlag. p. 340. ISBN 3-7692-3483-9.
  62. 1 2 "Azathioprine Pathway". Small Molecule Pathway Database. Archived from the original on 2 July 2012. Retrieved 31 August 2012.
  63. ↑ 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.
  64. ↑ US Patent 3056785, G. H. Hitchings; Yonkers & G. B. Elion, "Purine Derivatives", issued 1962-10-06.
  65. ↑ Blicke, F. F.; Godt, H. C. (1954). "Diuretics. I. 3-Substituted Paraxanthines". Journal of the American Chemical Society. 76 (14): 3653–3655. doi:10.1021/ja01643a015.
  66. ↑ 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.
  67. ↑ 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 (3): 297–302. doi:10.1530/jrf.0.0040297. PMID 13980986.
  68. ↑ 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. doi:10.3181/00379727-99-24281. PMID 13601801.
  69. ↑ Calne, R. Y. (1960). "The rejection of renal homografts". The Lancet. 275 (7121): 417–418. doi:10.1016/S0140-6736(60)90343-3.
  70. ↑ 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.
  71. ↑ 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.
  72. ↑ 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): 533–536. doi:10.1016/0002-9610(85)90431-3.
  73. ↑ 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.; Moran, M. (1985). "Cyclosporine in heart and heart-lung transplantation". Canadian Journal of Surgery. 28 (3): 274–280, 282. PMID 3922606.
  74. ↑ 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.

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