Azathioprine Explained

Watchedfields:changed
Verifiedrevid:458437709
Width:125
Width2:200
Tradename:Azasan, Imuran, Jayempi, others
Dailymedid:Azathioprine
Pregnancy Au:D
Routes Of Administration:By mouth, intravenous
Atc Prefix:L04
Atc Suffix:AX01
Legal Au:S4
Legal Ca:Rx-only
Legal Uk:POM
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Eu Comment:[1] [2]
Bioavailability:60±31%
Protein Bound:20–30%
Metabolism:Activated non-enzymatically, deactivated mainly by xanthine oxidase
Elimination Half-Life:26–80 minutes (azathioprine)
3–5 hours (drug plus metabolites)
Excretion:Kidney, 98% as metabolites
Cas Number:446-86-6
Cas Supplemental:
(sodium salt)
Pubchem:2265
Drugbank:DB00993
Chemspiderid:2178
Unii:MRK240IY2L
Kegg:D00238
Chebi:2948
Chembl:1542
Synonyms:AZA
Iupac Name:6-[(1-Methyl-4-nitro-1''H''-imidazol-5-yl)sulfanyl]-7H-purine
C:9
H:7
N:7
O:2
S:1
Smiles:Cn1cnc(N(=O)=O)c1Sc2ncnc3nc[nH]c23
Stdinchi: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)
Stdinchikey:LMEKQMALGUDUQG-UHFFFAOYSA-N
Melting Point:238
Melting High:245

Azathioprine, sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used for the treatment of rheumatoid arthritis, granulomatosis with polyangiitis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus; and in kidney transplants to prevent rejection. It is listed by the International Agency for Research on Cancer as a group 1 human carcinogen.[3] [4] [5] It is taken by mouth or injected into a vein.[6]

Common side effects include bone-marrow suppression and vomiting.[6] Bone-marrow suppression is especially common in people with a genetic deficiency of the enzyme thiopurine S-methyltransferase.[6] Other serious risk factors include an increased risk of certain cancers.[6] Use during pregnancy may result in harm to the baby.[6] Azathioprine belongs to the purine analogues subclass of antimetabolites family of medications.[6] It works via 6-thioguanine to disrupt the making of RNA and DNA by cells.[6]

Azathioprine was first made in 1957.[7] It is on the World Health Organization's List of Essential Medicines.[8] In 2018, it was the 358th most commonly prescribed medication in the United States, with more than 800,000 prescriptions.[9]

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.[10] 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.[11]

In the United States, it is approved by the Food and Drug Administration for use in kidney transplantation from human donors, and for rheumatoid arthritis.[12]

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.[13] The administration protocol starts either at the time of transplantation or within the following two days.[12]

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.[14] Nonsteroidal anti-inflammatory drugs and corticosteroids may be combined or continued (if they were already in use) with azathioprine, but the combination with other DMARDs is not recommended.[12]

Inflammatory bowel disease

Azathioprine has been used in the management of moderate to severe chronically active Crohn's disease,[15] to maintain clinical remission (absence of disease activity) in corticosteroid-dependent patients,[16] and to provide benefit in people with fistulizing Crohn's disease.[17] The onset of action is slow, and it may require several months to achieve clinical response.

Azathioprine treatment is associated with an increased risk of lymphoma, but if this is due to the drug or a predisposition related to Crohn's disease is unclear.[18] Lower doses of azathioprine are used as a therapy in children with refractory or corticosteroid-dependent Crohn's disease, without causing many side effects.[19] It may also be used to prevent flares in those with ulcerative colitis.[20]

Others

Azathioprine is sometimes used in systemic lupus erythematosus, requiring a maintenance dose of 15 mg or higher of prednisone in those who experience recurrent flares.[21]

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.[22] [23] Azathioprine is also used to maintain remission in people who have granulomatosis with polyangiitis.[4]

It can be very effective in eczema and atopic dermatitis, though it is not commonly used. The British National Eczema Society lists it as a third-line treatment for severe to moderate cases of these skin diseases.[24]

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 people who frequently relapse.[25] A 2007 Cochrane review found that azathioprine reduced the number of relapses in the first year of treatment and disease progression in the first two to three years and did not find an increase in cancer, and noted the need for direct comparison of azathioprine and interferon beta, conflicting conclusions regarding cancer, and the potential for long-term risks.[26]

A widely used therapy for idiopathic pulmonary fibrosis was azathioprine in combination with prednisone and N-acetylcysteine. A 2012 study showed that outcomes were worse with this combination than with placebo.[27]

Adverse effects

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 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 be more susceptible to infection; regular monitoring of the blood count is recommended during treatment.[12] [28] Acute pancreatitis can also occur, especially in patients with Crohn's disease.[29] Treatment is discontinued in up to 30% of patients due these effects but therapeutic drug monitoring of the biologically active metabolites, i.e. thiopurine nucleotides can help to optimize the efficacy and safety. Clinically, most hospitals resort to ion-exchange LC-MS (liquid chromotography – mass spectrometry) but the newly developed approach of porous graphitic carbon based chromatography hyphenated with mass spectrometry appears superior with respect to patient care in this respect.[30]

It is listed by the International Agency for Research on Cancer as a group 1 carcinogen (carcinogenic to humans).

Pharmacogenetics

The enzyme thiopurine S-methyltransferase (TPMT) is responsible for various activation and deactivation steps in azathioprine's mechanism of action.[31] 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.[32] [33] 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.[32] [34] 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.[35] 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.[35] [36] 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.[35] [37] The FDA-approved drug label for azathioprine recommends testing for TPMT activity to identify patients at risk for myelotoxicity.[38] Indeed, testing for TPMT activity is one of the few examples of pharmacogenetics being translated into routine clinical care.[39] Missense SNP in NUDT15 (e.g., rs116855232, inducing R139C)) has been identified to be a causal factor for AZA-induced leukopenia through a genome wide association study (GWAS) in East Asians.[40]

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."[41] Since August 2009, the U.S. FDA has required warnings to be placed on packaging with respect to increased risks of certain cancers.[42]

The risks involved seem to be related both to the duration and 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 have provided "sufficient" evidence of azathioprine carcinogenicity in humans (group 1),[43] although the methodology of past studies and the possible underlying mechanisms are questioned.[44]

The various diseases requiring transplantation may in themselves increase the risks of non-Hodgkin 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.[45]

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.[46] 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.[47]

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.[48] 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.[49]

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 its bone-marrow suppression.

Interactions

Other purine analogues, such as allopurinol, inhibit xanthine oxidase, the enzyme that breaks down azathioprine, thus increasing the toxicity of azathioprine.[50] Low doses of allopurinol, though, have been shown to safely enhance the efficacy of azathioprine, especially in inflammatory bowel disease nonresponders.[51] [52] [53] This may still lead to lower lymphocyte counts and higher rates of infection, therefore the combination requires careful monitoring.[54] [55]

Azathioprine decreases the effects of the anticoagulant warfarin and of nondepolarizing muscle relaxants, but increases the effect of depolarizing muscle relaxants. It can also interfere with niacin (vitamin B3), resulting in at least one case to pellagra and fatal medullary aplasia.[56]

Pregnancy and breastfeeding

Azathioprine can cause birth defects.[57] [58] [59] 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.[60] Birth defects in a child whose father was taking azathioprine have also been reported.[61] 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.[62] 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.[57]

Traditionally, as for all cytotoxic drugs, the manufacturer advises not to breastfeed whilst taking azathioprine, but the "lactation risk category" reported by Thomas Hale in his book Medications and Mothers' Milk lists azathioprine as "L3", termed "moderately safe".[63]

Pharmacology

Pharmacokinetics

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 1–2 hours, and the average plasma half-life is 26 to 80 minutes for azathioprine and 3–5 hours for drug plus metabolites. 20 to 30% are bound to plasma proteins while circulating in the bloodstream.[64] [65]

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 thiodeoxyguanosine 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.

Mechanism of action

Azathioprine inhibits purine synthesis. Purines are needed to produce DNA and RNA. By inhibiting purine synthesis, less DNA and RNA are produced for the synthesis of white blood cells, thus causing immunosuppression.

Azathioprine is converted within tissues to 6-MP, some of which is converted, in turn, to 6-thioguanine by the addition of an amino group. Both 6-MP and 6-thioguanine are conjugated with ribose, and then phosphorylated to form the nucleotides thioinosinic acid and thioguanylic acid, respectively. These nucleotides masquerade, respectively, as inosinic acid and guanylic acid; the former is the starting point for purine nucleotide biosynthesis, while the latter is one of the building blocks of DNA and RNA.

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.

Azathioprine is synthesized from 5-chloro-1-methyl-4-nitro-1H-imidazole and 6-mercaptopurine in dimethyl sulfoxide.[68] The synthesis of the former starts with an amide from methylamine and diethyl oxalate, which is then cyclized and chlorinated with phosphorus pentachloride;[69] 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-MP in a metabolically active, but masked form, and at first used as a chemotherapy drug.[70] [71]

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.[72] 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.[73] 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.[74]

In April 1962, with regimens consisting of azathioprine and prednisone, the transplantation of kidneys to unrelated recipients (allotransplantation) was successful for the first time.[75] For many years, this kind of dual therapy with azathioprine and glucocorticoids was the standard antirejection regimen, until cyclosporin was introduced into clinical practice (by Calne as well) in 1978.

Cyclosporin has now replaced some of the azathioprine use due to a longer survival time, especially in heart-related transplantations.[76] [77] [78] 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.[79] [80]

Further reading

Notes and References

  1. Web site: Jayempi EPAR . European Medicines Agency . 20 April 2021 . 4 March 2023.
  2. Web site: Jayempi Product information . Union Register of medicinal products . 3 March 2023.
  3. Axelrad JE, Lichtiger S, Yajnik V . Inflammatory bowel disease and cancer: The role of inflammation, immunosuppression, and cancer treatment . World Journal of Gastroenterology . 22 . 20 . 4794–4801 . May 2016 . 27239106 . 4873872 . 10.3748/wjg.v22.i20.4794 . Review . free .
  4. Singer O, McCune WJ . Update on maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis . Current Opinion in Rheumatology . 29 . 3 . 248–253 . May 2017 . 28306595 . 10.1097/BOR.0000000000000382 . 35805200 .
  5. Jordan N, D'Cruz D . Current and emerging treatment options in the management of lupus . ImmunoTargets and Therapy . 5 . 9–20 . 2016 . 27529058 . 4970629 . 10.2147/ITT.S40675 . free .
  6. Web site: Azathioprine. The American Society of Health-System Pharmacists. 8 December 2016. live. https://web.archive.org/web/20160820215808/https://www.drugs.com/monograph/azathioprine.html. 20 August 2016.
  7. Book: Sami N . Autoimmune Bullous Diseases: Approach and Management. 2016. Springer. 9783319267289. 83. live. https://web.archive.org/web/20161221162220/https://books.google.ca/books?id=eMSbCwAAQBAJ&pg=PA83. 2016-12-21.
  8. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 21st list 2019 . 2019 . 10665/325771 . World Health Organization . World Health Organization . Geneva . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO . free .
  9. Web site: Azathioprine - Drug Usage Statistics . ClinCalc . 7 October 2022.
  10. Patel AA, Swerlick RA, McCall CO . Azathioprine in dermatology: the past, the present, and the future . Journal of the American Academy of Dermatology . 55 . 3 . 369–389 . September 2006 . 16908341 . 10.1016/j.jaad.2005.07.059 .
  11. Evans WE . Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy . Therapeutic Drug Monitoring . 26 . 2 . 186–191 . April 2004 . 15228163 . 10.1097/00007691-200404000-00018 . 34015182 .
  12. Book: AHFS Drug Information 2012 . January 2012 . American Society of Health-System Pharmacists . 978-1-58528-267-8 . Azathioprine, Azathioprine Sodium . American Society of Health-System Pharmacists . American Society of Health-System Pharmacists .
  13. Nuyttens JJ, Harper J, Jenrette JM, Turrisi AT . Outcome of radiation therapy for renal transplant rejection refractory to chemical immunosuppression . Radiotherapy and Oncology . 74 . 1 . 17–19 . January 2005 . 15683663 . 10.1016/j.radonc.2004.08.011 .
  14. Suarez-Almazor ME, Spooner C, Belseck E . Azathioprine for treating rheumatoid arthritis . The Cochrane Database of Systematic Reviews . 2010 . 4 . CD001461 . 2000 . 11034720 . 8406472 . 10.1002/14651858.CD001461 . Suarez-Almazor ME .
  15. Sandborn WJ . Azathioprine: state of the art in inflammatory bowel disease . Scandinavian Journal of Gastroenterology. Supplement . 225 . 234 . 92–99 . 1998 . 9515759 . 10.1080/003655298750027290 .
  16. Biancone L, Tosti C, Fina D, Fantini M, De Nigris F, Geremia A, Pallone F . Review article: maintenance treatment of Crohn's disease . Alimentary Pharmacology & Therapeutics . 17 . Suppl 2 . 31–37 . June 2003 . 12786610 . 10.1046/j.1365-2036.17.s2.20.x . 23554085 .
  17. Rutgeerts P . Review article: treatment of perianal fistulizing Crohn's disease . Alimentary Pharmacology & Therapeutics . 20 . Suppl 4 . 106–110 . October 2004 . 15352905 . 10.1111/j.1365-2036.2004.02060.x . 71968695 . free .
  18. Kandiel A, Fraser AG, Korelitz BI, Brensinger C, Lewis JD . Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine . Gut . 54 . 8 . 1121–1125 . August 2005 . 16009685 . 1774897 . 10.1136/gut.2004.049460 .
  19. Kirschner BS . Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease . Gastroenterology . 115 . 4 . 813–821 . October 1998 . 9753482 . 10.1016/S0016-5085(98)70251-3 . free .
  20. Timmer A, Patton PH, Chande N, McDonald JW, MacDonald JK . Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis . The Cochrane Database of Systematic Reviews . 2016 . 5 . CD000478 . May 2016 . 27192092 . 7034525 . 10.1002/14651858.CD000478.pub4 .
  21. Abu-Shakra M, Shoenfeld Y . Azathioprine therapy for patients with systemic lupus erythematosus . Lupus . 10 . 3 . 152–153 . 2001 . 11315344 . 10.1191/096120301676669495 . 71558242 .
  22. Olszewska M, Kolacinska-Strasz Z, Sulej J, Labecka H, Cwikla J, Natorska U, Blaszczyk M . Efficacy and safety of cyclophosphamide, azathioprine, and cyclosporine (ciclosporin) as adjuvant drugs in pemphigus vulgaris . American Journal of Clinical Dermatology . 8 . 2 . 85–92 . 2007 . 17428113 . 10.2165/00128071-200708020-00004 . 10699017 .
  23. Richman DP, Agius MA . Treatment of autoimmune myasthenia gravis . Neurology . 61 . 12 . 1652–1661 . December 2003 . 14694025 . 10.1212/01.wnl.0000098887.24618.a0 . 24755812 .
  24. Meggitt SJ, Gray JC, Reynolds NJ . Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind, randomised controlled trial . Lancet . 367 . 9513 . 839–846 . March 2006 . 16530578 . 10.1016/S0140-6736(06)68340-2 . 1616660 .
  25. Casetta I, Iuliano G, Filippini G . Azathioprine for multiple sclerosis . Journal of Neurology, Neurosurgery, and Psychiatry . 80 . 2 . 131–2; discussion 132 . February 2009 . 19151017 . 10.1136/jnnp.2008.144972 . 207001537 .
  26. Casetta I, Iuliano G, Filippini G . Azathioprine for multiple sclerosis . The Cochrane Database of Systematic Reviews . 2007 . 4 . CD003982 . October 2007 . 17943809 . 6823213 . 10.1002/14651858.CD003982.pub2 .
  27. Raghu G, Anstrom KJ, King TE, Lasky JA, Martinez FJ . Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis . The New England Journal of Medicine . 366 . 21 . 1968–1977 . May 2012 . 22607134 . 3422642 . 10.1056/NEJMoa1113354 .
  28. Book: Austria-Codex. Jasek, W. Österreichischer Apothekerverlag. Vienna. 2007. 62nd. 4103–9. 978-3-85200-181-4. de.
  29. Weersma RK, Peters FT, Oostenbrug LE, van den Berg AP, van Haastert M, Ploeg RJ, Posthumus MD, Homan van der Heide JJ, Jansen PL, van Dullemen HM . Increased incidence of azathioprine-induced pancreatitis in Crohn's disease compared with other diseases . Alimentary Pharmacology & Therapeutics . 20 . 8 . 843–850 . October 2004 . 15479355 . 10.1111/j.1365-2036.2004.02197.x . 21873238 .
  30. Pecher D, Zelinkova Z, Lucenicova J, Peppelenbosch M, Dokupilova S, Mikusova V, Mikus P . Porous graphitic carbon based chromatography hyphenated with mass spectrometry: A new strategy for profiling thiopurine nucleotides in patients with inflammatory bowel diseases . Analytica Chimica Acta . 1137 . 1137 . 64–73 . November 2020 . 33153610 . 10.1016/j.aca.2020.08.064 . 2020AcAC.1137...64P . 225287631 .
  31. Book: Medical Genetics Summaries . Azathioprine Therapy and TPMT Genotype . https://www.ncbi.nlm.nih.gov/books/NBK100661/ . Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ . 3 . National Center for Biotechnology Information (NCBI) . 2012 . 28520349 . Bookshelf ID: NBK100661 . Dean L .
  32. Zaza G, Cheok M, Krynetskaia N, Thorn C, Stocco G, Hebert JM, McLeod H, Weinshilboum RM, Relling MV, Evans WE, Klein TE, Altman RB . Thiopurine pathway . Pharmacogenetics and Genomics . 20 . 9 . 573–574 . September 2010 . 19952870 . 3098750 . 10.1097/FPC.0b013e328334338f .
  33. Stocco G, Pelin M, Franca R, De Iudicibus S, Cuzzoni E, Favretto D, Martelossi S, Ventura A, Decorti G . Pharmacogenetics of azathioprine in inflammatory bowel disease: a role for glutathione-S-transferase? . World Journal of Gastroenterology . 20 . 13 . 3534–3541 . April 2014 . 24707136 . 3974520 . 10.3748/wjg.v20.i13.3534 . free .
  34. Fujita K, Sasaki Y . Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy . Current Drug Metabolism . 8 . 6 . 554–562 . August 2007 . 17691917 . 10.2174/138920007781368890 . dead . https://archive.today/20130112103320/http://www.bentham-direct.org/pages/content.php?CDM/2007/00000008/00000006/0002F.SGM . 2013-01-12 .
  35. Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, Stein CM, Carrillo M, Evans WE, Klein TE . Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing . Clinical Pharmacology and Therapeutics . 89 . 3 . 387–391 . March 2011 . 21270794 . 3098761 . 10.1038/clpt.2010.320 . Clinical Pharmacogenetics Implementation Consortium .
  36. Book: Mutschler E, Schäfer-Korting M . Arzneimittelwirkungen. 107, 936. de. Stuttgart. Wissenschaftliche Verlagsgesellschaft. 2001. 8th. 978-3-8047-1763-3.
  37. Payne K, Newman W, Fargher E, Tricker K, Bruce IN, Ollier WE . TPMT testing in rheumatology: any better than routine monitoring? . Rheumatology . 46 . 5 . 727–729 . May 2007 . 17255139 . 10.1093/rheumatology/kel427 . free .
  38. Web site: Label: Imuran - azathioprine tablet. 19 October 2014. live. https://web.archive.org/web/20141020220249/http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aaa6c540-4c84-48a0-939c-cd423134fa2a. 20 October 2014.
  39. Wang L, Pelleymounter L, Weinshilboum R, Johnson JA, Hebert JM, Altman RB, Klein TE . Very important pharmacogene summary: thiopurine S-methyltransferase . Pharmacogenetics and Genomics . 20 . 6 . 401–405 . June 2010 . 20154640 . 3086840 . 10.1097/FPC.0b013e3283352860 .
  40. Yang SK, Hong M, Baek J, Choi H, Zhao W, Jung Y, Haritunians T, Ye BD, Kim KJ, Park SH, Park SK, Yang DH, Dubinsky M, Lee I, McGovern DP, Liu J, Song K . A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia . Nature Genetics . 46 . 9 . 1017–1020 . September 2014 . 25108385 . 4999337 . 10.1038/ng.3060 .
  41. Web site: National Toxicology Program. National Toxicology Program. Report On Carcinogens – Twelfth Edition – 2011. 10 June 2011. National Toxicology Program. June 20, 2012. live. https://web.archive.org/web/20120716214414/http://ntp.niehs.nih.gov/ntp/roc/twelfth/roc12.pdf. 16 July 2012.
  42. Web site: FDA: Cancer Warnings Required for TNF Blockers . August 4, 2009 . FDA . June 20, 2012 . live . https://web.archive.org/web/20120703083928/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm175803.htm . July 3, 2012 .
  43. International Agency for Research on Cancer (IARC). International Agency for Research on Cancer. 1981. Azathioprine – 5. Summary of Data Reported and Evaluation. Summaries & Evaluations. 26. 47. live. https://web.archive.org/web/20060906064533/http://www.inchem.org/documents/iarc/vol26/azathioprine.html. 2006-09-06.
  44. Gombar VK, Enslein K, Blake BW . Carcinogenicity of azathioprine: an S-AR investigation . Mutation Research . 302 . 1 . 7–12 . May 1993 . 7683109 . 10.1016/0165-7992(93)90083-8 .
  45. International Agency for Research on Cancer (IARC). International Agency for Research on Cancer. 1987. Azathioprine. Summaries & Evaluations. suppl. 7. 119. live. https://web.archive.org/web/20060604004241/http://www.inchem.org/documents/iarc/suppl7/azathioprine.html. 2006-06-04.
  46. McGovern DP, Jewell DP . Risks and benefits of azathioprine therapy . Gut . 54 . 8 . 1055–1059 . August 2005 . 16009676 . 1774869 . 10.1136/gut.2004.053231 .
  47. Web site: Imuran (azathioprine) Tablets and Injection . May 2011 . FDA . June 20, 2012 . live . https://web.archive.org/web/20120302092152/https://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm258794.htm . March 2, 2012 .
  48. Web site: Skin cancer alert for organ drug . September 15, 2005 . . . June 10, 2012 . live . https://web.archive.org/web/20121014205054/http://news.bbc.co.uk/2/hi/health/4248356.stm . October 14, 2012 .
  49. O'Donovan P, Perrett CM, Zhang X, Montaner B, Xu YZ, Harwood CA, McGregor JM, Walker SL, Hanaoka F, Karran P . Azathioprine and UVA light generate mutagenic oxidative DNA damage . Science . 309 . 5742 . 1871–1874 . September 2005 . 16166520 . 2426755 . 10.1126/science.1114233 . 2005Sci...309.1871O .
  50. Sahasranaman S, Howard D, Roy S . Clinical pharmacology and pharmacogenetics of thiopurines . European Journal of Clinical Pharmacology . 64 . 8 . 753–767 . August 2008 . 18506437 . 10.1007/s00228-008-0478-6 . 27475772 .
  51. Chocair P, Duley J, Simmonds HA, Cameron JS, Ianhez L, Arap S, Sabbaga E . Low-dose allopurinol plus azathioprine/cyclosporin/prednisolone, a novel immunosuppressive regimen . Lancet . 342 . 8863 . 83–84 . July 1993 . 8100914 . 10.1016/0140-6736(93)91287-V . 13419507 .
  52. Sparrow MP, Hande SA, Friedman S, Lim WC, Reddy SI, Cao D, Hanauer SB . Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine . Alimentary Pharmacology & Therapeutics . 22 . 5 . 441–446 . September 2005 . 16128682 . 10.1111/j.1365-2036.2005.02583.x . 9356163 . free .
  53. Sparrow MP, Hande SA, Friedman S, Cao D, Hanauer SB . Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine . Clinical Gastroenterology and Hepatology . 5 . 2 . 209–214 . February 2007 . 17296529 . 10.1016/j.cgh.2006.11.020 . free .
  54. Govani SM, Higgins PD . Combination of thiopurines and allopurinol: adverse events and clinical benefit in IBD . Journal of Crohn's & Colitis . 4 . 4 . 444–449 . October 2010 . 21122542 . 3157326 . 10.1016/j.crohns.2010.02.009 .
  55. Ansari A, Patel N, Sanderson J, O'Donohue J, Duley JA, Florin TH . Low-dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease . Alimentary Pharmacology & Therapeutics . 31 . 6 . 640–647 . March 2010 . 20015102 . 10.1111/j.1365-2036.2009.04221.x . 6000856 . free .
  56. Oliveira A, Sanches M, Selores M . Azathioprine-induced pellagra . The Journal of Dermatology . 38 . 10 . 1035–1037 . October 2011 . 21658113 . 10.1111/j.1346-8138.2010.01189.x . 3396280 .
  57. Book: British National Formulary, Issue 45 . March 2003 . . . 978-0-85369-555-4 . Mehta DK . . British National Formulary .
  58. Cleary BJ, Källén B . Early pregnancy azathioprine use and pregnancy outcomes . Birth Defects Research. Part A, Clinical and Molecular Teratology . 85 . 7 . 647–654 . July 2009 . 19343728 . 10.1002/bdra.20583 .
  59. Tagatz GE, Simmons RL . Pregnancy after renal transplantation . Annals of Internal Medicine . 82 . 1 . 113–114 . January 1975 . 799904 . 10.7326/0003-4819-82-1-113 .
  60. Nørgård B, Pedersen L, Fonager K, Rasmussen SN, Sørensen HT . Azathioprine, mercaptopurine and birth outcome: a population-based cohort study . Alimentary Pharmacology & Therapeutics . 17 . 6 . 827–834 . March 2003 . 12641505 . 10.1046/j.1365-2036.2003.01537.x . 25314258 . free .
  61. Tallent MB, Simmons RL, Najarian JS . Birth defects in child of male recipient of kidney transplant . JAMA . 211 . 11 . 1854–1855 . March 1970 . 4905893 . 10.1001/jama.211.11.1854 .
  62. Polifka JE, Friedman JM . Teratogen update: azathioprine and 6-mercaptopurine . Teratology . 65 . 5 . 240–261 . May 2002 . 11967923 . 10.1002/tera.10043 . 10.1.1.566.7676 .
  63. Book: Medications and Mothers' Milk: A Manual of Lactational Pharmacology . April 2010 . Hale Pub. . 978-0-9823379-9-8 . Hale TW .
  64. Book: Arzneistoff-Profile. Dinnendahl, V . Fricke, U . Govi Pharmazeutischer Verlag. Eschborn, Germany. 2011. 25th. 2. 978-3-7741-9846-3. de.
  65. Book: Medizinische Chemie. Steinhilber D, Schubert-Zsilavecz M, Roth HJ . Deutscher Apotheker Verlag. Stuttgart. 2005. 340. 978-3-7692-3483-1. de.
  66. Web site: Azathioprine Pathway . Small Molecule Pathway Database . 31 August 2012 . dead . https://web.archive.org/web/20120702065409/http://pathman.smpdb.ca/pathways/SMP00427/pathway . 2 July 2012 .
  67. Maltzman JS, Koretzky GA . Azathioprine: old drug, new actions . The Journal of Clinical Investigation . 111 . 8 . 1122–1124 . April 2003 . 12697731 . 152947 . 10.1172/JCI18384 .
  68. US . 3056785 . Patent . Purine Derivatives . 1962-10-06 . 1960-05-21 . G. H. Hitchings . Yonkers . G. B. Elion . .
  69. Blicke FF, Godt HC . Diuretics. I. 3-Substituted Paraxanthines . Journal of the American Chemical Society . 76 . 14 . 3653–3655 . 1954 . 10.1021/ja01643a015 .
  70. Elion GB, Callahan SW, Hitchings GH, Rundles RW . The metabolism of 2-amino-6-[(1-methyl-4-nitro-5-imidazolyl)thio]purine (B.W. 57-323) in man . Cancer Chemotherapy Reports . 8 . 47–52 . July 1960 . 13849699 .
  71. Thiersch JB . 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 . December 1962 . 13980986 . 10.1530/jrf.0.0040297 .
  72. Schwartz R, Stack J, Dameshek W . Effect of 6-mercaptopurine on antibody production . Proceedings of the Society for Experimental Biology and Medicine . 99 . 1 . 164–167 . October 1958 . 13601801 . 10.3181/00379727-99-24281 . 8043359 .
  73. Calne RY . The rejection of renal homografts. Inhibition in dogs by 6-mercaptopurine . Lancet . 1 . 7121 . 417–418 . February 1960 . 13807024 . 10.1016/S0140-6736(60)90343-3 .
  74. Elion GB . The purine path to chemotherapy . Science . 244 . 4900 . 41–47 . April 1989 . 2649979 . 10.1126/science.2649979 . 1989Sci...244...41E .
  75. Murray JE, Merrill JP, Harrison JH, Wilson RE, Dammin GJ . Prolonged survival of human-kidney homografts by immunosuppressive drug therapy . The New England Journal of Medicine . 268 . 24 . 1315–1323 . June 1963 . 13936775 . 10.1056/NEJM196306132682401 .
  76. Bakker RC, Hollander AA, Mallat MJ, Bruijn JA, Paul LC, de Fijter JW . Conversion from cyclosporine to azathioprine at three months reduces the incidence of chronic allograft nephropathy . Kidney International . 64 . 3 . 1027–1034 . September 2003 . 12911553 . 10.1046/j.1523-1755.2003.00175.x . free .
  77. Henry ML, Sommer BG, Ferguson RM . Beneficial effects of cyclosporine compared with azathioprine in cadaveric renal transplantation . American Journal of Surgery . 150 . 5 . 533–536 . November 1985 . 2998215 . 10.1016/0002-9610(85)90431-3 .
  78. Modry DL, Oyer PE, Jamieson SW, Stinson EB, Baldwin JC, Reitz BA, Dawkins KD, McGregor CG, Hunt SA, Moran M . Cyclosporine in heart and heart-lung transplantation . Canadian Journal of Surgery. Journal Canadien de Chirurgie . 28 . 3 . 274–80, 282 . May 1985 . 3922606 .
  79. Remuzzi G, Lesti M, Gotti E, Ganeva M, Dimitrov BD, Ene-Iordache B, Gherardi G, Donati D, Salvadori M, Sandrini S, Valente U, Segoloni G, Mourad G, Federico S, Rigotti P, Sparacino V, Bosmans JL, Perico N, Ruggenenti P . Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial . Lancet . 364 . 9433 . 503–512 . August 2004 . 15302193 . 10.1016/S0140-6736(04)16808-6 . 22033113 .
  80. Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, Taylor RS . Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study . Health Technology Assessment . 9 . 21 . 1–194 . May 2005 . 15899149 . 10.3310/hta9210 . free .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Azathioprine".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.