Azathioprine

Last updated
Azathioprine
Azathioprine.svg
Azathioprine xtal 1984.png
Clinical data
Pronunciation /ˌæzəˈθaɪəˌpriːn/ [1]
Trade names Azasan, Imuran, Jayempi, others
Other namesAZA
AHFS/Drugs.com Monograph
MedlinePlus a682167
License data
Pregnancy
category
  • AU:D
Routes of
administration 		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 60±31%
Protein binding 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
Identifiers
  • 6-[(1-Methyl-4-nitro-1H-imidazol-5-yl)sulfanyl]-7H-purine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.006.525 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C9H7N7O2S
Molar mass 277.26 g·mol−1
3D model (JSmol)
Melting point 238 to 245 °C (460 to 473 °F)
  • Cn1cnc(N(=O)=O)c1Sc2ncnc3nc[nH]c23
  • 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) Yes check.svgY
  • Key:LMEKQMALGUDUQG-UHFFFAOYSA-N Yes check.svgY
   (verify)

Azathioprine, sold under the brand name Imuran, among others, is an immunosuppressive medication. [5] 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. [5] [6] [7] [8] It is taken by mouth or injected into a vein. [5]

Contents

Common side effects include bone-marrow suppression and vomiting. [5] Bone-marrow suppression is especially common in people with a genetic deficiency of the enzyme thiopurine S-methyltransferase. [5] Other serious risk factors include an increased risk of certain cancers. [5] Use during pregnancy may result in harm to the baby. [5] Azathioprine belongs to the purine analogues subclass of antimetabolites family of medications. [5] [9] It works via 6-thioguanine to disrupt the making of RNA and DNA by cells. [5] [9]

Azathioprine was first made in 1957. [9] It is on the World Health Organization's List of Essential Medicines. [10] In 2018, it was the 358th most commonly prescribed medication in the United States, with more than 800,000 prescriptions. [11]

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. [12] 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. [13]

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. [14]

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. [15] [16] The administration protocol starts either at the time of transplantation or within the following two days. [14]

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. [17] 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. [14]

Inflammatory bowel disease

Azathioprine has been used in the management of moderate to severe chronically active Crohn's disease, [18] to maintain clinical remission (absence of disease activity) in corticosteroid-dependent patients, [19] and to provide benefit in people with fistulizing Crohn's disease. [20] The onset of action is slow, and it may require several months to achieve clinical response. [18]

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. [21] Lower doses of azathioprine are used as a therapy in children with refractory or corticosteroid-dependent Crohn's disease, without causing many side effects. [22] It may also be used to prevent flares in those with ulcerative colitis. [23]

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. [24]

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. [12] [25] [26] Azathioprine is also used to maintain remission in people who have granulomatosis with polyangiitis. [7]

It can be very effective in eczema and atopic dermatitis, though it is not commonly used. [12] The British National Eczema Society lists it as a third-line treatment for severe to moderate cases of these skin diseases. [27]

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. [28] 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. [29]

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. [30]

Adverse effects

Two generic azathioprine oral tablets, 50 mg each 000040lg Azathioprine 50 MG Oral Tablet.jpg
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 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. [14] [31] Acute pancreatitis can also occur, especially in patients with Crohn's disease. [32] 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. [33]

It is listed by the International Agency for Research on Cancer as a group 1 carcinogen (carcinogenic to humans). [34]

Pharmacogenetics

The enzyme thiopurine S-methyltransferase (TPMT) is responsible for various activation and deactivation steps in azathioprine's mechanism of action. [35] 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. [36] [37] 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. [36] [38] 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. [39] 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. [39] [40] 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. [39] [41] The FDA-approved drug label for azathioprine recommends testing for TPMT activity to identify patients at risk for myelotoxicity. [42] Indeed, testing for TPMT activity is one of the few examples of pharmacogenetics being translated into routine clinical care. [43] 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. [44]

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." [45] Since August 2009, the U.S. FDA has required warnings to be placed on packaging with respect to increased risks of certain cancers. [46]

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), [47] although the methodology of past studies and the possible underlying mechanisms are questioned. [48]

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. [34]

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. [49] 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. [50]

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. [51] 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. [52]

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. [31]

Interactions

Other purine analogues, such as allopurinol, inhibit xanthine oxidase, the enzyme that breaks down azathioprine, thus increasing the toxicity of azathioprine. [53] Low doses of allopurinol, though, have been shown to safely enhance the efficacy of azathioprine, especially in inflammatory bowel disease nonresponders. [54] [55] [56] This may still lead to lower lymphocyte counts and higher rates of infection, therefore the combination requires careful monitoring. [57] [58]

Azathioprine decreases the effects of the anticoagulant warfarin and of nondepolarizing muscle relaxants, but increases the effect of depolarizing muscle relaxants. [31] It can also interfere with niacin (vitamin B3), resulting in at least one case to pellagra and fatal medullary aplasia. [59]

Pregnancy and breastfeeding

Azathioprine can cause birth defects. [60] [61] [62] 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. [63] Birth defects in a child whose father was taking azathioprine have also been reported. [64] 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. [65] 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. [60]

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". [66]

Pharmacology

Pharmacokinetics

Metabolic pathway for azathioprine (AZA). Active metabolites are highlighted. .mw-parser-output .hlist dl,.mw-parser-output .hlist ol,.mw-parser-output .hlist ul{margin:0;padding:0}.mw-parser-output .hlist dd,.mw-parser-output .hlist dt,.mw-parser-output .hlist li{margin:0;display:inline}.mw-parser-output .hlist.inline,.mw-parser-output .hlist.inline dl,.mw-parser-output .hlist.inline ol,.mw-parser-output .hlist.inline ul,.mw-parser-output .hlist dl dl,.mw-parser-output .hlist dl ol,.mw-parser-output .hlist dl ul,.mw-parser-output .hlist ol dl,.mw-parser-output .hlist ol ol,.mw-parser-output .hlist ol ul,.mw-parser-output .hlist ul dl,.mw-parser-output .hlist ul ol,.mw-parser-output .hlist ul ul{display:inline}.mw-parser-output .hlist .mw-empty-li{display:none}.mw-parser-output .hlist dt::after{content:": "}.mw-parser-output .hlist dd::after,.mw-parser-output .hlist li::after{content:" * ";font-weight:bold}.mw-parser-output .hlist dd:last-child::after,.mw-parser-output .hlist dt:last-child::after,.mw-parser-output .hlist li:last-child::after{content:none}.mw-parser-output .hlist dd dd:first-child::before,.mw-parser-output .hlist dd dt:first-child::before,.mw-parser-output .hlist dd li:first-child::before,.mw-parser-output .hlist dt dd:first-child::before,.mw-parser-output .hlist dt dt:first-child::before,.mw-parser-output .hlist dt li:first-child::before,.mw-parser-output .hlist li dd:first-child::before,.mw-parser-output .hlist li dt:first-child::before,.mw-parser-output .hlist li li:first-child::before{content:" (";font-weight:normal}.mw-parser-output .hlist dd dd:last-child::after,.mw-parser-output .hlist dd dt:last-child::after,.mw-parser-output .hlist dd li:last-child::after,.mw-parser-output .hlist dt dd:last-child::after,.mw-parser-output .hlist dt dt:last-child::after,.mw-parser-output .hlist dt li:last-child::after,.mw-parser-output .hlist li dd:last-child::after,.mw-parser-output .hlist li dt:last-child::after,.mw-parser-output .hlist li li:last-child::after{content:")";font-weight:normal}.mw-parser-output .hlist ol{counter-reset:listitem}.mw-parser-output .hlist ol>li{counter-increment:listitem}.mw-parser-output .hlist ol>li::before{content:" "counter(listitem)"\a0 "}.mw-parser-output .hlist dd ol>li:first-child::before,.mw-parser-output .hlist dt ol>li:first-child::before,.mw-parser-output .hlist li ol>li:first-child::before{content:" ("counter(listitem)"\a0 "} XO: xanthine oxidase 6-MP: 6-mercaptopurine TPMT: thiopurine methyltransferase 6-MMP: 6-methylmercaptopurine HPRT: hypoxanthine-guanine phosphoribosyltransferase TIMP: thioinosine monophosphate, thioinosinic acid MeTIMP: methyl-thioinosine monophosphate TGTP: thioguanosine triphosphate TdGTP: thio-deoxyguanosine triphosphate AZA metabolism.svg
Metabolic pathway for azathioprine (AZA). 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 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. [12] [31] [69] [70]

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. [40] [69] [70]

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. [13] 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. [69]

Azathioprine is synthesized from 5-chloro-1-methyl-4-nitro-1H-imidazole and 6-mercaptopurine in dimethyl sulfoxide. [73] The synthesis of the former starts with an amide from methylamine and diethyl oxalate, which is then cyclized and chlorinated with phosphorus pentachloride; [74] the nitro group is introduced with nitric and sulfuric acid.

Azathioprine synthesis.svg

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. [75] [76] [77]

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. [78] 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. [79] 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. [75] [12]

In April 1962, with regimens consisting of azathioprine and prednisone, the transplantation of kidneys to unrelated recipients (allotransplantation) was successful for the first time. [12] [80] 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. [81] [82] [83] 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. [16] [84]

Related Research Articles

<span class="mw-page-title-main">Crohn's disease</span> Type of inflammatory bowel disease

Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the gastrointestinal tract may include anemia, skin rashes, arthritis, inflammation of the eye, and fatigue. The skin rashes may be due to infections as well as pyoderma gangrenosum or erythema nodosum. Bowel obstruction may occur as a complication of chronic inflammation, and those with the disease are at greater risk of colon cancer and small bowel cancer.

<span class="mw-page-title-main">Ulcerative colitis</span> Inflammatory bowel disease that causes ulcers in the colon

Ulcerative colitis (UC) is one of the two types of inflammatory bowel disease (IBD), with the other type being Crohn's disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and anemia may also occur. Often, symptoms come on slowly and can range from mild to severe. Symptoms typically occur intermittently with periods of no symptoms between flares. Complications may include abnormal dilation of the colon (megacolon), inflammation of the eye, joints, or liver, and colon cancer.

<span class="mw-page-title-main">Immunosuppressive drug</span> Drug that inhibits activity of immune system

Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.

<span class="mw-page-title-main">Allopurinol</span> Medication

Allopurinol is a medication used to decrease high blood uric acid levels. It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy. It is taken orally or intravenously.

<span class="mw-page-title-main">Mycophenolic acid</span> Immunosuppressant medication

Mycophenolic acid is an immunosuppressant medication used to prevent rejection following organ transplantation and to treat autoimmune conditions such as Crohn's disease and lupus. Specifically it is used following kidney, heart, and liver transplantation. It can be given by mouth or by injection into a vein. It comes as mycophenolate sodium and mycophenolate mofetil.

<span class="mw-page-title-main">Inflammatory bowel disease</span> Medical condition

Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, with Crohn's disease and ulcerative colitis (UC) being the principal types. Crohn's disease affects the small intestine and large intestine, as well as the mouth, esophagus, stomach and the anus, whereas UC primarily affects the colon and the rectum.

<span class="mw-page-title-main">Mercaptopurine</span> Chemical compound

Mercaptopurine (6-MP), sold under the brand name Purinethol among others, is a medication used for cancer and autoimmune diseases. Specifically it is used to treat acute lymphocytic leukemia (ALL), acute promyelocytic leukemia (APL), Crohn's disease, and ulcerative colitis. For acute lymphocytic leukemia it is generally used with methotrexate. It is taken orally.

<span class="mw-page-title-main">Thiopurine methyltransferase</span>

Thiopurine methyltransferase or thiopurine S-methyltransferase (TPMT) is an enzyme that in humans is encoded by the TPMT gene. A pseudogene for this locus is located on chromosome 18q.

Pharmacotherapy, also known as pharmacological therapy or drug therapy, is defined as medical treatment that utilizes one or more pharmaceutical drugs to improve ongoing symptoms, treat the underlying condition, or act as a prevention for other diseases (prophylaxis).

<span class="mw-page-title-main">Tioguanine</span> Chemical compound

Tioguanine, also known as thioguanine or 6-thioguanine (6-TG) or tabloid is a medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic myeloid leukemia (CML). Long-term use is not recommended. It is given by mouth.

A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma, so TNF inhibitors may be used in their treatment. The important side effects of TNF inhibitors include lymphomas, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects.

Management of Crohn's disease involves first treating the acute symptoms of the disease, then maintaining remission. Since Crohn's disease is an immune system condition, it cannot be cured by medication or surgery. Treatment initially involves the use of medications to eliminate infections and reduce inflammation. Surgery may be required for complications such as obstructions, fistulae, abscesses, or if the disease does not respond to drugs within a reasonable time. However, surgery cannot cure Crohn's disease. It involves removing the diseased part of the intestine and rejoining the healthy ends, but the disease tends to recur after surgery.

Management of ulcerative colitis involves first treating the acute symptoms of the disease, then maintaining remission. Ulcerative colitis is a form of colitis, a disease of the intestine, specifically the large intestine or colon, that includes characteristic ulcers, or open sores, in the colon. The main symptom of active disease is usually diarrhea mixed with blood, of gradual onset which often leads to anaemia. Ulcerative colitis is, however, a systemic disease that affects many parts of the body outside the intestine.

<span class="mw-page-title-main">Biological therapy for inflammatory bowel disease</span>

Biological therapy, the use of medications called biopharmaceuticals or biologics that are tailored to specifically target an immune or genetic mediator of disease, plays a major role in the treatment of inflammatory bowel disease. Even for diseases of unknown cause, molecules that are involved in the disease process have been identified, and can be targeted for biological therapy. Many of these molecules, which are mainly cytokines, are directly involved in the immune system. Biological therapy has found a niche in the management of cancer, autoimmune diseases, and diseases of unknown cause that result in symptoms due to immune related mechanisms.

<span class="mw-page-title-main">Thiopurine</span> Class of chemical compounds

The thiopurine drugs are purine antimetabolites widely used in the treatment of acute lymphoblastic leukemia, autoimmune disorders, and organ transplant recipients.

Purine analogues are antimetabolites that mimic the structure of metabolic purines.

Vedolizumab, sold under the brand name Entyvio, is a monoclonal antibody medication developed by Millennium Pharmaceuticals, Inc. for the treatment of ulcerative colitis and Crohn's disease. It binds to integrin α4β7, blocking the α4β7 integrin results in gut-selective anti-inflammatory activity.

The molecular formula C5H4N4S (molar mass : 152.18 g/mol) may refer to :

<span class="mw-page-title-main">Cancer pharmacogenomics</span>

Cancer pharmacogenomics is the study of how variances in the genome influences an individual’s response to different cancer drug treatments. It is a subset of the broader field of pharmacogenomics, which is the area of study aimed at understanding how genetic variants influence drug efficacy and toxicity.

Shomron Ben-Horin is an Israeli physician, a co-founder & Chief Medical Officer of Evinature, and professor of medicine at the Tel-Aviv University.

References

  1. ↑ "Azathioprine". Merriam-Webster.com Dictionary .
  2. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  3. ↑ "Jayempi EPAR". European Medicines Agency. 20 April 2021. Retrieved 4 March 2023.
  4. ↑ "Jayempi Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  5. 1 2 3 4 5 6 7 8 9 "Azathioprine". The American Society of Health-System Pharmacists. Archived from the original on 20 August 2016. Retrieved 8 December 2016.
  6. ↑ Axelrad JE, Lichtiger S, Yajnik V (May 2016). "Inflammatory bowel disease and cancer: The role of inflammation, immunosuppression, and cancer treatment". World Journal of Gastroenterology (Review). 22 (20): 4794–4801. doi: 10.3748/wjg.v22.i20.4794 . PMC   4873872 . PMID   27239106.
  7. 1 2 Singer O, McCune WJ (May 2017). "Update on maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis". Current Opinion in Rheumatology. 29 (3): 248–253. doi:10.1097/BOR.0000000000000382. PMID   28306595. S2CID   35805200.
  8. ↑ Jordan N, D'Cruz D (2016). "Current and emerging treatment options in the management of lupus". ImmunoTargets and Therapy. 5: 9–20. doi: 10.2147/ITT.S40675 . PMC   4970629 . PMID   27529058.
  9. 1 2 3 Sami N (2016). Autoimmune Bullous Diseases: Approach and Management. Springer. p. 83. ISBN   9783319267289. Archived from the original on 2016-12-21.
  10. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  11. ↑ "Azathioprine - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  12. 1 2 3 4 5 6 7 Patel AA, Swerlick RA, McCall CO (September 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.
  13. 1 2 Evans WE (April 2004). "Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy". Therapeutic Drug Monitoring. 26 (2): 186–191. doi:10.1097/00007691-200404000-00018. PMID   15228163. S2CID   34015182.
  14. 1 2 3 4 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.
  15. ↑ Nuyttens JJ, Harper J, Jenrette JM, Turrisi AT (January 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.
  16. 1 2 Remuzzi G, Lesti M, Gotti E, Ganeva M, Dimitrov BD, Ene-Iordache B, et al. (August 2004). "Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial". Lancet. 364 (9433): 503–512. doi:10.1016/S0140-6736(04)16808-6. PMID   15302193. S2CID   22033113.
  17. ↑ Suarez-Almazor ME, Spooner C, Belseck E (2000). Suarez-Almazor ME (ed.). "Azathioprine for treating rheumatoid arthritis". The Cochrane Database of Systematic Reviews. 2010 (4): CD001461. doi:10.1002/14651858.CD001461. PMC   8406472 . PMID   11034720.
  18. 1 2 Sandborn WJ (1998). "Azathioprine: state of the art in inflammatory bowel disease". Scandinavian Journal of Gastroenterology. Supplement. 225 (234): 92–99. doi:10.1080/003655298750027290. PMID   9515759.
  19. ↑ Biancone L, Tosti C, Fina D, Fantini M, De Nigris F, Geremia A, et al. (June 2003). "Review article: maintenance treatment of Crohn's disease". Alimentary Pharmacology & Therapeutics. 17 (Suppl 2): 31–37. doi:10.1046/j.1365-2036.17.s2.20.x. PMID   12786610. S2CID   23554085.
  20. ↑ Rutgeerts P (October 2004). "Review article: treatment of perianal fistulizing Crohn's disease". Alimentary Pharmacology & Therapeutics. 20 (Suppl 4): 106–110. doi: 10.1111/j.1365-2036.2004.02060.x . PMID   15352905. S2CID   71968695.
  21. ↑ Kandiel A, Fraser AG, Korelitz BI, Brensinger C, Lewis JD (August 2005). "Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine". Gut. 54 (8): 1121–1125. doi:10.1136/gut.2004.049460. PMC   1774897 . PMID   16009685.
  22. ↑ Kirschner BS (October 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.
  23. ↑ Timmer A, Patton PH, Chande N, McDonald JW, MacDonald JK (May 2016). "Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis". The Cochrane Database of Systematic Reviews. 2016 (5): CD000478. doi:10.1002/14651858.CD000478.pub4. PMC   7034525 . PMID   27192092.
  24. ↑ 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. S2CID   71558242.
  25. ↑ Olszewska M, Kolacinska-Strasz Z, Sulej J, Labecka H, Cwikla J, Natorska U, et al. (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. S2CID   10699017.
  26. ↑ Richman DP, Agius MA (December 2003). "Treatment of autoimmune myasthenia gravis". Neurology. 61 (12): 1652–1661. doi:10.1212/01.wnl.0000098887.24618.a0. PMID   14694025. S2CID   24755812.
  27. ↑ Meggitt SJ, Gray JC, Reynolds NJ (March 2006). "Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind, randomised controlled trial". Lancet. 367 (9513): 839–846. doi:10.1016/S0140-6736(06)68340-2. PMID   16530578. S2CID   1616660.
  28. ↑ Casetta I, Iuliano G, Filippini G (February 2009). "Azathioprine for multiple sclerosis". Journal of Neurology, Neurosurgery, and Psychiatry. 80 (2): 131–2, discussion 132. doi:10.1136/jnnp.2008.144972. PMID   19151017. S2CID   207001537.
  29. ↑ Casetta I, Iuliano G, Filippini G (October 2007). "Azathioprine for multiple sclerosis". The Cochrane Database of Systematic Reviews. 2007 (4): CD003982. doi:10.1002/14651858.CD003982.pub2. PMC   6823213 . PMID   17943809.
  30. ↑ Raghu G, Anstrom KJ, King TE, Lasky JA, Martinez FJ (May 2012). "Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis". The New England Journal of Medicine. 366 (21): 1968–1977. doi:10.1056/NEJMoa1113354. PMC   3422642 . PMID   22607134.
  31. 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.
  32. ↑ Weersma RK, Peters FT, Oostenbrug LE, van den Berg AP, van Haastert M, Ploeg RJ, et al. (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. S2CID   21873238.
  33. ↑ Pecher D, Zelinkova Z, Lucenicova J, Peppelenbosch M, Dokupilova S, Mikusova V, et al. (November 2020). "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. Bibcode:2020AcAC.1137...64P. doi:10.1016/j.aca.2020.08.064. PMID   33153610. S2CID   225287631.
  34. 1 2 International Agency for Research on Cancer (IARC) (1987). "Azathioprine". Summaries & Evaluations (suppl. 7): 119. Archived from the original on 2006-06-04.
  35. ↑ Dean L (2012). "Azathioprine Therapy and TPMT Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID   28520349. Bookshelf ID: NBK100661.
  36. 1 2 Zaza G, Cheok M, Krynetskaia N, Thorn C, Stocco G, Hebert JM, et al. (September 2010). "Thiopurine pathway". Pharmacogenetics and Genomics. 20 (9): 573–574. doi:10.1097/FPC.0b013e328334338f. PMC   3098750 . PMID   19952870.
  37. ↑ Stocco G, Pelin M, Franca R, De Iudicibus S, Cuzzoni E, Favretto D, et al. (April 2014). "Pharmacogenetics of azathioprine in inflammatory bowel disease: a role for glutathione-S-transferase?". World Journal of Gastroenterology. 20 (13): 3534–3541. doi: 10.3748/wjg.v20.i13.3534 . PMC   3974520 . PMID   24707136.
  38. ↑ Fujita K, Sasaki Y (August 2007). "Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy". Current Drug Metabolism. 8 (6): 554–562. doi:10.2174/138920007781368890. PMID   17691917. Archived from the original on 2013-01-12.
  39. 1 2 3 Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, et al. (March 2011). "Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing". Clinical Pharmacology and Therapeutics. 89 (3). Clinical Pharmacogenetics Implementation Consortium: 387–391. doi:10.1038/clpt.2010.320. PMC   3098761 . PMID   21270794.
  40. 1 2 Mutschler E, Schäfer-Korting M (2001). Arzneimittelwirkungen (in German) (8th ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. pp. 107, 936. ISBN   978-3-8047-1763-3.
  41. ↑ Payne K, Newman W, Fargher E, Tricker K, Bruce IN, Ollier WE (May 2007). "TPMT testing in rheumatology: any better than routine monitoring?". Rheumatology. 46 (5): 727–729. doi: 10.1093/rheumatology/kel427 . PMID   17255139.
  42. ↑ "Label: Imuran - azathioprine tablet". Archived from the original on 20 October 2014. Retrieved 19 October 2014.
  43. ↑ Wang L, Pelleymounter L, Weinshilboum R, Johnson JA, Hebert JM, Altman RB, et al. (June 2010). "Very important pharmacogene summary: thiopurine S-methyltransferase". Pharmacogenetics and Genomics. 20 (6): 401–405. doi:10.1097/FPC.0b013e3283352860. PMC   3086840 . PMID   20154640.
  44. ↑ Yang SK, Hong M, Baek J, Choi H, Zhao W, Jung Y, et al. (September 2014). "A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia". Nature Genetics. 46 (9): 1017–1020. doi:10.1038/ng.3060. PMC   4999337 . PMID   25108385.
  45. ↑ National Toxicology Program (10 June 2011). "Report On Carcinogens – Twelfth Edition – 2011". National Toxicology Program. Archived (PDF) from the original on 16 July 2012. Retrieved June 20, 2012.
  46. ↑ "FDA: Cancer Warnings Required for TNF Blockers". FDA. August 4, 2009. Archived from the original on July 3, 2012. Retrieved June 20, 2012.
  47. ↑ International Agency for Research on Cancer (IARC) (1981). "Azathioprine – 5. Summary of Data Reported and Evaluation". Summaries & Evaluations. 26: 47. Archived from the original on 2006-09-06.
  48. ↑ Gombar VK, Enslein K, Blake BW (May 1993). "Carcinogenicity of azathioprine: an S-AR investigation". Mutation Research. 302 (1): 7–12. doi:10.1016/0165-7992(93)90083-8. PMID   7683109.
  49. ↑ McGovern DP, Jewell DP (August 2005). "Risks and benefits of azathioprine therapy". Gut. 54 (8): 1055–1059. doi:10.1136/gut.2004.053231. PMC   1774869 . PMID   16009676.
  50. ↑ "Imuran (azathioprine) Tablets and Injection". FDA. May 2011. Archived from the original on March 2, 2012. Retrieved June 20, 2012.
  51. ↑ "Skin cancer alert for organ drug". BBC Online . BBC News. September 15, 2005. Archived from the original on October 14, 2012. Retrieved June 10, 2012.
  52. ↑ O'Donovan P, Perrett CM, Zhang X, Montaner B, Xu YZ, Harwood CA, et al. (September 2005). "Azathioprine and UVA light generate mutagenic oxidative DNA damage". Science. 309 (5742): 1871–1874. Bibcode:2005Sci...309.1871O. doi:10.1126/science.1114233. PMC   2426755 . PMID   16166520.
  53. ↑ Sahasranaman S, Howard D, Roy S (August 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. S2CID   27475772.
  54. ↑ Chocair P, Duley J, Simmonds HA, Cameron JS, Ianhez L, Arap S, et al. (July 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. S2CID   13419507.
  55. ↑ Sparrow MP, Hande SA, Friedman S, Lim WC, Reddy SI, Cao D, et al. (September 2005). "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. doi: 10.1111/j.1365-2036.2005.02583.x . PMID   16128682. S2CID   9356163.
  56. ↑ Sparrow MP, Hande SA, Friedman S, Cao D, Hanauer SB (February 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.
  57. ↑ Govani SM, Higgins PD (October 2010). "Combination of thiopurines and allopurinol: adverse events and clinical benefit in IBD". Journal of Crohn's & Colitis. 4 (4): 444–449. doi:10.1016/j.crohns.2010.02.009. PMC   3157326 . PMID   21122542.
  58. ↑ Ansari A, Patel N, Sanderson J, O'Donohue J, Duley JA, Florin TH (March 2010). "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. doi: 10.1111/j.1365-2036.2009.04221.x . PMID   20015102. S2CID   6000856.
  59. ↑ Oliveira A, Sanches M, Selores M (October 2011). "Azathioprine-induced pellagra". The Journal of Dermatology. 38 (10): 1035–1037. doi:10.1111/j.1346-8138.2010.01189.x. PMID   21658113. S2CID   3396280.
  60. 1 2 Mehta DK, et al. (Pharmaceutical Society of Great Britain) (March 2003). British National Formulary, Issue 45. London: British Medical Association. ISBN   978-0-85369-555-4.
  61. ↑ Cleary BJ, Källén B (July 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.
  62. ↑ Tagatz GE, Simmons RL (January 1975). "Pregnancy after renal transplantation". Annals of Internal Medicine. 82 (1): 113–114. doi:10.7326/0003-4819-82-1-113. PMID   799904.
  63. ↑ Nørgård B, Pedersen L, Fonager K, Rasmussen SN, Sørensen HT (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. S2CID   25314258.
  64. ↑ Tallent MB, Simmons RL, Najarian JS (March 1970). "Birth defects in child of male recipient of kidney transplant". JAMA. 211 (11): 1854–1855. doi:10.1001/jama.211.11.1854. PMID   4905893.
  65. ↑ Polifka JE, Friedman JM (May 2002). "Teratogen update: azathioprine and 6-mercaptopurine". Teratology. 65 (5): 240–261. CiteSeerX   10.1.1.566.7676 . doi:10.1002/tera.10043. PMID   11967923.
  66. ↑ Hale TW (April 2010). Medications and Mothers' Milk: A Manual of Lactational Pharmacology. Hale Pub. ISBN   978-0-9823379-9-8.
  67. ↑ Cronstein BN (November 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.
  68. ↑ Karran P, Attard N (January 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. S2CID   23327335.
  69. 1 2 3 Dinnendahl, V, Fricke, U, eds. (2011). Arzneistoff-Profile (in German). Vol. 2 (25th ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN   978-3-7741-9846-3.
  70. 1 2 Steinhilber D, Schubert-Zsilavecz M, Roth HJ (2005). Medizinische Chemie (in German). Stuttgart: Deutscher Apotheker Verlag. p. 340. ISBN   978-3-7692-3483-1.
  71. ↑ "Azathioprine Pathway". Small Molecule Pathway Database. Archived from the original on 2 July 2012. Retrieved 31 August 2012.
  72. 1 2 Maltzman JS, Koretzky GA (April 2003). "Azathioprine: old drug, new actions". The Journal of Clinical Investigation. 111 (8): 1122–1124. doi:10.1172/JCI18384. PMC   152947 . PMID   12697731.
  73. ↑ USPatent 3056785,G. H. Hitchings; Yonkers& G. B. Elion,"Purine Derivatives",issued 1962-10-06.
  74. ↑ Blicke FF, Godt HC (1954). "Diuretics. I. 3-Substituted Paraxanthines". Journal of the American Chemical Society. 76 (14): 3653–3655. doi:10.1021/ja01643a015.
  75. 1 2 Elion GB (April 1989). "The purine path to chemotherapy". Science. 244 (4900): 41–47. Bibcode:1989Sci...244...41E. doi:10.1126/science.2649979. PMID   2649979.
  76. ↑ Elion GB, Callahan SW, Hitchings GH, Rundles RW (July 1960). "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. PMID   13849699.
  77. ↑ Thiersch JB (December 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.
  78. ↑ Schwartz R, Stack J, Dameshek W (October 1958). "Effect of 6-mercaptopurine on antibody production". Proceedings of the Society for Experimental Biology and Medicine. 99 (1): 164–167. doi:10.3181/00379727-99-24281. PMID   13601801. S2CID   8043359.
  79. ↑ Calne RY (February 1960). "The rejection of renal homografts. Inhibition in dogs by 6-mercaptopurine". Lancet. 1 (7121): 417–418. doi:10.1016/S0140-6736(60)90343-3. PMID   13807024.
  80. ↑ Murray JE, Merrill JP, Harrison JH, Wilson RE, Dammin GJ (June 1963). "Prolonged survival of human-kidney homografts by immunosuppressive drug therapy". The New England Journal of Medicine. 268 (24): 1315–1323. doi:10.1056/NEJM196306132682401. PMID   13936775.
  81. ↑ Bakker RC, Hollander AA, Mallat MJ, Bruijn JA, Paul LC, de Fijter JW (September 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.
  82. ↑ Henry ML, Sommer BG, Ferguson RM (November 1985). "Beneficial effects of cyclosporine compared with azathioprine in cadaveric renal transplantation". American Journal of Surgery. 150 (5): 533–536. doi:10.1016/0002-9610(85)90431-3. PMID   2998215.
  83. ↑ Modry DL, Oyer PE, Jamieson SW, Stinson EB, Baldwin JC, Reitz BA, et al. (May 1985). "Cyclosporine in heart and heart-lung transplantation". Canadian Journal of Surgery. Journal Canadien de Chirurgie. 28 (3): 274–80, 282. PMID   3922606.
  84. ↑ Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, et al. (May 2005). "Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study". Health Technology Assessment. 9 (21): 1–194. doi: 10.3310/hta9210 . PMID   15899149.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.