Immunosuppressants azathioprine

A 42-year-old woman with a renal transplant taking triple immunosuppression (azathioprine, ciclosporin, and glucocorticoids) was converted after 7 years from azathioprine plus ciclosporin to mycophenolate (2 g/ day) because of ciclosporin nephrotoxicity (15). Within 2 months she had developed severe persistent watery diarrhea (5-10 stools/day) and lost 7 kg over 2 months. Investigations ruled out an infectious cause and there were features of duodenal villous atrophy on histological examination. Diarrhea disappeared after mycophenolate withdrawal and two subsequent duodenal biopsies showed improvement 2 months later and further complete recovery 6 months later. 

Mercaptopurine (CCS) Purine antimetabolite (S phase) bioactivated by HGPR transferase Acute lymphocytic leukemia immunosuppression (azathioprine forms 6-MP) BMS, hepatotoxicity (jaundice, necrosis), GI distress... 

Over-halogenation is a common theme in functionalization of unsubstituted imidazoles and often leads chemists to install functionality early if possible. The Wallach synthesis of imidazoles allows for the installation of a chlorine atom at the 5 position. Such chemistry provides an intermediate that is useful in the synthesis of the immunosuppressant, azathioprine. The Wallach reaction is the treatment of oxalylamides with PCI5 or POCI3 to yield the corresponding iV-methyl-5-chloroimidazole. Nitration is selective at the 4-position to provide the imidazole properly functionalized to provide azathioprine. ... 

On the basis of the autoimmune theory, Walford tested the effect of an immunosuppressant, azathioprine (Imuran) (IV), on the life-span of aging mice. Animals receiving a daily dose of 100 mg/kg showed a mean survival time 10 weeks longer than controls, but the maximum life-span (135-140 weeks) was not affected. Similar results were obtained with another immunosuppressant, cyclophosphamide (V). It seems probable that anti-aging therapy at this level may be too late in the chain of events. Moreover, suppression of the immune system may accelerate death from other causes. 

Maintenance of remission of ulcerative colitis may be achieved with oral or topical aminosalicylates. Immunosuppressants such as azathioprine or 6-mercaptopurine can be used for unresponsive patients or those who develop corticosteroid dependency. 

Maintenance of remission of Crohn s disease may be achieved with oral or topical aminosalicylate derivatives, immunosuppressants (such as azathioprine, 6-mercaptopurine, and methotrexate), or infliximab. 

Immunosuppressants such as azathioprine or 6-mercaptopurine can be used for unresponsive patients or those who develop corticosteroid dependency. Remission may be maintained in up to 58% of patients after 5 years of treatment.1,25 Intermittent infliximab dosing (5 mg/kg IV every 8 weeks) may be used to maintain disease remission and reduce the need for corticosteroids in patients with moderate to severe UC. Colectomy is an option for patients with progressive disease who cannot be maintained on drug therapy alone. 

Patients with CD are at high risk for disease relapse after induction of remission. Within 2 years, up to 80% of patients suffer a relapse therefore, most patients should be evaluated for indefinite maintenance therapy. Maintenance of remission of CD may be achieved with oral or topical aminosalicylate derivatives, immunosuppressants (such as azathioprine, 6-mercaptopurine, and methotrexate), or infliximab. 

The aminosalicylates, azathioprine, 6-MP, and infliximab are all viable options for treatment and maintenance of IBD in pediatric patients. Use of immunosuppressive therapy or infliximab may help reduce overall corticosteroid exposure. 

Azathioprine was originally approved by the FDA in 1968 as an adjunct immunosuppressant for use in renal transplant recipients. It is available in oral and IV dosage forms.11 Prior to the advent of cyclosporine, the combination of azathioprine and corticosteroids was the mainstay of immunosuppressive therapy. Over the past 10 years, the use of azathioprine has declined markedly due in large part to the success of the MPA derivatives, which are more specific inhibitors of T cell proliferation. 

MPA derivatives have replaced azathioprine as the antiproliferative agent of choice in most organ transplant centers. The MPA derivatives generally are considered to provide a more specific immunosuppressive effect compared with azathioprine. Mycophenolate mofetil and enteric-coated mycophe-nolic acid have similar safety and efficacy data in renal transplant recipients. 

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

When immunosuppressive therapy is administered for long periods, the patient must be monitored closely for chronic toxicity. Blood counts should be monitored routinely in patients on azathioprine because hematologic toxicity resulting in infection and bleeding may occur. Cushingoid effects, aseptic... 

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine dmgs, such as 6-mercaptopurine (6-MP), 6-thioguanine and azathioprine, to inactive metabolites [29-32]. Thiopurines form part of the routine treatment for patients with acute lymphoblastic leukemia, rheumatoid arthritis, and autoimmune diseases such as SLE and Crohn s disease, and are used as an immunosuppressant following organ transplantation. 

The major types of drug therapy used in IBD include aminosalicylates, glucocorticoids, immunosuppressive agents (azathioprine, mercaptopu-rine, cyclosporine, and methotrexate), antimicrobials (metronidazole and ciprofloxacin), and agents to inhibit tumor necrosis factor-a (TNF-a) (anti-TNF-a antibodies). 

Immunosuppressive agents such as azathioprine and mercaptopurine (a metabohte of azathioprine) are sometimes used for the treatment of IBD. These agents are generally reserved for cases that are refractory to steroids and may be associated with serious adverse effects such as lymphomas, pancreatitis, or nephrotoxicity. Cyclosporine has been of short-term benefit in acute, severe ulcerative colitis when used in a continuous infusion. 

The immunosuppressive agents (azathioprine and mercaptopurine) are generally limited to use in patients not achieving adequate response to standard medical therapy, or to reduce steroid doses when toxic doses are required. The usual dose of azathioprine is 2 to 3 mg/kg/day and 1 to 1.5 mg/kg/day for mercaptopurine. Up to 3 to 4 months may be required to observe a response. Starting doses are typically 50 mg/day and increased at 2-week intervals while monitoring complete blood count with differential. 

Immunosuppressants such as azathioprine and mercaptopurine have a significant potential for adverse reactions, including bone marrow suppression, and have been associated with lymphomas (in renal transplant patients) and pancreatitis. Myelosuppression resulting in leukopenia is related to a deficiency in TPMT in some patients. 

Armstrong, V.W., Oelleiich, M. (2001) New developments in the immunosuppressive drug monitoring of cyclosporine, tacrolimus, and azathioprine. Clin. Biochem. 34, 9-16. 

Several types of immunosuppression have also been tried. Azathioprine alone was found to have no effect on PBC [82], but additional benificial effects were found in combination with ursodeoxychohc add and corticosteroids [78]. Cyclosporin showed some success, espe-dally in corticosteroid-resistant autoimmune hepatitis [83], but its use is generally considerably hmited by severe side-effects. Corticosteroids were effective in the management of several types of autoimmune chronic active hepatitis [84,85] and in the management of acute al-cohohc hepatitis [86]. Their use, however, has to be brief hi order to minimize side-effects. In the treatment of PBC, corticosteroids alone were found to be toxic and had only limited efficacy [77]. 

HI. Disruption of cell metabolism with inhibition of proliferation. At dosages below those needed to treat malignancies, some cytostatics are also employed for immunosuppression, e.g., azathioprine, methotrexate, and cyclophosphamide (p. 298). The antiproliferative effect is not specific for lymphocytes and involves both T- and B-cells. 

Basiliximab is a mouse/human chimeric monoclonal antibody with specificity and high affinity for the a-subunit of the IL-2 receptor. The antibody acts as an lL-2Ra antagonist and inhibits lL-2-mediated activation and proliferation of T l)unphocytes. It is indicated for the prevention of acute organ rejection in adult and paediatric renal transplant recipients in combination with other immunosuppressive agents like cyclosporin, azathioprine, mycophenolate mofetU... 

In addition, one of the sulfur analogs of mercaptopurine, azathioprine, has been proposed as a cytotoxic drug, and it turned out to be more effective as an immunosuppressant. 

As a matter of fact, azathioprine is a prodrag since it turns into mercaptopurine in the body. This is a possibly reason why it is advantageous over mercaptopurine as an immunosuppressant. 

Chronic immunosuppression with azathioprine increases the risk of neoplasia. Physicians using this drug should be familiar with this risk as well as with the mutagenic potential to men and women and with possible hematologic toxicities. 

Concurrent immunosuppressants Sirolimus has been administered concurrently with cyclosporine and corticosteroids. The efficacy and safety of the use of sirolimus in combination with other immunosuppressive agents have not been determined. Renai function impairment Mean serum creatinine was increased and mean glomerular filtration rate was decreased in patients treated with sirolimus and cyclosporine compared with those treated with cyclosporine and placebo or azathioprine controls. Monitor renal function during the administration of maintenance immunosuppression regimens including sirolimus in combination with cyclosporine, and consider appropriate adjustment of the immunosuppression... 

Allogeneic transplants For prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. Gengraf and A/eora/have been used in combination with azathioprine and corticosteroids. Sanc//n n nne always is to be used with adrenal corticosteroids. Sandimmune a so may be used in the treatment of chronic rejection in patients previously treated with other immunosuppressive agents. Because of the risk of anaphylaxis, reserve Sandimmune injection for patients who are unable to... 

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