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At least 19 recordsLinked to original sources
PubMed2000

Azathioprine for rheumatoid arthritis.

OBJECTIVES: To assess the short-term effects of azathioprine for the treatment of rheumatoid arthritis (RA). SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Group's trials register, the Cochrane Controlled Trials Register, Medline up to and including July 1998 and Embase from 1988-1998. We also carried out a handsearch of the reference lists of the trials retrieved from the electronic search. SELECTION CRITERIA: All randomized controlled trials and controlled clinical trials comparing azathioprine against placebo in patients with rheumatoid arthritis. DATA COLLECTION AND ANALYSIS: Data was extracted independently by two reviewers (CS, EB); disagreements were resolved by discussion or third party adjudication (MS). The same reviewers (CS, EB) assessed the methodological quality of the trials using a validated quality assessment tool. Rheumatoid arthritis outcome measures were extracted from the publications for the six-month endpoint. The pooled analysis was performed using standardized mean differences for joint counts, pain and functional status assessments. Weighted mean differences were used for erythrocyte sedimentation rate (ESR). Toxicity was evaluated with pooled odds ratios for withdrawals and for adverse reactions. The 95% confidence intervals (95% CI) are presented. A chi-square test was used to assess heterogeneity among trials. Fixed effects models were used throughout, since no statistical heterogeneity was found. MAIN RESULTS: Three trials with a total of 81 patients were included in the analysis. Forty patients were randomized to azathioprine and forty-one to placebo. A pooled estimate was calculated for two outcomes. A statistically significant benefit was observed for azathioprine when compared to placebo for tender joint scores. The standardized weighted mean difference between treatment and placebo was -0.98 (95% CI -1.45, -0.50). Withdrawals from adverse reactions were significantly higher in the azathioprine group OR=4.56 (95% CI 1.16, 17.85). REVIEWER'S CONCLUSIONS: Azathioprine appears to have a statistically significant benefit on the disease activity in joints of patients with RA. This evidence however is based on a small number of patients, included in older trials. Its effects on long-term functional status and radiological progression were not assessed due to lack of data. Toxicity is shown to be higher and more serious than that observed with other disease-modifying anti-rheumatic drugs (DMARDs). Given this high risk to benefit ratio, there is no evidence to recommend the use of azathioprine over other DMARDs.

Antirheumatic Agents↗
PubMed1988

Comparison of three immunosuppressive regimens in cadaver renal transplantation: long-term cyclosporine, short-term cyclosporine followed by azathioprine and prednisolone, and azathioprine and prednisolone without cyclosporine.

We conducted a randomized trial in seven Australian hospitals of the efficacy and safety of three immunosuppressive regimens after first transplantation of a cadaver kidney: long-term cyclosporine, short-term (three months) cyclosporine followed by azathioprine and prednisolone, and azathioprine and prednisolone without cyclosporine. Patients assigned to long-term cyclosporine (n = 138) or short-term cyclosporine followed by azathioprine and prednisolone (n = 141) had similar actuarial 12-month survival (98.4 vs. 96.4 percent) and graft survival (83.9 vs. 82.1 percent). Patients assigned to receive only azathioprine and prednisolone (n = 138), with optional use of antithymocyte globulin, had a significantly poorer survival rate (91.3 percent, P = 0.015) because of deaths from cardiac causes and infection, but their graft survival of 76.0 percent (P = 0.31) did not differ significantly from that of either group receiving cyclosporine. After the switch from cyclosporine to azathioprine and prednisolone, 15 percent of patients had reversible rejection episodes, but the frequency of rejection and graft loss did not differ from that in the long-term cyclosporine group. After the change to azathioprine and prednisolone, serum creatinine levels declined in nearly all patients, so that after three months they were comparable to those in the group receiving azathioprine and prednisolone only, and significantly lower than those in the group receiving long-term cyclosporine therapy (P less than 0.003). We conclude that the two cyclosporine regimens result in comparable patient and graft survival, but that changing to azathioprine and prednisolone at three months improves graft function.

Adult↗
PubMed1999

Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease. North American Azathioprine Study Group.

BACKGROUND & AIMS: Azathioprine is effective for Crohn's disease but acts slowly. A loading dose may decrease the time to response. METHODS: A placebo-controlled study was conducted in patients with active Crohn's disease despite prednisone treatment. Patients were randomized to a 36-hour infusion of azathioprine, 40 mg/kg (51 patients), or placebo (45 patients) followed by oral azathioprine, 2 mg/kg, for 16 weeks. Prednisone was tapered over 5 weeks. The primary outcome measure was complete remission at week 8, defined by discontinuation of prednisone and a Crohn's Disease Activity Index of </=150 points. Erythrocyte concentrations of the azathioprine active metabolite, 6-thioguanine nucleotide, were measured. RESULTS: At week 8, 13 patients (25%) were in complete remission in the azathioprine-loaded group compared with 11 patients (24%) in the placebo group. The frequency of complete remission did not increase after 8 weeks in either group. Both groups achieved steady state of 6-thioguanine nucleotide by week 2, and no differences were found in mean concentrations between the groups. There were no significant differences in the frequency of adverse events between the groups. CONCLUSIONS: A loading dose does not decrease the time to response in patients with steroid-treated Crohn's disease beginning azathioprine therapy. Steady state of erythrocyte 6-thioguanine nucleotide and complete response occurred earlier than previously reported.

Administration, Oral↗
PubMed1990

Determination of plasma azathioprine and 6-mercaptopurine in patients with rheumatoid arthritis treated with oral azathioprine.

Two specific high-performance liquid chromatography methods for determining plasma concentrations of azathioprine and 6-mercaptopurine after oral administration of azathioprine are presented. It was shown that azathioprine is unstable in the blood samples unless immediately cooled in ice water. The 2-amino analog, guaneran, was used as internal standard for azathioprine, which was extracted from plasma with ethylacetate. A Nucleosil C18 column was used for the separation. The detection limit was 6 nM. For quantification of 6-mercaptopurine, 6-thioguanine was used as internal standard. Plasma was deproteinized with HClO4 and the sample was purified on mercurial cellulose. A Beckman ODS column was used and the detection limit was 5 nM. Pharmacokinetic data from two patients are presented. Unchanged azathioprine was seen until 6 h after an oral dose of 32 mg/m2.

Administration, Oral↗
PubMed1988

Double-masked trial of azathioprine in multiple sclerosis. British and Dutch Multiple Sclerosis Azathioprine Trial Group.

354 patients with multiple sclerosis were randomised to receive either azathioprine 2.5 mg/kg daily or placebo in a double-masked trial. During follow-up of at least 3 years only small differences emerged between the groups. After 3 years the mean deterioration in Kurtzke disability score was 0.62 in the azathioprine group and 0.80 in the placebo group, a difference of 0.18 (95% confidence intervals [CI] -0.15 to +0.52) and in the ambulation index it was 0.84 and 1.25, respectively, difference 0.41 (95% CI 0.03 to 0.80). After 3 years there had been slightly fewer relapses in the azathioprine group (average 2.2) than in the placebo group (average 2.5) but the difference of 0.3 (95% CI -0.2 to +0.9) was not significant. Although the results favour a small beneficial effect from azathioprine the benefit is so small that the use of azathioprine cannot be generally recommended for most patients with multiple sclerosis. Analysis of subgroups (by sex, age, severity, rate of progression, HLA status, relapsing or progressive course) has not revealed any that have shown clear clinical benefit.

Adolescent↗
PubMed1987

[Treatment of progressive and severe forms of multiple sclerosis using a combination of antilymphocyte serum, azathioprine and prednisone. Clinical and biological results. Comparison with a control group treated with azathioprine and prednisone only. 4-year follow-up].

45 patients were treated by combined application of antilymphocyte serum, azathioprine and prednisone: a control group of such 22 patients was besides treated by azathioprine and prednisone only. The treatment by antilymphocyte serum included a four weeks initial treatment, and one year continuous treatment one infusion per week. Azathioprine and prednisone were given every day during the same time. Azathioprine only was given during the three following year. The two groups were followed up during four years. This treatment was well accepted by patients under strict technical survey conditions. Serum sickness was noted in 11 p. cent of the cases. The equine antiglobulin antibody titre, increased during the initial treatment, was connected with serum sickness or, when the treatment was continued, with the inefficacy of the treatment. Rosettes titre decreased in ten cases, no clinical correlation was possible. The complement, immune complexes, were normal before treatment with most of the observed patients. The delayed hypersensitivity skin tests were negative after a month in 80 p. cent of the cases. The cerebrospinal fluid analysis, for the elements as well as for the rate of proteins and gammaglobulins, showed no significant variations before and after the treatment. The comparison with the control group showed a significant statistical difference as too the number of aggravated and improved patients after the first year. When grouping together stable and improved patients, the difference was statistically significant after the third year. The difference was not significant in years "two" or four. No difference in the frequency of the relapses could be noted, in the first year or the following three years. In spite of inconsistent results comparison showed favorable data after three years. The good results seemed due to the additional use of antilymphocyte serum. Such a treatment associating antilymphocyte serum to azathioprine and prednisone is beneficial in evolutive, remittent and recent multiple sclerosis. Through the length of the treatment remains difficult to determine, we conclude that it is really beneficial for such patients.

Antilymphocyte Serum↗
PubMed1978

The effects on polymorphonuclear leucocyte function of prednisolone and azathioprine in vivo and prednisolone, azathioprine and 6-mercaptopurine in vitro.

The effects of prednisolone azathioprine and 6-mercaptopurine on polymorphonuclear neutrophil chemotaxis, phagocytosis, and killing of Staphylococcus aureus and Candida albicans have been studied. In twenty patients with a functioning kidney graft, taking both azathioprine 2.5 mg/kg/day and prednisolone (mean dose 0.59 mg/kg/day; range 0.30-1.0 mg/kg/day), the polymorphonuclear function did not significantly differ from that in either twenty-two normal or eighteen uraemic controls. Addition of prednisolone, 1.2 X 10(-5) M, azathioprine, 2.1 X 10(-5) M, and 6-mercaptopurine, 2.1 X 10(-5) M, using each drug alone, to normal human polymorphonuclear cells in vitro did not significantly alter their function. It is concluded that prednisolone and azathioprine together in vivo and that both these drugs and 6-mercaptopurine singly in vitro have no significant deleterious effect on polymorphonuclear function and do not contribute, in this way, to the increased susceptibility of patients receiving these drugs to infection.

Adolescent↗
PubMedDate not supplied

Prednisone and azathioprine compared to prednisone plus low-dose azathioprine and cyclophosphamide in the treatment of diffuse lupus nephritis.

A 1-year double-blind crossover study comparing prednisone and azathioprine to prednisone plus low-dose azathioprine and cyclophosphamide was carried out in 14 patients with diffuse lupus nephritis. Low-dose triple therapy had no apparent therapeutic advantage over prednisone plus azathioprine. Cyclophosphamide-induced ovarian failure and hematuria were not avoided by its use in low dose.

Adolescent↗
PubMed1990

[Evaluation of immunotoxicity testings using azathioprine-treated rats: the International Collaborative Immunotoxicity Study (Azathioprine)].

The immunotoxicological effects of azathioprine (AZP) were examined by enhanced histopathological and function tests in the rat which is routinely used in toxicological tests. Male F344 rats were orally administered AZP in doses of 0, 2.5, 12.5 and 25.0 mg/kg/day for 28 days. Reductions in the organ weights of the thymus, spleen, liver, kidney, and testis in a dose-dependent manner were confirmed. Hematological examination revealed a marked decrease in the number of WBCs, which was associated with a decrease in the number of lymphocytes. In the femoral bone marrow, a significant reduction in the total cell number attributed to the decrease in the number of lymphocytes and granulocytes was observed. Histopathologically, atrophy and obfuscation of the corticomedullary junction in the thymus, the decrease of lymphocytes in the thymus and spleen, and the disappearance of germinal centers in the lymph nodes were observed. As for the functional testings, azathioprine treatment did not affect remarkably the PFC number and the NK cell activity per unit spleen cell number. However, the total spleen cell number per spleen was decreased in a dose-dependent manner. Therefore, the total functional activities (PFC and NK) per spleen were decreased. Thus, in the AZP-treated F344 rats, it was shown that the enhanced histopathological tests were useful to evaluate potential risks to the immune system.

Animals↗
PubMed1986

Serum azathioprine and 6-mercaptopurine levels and immunosuppressive activity after azathioprine in uremic patients.

The pharmacokinetics of azathioprine (AZA) and 6-mercaptopurine (6-MP) was studied in uremic patients after 100 mg AZA intravenously (fifteen patients) and orally (eight patients). 6-MP was analysed with gas chromatography mass spectrometry following extractive alkylation. AZA was determined indirectly assuming quantitative conversion to 6-MP in whole blood. The plasma concentration of AZA fell rapidly after i.v. administration. The mean half-time of elimination for the first rapid phase (t1/2 alpha) was 6.1 min (S.D. +/- 4.1) and for the terminal phase (t1/2 beta) 50 min (+/- 31). The total plasma clearance (Cl) was 6.9 1./min (+/- 3.0). AZA was rapidly converted to 6-MP in vivo, and maximal plasma concentrations of 6-MP were found as early as 5 min after i.v. injection of AZA. The mean t1/2 alpha was 4.6 min (+/- 2.2), t1/2 beta 74 min (+/- 58) and Cl 8.0 1./min (+/- 5.8). The plasma levels of both AZA and 6-MP were either low or undetectable 4-6 h after dose. In erythrocytes AZA levels were low or undetectable indicating rapid conversion to 6-MP in these cells. 6-MP concentration - time curve in erythrocytes was similar to that in plasma, except for a somewhat slower terminal phase of elimination. Oral administration of AZA generated flat plasma curves for AZA and 6-MP. The area under the concentration - time curve (AUC) was considerably smaller than after i.v. administration, 18 and 41% for AZA and 6-MP, respectively. There seems to be little danger of accumulation of AZA/6-MP in uremia. We also studied inhibition of Leucoagglutin (LA) stimulated lymphocyte proliferation by patient plasma at different times in six of the patients following AZA i.v. Sera drawn at 5, 10 and 30 min significantly inhibited the LA-induced proliferation, with an estimated minimum effective concentration of 6-MP in the cultures of about 0.02-0.04 microM. This suggests the possibility of a therapeutic effect even of the low plasma levels of 6-MP obtained after AZA orally. The combined use of sensitive pharmacokinetic and immunological assays as described should be useful in studying the relationship between plasma levels of AZA/6-MP and their immunosuppressive effect and toxicity.

Administration, Oral↗
PubMed1999

The impact of azathioprine on chronic viral hepatitis in renal transplantation: a long-term, single-center, prospective study on azathioprine withdrawal.

BACKGROUND: In transplanted patients, viral hepatitis progresses to chronic liver disease and patient's death after many years of transplantation. Also, it is well known that azathioprine (AZA) is harmful to the liver of these patients. However, it is unclear whether a low dose of AZA still represents a threat to the viral liver disease. METHODS: A total of 79 patients with hepatitis C, B, or both, transplanted between 1973 and 1990, were grouped according to whether they had AZA either withdrawn from the immunosuppressive regimen [group (G) I, n=45] or a dosage reduction only (group II, n=34). The decision to remove or to keep AZA was restricted to the patient's doctor. Patients records were reviewed by April 1997. RESULTS: After an equal time of follow-up, after the AZA changing (64+/-26 vs. 58+/-29 months), patients in GI showed a significant decrease in the serum liver parameters when compared to baseline [alanine aminotransferase (ALT): P=0.001; gamma-glutamyl transferase (gamma-GT): P=0.001 and total bilirubin: P=0.002], whereas in GII only ALT decreased (P=0.04) although gamma-GT and total bilirubin did not. Compared to baseline, serum creatinine (SCr) increased only in GI (P=0.001) but, at last follow-up, did not differ from GII. The intention-to-perform liver biopsies was equal in GI and GII (16 vs. 14) but the hystological findings of severe chronic liver disease (either chronic active hepatitis or cirrhosis) were more frequent in GII (P=0.004). Death with a functioning graft was much more frequent in GII than in GI (P=0.001). Infection and cirrhosis were more common as a cause of death in GII than in GI. CONCLUSIONS: The use AZA is harmful to renal transplantation patients with both chronic hepatitis C and B and, therefore, should be avoided. AZA withdrawal, but not dose adjustments, diminishes the serum liver enzymes and the progression rate of the chronic viral liver disease as well as the rate of death secondary to infection and cirrhosis.

Adult↗
PubMed1988

Histocompatibility antigens in multiple sclerosis patients participating in a multicentre trial of azathioprine. British & Dutch Multiple Sclerosis Azathioprine Trial Group.

The human leucocyte antigen (HLA) types of 283 patients with multiple sclerosis participating in a trial of azathioprine treatment were studied. The prevalence of HLA types was compared with those of over 3,300 controls from tissue typing centres in the UK. The prevalence of HLA A3 (38.5% cp 26.1%), HLA B7 (44.9% cp 27.3%) and HLA DR2 (58.3% cp 30.6%) was increased in the multiple sclerosis patients compared with the controls. Age at onset, disease status (relapsing-remitting or currently progressive) and disease severity did not show an association with any particular HLA type.

Adolescent↗
PubMed1982

Differential interference by azathioprine and 6-mercaptopurine with antibody-mediated immunoregulation: synergism of azathioprine and antibody in the control of an immune response.

Comparative studies on the effects of immunosuppressive agents azathioprine (AZ) and 6-mercaptopurine (6-MP) in antibody-mediated immunoregulation are reported. To determine the degree of interference of these agents with the generation of antibody molecules controlling an anti-SRBC response, the donors of mouse anti-SRBC sera were given daily doses of the drugs. Primary antisera from AZ-treated donors were not significantly inhibited by daily doses of 180, 270, and 360 mumol/kg in their ability to suppress the direct PFC response; on the other hand 6-MP was inhibitory at the two higher equimolar dose levels. When the antisera were used in the antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (AD phi) assays, similar differential effects of the two agents were found. Multiple doses of AZ and 6-MP given to the donors of ADCC effector cells enhanced the capacity of these cells to lyse antibody-sensitized SRBC target cells. The enhancement of ADCC with 6-MP was less manifest than that with AZ. When injected before the antigen, AZ acted synergistically with the antibody in the control of the direct PFC response. Possible mechanisms by which AZ can interact with antibody-mediated immune regulation are discussed.

Animals↗
PubMed1993

Cyclophosphamide as an alternative to azathioprine in cardiac transplant recipients with suspected azathioprine-induced hepatotoxicity.

AZA has been reported to cause liver dysfunction in some recipients of solid organ transplants. To assess the safety and efficacy of cyclophosphamide in maintenance immunosuppression in the setting of AZA-induced liver dysfunction, we retrospectively reviewed the records of 320 surviving cardiac transplant recipients in Utah. Cyclophosphamide was substituted for AZA in 29 patients due to elevated liver enzymes. Patients were switched to cyclophosphamide 689 +/- 104 days after transplantation; total follow-up after initiation of cyclophosphamide was 540 +/- 56 days. The dose of cyclophosphamide after 2 and 6 months of cyclophosphamide therapy was 62 +/- 6 mg/day (0.8 +/- 0.1 mg/kg/day) and 48 +/- 5 mg/day (0.6 +/- 0.1 mg/kg/day), respectively, compared with 233 +/- 20 mg/day (2.9 +/- 0.2 mg/kg/day) of AZA. The substitution of cyclophosphamide for AZA was associated with a significant improvement in liver function tests. Liver enzymes decreased by up to 49% (P = 0.027), while serum bilirubin decreased by 58% (P < 0.001). Rejection frequency did not increase; neither corticosteroid nor CsA dosage was altered significantly after the substitution of cyclophosphamide. Significant bone marrow suppression was not observed; specifically, no significant change in white blood cell count or hematocrit occurred. Complications of treatment with cyclophosphamide were few; only 1 patient discontinued cyclophosphamide because of alopecia. We conclude that cyclophosphamide appears to be safe in maintenance immunosuppression, permitting the discontinuation of AZA in patients with AZA-induced hepatic dysfunction without necessitating the augmentation of either corticosteroids or CsA.

Alanine Transaminase↗