Azathioprine Group Research Articles

Side effects of cyclosporin A treatment in patients with rheumatoid arthritis

Cyclosporin A (CyA) and azathioprine (Aza) were compared with respect to renal side effects in an open controlled, randomized study of patients with rheumatoid arthritis. Twelve patients were treated with CyA (mean dose 7.8 +/- 1.2 mg/kg/day) and 12 with azathioprine for 26 weeks. All patients also received prednisolone 5 mg/day. The patients had normal serum creatinine (less than 120 mumoles/liter) and protein-free urine before the trial. CyA increased serum creatinine in nine out of the 11 patients followed for 26 weeks, the mean increase was approximately 50%. Creatinine clearance was reduced by 31%. Mean arterial pressure (MAP) and serum potassium were significantly increased by CyA. Urinary beta 2-microglobulin excretion was significantly increased by CyA, in five of the patients more than ten times. Urinary kallikrein excretion was reduced by more than 50% and urinary albumin excretion was doubled. All these parameters remained normal and unchanged in the azathioprine group. CyA was withdrawn in seven patients after 26 weeks. Urinary beta 2-microglobulin was still increased by 85% nine months after CyA treatment. The other parameters were gradually normalized after three to nine months except for one patient who developed renal failure. Urinary beta 2-microglobulin excretion was a very sensitive parameter for renal tubular damage in this study.

Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis: Final results of an international trial

The effect of azathioprine on survival of patients with primary biliary cirrhosis was studied prospectively in a multinational, double-blind, randomized clinical trial including 248 patients of whom 127 received azathioprine and 121 placebo. There were 57 deaths in the azathioprine group and 62 in the placebo group. The actual survival was slightly longer during azathioprine than during placebo treatment. Using Cox multiple regression analysis and adjusting for slight imbalance between the two treatment groups, the therapeutic effect of azathioprine was statistically significant (p = 0.01), with azathioprine reducing the risk of dying to 59% of that observed during placebo treatment (95% confidence interval 40%–90%) or improving survival time by 20 mo in the average patient. Furthermore, azathioprine slowed down progressing incapacitation. Side effects of azathioprine were relatively few. The analysis revealed that the following five variables independently implied poor prognosis: high serum bilirubin, old age, cirrhosis, low serum albumin, and central cholestasis. These factors were combined to a “prognostic index” for prediction of outcome in new patients. The index was validated on independent patient data. On the basis of these results we recommend azathioprine as a routine treatment of primary biliary cirrhosis.

Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis

Abstract The effect of azathioprine on survival of patients with primary biliary cirrhosis was studied prospectively in a multinational, double-blind, randomized clinical trial including 248 patients of whom 127 received azathioprine and 121 placebo. There were 57 deaths in the azathioprine group and 62 in the placebo group. The actual survival was slightly longer during azathioprine than during placebo treatment. Using Cox multiple regression analysis and adjusting for slight imbalance between the two treatment groups, the therapeutic effect of azathioprine was statistically significant (p = 0.01), with azathioprine reducing the risk of dying to 59% of that observed during placebo treatment (95% confidence interval 40%–90%) or improving survival time by 20 mo in the average patient. Furthermore, azathioprine slowed down progressing incapacitation. Side effects of azathioprine were relatively few. The analysis revealed that the following five variables independently implied poor prognosis: high serum bilirubin, old age, cirrhosis, low serum albumin, and central cholestasis. These factors were combined to a prognostic for prediction of outcome in new patients. The index was validated on independent patient data. On the basis of these results we recommend azathioprine as a routine treatment of primary biliary cirrhosis.

THROMBOEMBOLIC COMPLICATIONS AND HAEMOSTATIC CHANGES IN CYCLOSPORIN-TREATED CADAVERIC KIDNEY ALLOGRAFT RECIPIENTS

The incidence of thromboembolic complications was compared retrospectively in 90 cadaveric kidney allograft recipients treated with cyclosporin and low-dose steroids and the same number of cadaveric kidney allograft recipients treated with azathioprine, antilymphocyte globulin, and high-dose steroids. In the cyclosporin group, 17 thromboembolic complications occurred in 13 patients: 10 pulmonary emboli, 1 renal vein thrombosis, 3 deep vein thromboses, and 3 haemorrhoidal thromboses. In the azathioprine group, the only thromboembolic complication was 1 episode of superficial thrombophlebitis. Haemostatic tests in cyclosporin-treated and azathioprine-treated patients and normal subjects (10 in each group) showed increased concentrations of factor VIII C, fibrinogen, antithrombin III, and protein C in the cyclosporin-treated patients. Adenosine-5'-diphosphate-induced platelet aggregation was also significantly enhanced in the cyclosporin group. The effect of cyclosporin on haemostasis may predispose to thromboembolic complications.

A Single Institution, Randomized, Prospective Trial of Cyclosporine Versus Azathioprine-Antilymphocyte Globulin for Immunosuppression in Renal Allograft Recipients

Between September 26, 1980 and December 31, 1983, 230 splenectomized, transfused renal allograft recipients were randomized to treatment with either cyclosporin-prednisone (N = 121, 68 diabetic and 53 nondiabetic recipients; 73 cadaver and 48 related donor grafts) or azathioprine-prednisone-antilymphocyte globulin (N = 109, 61 diabetic and 48 nondiabetic recipients; 69 cadaver and 40 related donor grafts). The results were analyzed on March 31, 1984. Actuarial patient survival rates at 2 years were 88% in the cyclosporin and 91% in the azathioprine groups (p = 0.649). Graft survival rates at 2 years were 82% in all cyclosporin and 77% in all azathioprine-treated recipients (p = 0.150); the corresponding figures in the recipients of related donor grafts were 87% vs. 83% (p = 0.656), and in the recipients of cadaver donor grafts were 78% vs. 73% (p = 0.178). The 2-year graft survival rates were 81% in cyclosporin and 74% in azathioprine-treated diabetic recipients (p = 0.150) and 83% in cyclosporin and 81% in azathioprine-treated nondiabetic recipients (p = 0.604). Within the cyclosporin and azathioprine treatment groups, the differences in graft survival rates between diabetic and nondiabetic recipients were not significant (p = 0.822 and 0.423, respectively). Although there were no significant differences in graft survival rates, the cumulative incidence of rejection episodes within the first post-transplant year was significantly lower in the cyclosporin (34%) than in the azathioprine (60%) treated recipients (p = 0.001). In recipients of technically successful cadaver kidney grafts, the incidence of acute tubular necrosis (ATN) was 31% in cyclosporin and 30% in azathioprine-treated recipients (p = 0.822). Graft survival rates in azathioprine- and cyclosporin-treated recipients who did or did not undergo ATN were 72% vs. 89% (p = 0.011). The mean (+/- S.D.) serum creatinine levels (mg/dl) at 1 year were higher in cyclosporin (2.0 +/- 0.6) than in azathioprine (1.5 +/- 0.5) treated recipients (p = less than 0.001). A reduction in cyclosporin dose because of nephrotoxicity was required in 96 of the cyclosporin-treated patients (70%), and 25 were switched to treatment with azathioprine (21%). The incidence of all infections in cyclosporin-treated patients was approximately half of that in azathioprine-treated patients, and only nine per cent of the cyclosporin-treated patients were diagnosed to have cytomegalovirus infections during the first post-transplant year vs. 28% in azathioprine-treated patients (p = 0.002).(ABSTRACT TRUNCATED AT 400 WORDS)

Unique features of human and monkey xenosensitization against anti-T cell murine monoclonals

OKT3 monoclonal anti-T cell antibody was used during the first 2 weeks following cadaveric renal transplantation to prevent rejection. When compared with a control group receiving triple immunosuppression with cyclosporine, azathioprine, and prednisone, the OKT3, azathioprine, and prednisone group had significantly fewer acute rejections during the first month (6% v 50%; P < 0.01), and the mean time of onset of the first rejection was significantly delayed (day 47 v day 8; P < 0.01) in the OKT3 prophylaxis group. OKT3 was administered intraoperatively safely and without complications on the day of transplantation. The well-reported first dose reaction to OKT3 was similar in these patients when compared with patients receiving OKT3 for treatment of rejection. Anti-OKT3 antibody development occurred in half of the patients receiving OKT3, and did not prevent the subsequent use of OKT3 in these patients, whose rejections following OKT3 prophylaxis were steroid reversible. There were no deaths among the patients receiving prophylactic OKT3, and during a 15-month follow-up, only three of 34 kidneys were lost for any reason. In addition to its use for primary and steroid-resistant rejection, OKT3 may be useful early after transplantation to prevent rejection.

Effect of azathioprine and carbon tetrachloride on induction of hyperplastic liver nodule and hepatocellular carcinoma by diethylnitrosamine and N-2-fluorenylacetamide in rats.

The enhancing or inhibitory action of the hepatotoxic agents, carbon tetrachloride (CCl4) and azathioprine (AZP), on the evolution of hyperplastic liver nodule (HN) and hepatocellular carcinoma (HCC) in diethylnitrosamine (DEN)- and N-2-fluorenylacetamide (FAA)-treated rats (control group) was tested. The area of gamma-glutamyl transpeptidase(gamma-GTP)-positive HN and/or foci in the eighth week was remarkably small in rats fed on a diet containing FAA and AZP (the AZP group), but was quite large in rats fed a diet containing FAA in addition to repeated CCl4 injections (the CCl4 group). HCC was first detected in the 21st week and the incidence of HCC within the 36 weeks of the experiment was very high in the CCl4 group. However, no tumor, including HCC, was detected in the AZP group during this observation period. No essential differences in the biochemical characteristics of HCC between the control group and the CCl4 group were observed with respect to several enzyme activities. The increased activity of liver aniline hydroxylase observed 12 hr after the administration of FAA, AZP, or DEN decreased when AZP was administered simultaneously with FAA to rats treated with DEN in advance. The mechanisms of the enhancing of inhibitory effect observed are discussed with special reference to the drug-drug interactions.

Antibody response after influenza immunization in renal transplant patients receiving cyclosporin A or azathioprine.

Nineteen renal transplant recipients receiving cyclosporin A and prednisone, eight kidney recipients receiving azathioprine and prednisone, and 12 healthy volunteers were immunized with 0.5 ml of trivalent influenza vaccine containing A/Bangkok/1/79 (H(3)N(2)), A/Brazil/11/78 (H(1)N(1)), and B/Singapore/222/79. Nine patients (47%) in the cyclosporin A group and five (63%) in the azathioprine group showed fourfold rises in titer to at least one virus strain compared with 12 (100%) in the control group.

Cyclosporin A in orthotopic canine hepatic transplants

Cyclosporin A, a potent yet selective immunosuppressant, does not appear to predispose to the infectious and metabolic complications seen with conventional immunosuppression. The purpose of this work is to determine the efficacy and dose requirements of Cyclosporin A in canine orthotopic hepatic transplantation and to assess potential toxicity in the hepatic allograft. Twenty dogs received orthotopic hepatic transplantation and survived 5 or more days postoperatively. Nine dogs received azathioprine 4–6 mg/kg, nine Cyclosporin A, 20 mg/kg incrementally decreased by 50% at 14 day intervals, and two dogs received no immunosuppression. Serial determinations of serum bilirubin, alkaline phophatase, WBC, Hgb, Hct, and serial percutaneous liver biopsies were performed. Average survival for the control dogs (no immunosuppression) was 11 days, the azathioprine group, 16.9 days, and the Cyclosporin A dogs, 37.7 days ( P < 0.05). Liver function studies at 7, 14, and 21 days were remarkably preserved in the Cyclosporin A-treated group compared to the controls and azathioprine group. No histologic or biochemical evidence of rejection appeared until the daily dose of Cyclosporin A fell below 20 mg/kg. No histologic or biochemical evidence of renal or hepatic toxicity was evident in the Cyclosporin A-treated dogs. Cyclosporin A at 20 mg/kg was found to be efficacious in canine hepatic transplants with significantly improved survival and liver function compared to azathioprine.

Long-term effects of azathioprine in rheumatoid arthritis.

Efficacy and safety of azathioprine in 'high' and 'low' dose regimens in rheumatoid arthritis (RA), both in short-term studies and in follow-up over 40 months, have previously been shown. In the present report, 36 patients with RA treated with azathioprine (group I) and 49 age-matched patients with RA (group II), were studied to detect potential early markers of malignancy. Chest x-rays were similar to both groups. One patient in group I had a positive PAP smear and was subsequently found to have uterine carcinoma. Alpha-fetoprotein was positive in one patient in group I and none in group II. CEA was negative in all patients in group I, but positive in seven in group II. On chromosomal analysis group I showed a greater frequency of breakage. Group I showed lower serum folates and a highly significant number of megaloblastic features in marrow aspirates. In group I seven tumours, three being malignant, occurred while taking azathioprine, and in group II six tumours, one malignant, were identified (p = 0.17). The apparent increased risk of malignancy previously suggested by others warrants further studies with larger populations and over a continuous longer period.

Treatment of interstitial cystitis with immunosuppression and chloroquine derivatives.

Azathioprine, an immunosuppressive agent, was given to 38 patients presenting with intestinal cystitis. Pain disappeared completely in 22 patients and pollakiuria did the same in 20 patients, including two very severe cases with very contracted bladder. Chloroquine or oxychloroquine, usually combined with salicylate, was given to 22 patients. Pain disappeared in 11 patients and pollakiuria in 4 patients. No effect was noted in 10 patients in the azathioprine group and in 8 patients in the chloroquine group. The remaining patients had partial alleviation. The results are analyzed separately for various grades of severity. Spontaneous cure can be expected only in 11% of cases of interstitial cystitis calculated from a large series. Immunosuppression or chloroquine derivates are indicated for patients who do not respond to other treatments.

A Controlled Trial of Azathioprine in the Management of Chronic Ulcerative Colitis

To determine the efficacy of azathioprine in the treatment of ulcerative colitis, a 6-month double blind trial was carried out. Thirty patients with chronic ulcerative colitis who required the equivalent of at least 10 mg of prednisone per day over the 3 months prior to entering the study were randomized into placebo and azathioprine (1.5 mg per kg) treatment groups. Reduction of steriods was a major objective of the trial. Age and sex distribution, number of bowel movements, sense of well being, steroid dosage, and findings on proctoscopy, rectal biopsy, and colon X-ray initially were similar in the two groups. No side effects were associated with azathioprine. Although steroid dose was lower (p less than 0.05) in the azathioprine group at the termination of the study, no difference between the two groups could be detected in the number of bowel movements, sense of well being, and findings on proctoscopy during the first 3 weeks compared with the last 3 and during the first 3 months compared with the last 3. Although azathioprine does not confer dramatic benefit upon patients with chronic ulcerative colitis who require steroids, it does permit reduction of steroid dosage without apparent worsening of the disease. Its major value in ulcerative colitis may be in facilitating significant decreases or complete discontinuance of steroids.

Treatment of lupus nephritis with prednisone and combined prednisone and azathioprine.

Abstract The relative effectiveness of high-dose prednisone (group A) was compared with the same regimen plus azathioprine (group B) for the treatment of lupus nephritis of mild or moderate severit...

Pancreas allotransplantation without duodenum

Pancreas allotransplantations without duodenum were successfully performed with preservation of both endocrine and exocrine functions of the pancreas. The cannulated duct of the tail of the pancreas was anastomosed to a jejunal loop in the recipient. Ten dogs received nonimmunosuppressive treatment and 10 dogs were treated with azathioprine. There was a slight extension of survival time in the azathioprine group. Azathioprine was effective in repressing the acute rejection but was unable to prevent the fibrotic process. Our results suggest that hyperglycemia, a poor response of the islets after glucose stimulation (glucose tolerance test) and a low circulating plasma insulin level along with a low amylase level indicate the end point of rejection. This was histologically proved by a fibrotic pancreas (dead organ). In our studies using this particular technique of pancreaticojejunostomy, it was difficult postoperatively to evaluate a high amylase level as far as the rejection process was concerned. A high amylase level in pancreas allotransplantation can, but does not necessarily, indicate a beginning rejection. The tail of the pancreas allografts was able to regulate the blood sugar and to sustain the life of the pancreatectomized dogs until the graft rejection took place.

Allotransplantation of the pancrease in dogs

En block transplantation of the pancreas and duodenum was performed in 30 pancreatectomized dogs, 10 of which served as a control group and the remaining 20 as the azathioprine group. The latter were orally administered (6 mg. per kilogram) azathioprine every day. The former group lived an average of 10 days; and the latter, 22 days. Rejection was a cause of death in 6 of the control group and in 6 of the azathioprine group. In 5 of these 12, however, the last fasting blood glucose level was over 150 mg. per deciliter, suggesting that hyperglycemia is not an initial sign of rejection but rather its terminal sign. Histological study revealed that acute rejection resembling acute pancreatitis was a phenomenon observed in the control group, while chronic rejection manifested by interstitial fibrosis was characteristic of the azathioprine group. Azathioprine is effective in suppressing the acute rejection process but is unable to prevent fibrotic process.