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At least 19 recordsLinked to original sources
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↗
PubMed1975

The effect of azathioprine (Imuran) on the cell cycle of promonocytes and the production of monocytes in the bone marrow.

The present communication concerns the effect of azathioprine on the mitotic activity of promonocytes and the production of monocytes. In vitro and in vivo labeling with [3H]thymidine showed that during azathioprine treatment the promonocytes synthesize DNA and that, contrary to expectation, the labeling index increases. Cytospectrophotometric determination of the Feulgen-DNA content of the promonocytes during azathioprine treatment showed an increase in the percentage of tetraploid promonocytes, and determination of the various phases of the cell cycle showed significantly increased DNA synthesis and cell cycle times as compared with the normal steady state. On the basis of these results it can be concluded that azathioprine arrests the cell cycle of the promonocytes late in the DNA synthesis phase or in the postsynthesis (G2) phase and mitosis does not occur. This timing of the effect of azathioprine had not been previously observed. The diminished mitotic activity of the promonocytes during azathioprine treatment depressed monocyte production. During treatment with 3 mg/kg azathioprine the cell cycle time of the promonocytes was on the average 5.5 h longer than in the normal steady state and the rate of monocyte production was reduced by 70%. During an acute inflammatory reaction too, monocyte production is affected by azathioprine. In animals not treated with azathioprine but with an acute inflammation the cell cycle time becomes shorter and the monocyte production increases, but animals treated with (3 mg/kg) azathioprine do not show this effect. The kinetics of the monocyte also changes under the low dosage of azathioprine. As consequence of the diminished production of monocytes, far fewer (about 50%) monocytes enter and leave the circulation than during the normal steady state. During an acute inflammatory reaction the numbers in transit through the circulation are slightly augmented but remain considerably lower than in nonazathioprine-trehat of animals not treated with azathioprine.

Acute Disease↗
PubMed1975

The mutagenicity of azathioprine in mice, Drosophila melanogaster and Neurospora crassa.

The chemotherapeutic coumpound azathioprine was tested for possible mutagenicity in Swiss Albino mice, Drosophila melanogaster and Neurospora crassa. Utilizing the dominant-lethal assay it was found that acute oral doses of azathioprine (2 times 25 mg/kg body weight), induced dominant-lethal mutations in mouse spermatocytes. Chronic oral doses of azathioprine (2 times 25 mg/kg body weight/week for 10 weeks) resulted in a greater rate of dominant-lethality. This increase was not permanent, and by week 4 of gamete sampling there was no significant increase in dominant-lethal mutations. Histological sections showed that chronic treatment of male mice with azathioprine caused pyknosis of spermatocyte nuclei and depletion of the spermatid population. Both acute and chronic doses of azathioprine caused a temporary reduction in sperm viability. Oral treatment of male Canton-S, D. melanogaster with azathioprine caused an increase in dominant-lethality in broods assumed to correspond to spermatid and spermaotcyte stages. Azathioprine also increased the rate of non-disjunction of the X and Y chromosomes, loss of the long arm of the Y chromosome, and loss of the X or Y chromosome in treated male R(I)2, vf/BsYy+D. melanogaster. Since sex-ratio deviation did not occur in progeny from treated rod-X (yv/B2Yy+) male D. melanogaster, it was concluded that the observed sex-ration deviation in the treated ring-X stock was the result of induced ring-X lethality. Azathioprine induced recessive-lethal mutations in the ad-3 region of a N. crassa heterokaryon. In the host-mediated assay using this same heterokaryon and male Swiss Albino mice as host, the mutagenic activity of azathioprine did not appear to be potentiated or detoxified by the host. The results show that azathioprine has a deleterious effect on reproduction in mice and probably induces mutational events in mice, D. melanogaster and N. crassa.

Animals↗
PubMed1992

Systemic toxicosis associated with azathioprine administration in domestic cats.

Five cats were treated with an azathioprine suspension (2.2 mg/kg of body weight on alternate days) and 2 cats were given vehicle (controls) for 9 weeks. Complete blood and platelet counts and serum biochemistry variables were monitored weekly. Bone marrow aspirates were evaluated every 3 weeks, and core bone marrow biopsy was performed at the end of the study. Profound neutropenia (less than 600 cells/microliters) was observed in all treated cats, and 1 cat developed pancytopenia. Treatment was discontinued if the WBC count was less than 3,000 cells/microliters. Four weeks after discontinuation of azathioprine, 1 treated cat again was given azathioprine at a lower dosage (1.1 mg of azathioprine/kg on alternate days) and neutropenia recurred within 2 weeks. During treatment, 3 cats developed thrombocytosis, and 2 developed thrombocytopenia. In 4 of 5 cats, neutropenia and thrombocytopenia resolved when azathioprine was discontinued. Bone marrow cytologic examination during treatment revealed reduction of the neutrophil line, with relative increase in monocytes. Core bone marrow biopsy at the completion of the study revealed hypocellular marrow with marked decrease in the myeloid series in cats given azathioprine. One of the cats that was treated with azathioprine had a hypercellular marrow with increased numbers of mature granulocytes and precursors; however, azathioprine had been discontinued 3 weeks prior to biopsy. Alterations in serum biochemical variables were not associated with azathioprine. Two cats that were treated with azathioprine developed respiratory tract infections, and 1 of them was euthanatized during the study.

Animals↗
PubMed1977

Interaction of azathioprine and glutathione in the liver of the rat.

Azathioprine was administered to rats in order to study its interaction with glutathione in vivo. Glutathione levels were measured sequentially in liver, red blood cells, kidney and small intestine after i.p. injections of azathioprine (6.25-100 micronmol/100 g b.wt.). Five minutes after drug administration, dose-related selective depletion of hepatic glutathione up to 50% of control was observed. By 60 minutes 80% depletion of hepatic glutathione was observed. Red cell glutathione depletion was also observed but lagged behind hepatic changes. Five minutes after azathioprine administrations, no change in red cell glutathione was seen with all doses of azathioprine, but a dose-related increase in plasma 6-mercaptopurine and azathioprine was observed. At all azathioprine doses and at all time intervals after drug administration, the hepatic contribution to total glutathione consumption predominated. No change in glutathione levels in kidney or small intestine was observed after azathioprine. Thus, the liver plays a major role in the metabolism of azathioprine through the interaction of the drug with glutathione.

Animals↗
PubMedDate not supplied

Long-term maintenance therapy with azathioprine in systemic lupus erythematosus.

One hundred ten patients with systemic lupus erythematosus (SLE) were classified into two groups, patients with central nervous system (CNS) or severe renal disease (usually associated with a poor prognosis) and patients without these manifestations, to define criteria for azathioprine therapy. Fifty-four of 68 patients with a poor prognosis received azathioprine. Azathioprine-treated patients showed improved long-term survival (72% vs 29%, P less than .005) and fewer hospitalizations (0.24/patient-years vs 0.89/patient-years, P less than .001). Azathioprine therapy in 19 of 42 patients with a good prognosis was associated with fewer hospitalizations (.02/patient-years vs .17/patient-years, P less than .05), but no decrease in maintenace prednisone requirement. Progression from a good to a poor prognosis was less frequent (1 of 20 vs 11 of 34, P = less than .05) among azathioprine-treated patients. Toxicity of azathioprine was minimal. Azathioprine therapy is indicated in patients with CNS or severe renal disease, and in patients whose prognosis was good with frequent hospitalizations or a maintenance prednisone requirement greater than 15 mg/day.

Adolescent↗
PubMed1979

Effect of ureteral ligation and nephrectomy on granulocyte-macrophage progenitor cells and azathioprine toxicity.

Using an in vitro quantitative clonal culture technique of bone marrow granulocyte-macrophage progenitor cells (colony-forming units culture (CFU-c)), we studied the hematopoietic toxicity of azathioprine after unilateral and bilateral ureteral ligation, unilateral and bilateral nephrectomy, and splenectomy in C57BL/6 mice. Analysis of femoral bone marrow 18 hr after i.p. injection of azathioprine (300 mg/m2) revealed increased CFU-c toxicity in comparison to controls as follows: (1) bilateral ureteral ligation, P less than 0.01; (2) bilateral nephrectomy, P less than 0.01; (3) unilateral ureteral ligation, P greater than 0.05 less than 0.1; (4) unilateral nephrectomy, P, not significant; and (5) splenectomy, P, not significant. Extrapolation from a dose-response curve for the toxicity of azathioprine on the bone marrow CFU-c indicated that bilateral ureteral ligation and bilateral nephrectomy had the effect of a 25 to 50% increase in the azathioprine dose. After bilateral ureteral ligation, serum granulocyte-macrophage colony-stimulating factor levels were increased and in vitro tritiated thymidine suicide studies showed an increased proliferative rate of the CFU-c. Since azathioprine is a predominantly cell cycle-specific agent, we suggest that increased sensitivity to azathioprine is related to the increased proliferative rate of the CFU-c. The findings provide a rationale for a clinical policy of azathioprine reduction when there is depressed renal function.

Animals↗
PubMed1977

Immunosuppressive properties of sera and urine dialysates from kidney-graft recipients treated with azathioprine, prednisolone, and niridazole.

Niridazole, an antischistosomal agent, was given to renal transplant recipients in addition to azathioprine and prednisolone, as there is experimental evidence that this combination of drugs is highly immunosuppressive. Sera obtained from kidney-graft recipients during the first two weeks after transplantation were examined for their ability to inhibit the one-way mixed lymphocyte reaction (MLR). Sera from seven patients receiving azathioprine, prednisolone, and niridazole (triple-drug treatment), five patients receiving azathioprine and prednisolone, and two other patients treated with niridazole alone for schistosomiasis produced MLR inhibition by comparison with pretreatment (control) sera.A mean of 78% inhibition was observed with sera taken after one day's treatment with the three-drug combination, whereas this level of in-vitro immunosuppression occurred only after eight days of treatment with azathioprine and prednisolone. Niridazole alone produced an effect similar to azathioprine and prednisolone. Concentrated dialysate of urine from a patient receiving triple-drug treatment not only inhibited the MLR but also significantly prolonged the survival of heterotopic heart allografts in rats, whereas dialysate from the same patient after niridazole had been stopped gave less MLR inhibition and failed to prolong heart allograft survival.Since niridazole thus increased the in-vitro and in-vivo immunosuppressive action of azathioprine and prednisolone, we suggest that this triple-drug combination might be useful for preventing early acute kidney graft rejection.

Azathioprine↗
PubMed1975

In vitro evaluation of methotrexate and azathioprine for antipsoriatic activity.

The effects of methotrexate and azathioprine, two drugs used in antipsoriatic therapy, on oxygen consumption of surviving human skin and on enzymatic activities of human skin homogenates were investigated. In concentrations of 1 mM/1, both substances provoked a significant decrease in oxygen consumption of human skin; in this respect, there was practically no difference between methotrexate and azathioprine. In the enzyme assays, however, azathioprine was, by far, less effective than methotrexate. After an incubation of 120 min azathioprine (1mM/1) inhibited lactate and glucose-6-phosphate dehydrogenase activities by about 10 per cent only, whereas the corresponding values with methotrexate amounted to 80 and 70 per cent, respectively. Methotrexate revealed an immediate inhibitory effect on pure glucose-6-phosphate dehydrogenase whereas azathioprine produced no changes in this mode. Furthermore, only methotrexate inhibited "acid" phosphatase activity of human skin homogenates.--These data sustain the theory that the better clinical efficacy of methotrexate in patients with psoriasis might be due to the more pronounced inhibition of important enzymes such as the enzymes of the pentose phosphate shunt.

Acid Phosphatase↗
PubMed1976

The immunosuppressive mechanism of azathioprine. I. In vitro effect on lymphocyte function in the baboon.

The effect of azathioprine on in vitro baboon lymphocyte function tests was evaluated using the mitogen stimulation test, the mixed lymphocyte culture test, the migration inhibition factor test, the cell-mediated lymphocytotoxicity test and the antibody dependent cell-mediated cytotoxicity test. It was found that azathioprine inhibited phytohemagglutinin and Concanavalin A stimulation at lower concentrations than those required to inhibit pokeweed mitogen stimulation. It inhibited the MLC reaction with as little as 0.2 mug/culture in the microculture system. Azathioprine had no effect on (a) the release of migration inhibition factor, (b) the cell-mediated lymphocytotoxicity assay if presensitized cells were used, and (c) the antibody-dependent cell-mediated cytotoxicity assay. However, azathioprine inhibited CML if it was added during in vitro sensitization and induction of killer cells. These in vitro results suggest that azathioprine inhibits those reactions which require cellular division.

Animals↗
PubMed1979

Azathioprine treatment of adjuvant arthritis.

Administration of azathioprine in the diet to Lewis rats reduced the lethality of this drug relative to various regimens by gavage. This mode of administration made it possible to administer effective doses with reduced toxicity. Azathioprine blocked the early development of adjuvant arthritis and decreased the joint scores of animals with established adjuvant disease. A combination of azathioprine and prednisolone produced an additive reduction of both developing and established joint scores. A 10 day pulse regimen of prednisolone resulted in a strong, rapid decrease in established joint scores. This decrease was sustained by continuous administration of azathioprine. In all cases removing azathioprine and/or prednisolone from the diet of animals with established adjuvant arthritis resulted in recurrence of disease. The results of these studies support the validity of the adjuvant model for prediction of anti-arthritic activity.

Animals↗
PubMed1975

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.

Adolescent↗
PubMed1975

A controlled trial of azathioprine in Crohn's disease.

To determine the efficacy of azathioprine in the treatment of Crohn's disease, a 26-week double-blind trial was performed. 20 patients with Crohn's disease, requiring at least 10 mg of prednisone/day over the 3 months prior to entering the study were randomized into placebo (10 patients) and major criterion of success in the trial. There were 7 relapses in the placebo group (5 patients) and 2 relapses in the azathioprine group (2 patients). Complications including fistulae were not affected by the medications. The mean reduction in steriod dosage in the azathioprine group at the end of the trial (-15.5 mg) was greater than in the placebo group (-6.1 mg). These results suggest that azathioprine may permit reduction or discontinuation of steroids without the worsening of symptoms in some patients who appear to require steroids for control of their symptoms. The clinical features of this "AZA-responsive subgroup" remain to be defined.

Adolescent↗
PubMed1979

Investigation into the mutagenic activity of azathioprine (Imuran) in different test systems.

The chromosome-damaging effect of azathioprine (Imuran) was investigated in the micronucleus test with mice and rats, in the pertussis-stimulated lymphocyte metaphase test with rabbits, and in children on azathioprine therapy. In the micronucleus test, there was a dose-dependent increase in the number of cells with micronuclei. The dose was given twice in 24 h, i.p., 25, 50 and 100 mg/kg body weight for mice, and 50, 100 and 200 mg/kg for rats. In the lymphocyte test, a dose of 5 and 20 mg azathioprine per kg body weight was given orally to rabbits on three successive days after pertussis injection. Compared with treatment in the control group these treatments induced a significantly increased number of cells with chromosomal abnormalities. These results were confirmed in lymphocyte cultures of children on long-term azathioprine therapy after kidney transplantation, where an increase in the number of structural chromosomal abnormalities was observed.

Animals↗
PubMed1978

Is azathioprine necessary in renal transplantation?

In renal-transplant patients in whom azathioprine therapy was withdrawn early because of bone-marrow suppression no rebound graft rejection was noted. Any subsequent rejection episodes were satisfactorily treated with methylprednisolone pulse therapy. Of 15 patients in whom azathioprine was stopped electively after at least 2 years, only 1 had a subsequent cellular rejection. It is concluded that azathioprine may not have a major role in the immunosuppressive management of renal-transplant patients. If azathioprine has to be stopped there seems to be no good indication for restarting it.

Adult↗