Azathioprine and inhibition of the anticoagulant effect of warfarin: evidence from a case report and a literature review.

BACKGROUND: Warfarin and azathioprine may be prescribed concurrently in patients requiring both anticoagulation and immunosuppression. However, a potential interaction between the 2 drugs, resulting in an increased warfarin requirement, may be overlooked in clinical practice. CASE SUMMARY: A 67-year-old woman was treated with warfarin (initial mean dose, 24 mg/wk [3.5 mg/d]) for >3 years for recurrent deep vein thrombosis associated with systemic lupus erythematosus. Soon after commencing warfarin, azathioprine 150 mg/d was introduced for its steroid-sparing effect. Warfarin was titrated to a mean dose of 60 to 75 mg/wk (8.5-10.5 mg/d) over the next 18 months. Her dose of azathioprine was then increased to 200 mg/d. Subtherapeutic international normalized ratio (INR) levels required an increase in the warfarin dose to a mean of 130 mg/wk (18.5 mg/d). Subsequent discontinuation of azathioprine resulted in a dramatic increase in her INR levels (from 1.8 to 14.0 four weeks after discontinuation). DISCUSSION: A temporal relationship, demonstrating the interaction between warfarin and azathioprine, was evident at various times during therapy for our patient. This case, together with 7 additional published cases, is comprehensively reviewed here using previously described criteria for establishing a definite interaction between warfarin and other drugs. CONCLUSIONS: The evidence supports a clinically important inhibitory action of azathioprine on warfarin and calls for closer monitoring of INR levels when azathioprine doses are altered during concurrent administration with warfarin.

Modulatory effect of quercetin on azathioprine induced membrane changes in the mouse spleen.

Modulatory effect of quercetin on azathioprine induced toxic changes was studied in spleen of experimental animals. Azathioprine treatment caused an increase in serum albumin/globin ratio and a decrease in total protein in spleen tissue. An increase in a membrane bound ATPases was also noted. Supplementation of quercetin with azathioprine increased the protein content and lowered the activities of membrane ATPase in spleen. There was a decrease in serum albumin globulin ratio. It was concluded that quercetin modulated the protein and membrane bound ATPase activities and protected the spleen from azathioprine induced membrane damage.

Does 2-mercaptoethane sulphonate (mesna) prevent cyclophosphamide and azathioprine induced immunosuppression? In vitro studies.

The effect of 2-mercaptoethane sulphonate (mesna) on the inhibition of the human MLR by 4-hydroxycyclophosphamide or azathioprine was studied. 4-Hydroxycyclophosphamide (34 microM) completely inhibited the MLR and this inhibition was unaffected by 122 microM of 2-mercaptoethane sulphonate or its disulphide. At high concentrations (mM) 2-mercaptoethane sulphonate inhibited the MLR reaching 85% at 24 mM. 2-Mercaptoethane sulphonate (15-122 microM) had no effect on azathioprine (36 microM) inhibition. The results of these in vitro studies suggest that 2-mercaptoethane sulphonate does not interfere with cyclophosphamide or azathioprine induced suppression of cellular immunity.

Effect of interleukin-2 on the inhibition of the human mixed lymphocyte reaction (MLR) by azathioprine.

The effect of interleukin-2 on the response of the human MLR to azathioprine was studied. Azathioprine (36 microM) inhibited the MLR by 86% and interleukin-2 (25%) stimulated the MLR by 99%. Only partial relief (16%) of azathioprine (36 microM) inhibition was found in the interleukin-2 treated MLR compared with azathioprine treatment alone. However, [3H]-thymidine incorporation by azathioprine (36 microM) + interleukin-2 treated MLR was 4.3 times greater than that exposed to azathioprine alone. As the residual number of immunocompetent cells after drug exposure is pathologically more important than the fraction suppressed, this result may be of clinical relevance. These results show that the major mode of action of azathioprine is not the inhibition of interleukin-2 production.

Effect of the rat liver S9 fraction on the mutagenicity of azathioprine in the Salmonella/mammalian microsome assay.

Azathioprine is a direct acting mutagen in Salmonella typhimurium TA100 and TA1535. Addition of rat liver S9 fraction with or without co-factors, or glutathione, causes a decrease in the mutagenicity of azathioprine in TA100 and an increase in TA1535, indicating the effect of SH groups.

Azathioprine-associated pulmonary dysfunction.

We present a case of azathioprine-associated alveolitis diagnosed by gallium-67 scanning and transbronchial biopsy. The patient denied respiratory symptoms, exhibited spiking fevers, and had normal chest roentgenograms. Allopurinol inhibition of azathioprine metabolism may have been a contributing factor.

The effects of azathioprine and levamisole on rosette-forming cells of healthy subjects and cancer patients.

The in vitro effects of azathioprine and levamisole on the capacity of peripheral lymphocytes to form rosettes with sheep erythrocytes were studied in fifteen healthy subjects and forty-one cancer patients. Azathioprine significantly inhibited rosette formation of T lymphocytes in healthy subjects and cancer patients in remission. In contrast, azathioprine could not inhibit rosette formation of T lymphocytes in cancer patients with advanced disease. Patients with advanced tumour had also fewer rosette-forming cells (RFC) than healthy subjects. Levamisole, an anti-anergic chemotherapeutic agent, restored azathioprine-inhibited RFC in healthy subjects and in fifteen out of twenty-two cancer patients. Levamisole alone significantly enhanced low RFC in cancer patients.

[Influence of phenobarbital on the immunodepressive action of antitumor substances]. / Vliianie fenobarbitala na immunodepressivnoe deistvie protivoopukholevykh sredstv

In the experiments on mice, immunized by mutton erythrocytes, the authors have studied the effect of phenobarbital, in the doses activating drug-metabolizing hepatic systems, on immunodepressive action of imurane, 6-mercaptopurine and cyclophosphane. It has been found that phenobarbital eliminates the immunodepression and reduces considerably the toxicity of the mentioned cytostatics. Under these conditions imurane and 6-mercaptopurine in certain doses render an immunostimulative instead of immunodepressive effect.