Favorable therapeutic index of the direct factor Xa inhibitors, apixaban and rivaroxaban, compared with the thrombin inhibitor dabigatran in rabbits.

BACKGROUND: Apixaban is an oral, direct factor Xa (FXa) inhibitor in late-stage clinical development. This study assessed effects of the direct FXa inhibitors, apixaban and rivaroxaban, vs. the direct thrombin inhibitor, dabigatran, on venous thrombosis (VT), bleeding time (BT) and clotting times in rabbits. METHODS: We induced the formation of non-occlusive thrombus in VT models by placing threads in the vena cava, and induced bleeding by the incision of cuticles in anesthetized rabbits. Apixaban, rivaroxaban and dabigatran were infused IV to achieve a stable plasma level. Clotting times, including the activated partial thromboplastin time (aPTT), prothrombin time (PT), modified PT (mPT) and thrombin time (TT), were measured. RESULTS: Apixaban, rivaroxaban and dabigatran exhibited dose-related efficacy in preventing VT with EC(50) of 65, 33 and 194 nm, respectively. At doses for 80% reduction of control thrombus, apixaban, rivaroxaban and dabigatran prolonged BT by 1.13 +/- 0.02-, 1.9 +/- 0.1-* and 4.4 +/- 0.4-fold*, respectively (*P < 0.05, vs. apixaban). In the treatment model, these inhibitors equally prevented growth of a preformed thrombus. Antithrombotic doses of apixaban and rivaroxaban prolonged aPTT and PT by <3-fold with no effect on TT. Dabigatran was > or = 50-fold more potent in prolonging TT than aPTT and PT. Of the clotting assays studied, apixaban, rivaroxaban and dabigatran responded the best to mPT. CONCLUSION: Comparable antithrombotic efficacy was observed between apixaban, rivaroxaban and dabigatran in the prevention and treatment of VT in rabbits. Apixaban and rivaroxaban exhibited lower BT compared with dabigatran at equivalent antithrombotic doses. The clinical significance of these findings remains to be determined.

The effect of thalidomide on experimental autoimmune myasthenia gravis.

Thalidomide is reported to have immunosuppressive and anti-inflammatory effects which have led to its use in the treatment of a number of immune-mediated disorders including leprosy, prurigo, discoid lupus, and Behcet's disease. In addition, thalidomide has recently been used to prevent immunological rejection phenomena following skin and bone-marrow grafts. The immune responses in these conditions are thought to be cell-mediated. However, little is known about the effectiveness of thalidomide in suppressing antibody-mediated immune responses. In the present study, we have examined the effect of thalidomide in a model antibody-mediated autoimmune disorder--experimental autoimmune myasthenia gravis (EAMG). To induce EAMG, Lewis rats were immunized with acetylcholine receptor (AChR) purified from the electric organ of Torpedo californicus. Groups of rats were treated daily, either with thalidomide in excess of doses reported to prevent graft-versus-host (GVH) disease in bone-marrow-transplanted rats, or with control treatments. Our results show that thalidomide failed to inhibit AChR antibody production despite good absorption and high blood levels of the drug. This suggests that thalidomide is not likely to be generally useful in the treatment of antibody-mediated autoimmune conditions. However the selective effect of thalidomide in suppressing certain presumably cellular immune responses, while sparing antibody production, is inherently interesting, and merits further study.