Immunomodulating effect of oral and transdermal varfarine therapy

Abstract

Warfarin is an anticoagulant that is widely used in the prevention and treatment of thromboembolic disorders in humans. Numerous side effects of oral therapy with this agent are known, which has led to the recommendation for transdermal administration of this agent. This study examined the effect of oral warfarin consumption (0.35 mg / l and 3.5 mg / l in drinking water, 30 days) on the intestinal immune system in rats, as well as the systemic effect (on peripheral blood leukocytes) of epicutaneous administration of this agent. µg or 100 µg, once a day, for three days).The anticoagulant effect, determined on the basis of the increase in prothrombin time, was observed after oral consumption of both doses, as well as after epicutaneous application. Orally administered warfarin leads to histologically evident damage to intestinal tissue and inflammation (cellular infiltration, myeloperoxidase activity, malodialdehyde content and superoxide dismutase and catalase activities), as well as increased concentrations of proinflammatory cytokines (IFN-γ, IL-17) in intestinal homogenate.In mesenteric lymph nodes, however, suppression of the immune response has been observed (decreased ability of cells to proliferate and produce IFN-γ and IL-17 in response to cannavalin A stimulation). Decreased production of IL-10 by mesenteric lymph node cells indicates the formation of a microenvironment that does not allow the activation of a potentially harmful immune response in this tissue. Epicutaneous administration of a higher dose of warfarin leads to an increase in the number of neutrophilic leukocytes and intracellular myeloperoxidase activity, as well as an increase in granular CD11b + cells. In contrast to this increase, a decrease in TNF and IL-6 production as well as mRNA levels for these cytokines was observed.After administration of a higher dose of warfarin, there is a decrease in the number of mononuclear cells with an increase in the presence of CD11b + in this population, but without an effect on cytokine production, indicating the differential effects of transdermal administration of warfarin. Taken together, the results indicate the need to monitor the (adverse) effects of warfarin therapy.