The pathogenesis of cianidanol-induced fever

Recently, there has been a variety of reports of adverse drug reactions during therapy with the flavonoid Cianidanol (Ci), a cytoprotective radical scavenger, especially involving haemolytic anaemia and drug fever. To elucidate whether the fever was due to a direct, antigen-independent interaction of Ci with immune competent cells, its effect on macrophage (M phi) function and early biochemical events during lymphocyte activation has been examined. A direct interaction of Ci with M phi was demonstrated, resulting in increased secretion of interleukin-1 (IL-1). The influence of Ci on lymphocyte activation was assessed by measuring levels of cyclic AMP and GMP. At high concentrations of Ci, cAMP levels were increased, and at low Ci concentrations cGMP levels were elevated. Both findings are correlated with lymphocyte proliferation and function, which is increased at low and decreased at high concentrations of Ci. The synthesis of prostaglandin E2 by M phi, an important factor in M phi-mediated suppression, was reduced by increasing doses of Ci, which inhibited M phi-cyclooxygenase. Ci did not affect phospholipase A2 activity. These findings indicate that flavonoid-induced fever may be due to allergic as well as pseudo-allergic mechanisms, the latter probably caused by increased antigen-independent release of IL-1, the endogenous mediator of fever.