Effect of salicylates on the circulating eosinophils and urinary 17-ketosteroids in man.

The anti-inflammatory and analgesic effects of salicylates have been observed for centuries, but their mode of action remains obscure. Their recommendation as the cheapest and often the safest medicament in rheumatoid arthritis (Ragan, 1949) and in rheumatic fever (McEwen, 1954; Coburn, 1943) has led to renewed efforts to discover how they work. Salicylates and cortisone may act similarly in stimulating the pituitary to produce adrenocorticotropin, and subsequently in stimulating the adrenal cortex to increase its production of cortisone. Salicylates act like cortisone in some respects, but are totally unlike it in many effects (Hailman, 1952). The evidence for and against stimulation of the hypothalamus or the anterior pituitary by salicylate to produce an ACTH-like effect is conflicting and fragmentary (Smith, Gray, and Lunnon, 1954a, b; Bayliss and Steinbeck, 1953, 1954a, b; Meade and Smith, 1951; Shuman and Finestone, 1950; Feeney, Carlo, and Smith, 1955; Done and Kelley, 1956; Marson, 1953; Cronheim, King, and Hyder, 1952, 1953; Cronheim and Hyder, 1954; Roskam and van Cauwenberge, 1951; Hetzel and Hine, 1951). The earlier studies suggested a salicylate effect via the pituitary-adrenal axis, but later reports discount this idea, since salicylates are able to exert their effect in the adrenalectomized animal (Ingle, 1941). Two tests according evidence of anterior pituitary and, subsequently, adrenal cortex activation are in common use. Adrenocorticotropic hormone in adequate doses indirectly and cortisone directly decrease the circulating eosinophils of the peripheral blood, while increasing the urinary excretion of ketosteroids. Most authorities approve of eosinopenia (the Thorn test) as a criterion of adrenal cortical stimulation (Thorn, Forsham, Prunty, and Hills, 1948; Shands and Bartter, 1952; Best, Kark, and Muehrcke, 1953). Effect on Eosinophils.-A minimal depression of the circulating eosinophils (50-60 per cent.) is usually held to be necessary to establish a positive Thorn test. A distinction between the reaction of rheumatic and non-rheumatic individuals as regards eosinophil response and corticosteroid excretion has not been reported or, at least, the idea has not been accepted. The published reports lack unanimity in describing the effect of salicylate upon the circulating eosinophils. Early studies indicated an eosinopenia following salicylate administration (Shuman and Finestone, 1950; Roskam and van Cauwenberge, 1951; Bertolani, Lorenzini, and Bonati, 1951), but recent workers have not confirmed this reported depression of the eosinophil count (McEwen, 1954; Meade and Smith, 1951; Marson, 1953; O'Connell, Roy, and Massell, 1955). It is suggested that the earlier results were due to the use of too large (i.e. toxic) doses of salicylate, so inducing a stress reaction (McEwen, 1954). According to Roskam and van Cauwenberge (1951), salicylates caused the eosinophils to decrease by 50 per cent. in 6 hours in rats. O'Connell and others (1955) found a salicylate potentiation of the eosinopenic effect of ACTH in humans; this was not interpreted as an effect upon the pituitary gland, but rather as a possible increase in peripheral utilization of the ACTH which was being given at the same time. Meade and Smith (1951) found that therapeutic doses produced no significant eosinopenia in 4 hours in humans. Lichtwitz (1944) again emphasized the distinction between the effects of therapeutic and toxic doses of salicylate in animal experiments.