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Ketoconazole is an inhibitor of adrenal steroidogenesis used in the treatment of Cushing's disease. Previous data obtained with single blood sampling were controversial as to increased ACTH levels compensatory to the cortisol fall. We have evaluated by chronobiological procedures the circadian profiles of plasma ACTH and cortisol in three patients with Cushing's disease before and after a six-month course of therapy with ketoconazole (600 mg daily). None of the patients complained of any adverse subjective reaction; in particular no sign or symptom of hypoadrenalism and/or hepatotoxicity was recorded. Ketoconazole treatment markedly improved the clinical setting and caused a highly significant (p less than 0.0001) reduction of mean 24-h cortisol values (ciradian MESOR). The expected rise of ACTH did not take place; rather, we detected a slight decrease of the mean circadian MESOR (p less than 0.05). Our data, althought obtained in a very small number of patients, suggest that ketoconazole may have an additional action at central level, at least in some cases of Cushing's disease.
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