Adrenal response to corticotropin during therapy with itraconazole

Abstract

Itraconazole is a triazole with a mechanism of action similar to that of ketoconazole. Endocrine side effects of ketoconazole, including impaired cortisol synthesis, have been well documented (A. Pont, J. R. Graybill, P. C. Craven, J. N. Galgiani, W. E. Dismukes, R. E. Reitz, and D. A. Stevens, Arch. Intern. Med. 144:2150Med. 144: -2153Med. 144: , 1984. We examined the adrenal response to corticotropin in 10 patients being treated with itraconazole. No impairment of cortisol synthesis could be demonstrated.Itraconazole (R 51,211) is a broad-spectrum oral antifungal agent currently undergoing clinical trials in both dermatophyte infections and the systemic mycoses. This compound shares structural similarities with the imidazole derivative ketoconazole (5). Furthermore, the drugs are believed to have similar mechanisms of action (19).Ketoconazole was first recognized to have endocrine side effects when some patients receiving the drug developed gynecomastia (3). Further studies demonstrated interference of ketoconazole with androgen (6,12,14,15), estrogen (10,20), and glucocorticoid synthesis (9, 13). Studies of steroidogenesis in cultured mouse adrenal cortex tumor cells indicate that ketoconazole directly inhibits 1-hydroxylase activity (7). There are only a few reports in which clinically significant hypoadrenalism has been attributed to ketoconazole therapy (17,18,21). The similarities between itraconazole and ketoconazole prompted us to study the adrenal response to corticotropin in patients receiving itraconazole therapy for a variety of mycotic infections.Of 10 patients referred for therapy of documented mycotic infections, 6 had coccidioidomycosis and 1 each had mucocutaneous candidiasis, aspergilloma, cutaneous sporotrichosis, and pulmonary cryptococcosis. A brief clinical outline of the patients studied is presented in Table 1.Several patients had received prior antifungal therapy, and five (patients no. 1, 2, 4, 6, and 7) had been treated with ketoconazole. None of the patients received concomitant antifungal agents during itraconazole therapy.Three additional patients (one each with aspergilloma, pulmonary coccidioidomycosis, and disseminated coccidioidomycosis) who completed baseline adrenal testing before itraconazole therapy did not consent to follow-up corticotropin studies.The 1-h corticotropin stimulation tests were performed as previously described (1). The 8-h tests were conducted with a continuous 8-h infusion of corticotropin (cosyntropin; 400 p.g in 500 ml of 5% glucose in water

High-dose itraconazole in the treatment of severe mycoses

“…Until the present report, adrenal suppression was not associated with itraconazole (24). The higher (600-mg) dose of itraconazole gave serum values above those previously reported for a dose of 400 mg/day (12).…”

“…1). Seven patients (1 through 7) had normal responses in comparison with previously published data on responses before and during treatment with lower doses of itraconazole (24). Patient 8 had a slightly reduced cortisol response 2 weeks after beginning high-dose itraconazole (Fig.…”

“…Adverse reactions at 50 to 100 mg/day are minimal. There is no evidence of endocrine system deficiencies during treatment with low doses given for relatively brief durations, and the effects irregularly seen at 600 mg/day should not deter physicians from using lower doses of itraconazole for less severe infections (4,24).…”

“…The consistency in values measured in individual patients after 12 h was anticipated and supports the validity of the bioassay. As described above, patients on long-term twice-daily dosing were admitted the evening prior to evaluation, with only the morning dose administered during the 24 h of pharmacokinetic analysis. Preadmission compliance could not be assured.…”

Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide

“…dexamethasone and methylprednisolone [17]. Although other azole compounds (itraconazole, fluconazole and miconazole) have a higher affinity to the fungal than the human enzyme system and are assumed to induce less side-effects [26,27,31], these drugs may also compromise the adrenal function when given in high doses and over long periods of time [25].…”