PMC:3724972 / 27612-29508 JSONTXT

{"project":"2_test","denotations":[{"id":"23673515-22369976-63233680","span":{"begin":232,"end":234},"obj":"22369976"},{"id":"23673515-8043488-63233681","span":{"begin":399,"end":401},"obj":"8043488"},{"id":"23673515-18413427-63233682","span":{"begin":599,"end":601},"obj":"18413427"},{"id":"23673515-20478050-63233683","span":{"begin":603,"end":605},"obj":"20478050"},{"id":"23673515-18166822-63233684","span":{"begin":671,"end":673},"obj":"18166822"},{"id":"23673515-22815335-63233685","span":{"begin":675,"end":677},"obj":"22815335"},{"id":"23673515-22369976-63233686","span":{"begin":804,"end":806},"obj":"22369976"},{"id":"23673515-22369976-63233687","span":{"begin":943,"end":945},"obj":"22369976"},{"id":"23673515-23040750-63233688","span":{"begin":1726,"end":1728},"obj":"23040750"},{"id":"23673515-23040750-63233689","span":{"begin":1865,"end":1867},"obj":"23040750"}],"text":"Adrenal-targeted drugs\nDrugs inhibiting adrenocortical steroidogenesis include ketoconazole, mitotane, etomidate and metyrapone. In general, use of these drugs requires careful clinical monitoring for adverse effects, including AI [77]. Ketoconazole has been widely used to treat CD because it inhibits several steps in adrenal steroid synthesis and reduces UFC in the majority of patients with CD [78]. However, it also inhibits androgen synthesis and is associated with liver toxicity in some patients [79]. There is little prospective information on the long-term use of adrenal-targeted agents [11, 80]; however, 1 small retrospective study showed promising results [81, 82]. Mitotane also inhibits several steps in steroidogenesis, and can be adrenolytic during long-term therapy at doses \u003e4 g/day [77]. Because mitotane is sequestered in adipose tissue and eliminated slowly, pregnancy must be avoided for 5 years after discontinuation [77].\nLCI699 is a novel inhibitor of 11β-hydroxylase (the final enzyme in the cortisol synthesis pathway) under development for several indications, including CD. In a recent proof-of-concept study in patients with CD (UFC \u003e1.5× ULN), all participants (N = 12) achieved either UFC normalization or ≥50 % reduction from baseline after 70 days of treatment. While all patients experienced ≥1 AE, most were mild or moderate. Some AEs consistent with AI were reported, and resolved after dose reduction. Four patients experienced hypokalemia; all cases were managed without dose reduction, and 3 patients received oral potassium supplementation [83]. A larger-scale, 22-week expansion trial is currently underway [84]. A summary of potential therapeutic targets in CD is shown in Fig. 4 [85].\nFig. 4 Potential targets and medical therapies in Cushing’s disease. From Fleseriu, M (2012) Neurosurg Clin N Am volume 23, page 657 [85]. Reproduced with permission"}