Role of “old” pharmacological agents in the treatment of Cushing’s syndrome

Ambrogio, Alberto Giacinto; Cavagnini, Francesco

doi:10.1007/s40618-016-0462-4

Cited by 11 publications

(7 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Until relatively recently the treatment of the EAS involved the use of bilateral adrenalectomy(preferably after period of control of the EAS), and medical treatment of the hypercortisolemia using mitotane, metapyrone and ketoconazole[131, •132, 133, 134]. Recently other classes of drugs have been used and reported to be helpful including glucocorticoid receptor antagonists(mifepristone[•135], etc.…”

Section: Summary Of Recent Advances/controversies In Management Ofmentioning

confidence: 99%

“…); adrenal specific therapy(etomidate, osilodrostat and fluconazole=11B-hydroxylase inhibitors); somatostatin analogues including pasireotide; and dopamine receptor agonists(cabergoline, etc. )[ 131, •132, 133, 134]. In addition PRRT has been reported to be helpful in controlling the hypercortisolism with EAS and will be discussed under the specific syndromes in a later section.…”

Section: Summary Of Recent Advances/controversies In Management Ofmentioning

confidence: 99%

See 1 more Smart Citation

Treatment of symptomatic neuroendocrine tumor syndromes: recent advances and controversies

Ito¹,

Lee²,

Jensen³

2016

Expert Opinion on Pharmacotherapy

View full text Add to dashboard Cite

Introduction Neuroendocrine tumors(NETs), once thought rare, are increasing in frequency in most countries and receiving increasing-attention. NETs present two-treatment problems. A proportion is functional, hormone-excess-state(F-NET), each of which must be treated. Recently, there are many advances, well-covered in reviews/consensus papers on imaging-NETs;new, novel anti-tumor treatments and understanding their pathogenesis. However, little attention has been paid to advances in the treatment of the hormone-excess-state. These advances are usually reported in case-series, and case-reports with few large studies. In this paper these advances are reviewed. Areas covered Advances in the last 5-years are concentrated on, but a review up to 10-years was performed. PubMed and other databases(Cochrane, etc) were searched for F-NET-syndromes including carcinoid-syndrome, as well as meeting-abstracts on NETs. All advances that controlled hormone-excess-states or facilitated-control were covered. These include new medical-therapies[serotonin-synthesis inhibitors(telotristat), Pasireotide, new agents for treating ACTHomas], increased dosing with conventional therapies(octreotide-LAR, Lanreotide-Autogel), mTor inhibitors(everolimus), Tyrosine-kinase inhibitors(sunitinib), cytoreductive surgery, liver-directed therapies(embolization, chemoembolization, radioembolization, RFA), peptide radio-receptor-therapy(PRRT) and 131I-MIBG, ablation of primary F-NETs. Expert Opinion Although many of the newer therapies controlling the hormone-excess-states in F-NETs are reported in relatively few patients, all the approaches show promise. Their description also generates some controversies/unresolved areas, such as the order of these new treatments, their longterm-efficacy, and effectiveness of combinations which may require large, controlled studies.

show abstract

Section: Summary Of Recent Advances/controversies In Management Ofmentioning

confidence: 99%

Section: Summary Of Recent Advances/controversies In Management Ofmentioning

confidence: 99%

Treatment of symptomatic neuroendocrine tumor syndromes: recent advances and controversies

Ito¹,

Lee²,

Jensen³

2016

Expert Opinion on Pharmacotherapy

View full text Add to dashboard Cite

show abstract

“…They reduce steroid synthesis by reversibly inhibiting the function of one or more enzymes in the adrenocortical steroid biosynthetic pathway. Although there are currently no U.S. Food and Drug Administration-approved steroidogenesis inhibitors, ketoconazole, metyrapone, mitotane, and etomidate are clinically available for other uses and are used off-label to treat patients with Cushing's syndrome (Daniel and Newell-Price, 2015;Ambrogio and Cavagnini, 2016). Unfortunately, adverse effects and treatment failures with these drugs are common, and only etomidate-which is the most potent of the inhibitors-is completely efficacious (Lambert et al, 1986;Lamberts et al, 1987;Preda et al, 2012;Cuevas-Ramos and Fleseriu, 2014;Gadelha and Vieira Neto, 2014;Ambrogio and Cavagnini, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Although there are currently no U.S. Food and Drug Administration-approved steroidogenesis inhibitors, ketoconazole, metyrapone, mitotane, and etomidate are clinically available for other uses and are used off-label to treat patients with Cushing's syndrome (Daniel and Newell-Price, 2015;Ambrogio and Cavagnini, 2016). Unfortunately, adverse effects and treatment failures with these drugs are common, and only etomidate-which is the most potent of the inhibitors-is completely efficacious (Lambert et al, 1986;Lamberts et al, 1987;Preda et al, 2012;Cuevas-Ramos and Fleseriu, 2014;Gadelha and Vieira Neto, 2014;Ambrogio and Cavagnini, 2016). However, such efficacy is achieved with etomidate only by using doses that risk producing sedation or hypnosis (Engelhardt and Weber, 1994;Preda et al, 2012;Cuevas-Ramos and Fleseriu, 2014;Tritos and Biller, 2014b;Daniel and Newell-Price, 2015).…”

Section: Introductionmentioning

confidence: 99%

Dimethoxy-etomidate: A Nonhypnotic Etomidate Analog that Potently Inhibits Steroidogenesis

McGrath

Raines

2017

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Cushing's syndrome is characterized by the overproduction of adrenocortical steroids. Steroidogenesis inhibitors are mainstays of medical therapy for Cushing's syndrome; unfortunately, adverse side effects and treatment failures are common with currently available drugs. The general anesthetic induction agent etomidate is among the most potent inhibitors of adrenocortical steroidogenesis. However, its use as a treatment of Cushing's syndrome is complicated by its sedative-hypnotic activity and ability to produce myoclonus, central nervous system actions thought to be mediated by the GABA receptor. Here, we describe the pharmacology of the novel etomidate analog ()-ethyl 1-(1-(3,5-dimethoxyphenyl)ethyl)-1-imidazole-5-carboxylate (dimethoxy-etomidate). In contrast to etomidate, dimethoxy-etomidate minimally enhanced GABA-evoked GABA receptor-mediated currents even at a near-saturating aqueous concentration. In Sprague-Dawley rats, dimethoxy-etomidate's potency for producing loss of righting reflexes-an animal model of sedation/hypnosis-was 2 orders of magnitude lower than that of etomidate, and it did not produce myoclonus. However, similar to etomidate, dimethoxy-etomidate potently suppressed adrenocortical steroid synthesis primarily by inhibiting 11-hydroxylase. [H]etomidate binding to rat adrenocortical membranes was inhibited by dimethoxy-etomidate in a biphasic manner with IC values of 8.2 and 3970 nM, whereas that by etomidate was monophasic with an IC of 22 nM. Our results demonstrate that, similar to etomidate, dimethoxy-etomidate potently and dose-dependently suppresses adrenocortical steroid synthesis by inhibiting 11-hydroxylase. However, it is essentially devoid of etomidate's GABA receptor positive modulatory and sedative-hypnotic activities and produces no myoclonus, providing proof of concept for the design of etomidate analogs without important central nervous system actions for the pharmacologic treatment of Cushing's syndrome.

show abstract

“…Medical therapy has taken an important place in the treatment of patients with CS during the whole period of our study. Concerning the lack of long-term remission in many patients after surgery, and the delayed response to radiotherapy along with potential side effects, the strong need for an effective pharmacological therapy has always been reported in the literature [37][38][39][40][41][42]. Still there is not a consensus available regarding the ideal medical treatment of CD, and published studies include small cohort samples.…”

Section: Cushing's Disease (Cd)mentioning

confidence: 99%

Cushing’s Syndrome: A Historic Review of the Treatment Strategies and Corresponding Outcomes in a Single Tertiary Center over the Past Half-Century

et al. 2018

View full text Add to dashboard Cite

Cushing's syndrome (CS) is associated with serious comorbidities and an increased mortality rate that could be reduced only if strict biochemical control is achieved. The aim of this study was to show the 50-year experience of a single tertiary center in the management of CS patients - the different treatment modalities used over the years and the corresponding outcomes. It was a retrospective study of a large cohort of patients from the Bulgarian CS database: 613 patients (374 with ACTH-dependent and 239 with ACTH-independent CS). Pituitary surgery was applied to 242 patients with Cushing's disease (CD) with initial remission rate of 74% of which 10% relapsed. Approximately 36% manifested with active disease during the long-term follow-up (26% with persistent disease, 10% relapses) most of which were subjected to a secondary treatment (13.6% to pituitary resurgery, 14% to pituitary radiotherapy, and 5.4% to bilateral adrenalectomy). A total of 294 CD patients received medical therapy with overall remission rates for the most commonly used drugs: dopamine agonists 20%, pasireotide 30%, and ketoconazole 63%. Significant improvement of results was achieved by combining drugs with different mechanisms of action. Regardless of the progress in the neurosurgery and radiotherapy techniques and new drugs discovery, the management of patients with CS remains a real challenge for physicians. Not only patients with adrenal carcinoma but also significant percentage of subjects with persistent and recurrent Cushing's disease often require a polymodal approach and the efforts of a multidisciplinary highly qualified, experienced, and motivated team in order to achieve a long-term remission.

show abstract

Role of “old” pharmacological agents in the treatment of Cushing’s syndrome

Cited by 11 publications

References 89 publications

Treatment of symptomatic neuroendocrine tumor syndromes: recent advances and controversies

Treatment of symptomatic neuroendocrine tumor syndromes: recent advances and controversies

Dimethoxy-etomidate: A Nonhypnotic Etomidate Analog that Potently Inhibits Steroidogenesis

Cushing’s Syndrome: A Historic Review of the Treatment Strategies and Corresponding Outcomes in a Single Tertiary Center over the Past Half-Century

Contact Info

Product

Resources

About