Metyrapone for Long-Term Medical Management of Cushing’s Syndrome

Traina, Andrea; Farr, Ashley; Malik, Ritu; Bingham, R.

doi:10.1155/2013/782068

Cited by 3 publications

(3 citation statements)

References 9 publications

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“…Treatment with metyrapone in CD has been documented in case reports (525)(526)(527) and in five main studies including a total of 120 patients with CD (506,507,524,528,529). In these studies, the dosage of metyrapone ranged from 500 to 6000 mg/d (mean, 2127.5 mg/d; median, 1750 mg/d), with a follow-up ranging from 0.25 to 66 months (mean, 8.7 mo; median, 5.5 mo).…”

Section: Metyraponementioning

confidence: 99%

The Treatment of Cushing's Disease

et al. 2015

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Cushing's disease (CD), or pituitary-dependent Cushing's syndrome, is a severe endocrine disease caused by a corticotroph pituitary tumor and associated with increased morbidity and mortality. The first-line treatment for CD is pituitary surgery, which is followed by disease remission in around 78% and relapse in around 13% of patients during the 10-year period after surgery, so that nearly one third of patients experience in the long-term a failure of surgery and require an additional second-line treatment. Patients with persistent or recurrent CD require additional treatments, including pituitary radiotherapy, adrenal surgery, and/or medical therapy. Pituitary radiotherapy is effective in controlling cortisol excess in a large percentage of patients, but it is associated with a considerable risk of hypopituitarism. Adrenal surgery is followed by a rapid and definitive control of cortisol excess in nearly all patients, but it induces adrenal insufficiency. Medical therapy has recently acquired a more important role compared to the past, due to the recent employment of novel compounds able to control cortisol secretion or action. Currently, medical therapy is used as a presurgical treatment, particularly for severe disease; or as postsurgical treatment, in cases of failure or incomplete surgical tumor resection; or as bridging therapy before, during, and after radiotherapy while waiting for disease control; or, in selected cases, as primary therapy, mainly when surgery is not an option. The adrenal-directed drug ketoconazole is the most commonly used drug, mainly because of its rapid action, whereas the glucocorticoid receptor antagonist, mifepristone, is highly effective in controlling clinical comorbidities, mainly glucose intolerance, thus being a useful treatment for CD when it is associated with diabetes mellitus. Pituitary-directed drugs have the advantage of acting at the site responsible for CD, the pituitary tumor. Among this group of drugs, the dopamine agonist cabergoline and the somatostatin analog pasireotide result in disease remission in a consistent subgroup of patients with CD. Recently, pasireotide has been approved for the treatment of CD when surgery has failed or when surgery is not an option, and mifepristone has been approved for the treatment of Cushing's syndrome when associated with impairment of glucose metabolism in case of the lack of a surgical indication. Recent experience suggests that the combination of different drugs may be able to control cortisol excess in a great majority of patients with CD.

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Section: Metyraponementioning

confidence: 99%

The Treatment of Cushing's Disease

et al. 2015

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“…Mineralocorticoid overproduction occurs due to 11-beta hydroxylase inhibition and accumulation of aldosterone precursors. To avoid mineralocorticoid-related adverse events, metyrapone is therefore often used in the short-term, for pre-operative control and in severe CD in combination with ketoconazole [ 33 ], though cases of long-term use have been reported [ 34 ].…”

Section: Medical Treatments Currently Used In Cushing’s Diseasementioning

confidence: 99%

Update on medical treatment for Cushing’s disease

Cuevas‐Ramos

Lim

Fleseriu

2016

Clin Diabetes Endocrinol

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Cushing’s disease (CD) is the most common cause of endogenous Cushing’s syndrome (CS). The goal of treatment is to rapidly control cortisol excess and achieve long-term remission, to reverse the clinical features and reduce long-term complications associated with increased mortality.While pituitary surgery remains first line therapy, pituitary radiotherapy and bilateral adrenalectomy have traditionally been seen as second-line therapies for persistent hypercortisolism. Medical therapy is now recognized to play a key role in the control of cortisol excess. In this review, all currently available medical therapies are summarized, and novel medical therapies in phase 3 clinical trials, such as osilodrostat and levoketoconazole are discussed, with an emphasis on indications, efficacy and safety. Emerging data suggests increased efficacy and better tolerability with these novel therapies and combination treatment strategies, and potentially increases the therapeutic options for treatment of CD. New insights into the pathophysiology of CD are highlighted, along with potential therapeutic applications. Future treatments on the horizon such as R-roscovitine, retinoic acid, epidermal growth factor receptor inhibitors and somatostatin-dopamine chimeric compounds are also described, with a focus on potential clinical utility.

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“…Metyrapone is an orphan medication that holds the FDA approval for the diagnosis of Cushing's syndrome and is occasionally used off-label for short-term treatment of Cushing's syndrome before surgery. However, treatment with metyrapone or other steroidogenic inhibitors is usually discouraged because of poor tolerability and the contradictory increase in ACTH production and mineralocorticoid effects (Díez and Iglesias, 2007;Traina et al, 2013). Therefore, alternative medical treatments for the curtailing of HPA-axis activity are needed.…”

Section: Po0mentioning

confidence: 99%

The Vasopressin 1b Receptor Antagonist A-988315 Blocks Stress Effects on the Retrieval of Object-Recognition Memory

Barsegyan

Atsak

Hornberger

et al. 2015

Neuropsychopharmacol

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Stress-induced activation of the hypothalamo-pituitary-adrenocortical (HPA) axis and high circulating glucocorticoid levels are well known to impair the retrieval of memory. Vasopressin can activate the HPA axis by stimulating vasopressin 1b (V1b) receptors located on the pituitary. In the present study, we investigated the effect of A-988315, a selective and highly potent non-peptidergic V1b-receptor antagonist with good pharmacokinetic properties, in blocking stress effects on HPA-axis activity and memory retrieval. To study cognitive performance, male Sprague-Dawley rats were trained on an object-discrimination task during which they could freely explore two identical objects. Memory for the objects and their location was tested 24 h later. A-988315 (20 or 60 mg/kg) or water was administered orally 90 min before retention testing, followed 60 min later by stress of footshock exposure. A-988315 dose-dependently dampened stressinduced increases in corticosterone plasma levels, but did not significantly alter HPA-axis activity of non-stressed control rats. Most importantly, A-988315 administration prevented stress-induced impairment of memory retrieval on both the object-recognition and the object-location tasks. A-988315 did not alter the retention of non-stressed rats and did not influence the total time spent exploring the objects or experimental context in either stressed or non-stressed rats. Thus, these findings indicate that direct antagonism of V1b receptors is an effective treatment to block stress-induced activation of the HPA axis and the consequent impairment of retrieval of different aspects of recognition memory.

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Metyrapone for Long-Term Medical Management of Cushing’s Syndrome

Cited by 3 publications

References 9 publications

The Treatment of Cushing's Disease

The Treatment of Cushing's Disease

Update on medical treatment for Cushing’s disease

The Vasopressin 1b Receptor Antagonist A-988315 Blocks Stress Effects on the Retrieval of Object-Recognition Memory

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