Acute Consequences of Glucocorticoid Secretion in Overweight and Obese Individuals During Maximum Calorie Intake: a Double-blind, Randomized, Placebo-controlled, Cross-over Study

The investigator aim to understand whether food-induced glucocorticoids influence fat mass in overweight and obese people.
In a randomized, cross-over study, 23 overweight and obese volunteers will receive a block and replace therapy that mimics physiological glucocorticoid (GC) rhythm (metyrapone plus hydrocortisone) or placebo. Participants will undergo two identical overfeeding periods with each treatment. With the block and replace therapy food-induced GC peak will be suppressed. Metabolic and immunological parameters will be compared to reveal the effects of GCs during excessive overfeeding, particularly to understand changes in body fat.

Start Date01 Sep 2024

Sponsor / Collaborator-

NCT06106295 / RecruitingPhase 2IIT

Metyrapone Intervention in Patients With Mild Autonomous Cortisol Secretion (MACS)

The purpose of this study is to find out whether the study drug, metyrapone, is safe and effective in treating participants with Mild Autonomous Cortisol Secretion (MACS).

Start Date19 Dec 2023

Sponsor / Collaborator

Mayo Clinic

NCT05919992 / CompletedEarly Phase 1IIT

The Role of Glucocorticoids to Maintain Energy Homeostasis During Starvation

In a randomized, cross-over study, 20 healthy volunteers will receive a block and replace therapy that mimics physiological GC rhythm (metyrapone plus hydrocortisone) or placebo. Participants will undergo two identical fasting periods with each treatment. With the block and replace therapy, fasting-induced GC peak will be suppressed. Metabolic and autonomic parameters will be compared to reveal whether GCs mediate the physiological adaptions to caloric restriction.
Understanding acute effects of GCs upon caloric restriction is critical, since repetitive disruptions of GC secretion may become harmful in chronic conditions.

Start Date15 May 2023

Sponsor / Collaborator

Universitätsspital Basel

100 Clinical Results associated with Metyrapone

100 Translational Medicine associated with Metyrapone

100 Patents (Medical) associated with Metyrapone

3,566

Literatures (Medical) associated with Metyrapone

01 Feb 2025·BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

Depression decreases immunity and PD-L1 inhibitor efficacy via the hypothalamic–pituitary–adrenal (HPA) axis in triple-negative breast cancer

Article

Author: Huang, Runze ; Gan, Chen ; Cheng, Ling ; Cai, Yinlian ; Xu, Jian ; Cheng, Huaidong ; Li, Wen ; Yu, Sheng ; Yao, Senbang ; Zhang, Qianqian

BACKGROUND:

Depression weakens antitumor immunity, yet the underlying mechanisms linking depression and tumor growth remain unclear. This study examines the influence of depression on the hypothalamic-pituitary-adrenal (HPA) axis, immunological function, and effectiveness of immunotherapy in triple-negative breast cancer (TNBC) patients.

METHODS:

A mouse model of comorbid TNBC and depression was established via chronic restraint stress (CRS) and 4T1 tumor transplantation. A programmed cell death ligand 1 (PD-L1) inhibitor was used to manage mice with TNBC, and the ability of metyrapone to reverse the immune system changes induced by HPA axis activation in depression was evaluated. Mouse peripheral blood was used to measure HPA axis activity, immune cell numbers and cytokine levels.

RESULTS:

Depression activates the HPA axis, leading to increased levels of glucocorticoids. Depression led to an increase in the B-cell number and a reduction in the CD4⁺ T-cell and CD8⁺ T-cell numbers, without a statistically significant difference in the regulatory T (Treg) cell number. Furthermore, depression increased the levels of the cytokines interferon-gamma (IFN-γ), interleukin (IL)-1β, IL-4, IL-6, IL-8, and tumor necrosis factor (TNF)-α while decreasing the levels of IL-2 and IL-10. Similar results were observed in the context of PD-L1 inhibitor therapy. The depressed mice presented an increased tumor burden and a poor response to the PD-L1 inhibitor. The application of metyrapone during PD-L1 inhibitor treatment resulted in partial restoration of these depression-related alterations.

CONCLUSIONS:

Depression reduces the effectiveness of PD-L1 inhibitors by altering the number of immune cells and the levels of cytokines through activation of the HPA axis.

TRANSLATIONAL RELEVANCE:

Depression is common in breast cancer patients and is associated with reduced antitumor immunity. There is limited knowledge regarding the specific mechanisms through which depression impairs antitumor immunity. Immunotherapy, which promotes the restoration of antitumor immunity, represents a promising treatment strategy for TNBC patients. However, the efficacy of immunotherapy can be compromised by depressive symptoms and the administration of glucocorticoids during treatment. It is still uncertain whether increasing glucocorticoid levels can reduce the efficacy of immunotherapy in patients with depression. The potential benefits of combining immunotherapy with glucocorticoid inhibitors compared with immunotherapy alone need to be evaluated for TNBC patients with concurrent depressive symptoms. Therefore, further clarification of the specific mechanisms by which depression impairs antitumor immunity is needed to inform future optimization of immunotherapy strategies.

01 Dec 2024·COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY A-MOLECULAR & INTEGRATIVE PHYSIOLOGY

Early metabolic and transcriptomic regulation in rainbow trout (Oncorhynchus mykiss) liver by 11-deoxycorticosterone through two corticosteroid receptors pathways

Article

Author: Aedo, Jorge Eduardo ; Valdés, Juan Antonio ; Ahumada-Langer, Luciano ; Molina, Alfredo ; Zuloaga, Rodrigo

Cortisol hormone is considered the main corticosteroid in fish stress, acting through glucocorticoid (GR) or mineralocorticoid (MR) receptor. The 11-deoxycorticosterone (DOC) corticosteroid is also secreted during stress and could complement the cortisol effects, but this still not fully understood. Hence, we evaluated the early transcriptomic response of rainbow trout (Oncorhynchus mykiss) liver by DOC through GR or MR. Thirty juvenile trout were pretreated with an inhibitor of endogenous cortisol synthesis (metyrapone) by intraperitoneal injection in presence or absence of GR (mifepristone) and MR (eplerenone) pharmacological antagonists for one hour. Then, fish were treated with a physiological DOC dose or vehicle (DMSO-PBS1X as control) for three hours (n = 5 per group). We measured several metabolic parameters in plasma, together with the liver glycogen content. Additionally, we constructed cDNA libraries from liver of each group, sequenced by HiseqX Illumina technology and then analyzed by RNA-seq. Plasma pyruvate and cholesterol levels decreased in DOC-administered fish and only reversed by eplerenone. Meanwhile, DOC increased liver glycogen contents depending on both corticosteroid receptor pathways. RNA-seq analysis revealed differential expressed transcripts induced by DOC through GR (448) and MR (1901). The enriched biological processes to both were mainly related to stress response, protein metabolism, innate immune response and carbohydrates metabolism. Finally, we selected sixteen genes from enriched biological process for qPCR validation, presenting a high Pearson correlation (0.8734 average). These results describe novel physiological effects of DOC related to early metabolic and transcriptomic responses in fish liver and differentially modulated by MR and GR.

01 Nov 2024·Neurobiology of Stress

Emotional comorbidities in epilepsy result from seizure-induced corticosterone activity

Article

Author: Hill, Matthew N ; Bhatt, Dhyey ; Harris, Sydney A ; Teskey, G. Campbell ; Wickramarachchi, Pasindu ; Gom, Renaud C ; George, Antis G. ; Pittman, Quentin J ; Pittman, Quentin J. ; Colangeli, Roberto ; Hill, Matthew N. ; Teskey, G Campbell ; Acharjee, Shaona ; Gom, Renaud C. ; George, Antis G ; Harris, Sydney A.

People with epilepsy often have psychiatric comorbidities that can significantly impair their quality of life. We previously reported that repeated seizure activity persistently alters endocannabinoid (eCB) signaling in the amygdala which accounts for comorbid emotional dysregulation in rats, however, the mechanism by which these alterations in eCB signaling within the epileptic brain occur is unclear. Endocannabinoid signaling is influenced by corticosterone (CORT) to modulate cognitive and emotional processes and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis occurs in both people with epilepsy and nonhuman animal models of epilepsy. We employed selective pharmacological tools and a variety of approaches including whole-cell patch-clamp electrophysiology, behavioural paradigms and biochemical assays in amygdala kindled adult male Long-Evans rats. We aimed to determine whether seizures induce hypersecretion of CORT and the role this plays in eCB system dysregulation, impaired fear memory, and anxiety-like behaviours associated with seizure activity. Plasma CORT levels were significantly and consistently elevated following seizures over the course of kindling. Pre-seizure administration with the CORT synthesis inhibitor metyrapone prevented this seizure-induced CORT increase, prevented amygdala anandamide downregulation, and synaptic alteration induced by seizure activity. Moreover, treatment with metyrapone or combined glucocorticoid receptor (GR)/mineralocorticoid receptor (MR) antagonists prior to each elicited seizure were equally effective in preventing chronically altered anxiety-like behaviour and fear memory responses. Inhibiting seizure-induced corticosterone synthesis, or directly blocking the effects of CORT at GR/MR prevents deleterious changes in emotional processing and could be a treatment option for emotional comorbidities in epilepsy.

News (Medical) associated with Metyrapone

10 Jul 2024

·www.esteve.com

ESTEVE ACQUIRES HRA PHARMA RARE DISEASES

ESTEVE has completed the acquisition of HRA Pharma Rare Diseases, a business specialized in rare diseases, from Perrigo Company plc. With this acquisition, ESTEVE expands its portfolio in rare and severe diseases adding, to the current existing offer, three new medications to treat Cushing's syndrome and adrenocortical carcinoma: Metopirone, Lysodren, and Ketoconazole HRA. HRA Pharma Rare Diseases has been a leading company for over 15 years in rare and severe diseases, providing the best care and services to individuals living with rare diseases, and is committed to supporting healthcare professionals worldwide. "This acquisition allows us to accelerate our international expansion, strengthening our global presence and ability to better address unmet needs, thus improving the lives of more people," highlights Staffan Schüberg, Chief Executive Officer of ESTEVE. With annual net revenues in 2023 of approximately 50 million euros, HRA Pharma Rare Diseases has a presence in numerous European countries and the United States with a team of 49 individuals. This agreement represents an investment of up to 275 million euros, structured with an initial fixed contribution and future variable payments tied to revenue. Share

Acquisition

26 Apr 2024

·firstwordpharma.com

Perrigo to divest rare diseases unit to Spain's Esteve for €275 million

Perrigo is offloading its HRA Pharma Rare Diseases business to Barcelona-based pharmaceutical company Esteve Healthcare for a total of up to €275 million ($294 million) and plans to use the proceeds to help pay down its debt.The transaction, which includes €190 million in cash upfront plus up to €85 million in potential earnouts if certain sales targets are reached, is expected to close in the third quarter.The unit's three-product portfolio includes the Cushing's syndrome treatments Metopirone (metyrapone) and ketoconazole, as well as Lysodren (mitotane), which is prescribed to treat adrenal cortical carcinoma. Staffan Schüberg, chief executive at Esteve, said the deal is "another step towards the company's vision of being an international and specialist pharma company."Meanwhile, Perrigo CEO Patrick Lockwood-Taylor said the divestment "further supports our position as a leading fast-moving consumer goods company," adding that the upfront cash proceeds would allow the company "to reduce net leverage to below 4.0x by the end of 2024."

AcquisitionDrug Approval

24 Apr 2024

·www.esteve.com

ESTEVE SIGNS A BINDING OFFER TO ACQUIRE HRA PHARMA RARE DISEASES, A PERRIGO COMPANY AFFILIATE

ESTEVE has signed a binding offer with Perrigo Company plc to acquire Perrigo's HRA Pharma Rare Diseases, a business specialized in rare and ultra-rare diseases, following the information and consultation process with HRA Pharma Works Council in France and subject to the satisfaction of customary closing conditions, including receipt of regulatory approvals. ESTEVE will increase its portfolio in the rare and severe diseases therapeutic area, adding to its current portfolio three new medicines that address Cushing's syndrome and Adrenocortical Carcinoma: Metopirone, Lysodren, and Ketoconazole HRA. HRA Pharma Rare Diseases has over 15 years' experience in rare and ultra-rare diseases and is dedicated to bringing the best care and services to people living with rare diseases and committed to supporting healthcare professionals all over the world. With annual Net Revenues in 2023 around €50M, the HRA Pharma Rare Diseases business has a presence in several European countries as well as in the US. "This transaction aims to advance ESTEVE on the path of covering the unmet patients' needs, in line with ESTEVE's purpose of improving people's lives and is another step towards the company's vision of being an international specialty pharma company", concludes Staffan Schüberg, Chief Executive Officer of ESTEVE. Patrick Lockwood-Taylor, Perrigo's President and Chief Executive Officer, states: "We are pleased that ESTEVE, with its track record of growth and international footprint, will look to increase global access to these effective treatment options for all those patients in need". The binding offer is for up to €275 million, consisting of an upfront payment and potential earnout payments. The closing of the transaction should take place during the third quarter of 2024, following the required works council consultation and subject to customary regulatory approvals. Perella Weinberg Partners and Clifford Chance served as ESTEVE's lead advisors on this transaction. Morgan Stanley & Co. LLC and Wachtell, Lipton, Rosen & Katz served as Perrigo's lead advisors on this transaction.

100 Deals associated with Metyrapone

External Link

KEGG	Wiki	ATC	Drug Bank
D00410	Metyrapone	V04CD01	DB01011

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Adrenal Insufficiency	-	Novartis AG	30 May 2014
Cushing Syndrome	AU	CHIESI Farmaceutici SpA	02 Aug 1991
Pituitary ACTH Hypersecretion	US	HRA Pharma Rare Diseases SAS	04 Dec 1961

Developing

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Endogenous Cushing Syndrome	Phase 3	BE	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Phase 3	DE	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Phase 3	HU	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Phase 3	IT	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Phase 3	PL	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Phase 3	RO	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Phase 3	ES	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Phase 3	TR	HRA Pharma Development SARL	01 Apr 2015

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ESPE2016	Not Applicable	Cushing Syndrome	-	Metyrapone	xplsdrekfu(hjboaqfkbm) = lcblyfrljl fopxzpxmxm (vzqiigoowy )	-	10 Sep 2016
Pubmed \| J Clin Endocrinol Metab	Not Applicable	Cushing Syndrome	195	Metyrapone	wxxktriuso(qbnxqkinqg) = orucsxxwsx pbuqysrxmm (eybceoqqrl ) View more	Positive	01 Nov 2015
SFN2011	Not Applicable	-	-	Metyrapone	ocjdtrfnlw(hacrhixvdo) = nkcrcczlpw uhmiesmmys (okwsuktlnb )	-	16 Nov 2011
				Placebo	ocjdtrfnlw(hacrhixvdo) = kgitazaxni uhmiesmmys (okwsuktlnb )
NINDS PO1 NS37520, NINDS R01 NS27292 (SFN2005)	Not Applicable	Ischemia	-	Metyrapone 200 mg/kg (30 min before ischemia)	vaklgcvcue(uucnaoznad) = lwmuekoicy tozoparhkn (ebreskmerz )	Positive	14 Nov 2005
				Metyrapone 200 mg/kg (2 h after ischemia)	rjqycaosrs(fscinosfmz) = vvbcurpynw zrdeqcdfma (lwehknzjth ) View more
SFN2002	Not Applicable	-	-	Metyrapone	eqtzclpjeb(rnzqiiayoa) = hupumwhwjl txiypkmnlg (bsdypbjvuw )	-	03 Nov 2002
				Vehicle	eqtzclpjeb(rnzqiiayoa) = xlugqxvheb txiypkmnlg (bsdypbjvuw )
SFN2000	Not Applicable	Memory Disorders	-	Metyrapone 50 mg/kg	pheroubpew(dydpvxpiup) = uidirmwrhz mwfpdqwonf (klkzhsiqzz )	-	08 Nov 2000
				Vehicle	pheroubpew(dydpvxpiup) = bqcodidmxl mwfpdqwonf (klkzhsiqzz )

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