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

3,586

Literatures (Medical) associated with Metyrapone

01 Dec 2024·Comparative Biochemistry and Physiology Part 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: Ahumada-Langer, Luciano ; Valdés, Juan Antonio ; Zuloaga, Rodrigo ; Molina, Alfredo ; Aedo, Jorge Eduardo

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

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.

01 Nov 2024·Journal of Neuroendocrinology

Understanding negative feedback: Changes in high‐molecular‐weight adrenocorticotropic hormone in adrenocorticotropic hormone‐independent Cushing's syndrome

Article

Author: Fukuoka, Hidenori ; Bando, Hironori ; Ogawa, Wataru ; Nakatsuji, Mei ; Kanzawa, Maki ; Ichinose, Yuto ; Yoshino, Kei ; Yamamoto, Masaaki

AbstractCushing's syndrome is characterized by chronic glucocorticoid oversecretion and diverse clinical manifestations. Distinguishing between adrenocorticotropic hormone (ACTH)‐independent and ACTH‐dependent forms is crucial for determining treatment options. Plasma ACTH levels aid in the differential diagnosis, with undetectable or low levels suggesting ACTH‐independent hypercortisolemia. ACTH is derived from pro‐opiomelanocortin, and its processing involves prohormone convertase 1/3. High‐molecular‐weight ACTH is generally found in ACTH‐producing pituitary tumors and ectopic ACTH syndrome. The mechanism of negative feedback and the process of high‐molecular‐weight ACTH alternation during ACTH‐independent Cushing's syndrome remain unclear. A 40‐year‐old woman with hypertension and multiple fractures developed symptoms suggestive of Cushing's syndrome. Computed tomography revealed a left adrenocortical tumor along with atrophy of the right adrenal gland. ACTH levels were undetectable at the previous clinic, indicating ACTH‐independent Cushing's syndrome. However, subsequent measurements at our hospital revealed non‐suppressed ACTH (18.1 pg/mL), prompting further investigation. Gel exclusion chromatography confirmed the presence of high‐molecular‐weight ACTH. Metyrapone treatment decreased the cortisol levels. In this situation, in which ACTH levels should be elevated, a decrease in high‐molecular‐weight ACTH levels was observed. Histological findings revealed cortisol‐producing adenoma without ACTH expression. This case highlights the importance of assay differences in evaluating ACTH concentrations and introduces a novel finding of circulating high‐molecular‐weight ACTH. The observed decline in high‐molecular‐weight ACTH levels suggests a potential time lag in the negative feedback within the hypothalamic–pituitary–adrenal axis exhibited by glucocorticoids. This temporal aspect of the regulation of ACTH‐related molecules warrants further exploration to enhance our understanding of the hypothalamic–pituitary–adrenal axis feedback mechanism.

News (Medical) associated with Metyrapone

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

09 May 2023

·www.pharmaceutical-technology.com

FibroGen and Fortis sign exclusive licence deal for mCRPC drug candidate

FOR46 is being developed as a potential treatment for metastatic castration-resistant prostate cancer. Credit: Nephron/commons.wikimedia.org FibroGen has signed an exclusive licence agreement with Fortis Therapeutics for the FOR46 antibody-drug conjugate (ADC) that targets a new epitope on CD46, a protein-coding gene. FOR46 is currently being investigated in a Phase I trial as a potential treatment for metastatic castration-resistant prostate cancer (mCRPC). Recommended Reports Reports LOA and PTSR Model - (Metyrapone + Oxazepam) in Substance (Drug) Abuse GlobalData Reports LOA and PTSR Model - Esmethadone Hydrochloride in Substance (Drug) Abuse GlobalData View all The trial is also studying the capability of FOR46 for use in other CD46-expressing cancers. The new deal, which does not include any initial consideration, will see FibroGen conducting and financing new research, development and production of FOR46 and PET46. Throughout the deal’s four-year evaluation period, FibroGen has an option to buy Fortis Therapeutics for $80m. Fortis can also receive up to $200m in total on the basis of multiple regulatory approvals. Under the clinical development strategy, FibroGen will continue the work of Fortis Therapeutics to develop a PET-based biomarker using a radiolabeled version of the targeting antibody (PET46) for selecting patients. FibroGen CEO Enrique Conterno stated: “The agreement with Fortis Therapeutics bolsters FibroGen’s clinical pipeline in a capital-efficient manner, providing a product candidate with the potential to address a significant unmet medical need in oncology. “FOR46 is a natural fit with our research and development capabilities and expertise. “The flexibility of the agreement gives us the opportunity to clinically develop FOR46, and ultimately acquire it as a Phase III-ready asset, potentially delivering a therapy that may transform the treatment of patients with mCRPC and other CD46-expressing cancers.” In early May 2023, FibroGen announced that it would receive a $150m non-dilutive term loan facility from funds managed by Morgan Stanley Tactical Value (MSTV) to accelerate the commercialisation of pamrevlumab.

Phase 1License out/inADCAcquisition

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Endogenous Cushing Syndrome	Phase 1	IT	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Phase 1	TR	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Phase 1	DE	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Discovery	RO	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Discovery	ES	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Discovery	PL	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Discovery	HU	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Discovery	BE	HRA Pharma Development SARL	01 Apr 2015

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ESPE2016	Not Applicable	Cushing Syndrome	-	Metyrapone	(hvvxmsyyad) = flotickgss ztxvoydhtq (hoxtkjvqbu )	-	10 Sep 2016
Pubmed	Not Applicable	Cushing Syndrome	195	Metyrapone	ticrwolqma(ppfyrlxzvq) = xelxbhpkfa ochmojvwew (vuelsrdqjq ) View more	Positive	01 Nov 2015

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