美替拉酮(Metyrapone) - 药物靶点：CYP11B1_在研适应症：肾上腺皮质功能不全，库欣综合征，垂体ACTH分泌过多_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Cormeto、Metirapona、Metycor

+ [7]

靶点

CYP11B1

作用机制

CYP11B1抑制剂(细胞色素P450家族成员11B1抑制剂)

治疗领域

神经系统疾病内分泌与代谢疾病

在研适应症

肾上腺皮质功能不全库欣综合征垂体ACTH分泌过多

非在研适应症

内源性库欣综合征

原研机构

Novartis SA

在研机构

HRA Pharma Development SARL

Novartis AGHRA Pharma Rare Diseases

+ [2]

非在研机构-

最高研发阶段批准上市

首次获批日期

美国 (1961-12-04),

垂体ACTH分泌过多

最高研发阶段(中国)-

特殊审评孤儿药 (美国)

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结构

分子式C14H14N2O

InChIKeyFJLBFSROUSIWMA-UHFFFAOYSA-N

CAS号54-36-4

关联

17

项与美替拉酮相关的临床试验

NCT06106295 / Recruiting临床2期

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).

开始日期2023-12-19

申办/合作机构

Mayo Clinic

NCT05919992 / Recruiting早期临床1期

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.

开始日期2023-05-15

申办/合作机构

Universitätsspital Basel

NCT05255900 / RecruitingN/AIIT

Metabolic, Pressor and Neuropsychological Effects of Metyrapone Treatment in Patients With Hypercortisolism

The aims of the present study are to evaluate in patients with mild hypercortisolism the effect of metyrapone treatment on glycometabolic control, blood pressure, thrombotic risk parameters, lipid profile, bone turnover markers, mental health and cortisol circadian rhythm.

开始日期2022-04-28

申办/合作机构

Istituto Auxologico Italiano

[+1]

100 项与美替拉酮相关的临床结果

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100 项与美替拉酮相关的转化医学

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100 项与美替拉酮相关的专利（医药）

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3,454

项与美替拉酮相关的文献（医药）

2024-02-13·Cardiovascular toxicology

Comparative In Vitro Study of the Cytotoxic Effects of Doxorubicin's Main Metabolites on Cardiac AC16 Cells Versus the Parent Drug.

Article

作者: Ana Reis-Mendes ; Cláudia Vitorino-Oliveira ; Mariana Ferreira ; Félix Carvalho ; Fernando Remião ; Emília Sousa ; Maria de Lourdes Bastos ; Vera Marisa Costa

Doxorubicin (DOX; also known as adriamycin) serves as a crucial antineoplastic agent in cancer treatment; however, its clinical utility is hampered by its' intrinsic cardiotoxicity. Although most DOX biotransformation occurs in the liver, a comprehensive understanding of the impact of DOX biotransformation and its' metabolites on its induced cardiotoxicity remains to be fully elucidated. This study aimed to explore the role of biotransformation and DOX's main metabolites in its induced cardiotoxicity in human differentiated cardiac AC16 cells. A key discovery from our study is that modulating metabolism had minimal effects on DOX-induced cytotoxicity: even so, metyrapone (a non-specific inhibitor of cytochrome P450) increased DOX-induced cytotoxicity at 2 µM, while diallyl sulphide (a CYP2E1 inhibitor) decreased the 1 µM DOX-triggered cytotoxicity. Then, the toxicity of the main DOX metabolites, doxorubicinol [(DOXol, 0.5 to 10 µM), doxorubicinone (DOXone, 1 to 10 µM), and 7-deoxydoxorubicinone (7-DeoxyDOX, 1 to 10 µM)] was compared to DOX (0.5 to 10 µM) following a 48-h exposure. All metabolites evaluated, DOXol, DOXone, and 7-DeoxyDOX caused mitochondrial dysfunction in differentiated AC16 cells, but only at 2 µM. In contrast, DOX elicited comparable cytotoxicity, but at half the concentration. Similarly, all metabolites, except 7-DeoxyDOX impacted on lysosomal ability to uptake neutral red. Therefore, the present study showed that the modulation of DOX metabolism demonstrated minimal impact on its cytotoxicity, with the main metabolites exhibiting lower toxicity to AC16 cardiac cells compared to DOX. In conclusion, our findings suggest that metabolism may not be a pivotal factor in mediating DOX's cardiotoxic effects.

2024-02-10·Endocrinology

Effects of the cortisol milieu on tumor-infiltrating immune cells (TIICs) in corticotroph tumors.

Article

作者: Maki Kanzawa ; Hiroki Shichi ; Keitaro Kanie ; Masaaki Yamamoto ; Naoki Yamamoto ; Yasutaka Tsujimoto ; Hironori Bando ; Genzo Iguchi ; Shigehisa Kitano ; Naoko Inoshita ; Shozo Yamada ; Wataru Ogawa ; Tomoo Itoh ; Hidenori Fukuoka

BACKGROUND:

Corticotrophs are susceptible to lymphocyte cytotoxicity, as seen in hypophysitis, suggesting that an immunological approach may be a potential strategy for corticotroph-derived tumors.

OBJECTIVES:

We aimed clarify whether corticotroph tumors that induce hypercortisolemia (ACTHomas) could be targets for immunotherapy.

METHODS:

Tumor-infiltrating immune cells were immunohistochemically analyzed. ACTHomas (Naïve: ACTHomas without preoperative treatment) were compared with other pituitary tumors, and further divided into three different cortisol-exposed milieus: Naïve, Met (ACTHomas with preoperative metyrapone), and SCA (silent corticotroph adenomas). A three-dimensional cell culture of resected tumors was used to analyze the effects of immune checkpoint inhibitors.

RESULTS:

The number of tumor-infiltrating lymphocytes (TILs) was low in ACTHomas. Among these, the number of CD8+ cells was lower in ACTHomas than in both somatotroph) and gonadotroph tumors (P < 0.01 and P < 0.01, respectively). Then we compared the differences in TILs among Naïve, Met, and SCA. The number of CD4+ cells, but not CD8+ cells, was higher in both Met and SCA than in Naïve. Next, we investigated tumor-associated macrophages, which could negatively affect T cell infiltration. The numbers of CD163+ and CD204+ cells were positively associated with cortisol levels. Moreover, tumor size was positively correlated with the number of CD204+ cells.

CONCLUSIONS:

We found the possibility that ACTHomas were immunologically cold in a cortisol-independent manner. In contrast, the tumor infiltration of CD4+ cells and M2-macrophages were associated with the cortisol milieu. Future studies are needed to validate these results and develop effective immunotherapy while considering the cortisol milieu.

2024-02-04·Journal of endocrinological investigation

Glucocorticoid-induced adrenal insufficiency after therapy with intravenous methylprednisolone in patients with moderate-to-severe and active Graves' orbitopathy: assessment with a low-dose corticotropin test.

Article

作者: K Pelewicz ; P Miśkiewicz

PURPOSE:

We aimed to assess adrenal function following treatment of moderate-to-severe and active Graves' orbitopathy (GO) with intravenous methylprednisolone (IVMP) in weekly pulses in a cumulative dose of 4.5 or 7.5 g. We evaluated the impact of IVMP pulses on adrenal reserve using a low-dose (1 μg) ACTH stimulation test (LDT) for the first time.

METHODS:

In this prospective study we evaluated adrenal function in 21 patients with moderate-to-severe and active GO treated with 12 weekly IVMP pulses according to the European Group on Graves' Orbitopathy (EUGOGO) recommendations. We assessed serum cortisol, plasma adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate (DHEA-S) levels before the 1st and 12th IVMP pulse. We performed dynamic testing using LDT before the 12th IVMP pulse in all patients. In those who failed LDT, adrenal function was reassessed with LDT and the overnight metyrapone test after 4-7 weeks.

RESULTS:

Two patients failed to achieve serum cortisol levels ≥ 18.1 μg/dL at 30 and 60 min in LDT and were diagnosed with glucocorticoid-induced adrenal insufficiency (GC-induced AI). They were recommended to take hydrocortisone in situations of acute stress. Both patients were reassessed within 4-7 weeks after treatment cessation and showed an adequate response in LDT and overnight metyrapone test. We observed a statistically significant decrease in DHEA-S levels (p = 0.004) before the 12th IVMP pulse compared to baseline in all patients.

CONCLUSION:

For the first time, our research shows that administering IVMP in 12 weekly pulses can result in GC-induced AI. We suggest that patients should undergo careful evaluation for GC-induced AI, including LDT, after therapy with IVMP according to EUGOGO guidelines. Screening for altered adrenal reserve could prevent life-threatening complications, particularly during acute stress situations.

1

项与美替拉酮相关的新闻（医药）

2023-05-09

·Pharmaceutical Technology

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.

临床1期引进/卖出抗体药物偶联物并购

100 项与美替拉酮相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D00410	美替拉酮	V04CD01	DB01011

研发状态

适应症	最高研发状态	国家/地区	公司
垂体ACTH分泌过多	批准上市	美国更多	HRA Pharma Rare Diseases 更多
库欣综合征	批准上市	西班牙更多	HRA Pharma Development SARL 更多
-	批准上市	日本更多	Ceolia Pharma Co., Ltd. 更多
诊断试剂	批准上市	美国更多	HRA Pharma Rare Diseases 更多
肾上腺皮质功能不全	批准上市	-	Novartis AG 更多

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ESPE2021	N/A	-	-	Metyrapone	(築齋選壓糧憲鏇觸構餘) = 衊窪鹹憲窪鹹鑰壓壓鹽糧壓襯壓憲遞遞醖鏇願 (齋廠廠觸壓淵壓觸窪願 )	积极	2021-09-22
ESPE2021	N/A	多发性骨纤维性发育不良	-	Metyrapone	(範觸夢衊襯壓築窪憲顧) = 簾夢鏇顧遞夢廠築簾襯窪壓鏇繭築夢襯鬱顧憲 (積廠選夢衊觸襯蓋鏇憲 ) 更多	-	2021-09-22
Pubmed	N/A	库欣综合征	195	Metyrapone	齋選壓艱鏇繭襯網鹹窪(遞鏇顧壓觸憲餘憲鏇鹽) = 選簾顧壓醖範觸淵壓窪廠鬱鑰積壓鹹鑰糧齋齋 (鏇襯憲蓋餘鏇顧築獵獵 ) 更多	积极	2015-11-01
ESPE2022	N/A	垂体ACTH分泌过多 hypercortisolism \| excess adrenocorticotropic hormone (ACTH) secretion	-	Metyrapone	(餘範選遞築衊壓醖範鹹) = the boy had clinical deterioration due to sepsis caused by Coagulase negative staphylococcus followed by pulmonary edema 齋夢鏇窪鹽衊繭繭選醖 (憲糧廠範築膚範憲遞膚 ) 更多	-	2022-09-15
ESPE2016	N/A	库欣综合征	-	Metyrapone	(鬱鏇觸製構繭網願顧糧) = 積願膚膚蓋衊鬱夢顧願夢襯蓋窪遞鑰網遞餘鬱 (糧製夢蓋窪積網艱艱鑰 )	-	2016-09-10