Background:
Cushing s disease is caused by a pituitary gland tumor. Patients with Cushing s disease suffer obesity, diabetes, osteoporosis, weakness, and hypertension. The cure is surgery to remove the pituitary tumor. Currently, MRI is the best way to find these tumors. But not all tumors can be seen with an MRI. Researchers hope giving the hormone CRH before a PET scan can help make these tumors more visible.
Objective:
To test whether giving CRH before a PET scan will help find pituitary gland tumors that might be causing Cushing s disease.
Eligibility:
People ages 8 and older with Cushing s disease that is caused by a pituitary gland tumor that cannot be reliably seen on MRI
Design:
Participants will be screened with their medical history, a physical exam, an MRI, and blood tests.
Participants will have at least one hospital visit. During their time in the hospital, they will have a physical exam and a neurological exam. They will have a PET scan of the brain. A thin plastic tube will be inserted into an arm vein. A small amount of radioactive sugar and CRH will be injected through the tube. Participants will lie in a darkened room for about an hour and be asked to urinate. Then they will lie inside the scanner for about 40 minutes. After the scan, they will be asked to urinate every 2-3 hours for the rest of the day. Blood will be drawn through a needle in the arm.
Participants will have surgery to remove their tumor within 3 months after the scan.
Participants will then continue regular follow-up in the clinic.

开始日期2024-11-13

申办/合作机构

National Institute of Neurological Disorders & Stroke

NCT04037605 / Active, not recruiting早期临床1期IIT

Hormonal Mechanisms of Sleep Restriction - Axis Study in Older Men and Postmenopausal Women

The purpose of this study is to 1) determine how hypothalamic-pituitary-adrenal axis (HPA axis) activation occurs with sleep restriction and 2) evaluate how hypothalamic-pituitary-gonadal axis (HPG axis) deactivation occurs with sleep restriction. The investigator will also examine the cognitive function associated with sleep restriction, including food intake and food cravings.

开始日期2020-02-09

申办/合作机构

The Lundquist Institute

NCT01373372 / WithdrawnN/AIIT

CRH Responsiveness in Children With Functional Dyspepsia: A Pilot Study

Chronic abdominal pain is the most common persistent pain condition in children and adolescents, affecting 10-15% of children at any given time. One of the most often diagnosed types of abdominal pain is functional dyspepsia (FD). FD is an abdominal pain or discomfort (e.g., nausea, bloating) in the upper abdomen that does not get better by going to the bathroom.
For some people it appears that stress can make FD worse. In adults, stress can cause the release of a hormone called corticotropin releasing hormone (CRH). The release of CRH can cause abdominal pain by affecting how fast things move through a person's stomach and intestines. This makes the organs in the abdomen more sensitive to pain, causing tenderness of the inside lining of the stomach and intestines.
Different people react differently when the body releases CRH. Some people have abdominal pain without feeling any stress or anxiety while other people who have a lot of stress or anxiety don't have any abdominal pain. Some people have neither stress, anxiety, or abdominal pain when CRH is released into the body.
In order to see how the bodies of children with functional dyspepsia and those without functional dyspepsia react to CRH, we will do a CRH stimulation test. A CRH stimulation test is routinely done in endocrine patients. It is not routinely done for patients with functional dyspepsia or for patients who do not have functional dyspepsia.
Part of the CRH stimulation test is giving a synthetic type of corticotropin, Acthrel® (brand name for Corticorelin), as injection. Acthrel® has been approved by the Food and Drug Administration (FDA) for use.
The purpose of this research study is to see if there are differences in how the bodies of children with functional dyspepsia react to CRH versus children who don't have functional dyspepsia.
Being in this study involves one clinic visit where an IV placed and a CRH stimulation test. In this test the child will be given an injection of CRH and then observed for one hour. During that hour the child will have five blood draws through the IV and will be asked questions about their anxiety and abdominal pain. This visit will take about 4 hours.
The following things will happen:
Your child will be asked to come to the clinic between 8a.m. and 10a.m. fasting. This means your child will have had nothing to eat or drink for 8 hours before coming to the clinic.
If your child is a female ten years of age or older, or has started having periods, a urine pregnancy test will be done before receiving the CRH infusion.
You and your child will each be asked to complete a survey that measures your child's anxiety.
Your child will have a biofeedback session that will measure your child's stress. In a biofeedback session, sensors are placed on your child's fingers, wrists and forehead. These sensors are connected to a computer that monitors your child's heartbeat, skin temperature and electrical pulses on your child's skin.
Your child will have an IV inserted into a vein in his/her arm. Your child may have a cream put on their arm to help with the pain of the IV insertion. The IV will be used to inject the CRH and draw blood. If the IV stops working and blood samples can no longer be drawn from it, your child may have another IV started or blood samples may be drawn by needle stick.
Your child will then have 30 minutes to relax.
Your child will then have CRH infused through the IV over one minute.
Your child will have blood drawn through the IV five times; right before the CRH stimulation test begins and 15, 30, 45 and 60 minutes after the CRH infusion. The total amount of blood drawn for the study will be about 2 ½ tablespoons.
Your child will be asked about their abdominal pain, nausea, bloating, stress and anxiety at three separate times during the 60 minutes.
Your child's heart rate will be measured throughout the CRH stimulation test.

开始日期2016-12-01

申办/合作机构

The Children's Mercy Hospital

100 项与可的瑞林相关的临床结果

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100 项与可的瑞林相关的转化医学

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100 项与可的瑞林相关的专利（医药）

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1,554

项与可的瑞林相关的文献（医药）

2024-11-01·JOURNAL OF GENERAL INTERNAL MEDICINE

Impact of a Remote Primary Care Telehealth Staffing Model on Primary Care Access in the Veterans Health Administration

Article

作者: Shahnazi, Ariana ; Haraldsson, Bjarni ; O'Shea, Amy M J ; Augustine, Matthew R ; Kaboli, Peter J ; Mulligan, Kailey

BACKGROUND:

The Veterans Health Administration (VHA) implemented the Clinical Resource Hub (CRH) program to fill staffing gaps in primary care (PC) clinics via telemedicine and maintain veterans' healthcare access.

OBJECTIVE:

To evaluate PC wait times before and after CRH implementation.

DESIGN:

Comparative interrupted time series analysis among a retrospective observational cohort of PC clinics who did and did not use CRH during pre-implementation (October 2018-September 2019) and post-implementation (October 2019-February 2020) periods.

PARTICIPANTS:

Clinics completing ≥10 CRH visits per month for 2 consecutive months and propensity matched control clinics.

MAIN MEASURES:

Two measures of patient access (i.e., established, and new patient wait times) and one measure of clinic capacity (i.e., third next available appointment) were assessed. Clinics using CRH were 1:1 propensity score matched across clinical and demographic characteristics. Comparative interrupted time series models used linear mixed effects regression with random clinic-level intercepts and triple interaction (i.e., CRH use, pre- vs. post-implementation, and time) for trend and point estimations.

KEY RESULTS:

PC clinics using CRH (N = 79) were matched to clinics not using CRH (N = 79). In the 12-month pre-implementation, third next available time increased in CRH clinics (0.16 days/month; 95% CI = [0.07, 0.25]), and decreased in the 5 months post-implementation (-0.58 days/month; 95% CI = [-0.90, -0.27]). Post-implementation third next available time also decreased in control clinics (-0.48 days/month; 95% CI = [-0.81, -0.17]). Comparative differences remained non-significant. There were no statistical differences in established or new patient wait times by CRH user status, CRH implementation, or over time.

CONCLUSIONS:

In a national VHA telemedicine program developed to provide gap coverage for PC clinics, no wait time differences were observed between clinics using and not using CRH services. This hub-and-spoke telemedicine service is an effective model to provide gap coverage while maintaining access. Further investigation of quality and long-term access remains necessary.

2024-08-15·Journal of the science of food and agriculture

Gluten‐free lentil cakes with optimal technological and nutritional characteristics

Article

作者: Puppo, María C ; Ferrero, Cristina ; Carboni, Angela D

Abstract:

BACKGROUND:

The celiac population usually struggle finding nutritive gluten‐free (GF) baked goods. GF foods can be improved using legume flours. Eleven GF cake formulations were elaborated according to different percentages of lentil flour (LF), corn flour (CF) and rice flour (RF) using a simplex lattice design. Water holding capacity and particle size of flours were evaluated. Moisture, aw, pH, specific volume, texture profile, relaxation, color and alveolar characteristics were determined for crumbs of all formulations. An optimization process was used to enhance the technological and nutritional attributes, selecting the three best formulations containing LF: 46% LF + 54% RF (CLF+RF); 49% LF + 51% CF (CLF+CF); and 100% LF (CLF), evaluated in their proximal composition and sensory characteristics. Linear and quadratic models for predicting the behavior of GF lentil cakes were obtained.

RESULTS:

LF and CF could favor water incorporation and show more resistance to enzymatic digestion than RF. Formulations with LF showed an improvement in specific volume and alveolar parameters, while use of RF led to better cohesiveness, elasticity and resilience but with a deterioration in chewiness and firmness. CLF can be labeled as high in protein and fiber and presented the lowest amounts of lipids, carbohydrates and energy content. Consumer preference leaned towards CLF+RF.

CONCLUSION:

2024-07-11·BLOOD

Complete remission with partial hematological recovery as a palliative endpoint for treatment of acute myeloid leukemia

Article

作者: Shen, Yuan Li ; De Claro, R. Angelo ; Norsworthy, Kelly ; Chen, Haiyan ; Przepiorka, Donna ; Theoret, Marc R. ; Pulte, E. Dianne ; Le, Robert Q.

Abstract:

Complete remission with partial hematological recovery (CRh) has been used as an efficacy endpoint in clinical trials of nonmyelosuppressive drugs for acute myeloid leukemia (AML). We conducted a pooled analysis to characterize the clinical outcomes for patients with AML who achieved CRh after treatment with ivosidenib, olutasidenib, enasidenib, or gilteritinib monotherapy in clinical trials used to support marketing applications. The study cohort included 841 adult patients treated at the recommended drug dosage; 64.6% were red blood cell or platelet transfusion dependent at study baseline. Correlations between disease response and outcomes were assessed by logistic regression modeling for categorical variables and by Cox proportional hazards modeling for time-to-event variables. Patients with CRh had a higher proportion with transfusion independence (TI) for at least 56 days (TI-56; 92.3% vs 22.3%; P < .0001) or TI for at least 112 days (TI-112; 63.5% vs 8.7%; P < .0001), a reduced risk over time for severe infection (hazard ratio [HR], 0.43; P = .0007) or severe bleeding (HR, 0.17; P = .01), and a longer overall survival (OS; HR, 0.31; P < .0001) than patients with no response. The effects were consistent across drugs. In comparison with patients with CR, the effect sizes for CRh were similar for TI-56 and for risk over time of infection or bleeding but less for TI-112 and OS. CRh is associated with clinical benefits consistent with clinically meaningful palliative effects for the treatment of AML with nonmyelosuppressive drugs, although less robustly than for CR.

项与可的瑞林相关的新闻（医药）

2023-08-01

·药时代

Nature | 上海药物所揭示B类GPCRs新型小分子药物靶点的偏向性激活机制

G-蛋白偶联受体（G protein-coupled receptor，GPCR）是细胞表面受体家族中最大的一类，调控着人体各种生命活动且与疾病密切相关，有超过30%的药物作用于 GPCR。而B类GPCRs是一类重要的多肽激素受体，包括胰高血糖素受体（GCGR）、胰高血糖素样肽-1受体(GLP-1R)、葡萄糖依赖性胰岛素释放多肽受体（GIPR）和甲状旁腺激素受体1（PTH1R）等在内的共15个激素受体，它们主要通过调节多肽类激素的信号传导来调控多种生理功能，包括血糖调节、骨代谢、胃肠道功能、神经调节和生长调节等，并涉及许多疾病的发病机制，如糖尿病、骨质疏松症和癌症等，因此，B类GPCRs成为治疗肥胖、糖尿病和骨质疏松症、抑郁、心血管疾病、癌症等多种疾病的重要药物靶点。然而，由于B类GPCRs的复杂结构和信号传递机制，针对这些受体的药物开发，尤其是小分子激动剂药物一直面临挑战。虽然一些针对B类GPCRs的多肽药物已成功上市，包括用于治疗2型糖尿病药物GLP-1类似物以及骨质疏松症药物PTH和PTHrP类似物等，但是这类多肽类药物需要皮下注射，使用不便，费用昂贵，且伴有头痛、恶心等副作用。与注射肽类药物不同，小分子药物可以开发成片剂，并具有更好的药物特性，因此，小分子激动剂药物研发在近年来受到科学家的广泛追捧。然而，针对B类GPCRs的小分子激动剂药物临床应用却一直没有突破。在这种背景下，中国科学院上海药物研究所徐华强/赵丽华研究团队系统地开展B类GPCRs的结构解析和分子机制研究，在过去十多年里，在B类GPCRs激动剂作用机制研究领域取得了一系列突破性进展。研究团队早在2008年到2010年期间就解析了多个B类GPCRs的胞外结构域（ECD）晶体结构，阐述了内源性多肽与B类GPCRs的识别作用机制【1-3】。2016年，研究团队合作揭示 B 类 GPCRs 激活对 ECD 的需求不同的作用机制【4】，并阐述GLP-1R的ECD激活内在的激动作用机理，为 GLP-1R 及下游信号转导激活机制研究奠定基础【5】。2017年与王明伟团队合作在J Biol Chem以封面文章提出了B类GPCRs受体第六跨膜的构象发生改变从而产生自我激活效应的分子机制【6】。2019年在全长B类GPCRs激活机制方面又取得突破性进展，研究团队与浙江大学张岩团队、上海药物所王明伟团队等多方合作在Science上首次报道了1型人源甲状旁腺激素受体（Parathyroid hormone type 1 receptor, PTH1R）与Gs蛋白复合物的三维结构，揭示了其长效激活状态下的分子动力学机制，为创制治疗骨质疏松症等疾病的新药奠定了坚实的基础【7】。2020年，研究团队与张岩团队合作在Molecular Cell揭示促肾上腺皮质激素释放因子受体的激活机制【8】；与王明伟/杨德华研究团队、张岩团队合作在Nature Communications首次揭示了GHRHR的配体识别、信号激活及疾病发生的分子机制，为相关新药的研发奠定了坚实的基础【9】。在Cell research上揭示 GLP-2R 独特的配体识别和受体激活机制，为小肠短小综合症（Short bowel syndrome, SBS）和克罗恩氏病（Crohn's disease）的药物研发提供重要的结构信息【10】。在Nature Communications报道了VIP1R与多肽配体PACAP27和Gs蛋白复合物的冷冻电镜结构【11】。在Cell research上首次解析了完全激动剂小分子化合物与GLP-1R复合物的冷冻电镜结构，阐述了小分子完全激动剂激活GLP-1R的分子机制【12】。2021年，研究团队与王明伟/杨德华研究团队合作在PNAS上揭示了PTH2R 的配体选择性及疾病发的分子机制【13】，在Elife揭示了 GIPR 的配体识别和信号转导的分子机制，为基于GIPR 药理学的2型糖尿病的药物发现提供了重要的结构信息【14】, 在Nature Communications上揭示了GLP-1R变构激动调节的分子机制【15】。在PNAS上阐述了B类GPCRs结构性信号偏向转导机制【16】。2022年，研究团队与王明伟/杨德华团队合作在Nature Communications系统阐明了GLP-1R/GCGR/GIPR双重和三重激动剂的配体识别和受体激活机制，在原子水平揭示了它们发挥多重药理效应的关键位点，为治疗2型糖尿病设计和开发更为有效的新型多重激动剂提供新思路【17】。研究团队合作解析B类GPCRs受体家族15个成员中最后一个受体，VIP2R的三维结构【18】。研究团队与山东大学于晓团队、浙江大学张岩团队合作在Nature Communications上揭示B类GPCRs的G蛋白选择性偶联激活机制【19】，与王明伟/杨德华研究团队合作在APS上进一步揭示甲状旁腺激素受体1的两个内源性多肽激素的分子识别和激活机制【20】。2023年7月31日，团队在Nature杂志以“快速通道”的方式发表了最新研究成果“Conserved class B GPCR activation by a biased intracellular agonist”，在B类GPCRs小分子激动剂激活作用机制方面取得突破性进展。团队发现了B类GPCRs的新型小分子激动剂结合口袋，由于该结合口袋在B类GPCRs中具有较高的保守性，并且能够激活多种受体，这为研发针对该口袋的小分子激动剂提供了新的可能性。因此，该药物口袋的发现为治疗糖尿病、肥胖、骨质疏松和其他涉及B类GPCRs的疾病的药物研发提供了新的方向和途径，为开发更具选择性和有效性的药物打开了新的视野。这种药物口袋的发现可以为未来的新药研发提供重要的基础和潜在机会（图1）。图1、右下角的小分子、受体和G蛋白复合物的三维结构是本研究中报道的PCO371-PTH1R-Gs复合物结构，呈现的是一种新型小分子结合口袋，气球代表B类GPCRs家族的15个成员，本研究中发现的新型小分子结合口袋的主要氨基酸序列在这15个受体中非常保守，宇航员带着这15个气球遨游在广阔的太空，并开启了对这个新型口袋的小分子药物研究新时代，未来针对这15个受体靶标的小分子药物研发将是科学家们探索的新领域，并且这个领域的未来发展将会是星辰大海。通过冷冻电镜技术，研究团队获得了B类GPCRs中最重要的成员之一PTH1R与小分子激动剂PCO371的高分辨率结构，通过结构分析和功能实验发现B类GPCRs存在类似PCO371结合的保守的小分子结合口袋，揭示了PCO371的新型的结合模式，同时发现PCO37具有G蛋白信号通路偏向性激活作用，为B类GPCR的小分子药物设计和开发提供了新的见解和新的途径，通过针对这个保守的口袋进行药物研发，有可能开发比当前治疗方法更具选择性且副作用更少的药物。该研究发现的新型小分子激动剂结合口袋，揭示了B类GPCRs激活的独特机制，为创新疗法铺平了道路，该工作展示了对B类GPCRs的开创性研究及其作为药物靶点的巨大潜力。具体地说，PCO371结合在PTH1R与Gs蛋白的胞内界面上，与以前报道的所有GPCR中配体的结合位点完全不同。PCO371作为偏向激动剂，优先通过G蛋白触发信号传递，而非通过阻遏蛋白arrestin。这种偏向性激动剂有助于减少阻遏蛋白arrestin信号通路引起的副作用，提高药物的安全性和有效性（图2）。具体地说，PCO371结合在PTH1R与Gs蛋白的胞内界面上，与以前报道的所有GPCR中配体的结合位点完全不同。这种新型的结合模式使得PCO371能够激活受体与多肽PTH结合的PTH1R呈现出不同的构象，从而实现对G蛋白和阻遏蛋白arrestin两种信号通路的偏向性调控。PCO371作为偏向激动剂，优先通过G蛋白触发信号传递，而非通过阻遏蛋白arrestin。这种偏向性激动剂有助于减少阻遏蛋白arrestin信号通路引起的副作用，提高药物的安全性和有效性（图2）。图2、 PCO371偏向激活G蛋白信号通路，但不激活阻遏蛋白arrestin信号通路；PCO371-PTH1R-Gs复合物冷冻电镜高分辨结构以及呈现的新型配体结合口袋。此外，研究团队通过结构分析和受体氨基酸序列比对发现，构成PCO371结合口袋的氨基酸残基在B类GPCRs中具有较高的保守性，使得PCO371能够激活B类GPCR中的8种受体，并且通过1个或2个点突变就可以使其他受体对PCO371产生反应（图3）。这些发现揭示了B类GPCRs小分子激动剂的独特结合位点，这个保守的结合口袋为开发新的治疗糖尿病、肥胖、骨质疏松和其他涉及B类GPCRs的疾病的口服药物提供了令人兴奋的机会，为针对2型糖尿病、肥胖症和骨质疏松症等疾病的不同类型B类GPCR小分子激动剂药物的设计和开发提供了新的思路和方法。图3、在B类GPCRs中普遍存在保守的类似PCO371的结合口袋该研究由上海药物所徐华强研究员和赵丽华研究员领导的B类GPCRs研究小组成员通力合作完成。上海药物所赵丽华研究员、博士研究生何倩以及高峰电镜中心执行主任袁青宁为该论文的共同第一作者。上海药物所徐华强研究员、赵丽华研究员为论文的共同通讯作者。参与本次研究的还有上海药物所硕士研究生顾奕敏、博士研究生何欣恒、单虹博士、李俊睿博士、王凯副研究员、硕士研究生李阳，高峰电镜中心工作人员胡雯和吴凯以及沈建华研究员。本研究冷冻电镜数据在上海药物所高峰电镜中心收集，该项研究工作得到了国家自然科学基金委员会、国家重点研发计划、上海市科学技术委员会、中国科学院青年创新促进会、中科院战略性先导科技专项(B类)和原创新药研究重点实验室等项目资助。参考文献：1、Pioszak, A. A. & Xu, H. E. Molecular recognition of parathyroid hormone by its G protein-coupled receptor. Proc Natl Acad Sci U S A 105, 5034-5039, doi:10.1073/pnas.0801027105 (2008).2、Pioszak, A. A., Parker, N. R., Gardella, T. J. & Xu, H. E. Structural basis for parathyroid hormone-related protein binding to the parathyroid hormone receptor and design of conformation-selective peptides. The Journal of biological chemistry 284, 28382-28391, doi:10.1074/jbc.M109.022905 (2009).3、Pal, K., Swaminathan, K., Xu, H. E. & Pioszak, A. A. Structural basis for hormone recognition by the Human CRFR2alpha G protein-coupled receptor. The Journal of biological chemistry 285, 40351-40361, doi:10.1074/jbc.M110.186072 (2010).4、Zhao, L. H. et al. Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors. The Journal of biological chemistry 291, 15119-15130, doi:10.1074/jbc.M116.726620 (2016).5、Yin, Y. et al. An intrinsic agonist mechanism for activation of glucagon-like peptide-1 receptor by its extracellular domain. Cell Discov 2, 16042, doi:10.1038/celldisc.2016.42 (2016).6、Yin, Y. et al. Rearrangement of a polar core provides a conserved mechanism for constitutive activation of class B G protein-coupled receptors. The Journal of biological chemistry 292, 9865-9881, doi:10.1074/jbc.M117.782987 (2017).7、Zhao, L. H. et al. Structure and dynamics of the active human parathyroid hormone receptor-1. Science 364, 148-153, doi:10.1126/science.aav7942 (2019).8、Ma, S. et al. Molecular Basis for Hormone Recognition and Activation of Corticotropin-Releasing Factor Receptors. Mol Cell 77, 669-680 e664, doi:10.1016/j.molcel.2020.01.013 (2020).9、Zhou, F. et al. Structural basis for activation of the growth hormone-releasing hormone receptor. Nat Commun 11, 5205, doi:10.1038/s41467-020-18945-0 (2020).10、Sun, W. et al. A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor. 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Constitutive signal bias mediated by the human GHRHR splice variant 1. Proc Natl Acad Sci U S A 118, doi:10.1073/pnas.2106606118 (2021).17、Zhao, F. et al. Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors. Nat Commun 13, 1057, doi:10.1038/s41467-022-28683-0 (2022).18、Xu, Y. et al. A distinctive ligand recognition mechanism by the human vasoactive intestinal polypeptide receptor 2. Nat Commun 13, 2272, doi:10.1038/s41467-022-30041-z (2022).19、Zhao, L. H. et al. Structure insights into selective coupling of G protein subtypes by a class B G protein-coupled receptor. Nat Commun 13, 6670, doi:10.1038/s41467-022-33851-3 (2022).20、Zhao, L. H. et al. Molecular recognition of two endogenous hormones by the human parathyroid hormone receptor-1. Acta Pharmacol Sin, doi:10.1038/s41401-022-01032-z (2022).点击这里，阅读全文！

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2023-03-16

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Nat Neurosci | 女性更受欢迎！实验小鼠对女实验员“偏爱”而对男性“厌恶”，将直接影响药物作用

本文转载自“iNature”公众号。一个女性生物学家在进行小鼠试验时，发现一个令人惊奇的现象：男性同事做出的试验现象，其他女性同事却怎么也做不出来。试验者的操作男女有别，那么操作者的性别对哪些试验产生了干扰？2022年8月30日，美国马里兰大学Todd D. Gould团队在Nature Neuroscience 杂志在线发表题为“Experimenters’ sex modulates mouse behaviors and neural responses to ketamine via corticotropin releasing factor”的研究论文，该研究发现人类实验者的性别会影响小鼠在服用速效抗抑郁药氯胺酮及其生物活性代谢物(2R,6R)-羟基去甲氯胺酮后的行为和反应。小鼠表现出厌恶男性实验者的气味，偏爱女性实验者的气味，并且在男性实验者处理时对压力的敏感性增加。进一步研究发现，实验者的性别通过促肾上腺皮质激素释放因子调节小鼠行为和对氯胺酮的神经反应。由此可见，更好地了解人类实验者的性别对啮齿动物研究结果具体和定量的贡献可能会提高研究之间的可复制性，揭示生物学和药理学机制。在实验室之间或实验室内难以复制实验结果，可能是由于未得到适当控制的无法识别的实验变量。人类实验者的性别很少被认为是可以影响实验结果的生物学变量，并且通常没有被考虑在哪，包括在统计分析中或在实验方法中特别说明。然而，有证据表明啮齿动物区分人类实验者性别的能力可以对其行为和/或生物学反应产生可测量的影响。例如，啮齿动物接触雄性而非雌性实验者的气味已被证明会增加焦虑相关的行为和压力诱发的镇痛作用。在该研究中，研究人员首先评估了与人类雌性相比，CD1、BALB/c或C57BL/6J 小鼠是否更喜欢与擦拭过人类男性皮肤（肘窝、内腕和乳突）的棉签相互作用。研究人员惊奇的发现，两性小鼠始终表现出对雌性气味拭子的偏好（图 1a）。这种偏好可能是气味驱动的，因为在用硫酸锌鼻内处理导致嗅觉丧失的小鼠中没有观察到它（图1b）。此外，当在用水润湿的拭子（对照气味）与人类男性或女性皮肤暴露拭子之间进行选择时，小鼠表现出对男性拭子的厌恶，而它们表现出对女性拭子的偏好（图1c）。图1. 小鼠在暴露于雄性和雌性实验者气味后表现出不同的行为反应（图源自Nature Neuroscience）接下来，研究人员根据人类实验者的性别影响小鼠行为这一发现提出了一个问题——它是否也会影响小鼠对实验操作（包括药物治疗）的反应呢？为了解决这个问题，研究人员评估了实验者的性别对小鼠对(R,S)-氯胺酮（KET）给药反应的影响。KET在临床上是亚麻醉剂量的有效速效抗抑郁药，在临床前啮齿动物模型中也观察到其抗抑郁样作用。研究人员发现，在五对不同的实验者中，雄性而不是雌性注射KET，实验者在治疗后1小时测试的雄性小鼠中减少了静止时间。实验者性别对KET反应的这种影响也在注射后24小时接受强迫游泳实验（forced-swimming test，FST）的雄性小鼠和暴露于预在药物注射前23小时和再次暴露于FST前24小时的雌性小鼠中（图 2）。图2. 人类实验者的性别影响小鼠对KET的反应（图源自Nature Neuroscience）进一步研究，发现这种人类-男性气味引起的厌恶和压力敏感性是由投射到海马区 CA1的内嗅皮层中促肾上腺皮质激素释放因子（corticotropin-releasing factor，CRF）神经元的激活所介导的。在给予氯胺酮之前暴露于男性实验者的气味会激活CA1投射的内嗅皮层CRF神经元，并且该CRF通路的激活会调节氯胺酮的体内和体外抗抑郁样作用。总的来说，该研究强调了人类实验者的性别与实验室内部和实验室之间结果的可复制性和解释的相关性。男性实验者引发的压力反应导致了预期的结果（KET的抗抑郁样作用）。其实许多其他因素可能会影响行为结果或导致实验者性别对实验结果的潜在影响。测试、独特的处理程序、所用小鼠的品系和亚品系、实验者的压力水平、实验者的饮食（肉食者与植物性饮食）以及实验者和/或动物的荷尔蒙状态，控制这些因素，并了解它们如何具体和定量地影响不同的实验结果，不仅可以减少研究之间的异质性，还可以发现新的生物学机制以推进科学知识和药物发现。责编|风立宵校对|风立宵End参考资料：[1]]https://www-nature-com.libproxy1.nus.edu.sg/articles/s41593-022-01146-x 往期精选围观 ‍Science：为什么多吃鱼能让大脑更聪明？热文每一口含糖饮料都要命！中国疾控中心研究：近30年我国含糖饮料死亡人数翻倍热文神经退行性疾病的新希望：唤醒“沉睡”的神经干细胞热文阿尔茨海默病治疗新策略！Nature：阻断T细胞预防神经退行性变热文阿斯利康和第一三共联合开发ADC药物Enhertu公布II期积极临床数据点击“阅读原文”，了解更多~

100 项与可的瑞林相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	可的瑞林	V04CD04	DB09067

研发状态

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适应症	国家/地区	公司	日期
库欣综合征	美国	Ferring Pharmaceuticals, Inc.	1996-05-23

未上市

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适应症	最高研发状态	国家/地区	公司	日期
胶质瘤	临床3期	美国	Celtic Pharma Development Services, Inc.	2006-01-01
胶质瘤	临床3期	加拿大	Celtic Pharma Development Services, Inc.	2006-01-01
脑恶性胶质瘤	临床3期	美国	Celtic Pharma Development Services, Inc.	2006-01-01
脑恶性胶质瘤	临床3期	加拿大	Celtic Pharma Development Services, Inc.	2006-01-01
脑癌	临床3期	加拿大	Celtic Pharma Development Services, Inc.	2004-05-01
脑水肿	临床3期	美国	Celtic Pharma Development Services, Inc.	2004-05-01
脑水肿	临床3期	加拿大	Celtic Pharma Development Services, Inc.	2004-05-01
水肿	临床3期	美国	Celtic Pharma Development Services, Inc.	2004-05-01
水肿	临床3期	加拿大	Celtic Pharma Development Services, Inc.	2004-05-01
脑转移瘤	临床2期	-	Celtic Pharma Development Services, Inc.	2008-11-01

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临床结果

适应症

分期

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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


NCT00088166 (XERECEPT®, CTgov)	临床3期	脑水肿 \| 水肿 \| 脑癌	200	hCRF (XERECEPT)+dexamethasone (hCRF)	願壓蓋艱醖遞願製鹹範(壓願憲窪淵網淵顧窪糧) = 糧糧餘夢鬱膚蓋顧憲衊襯遞齋繭鬱鹽夢廠糧鹽 (齋網築製鹹觸繭鬱網糧, 壓獵夢遞憲鏇膚糧齋鏇 ~ 壓願構繭廠壓艱顧壓願) 更多	-	2014-08-13
				placebo hCRF+dexamethasone (Placebo)	願壓蓋艱醖遞願製鹹範(壓願憲窪淵網淵顧窪糧) = 蓋鹽憲齋膚獵鹹獵壓鹹襯遞齋繭鬱鹽夢廠糧鹽 (齋網築製鹹觸繭鬱網糧, 鑰壓壓顧顧鏇壓鏇蓋淵 ~ 鬱構鹹齋獵簾製糧網窪) 更多