The purpose of this investigator-initiated randomized control trial is to determine whether oral Nifedipine versus oral Labetalol is superior in controlling high blood pressures in the postpartum period.

开始日期2024-12-01

申办/合作机构

Loma Linda University

NCT06093893 / Not yet recruiting临床4期IIT

A Comparison of Dexmedetomidine, Nicardipine, and Labetalol to Induce Hypotensive Anesthesia and Their Effects on Surgeon Visibility, Blood Loss, Hemodynamic Parameters, Operation Time, and Adverse Events During Orthognathic Surgery

The overall objective of this double blinded, randomized controlled trial (RCT) is to compare specific outcomes of three medications (Dexmedetomidine, Nicardipine, and Labetalol) which are routinely used to lower blood pressure used during general anesthesia for orthognathic (jaw) surgery. The outcome measures for the study will be surgical field visibility, estimated blood loss, hemodynamic parameters, operation time, and adverse events.
The specific objectives of this study are to compare:
1. Dexmedetomidine, Nicardipine, and Labetalol's effect on the quality of the surgical field. (Primary Outcome)
2. Dexmedetomidine, Nicardipine, and Labetalol's effect on estimated blood loss.
3. Dexmedetomidine, Nicardipine, and Labetalol's effect on hemodynamic parameters including systolic blood pressure, mean arterial pressure, and heart rate.
4. Dexmedetomidine, Nicardipine, and Labetalol's effect on operation time.
5. Dexmedetomidine, Nicardipine, and Labetalol's effect on adverse events.
The investigators will evaluate healthy adult male and female patients who require jaw surgery at Boston Medical Center. The anticipated 90 participants will be randomized into three groups: ) A Labetalol group in which the patients receive hypotensive anesthesia with the aid of labetalol, 2) A Nicardipine group in which the patients receive hypotensive anesthesia with the aid of nicardipine, and 3) A Dexmedetomidine group in which the patients receive hypotensive anesthesia with the aid of dexmedetomidine.
The time it will take for each individual participant ranges from 1-3 months. This time includes the pre-operative visit, the surgical procedure, a 1-week post-operation visit, and then followed for 30 days post-operatively after which the patient's participation in the study will conclude.

开始日期2024-11-01

申办/合作机构

Boston Medical Center

100 项与 β-adrenoceptors x α-adrenergic receptor 相关的临床结果

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项与 β-adrenoceptors x α-adrenergic receptor 相关的文献（医药）

2024-12-31·Stress

Adolescent high fat diet alters the transcriptional response of microglia in the prefrontal cortex in response to stressors in both male and female mice

Article

作者: Lloyd, Kelsey R ; Bollinger, Justin L ; Wohleb, Eric S ; Davis, Alyshia B ; Reyes, Teresa M

Both obesity and high fat diets (HFD) have been associated with an increase in inflammatory gene expression within the brain. Microglia play an important role in early cortical development and may be responsive to HFD, particularly during sensitive windows, such as adolescence. We hypothesized that HFD during adolescence would increase proinflammatory gene expression in microglia at baseline and potentiate the microglial stress response. Two stressors were examined, a physiological stressor [lipopolysaccharide (LPS), IP] and a psychological stressor [15 min restraint (RST)]. From 3 to 7 weeks of age, male and female mice were fed standard control diet (SC, 20% energy from fat) or HFD (60% energy from fat). On P49, 1 h before sacrifice, mice were randomly assigned to either stressor exposure or control conditions. Microglia from the frontal cortex were enriched using a Percoll density gradient and isolated via fluorescence-activated cell sorting (FACS), followed by RNA expression analysis of 30 genes (27 target genes, three housekeeping genes) using Fluidigm, a medium throughput qPCR platform. We found that adolescent HFD induced sex-specific transcriptional response in cortical microglia, both at baseline and in response to a stressor. Contrary to our hypothesis, adolescent HFD did not potentiate the transcriptional response to stressors in males, but rather in some cases, resulted in a blunted or absent response to the stressor. This was most apparent in males treated with LPS. However, in females, potentiation of the LPS response was observed for select proinflammatory genes, including Tnfa and Socs3. Further, HFD increased the expression of Itgam, Ikbkb, and Apoe in cortical microglia of both sexes, while adrenergic receptor expression (Adrb1 and Adra2a) was changed in response to stressor exposure with no effect of diet. These data identify classes of genes that are uniquely affected by adolescent exposure to HFD and different stressor modalities in males and females.

2024-10-01·Clinical Pharmacology & Therapeutics

Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4, and GRK5 Genotypes and Beta‐Blocker Therapy

Review

作者: Stein, C. Michael ; Huddart, Rachel ; Lee, Craig R. ; van Schaik, Ron H. N. ; Klein, Teri E. ; Schwab, Matthias ; Nagy, Mohamed ; Uppugunduri, Chakradhara Rao S. ; Agundez, Jose A. G. ; Thomas, Cameron D. ; Caudle, Kelly E. ; Donnelly, Roseann S. ; Lanfear, David E. ; Baye, Jordan F. ; Duarte, Julio D. ; Monte, Andrew A. ; Luzum, Jasmine A. ; Gaedigk, Andrea

Beta‐blockers are widely used medications for a variety of indications, including heart failure, myocardial infarction, cardiac arrhythmias, and hypertension. Genetic variability in pharmacokinetic (e.g., CYP2D6) and pharmacodynamic (e.g., ADRB1, ADRB2, ADRA2C, GRK4, GRK5) genes have been studied in relation to beta‐blocker exposure and response. We searched and summarized the strength of the evidence linking beta‐blocker exposure and response with the six genes listed above. The level of evidence was high for associations between CYP2D6 genetic variation and both metoprolol exposure and heart rate response. Evidence indicates that CYP2D6 poor metabolizers experience clinically significant greater exposure and lower heart rate in response to metoprolol compared with those who are not poor metabolizers. Therefore, we provide therapeutic recommendations regarding genetically predicted CYP2D6 metabolizer status and metoprolol therapy. However, there was insufficient evidence to make therapeutic recommendations for CYP2D6 and other beta‐blockers or for any beta‐blocker and the other five genes evaluated (updates at www.cpicpgx.org).

2024-05-01·Archives of Biochemistry and Biophysics

Capsaicin induces ATP-dependent thermogenesis via the activation of TRPV1/β3-AR/α1-AR in 3T3-L1 adipocytes and mouse model

Article

作者: Yun, Jong Won ; Abdillah, Alfin Mohammad

Capsaicin (CAP) is a natural bioactive compound in chili pepper that activates the transient receptor potential vanilloid subfamily 1 (TRPV1) and is known to stimulate uncoupling protein 1 (UCP1)-dependent thermogenesis. However, its effect on ATP-dependent thermogenesis remains unknown. In this study, we employed qRT-PCR, immunoblot, staining method, and assay kit to investigate the role of CAP on ATP-dependent thermogenesis and its modulatory roles on the TRPV1, β3-adrenergic receptor (β3-AR), and α1-AR using in vitro and in vivo models. The studies showed that CAP treatment in high-fat diet-induced obese mice resulted in lower body weight gain and elevated ATP-dependent thermogenic effectors' protein and gene expression through ATP-consuming calcium and creatine futile cycles. In both in vitro and in vivo experiments, CAP treatment elevated the protein and gene expressions of sarcoendoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), ryanodine receptor 2 (RYR2), creatine kinase B (CKB), and creatine kinase mitochondrial 2 (CKMT2) mediated by the activation of β3-AR, α1-AR, and TRPV1. Our study showed that CAP increased intracellular Ca²⁺ levels and the expression of voltage-dependent anion channel (VDAC) and mitochondrial calcium uniporter (MCU) which indicates that increased mitochondrial Ca²⁺ levels lead to increased expression of oxidative phosphorylation protein complexes as a result of ATP-futile cycle activation. A mechanistic study in 3T3-L1 adipocytes revealed that CAP induces UCP1- and ATP-dependent thermogenesis mediated by the β3-AR/PKA/p38MAPK/ERK as well as calcium-dependent α1-AR/TRPV1/CaMKII/AMPK/SIRT1 pathway. Taken together, we identified CAP's novel functional and modulatory roles in UCP1- and ATP-dependent thermogenesis, which is important for developing therapeutic strategies for combating obesity and metabolic diseases.

项与 β-adrenoceptors x α-adrenergic receptor 相关的新闻（医药）

2024-10-15

·BioSpace

CuraSen Therapeutics Appoints Kathleen Sereda Glaub Chief Executive Officer

Expands Adrenergic Pipeline to Address Neurogenic Orthostatic Hypotension and Major Depressive Disorder in Older Adults SAN CARLOS, Calif.--(BUSINESS WIRE)--CuraSen Therapeutics, Inc., a clinical-stage biopharmaceutical company developing oral, rapid onset, small molecule drugs to treat psychiatric and neurodegenerative diseases, announced today that it has appointed Kathleen Sereda Glaub, MBA, formerly executive chair, as chief executive officer. Dr. Anthony Ford will move to the role of president and chief scientific officer, and continue to lead research and development. Patrick Enright, managing director of Longitude Capital, will become chair of the board. Along with these executive changes, the company announced clinical program updates for its drug candidates that are each designed to restore adrenergic stimulus that declines with age or disease. CuraSen’s most recent development candidate is CuraAX (CST-3056), an alpha-1A adrenoceptor (α 1A -AR) agonist being developed as a treatment for neurogenic orthostatic hypotension (nOH). The company is planning to submit an investigational new drug (IND) application this quarter. A significant orphan indication affecting approximately 120,000-150,000 patients in the U.S., nOH is a dysfunction in the autonomic nervous system common in Parkinson’s disease (PD) and related diseases that causes sudden drops in blood pressure upon standing. This can lead to debilitating dizziness, weakness, cognitive decline and dangerous falls. CuraAX is a selective, CNS-penetrant, α 1A -AR agonist designed to provide cognitive benefit as well as control harmful blood pressure deviations. CuraCN (formerly known as CST-103/CST-107), a beta2 adrenoceptor (β 2 -AR) agonist combination, is targeted for a Phase 2b study in major depressive disorder in adults 65 and older, many of whom also suffer from cognitive decline. These plans are based on the company’s previous Phase 2 clinical study in patients that revealed compelling evidence of anti-depressant efficacy and improvements in cognition tests. CuraXN (formerly known as CST-2032/CST-107), a second β 2 -AR agonist combination, is in development for Alzheimer’s disease (AD) to address both cognitive symptoms and disease progression. All three drug candidates work by restoring adrenergic function that declines with age and, in particular, is lost early in neurodegenerative diseases such as AD & PD. CuraSen’s development candidates have strong potential to improve cognitive function and mood, in addition to addressing specific aspects of disease pathobiology. “We are thrilled to have Ms. Glaub assume the role of chief executive officer as CuraSen seeks to capitalize on the company’s adrenergic platform and clinical data to develop a broad pipeline of drugs for psychiatric and neurodegenerative diseases. These include opportunities for a significant, fast-to-market, orphan opportunity in neurogenic orthostatic hypotension,” said Mr. Enright, board chair. “CuraSen will benefit from the collective and complementary executive experience of both Ms. Glaub and Dr. Ford, both co-founders of the company.” Ms. Glaub brings more than 30 years of experience in biopharmaceutical corporate development, strategy, financing and company-building. She serves on the board of directors of IO Biotech, and previously served on the boards of Codexis, Aligos Pharmaceuticals and Escient Pharmaceuticals. Ms. Glaub was previously chief executive officer of Afferent Pharmaceuticals, which was acquired by Merck in 2016 for $1.25 billion. Under her leadership, the company advanced gefapixant to Phase 3 readiness for the treatment of chronic cough and raised $80 million in additional private funding for Afferent. Previously, she served as president of Plexxikon, and helped develop two FDA-approved drugs, Zelboraf® for metastatic melanoma and Turalio® for tenosynovial giant cell tumor (TGCT). She led Plexxikon’s business and financing strategy, negotiated multimillion-dollar partnerships, and led the sale of the company to Daiichi Sankyo for nearly $1 billion. She previously held positions as senior vice president and chief financial officer of Cell Genesys, treasurer of Genentech, and various finance and treasury roles with Intel Corporation. Ms. Glaub received her BA from the University of California, Berkeley, and her MBA from Northwestern University. “CuraSen’s expertise in adrenergic pharmacology, chemistry and clinical development has led to the discovery of three promising drug candidates focused on some of the most debilitating and common neurodegenerative and psychiatric diseases affecting patients and their families. Our adrenergic target mechanisms are already validated by approved drugs in a range of indications, and we have confirmed the ability to develop CNS-penetrant compounds with a unique approach to safety,” said Glaub. “Given the strong and rapid-onset efficacy signals pointing to an anti-depressant effect in our past studies and our understanding of adrenergic deficits in older adults, we believe there is a unique opportunity to address depression in these patients with CuraCN. With CuraXN, we hope to deliver a transformational treatment for Alzheimer’s disease with our holistic approach to restoring brain functionality and health. Lastly, with CuraAX, we believe we can offer major advantages over current treatments for nOH, including durability of efficacy and cognitive benefit, dosing convenience and improved safety.” About CuraSen Therapeutics CuraSen is focused on the development of new treatments for psychiatric and neurodegenerative diseases, including neurogenic orthostatic hypotension, major depressive disorder and Alzheimer’s disease. CuraSen’s drugs are small molecule, oral tablets designed to activate certain receptor populations in the brain to compensate for decline of the adrenergic system driven by aging and disease. The company has evaluated two β 2 -AR agonist candidates, CuraCN and CuraXN, in multiple Phase 2 clinical studies for effects on memory, attention, executive function and mood, as well as safety and tolerability. CuraSen is planning to submit an IND application by the end of 2024 for its third drug candidate CuraAX, an α 1A -AR agonist, for the treatment of nOH. For more information, please visit . Contacts Susan Kinkead Kinkead Communications susan@kinkeadcomm.com 415-509-3610

临床2期高管变更并购

2024-08-15

·奇点网

好人当了还不到三天，\x0d\x0a又露馅了。

*仅供医学专业人士阅读参考前两天奇点糕才刚说，肿瘤微环境中的成纤维细胞（CAFs）难得干一回好事，帮着搭建了能助力抗肿瘤免疫应答的三级淋巴结构，没想到一转眼的功夫，同样是针对结直肠癌的另一项基础科研里，CAFs又成促癌大反派了，而且这次它还有着明确的犯罪同伙。哥伦比亚大学Timothy C. Wang团队发表在Cancer Discovery期刊上的研究成果显示，结直肠癌微环境中存在由CAFs和去甲肾上腺素能神经通路共同构成的正反馈促癌回路：在去甲肾上腺素的作用下，CAFs可分泌神经生长因子（NGF），促进肿瘤内的交感神经形成和去甲肾上腺素积聚，且肾上腺素能刺激和CAFs分泌的NGF都能直接加快癌细胞的增殖。在这种“神经-间充质”相互作用的影响下，高表达NGF的人体结直肠癌更有可能呈现为间充质样亚型（mesenchymal-like），患者生存预后也相对较差，不过研究者们发现，使用已获批治疗罕见突变患者的原肌球蛋白相关激酶（TRK）抑制剂，可有效减轻“神经-间充质”正反馈相互作用的促癌效应，结直肠癌也有望就此迎来新的精准治疗药物[1]。论文首页截图用研究者们在论文开头的介绍，“我们知道CAFs能促癌，也知道交感神经对癌症发展有重要影响，但确实没想到它们之间还存在关联”，只能说到了肿瘤微环境这个大染缸里，啥坏事都有可能发生。而哥大研究者们一开始追寻的线索，是以NGF为代表的神经营养因子在结直肠癌中的来源，偏偏单细胞测序就显示，特定的CAFs亚群真就是NGF的唯一来源。原位杂交（ISH）分析显示，NGF信号在结直肠癌中水平较正常组织显著升高，且主要位于肿瘤的间质部分，分布也与密度显著升高的肾上腺素能交感神经重合，这就对上了NGF的生理功能；且在结直肠癌模型小鼠身上，肿瘤发生发展期间也存在NGF表达上调和交感神经支配的增加，但这毕竟还是隔着一层，交感神经和CAFs间有没有直接的相互作用呢？肠癌中增多的NGF可增加交感神经支配，且与癌症发展相关哥大研究者们想到在此前的研究中[2]，来自交感神经的去甲肾上腺素能够诱导胰腺癌细胞分泌NGF，就把相同的方法用到了CAFs身上，效果还真是大差不差，CAFs也出现了明显的NGF表达上调，且该效应是β2肾上腺素能受体（ADRB2）依赖性的，ADRB2会激活下游的PKA-CREB和MAPK通路，增加NGF分泌以促进肿瘤内交感神经支配并促癌。但去甲肾上腺素的影响还不止于此，研究者们推测它可能还会直接帮助癌细胞，并借助肿瘤类器官实验证实，去甲肾上腺素处理可另外通过结合α2A肾上腺素能受体（ADRA2A）/Gi蛋白，激活YAP蛋白信号通路的多个下游基因，直接加快癌细胞的增殖速率。相似地，NGF不仅可以促进肿瘤内交感神经支配，增强上述由ADRA2A和YAP蛋白介导的交感神经促癌作用，它本身也可以直接影响癌细胞，影响的主要途径则是TrkA-PI3K/AKT信号通路，而这正是使用TRK抑制剂精准干预的依据。研究者们选用在研的TRKA/TRKC抑制剂selitrectinib，在结直肠癌临床前研究模型中证实，抑制TRK可减少由NGF促进的YAP蛋白激活、AKT磷酸化等调控过程关键环节，从而延缓结直肠癌进展；而在人类结直肠癌患者中，NGF的高表达也确实与不良生存预后及肿瘤呈间充质样亚型（CMS4）[3]相关，因此TRK抑制剂的精准干预应该很有发挥空间。研究揭示的作用机制整体回顾参考文献：[1]Kobayashi H, Iida T, Ochiai Y, et al. Neuro-mesenchymal interaction mediated by a β2 adrenergic-nerve growth factor feedforward loop promotes colorectal cancer progression[J]. Cancer Discovery, 2024.[2]Renz B W, Takahashi R, Tanaka T, et al. β2 adrenergic-neurotrophin feedforward loop promotes pancreatic cancer[J]. Cancer Cell, 2018, 33(1): 75-90. e7.[3]Joanito I, Wirapati P, Zhao N, et al. Single-cell and bulk transcriptome sequencing identifies two epithelial tumor cell states and refines the consensus molecular classification of colorectal cancer[J]. Nature Genetics, 2022, 54(7): 963-975.本文作者丨谭硕

申请上市临床1期

2024-03-07

·BioSpace

CuraSen Therapeutics Announces Oral Presentation of Additional Positive Phase 2a Data with CST-2032/CST-107 in Patients with Alzheimer’s or Parkinson’s Disease at AD/PD™ 2024 International Conference

Drug Combination’s Unique Mechanism of Action Enables Reactivation of Brain Adrenergic Function, Showing Improvements in Multiple Areas of Cognition SAN CARLOS, Calif. & LISBON, Portugal--(BUSINESS WIRE)-- CuraSen Therapeutics, Inc., a clinical-stage company developing small molecule therapies to treat neurodegenerative disease, announced that it will present additional positive Phase 2a data with its combination adrenergic activator, CST-2032/CST-107, in patients with mild cognitive impairment (MCI) or mild dementia from either Alzheimer’s or Parkinson’s disease. The oral presentation will take place at AD/PD™ 2024: The International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders, being held March 5-9, 2024, in Lisbon, Portugal. CST-2032 is one of CuraSen’s two lead product candidates being tested in patients with Alzheimer’s and Parkinson’s disease. Both CST-2032 and CST-103, the company’s other lead clinical candidate, are oral, brain-permeant, beta2 adrenoceptor (β2-AR) agonists delivered in combination with CST-107 (nadolol, a brain-sparing beta blocker) to inhibit peripheral effects of β2-AR agonism. Both CST-2032 and CST-103 work by enabling reactivation of brain adrenergic function lost early in the neurodegenerative disease process. The updated Phase 2a data with CST-2032/CST-107 showed statistically and clinically important effects across several cognitive domains in patients with Alzheimer’s and Parkinson’s disease, such as memory, attention, executive function, facial recognition and impulse control — areas known to be impacted by adrenergic function. Target effect sizes of 0.2-0.3 or higher, as seen in this study, predict success in larger, longer studies. “These encouraging data build on earlier results presented at October 2023’s CTAD conference, reinforcing that treatment with CST 2032/CST-107 can produce meaningful quality-of-life cognitive improvements for Alzheimer’s and Parkinson’s patients, particularly those with mild cognitive impairment, rapidly and safely,” said Anthony Ford, PhD, chief executive officer of CuraSen. “The robust, collective data set from both CST-2032 and CST-103 demonstrate that this novel mechanism of action for restoring adrenergic function to the brain is a highly compelling strategy to address unmet symptoms of neurodegeneration. We plan to evaluate additional doses and refine optimal patient profiles in our upcoming Phase 2 studies, with the goal to significantly increase cognitive performance and ultimately, halt disease progression.” The randomized, placebo-controlled, double-blinded crossover study evaluated 64 patients with MCI or mild dementia from either Alzheimer’s disease or Parkinson’s diseases: AD with MCI = 30 patients randomized; 25 completed AD with dementia = 6 patients randomized; 5 completed PD with MCI = 22 patients randomized; 21 completed PD with dementia = 6 patients randomized; 4 completed Data highlights included: Digit Symbol Substitution test, which measures complex attention, memory and executive function: AD patients with MCI = 0.36 effect size; p=0.02 on Day 14 Facial Expression Recognition response time to accurately recognize facial expressions, which measures social cognition: AD patients with MCI = 0.66 effect size; p=0.04 on Day 14 for happy expression and 0.91 effect size; p = 0.01 on Day 14 for surprise expression Stop Signal test, which measures impulse control PD patients with MCI = 0.52 effect size; p=0.04 on Day 14 Excellent safety and tolerability pro /> No serious adverse events: no increases in heart rate observed one to four hours after dose The company plans to initiate longer studies with both CST-2032/CST-107 and CST-103/CST-107 in AD and PD patients with MCI later this year, as well as develop fixed-dose combination tablets for each of these drug candidates. Study Objectives and Design The study objectives were to establish safety and tolerability of CST-2032/CST-107, identify optimal dosing, and identify cognitive tests responsive to agonist stimulus within the two-week dosing period. Measures of cognition included the digit symbol substitution test, Cambridge neuropsychological test battery, and the facial expression recognition task. The study took place at multiple sites in the United States and New Zealand. Patients received either daily 3 mg of CST-2032 with 3 mg of nadolol for 14 days, or matching placebo, followed by a wash-out period (≥7-d) before crossing over to the other treatment arm. Blood samples are being analyzed for AD biomarkers, and DNA samples for AD and PD genotyping. Abstract Details Title: “CST-2032, a Novel Beta-2 Adrenoceptor Agonist, Improves Cognition in Patients with Impairment Due to Alzheimer’s or Parkinson’s Disease” Abstract #: PO34 Presenter: Gabriel Vargas, MD, PhD, chief medical officer, CuraSen Therapeutics Session: Translational Drug Discovery and Experimental Models 05 Date: Saturday, March 9, 2024 Time: 17:25-17:40 UTC, session time,16:40 - 18:40 UTC Location: Auditorium VII About CuraSen Therapeutics CuraSen is focused on the development of new treatments for neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease and other related orphan conditions. CuraSen’s drugs are designed to activate certain receptor populations in the brain to compensate for critical neuronal and glial functions that have otherwise been lost due to degeneration and represent a unique approach in the field. The company is evaluating CST-103 and CST-2032, both selective β2-AR agonists, in combination with CST-107, a β-AR blocker, in multiple Phase 2 clinical studies. CST-3056, an α1A-AR agonist, is in preclinical development for the treatment of Alzheimer’s disease. For more information, please visit .

临床2期临床结果