AbstractBackgroundDuring adolescence, neuronal circuits exhibit plasticity in response to physiological changes and to adapt to environmental events. Nigrostriatal dopaminergic pathways are in constant flux during development. Evidence suggests a relationship between early use of cannabinoids and psychiatric disorders characterized by altered dopaminergic systems, such as schizophrenia and addiction. However, the impact of adolescent exposure to cannabinoids on nigrostriatal dopaminergic pathways in adulthood remains unclear. The aim of this research was to determine the effects of repeated activation of cannabinoid receptors during adolescence on dopaminergic activity of nigrostriatal pathways and the mechanisms underlying this impact during adulthood.MethodsMale Sprague-Dawley rats were treated with 1.2 mg/kg WIN 55212-2 daily from postnatal day 40 to 65. Then no-net flux microdialysis of dopamine in the dorsolateral striatum, electrophysiological recording of dopaminergic neuronal activity, and microdialysis measures of gamma-aminobutyric acid (GABA) and glutamate in substantia nigra par compacta were carried out during adulthood (postnatal days 72–78).ResultsRepeated activation of cannabinoid receptors during adolescence increased the release of dopamine in dorsolateral striatum accompanied by increased population activity of dopamine neurons and decreased extracellular GABA levels in substantia nigra par compacta in adulthood. Furthermore, perfusion of bicuculline, a GABAa antagonist, into the ventral pallidum reversed the increased dopamine neuron population activity in substantia nigra par compacta induced by adolescent cannabinoid exposure.ConclusionsThese results suggest that adolescent exposure to cannabinoid agonists produces disinhibition of nigrostriatal dopamine transmission during adulthood mediated by decreased GABAergic input from the ventral pallidum.

2018-05-01·Toxicological Sciences2区 · 医学

In Vitro Screening for Seizure Liability Using Microelectrode Array Technology

2区 · 医学

Article

作者: Bradley, Jenifer A ; Metea, Monica R ; Strock, Christopher J ; Luithardt, Harry H

Drug-induced seizure liabilities produce significant compound attrition during drug discovery. Currently available in vitro cytotoxicity assays cannot predict all toxicity mechanisms due to the failure of these assays to predict sublethal target-specific electrophysiological liabilities. Identification of seizurogenic and other electrophysiological effects at early stages of the drug development process is important to ensure that safe candidate compounds can be developed while chemical design is taking place, long before these liabilities are discovered in costly preclinical in vivo studies. The development of a high throughput and reliable in vitro assay to screen compounds for seizure liabilities would de-risk compounds significantly earlier in the drug discovery process and with greater dependability. Here we describe a method for screening compounds that utilizes rat cortical neurons plated onto multiwell microelectrode array plates to identify compounds that cause neurophysiological disruptions. Changes in 12 electrophysiological parameters (spike train descriptors) were measured after application of known seizurogenic compounds and the response pattern was mapped relative to negative controls, vehicle control and neurotoxic controls. Twenty chemicals with a variety of therapeutic indications and targets, including GABAA antagonists, glycine receptor antagonists, ion channel blockers, muscarinic agonist, δ-opioid receptor agonist, dopaminergic D2/adrenergic receptor blocker and nonsteroidal anti-inflammatory drugs, were tested to assess this system. Sixteen of the seventeen seizurogenic/neurotoxic compounds tested positive for seizure liability or neurotoxicity, moreover, different endpoint response patterns for firing rate, burst characteristics and synchrony that distinguished the chemicals into groups relating to target and seizurogenic response emerged from the data. The negative and vehicle control compounds had no effect on neural activity. In conclusion, the multiwell microelectrode array platform using cryopreserved rat cortical neurons is a highly effective high throughput method for reliably screening seizure liabilities within an early de-risking drug development paradigm.

2017-05-15·Spine2区 · 医学

The Association Between Adjuvant Pain Medication Use and Outcomes Following Pediatric Spinal Fusion

2区 · 医学

Article

作者: Rosenberg, Rebecca E ; Trzcinski, Stacey ; Cohen, Mindy ; Erickson, Mark ; Errico, Thomas ; McLeod, Lisa

STUDY DESIGNA comparative effectiveness database study.OBJECTIVEThe aim of this study was to describe variation in use of adjuvant therapies for managing postoperative pain in in patients undergoing posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS) and determine association between use of these therapies and patient outcomes.SUMMARY OF BACKGROUND DATAVariation in postoperative pain management for children undergoing PSF for AIS likely impacts outcomes. Minimal evidence exists to support strategies that most effectively minimize prolonged intravenous (IV) opioids and hospitalizations.METHODSWe included patients aged 10 to 18 years discharged from one of 38 freestanding children's hospitals participating in a national database from December 1, 2012, to January 5, 2015, with ICD9 codes indicating scoliosis and PSF procedure. Use of ketorolac, gamma aminobutyric acid (GABA) analogues (GABAa), and benzodiazepines was compared across hospitals. Hierarchical logistic regression adjusting for confounders and accounting for clustering of patients within hospitals was used to estimate association between these therapies and odds of prolonged duration of IV opioids, prolonged length of stay (LOS), and early readmissions.RESULTSAcross hospitals, use of ketorolac and GABAa was highly variable and increased over time among 7349 subjects. Use of ketorolac was independently associated with significantly lower odds of prolonged LOS [odds ratio (OR) 0.75, 95% confidence interval (95% CI) 0.64-0.89] and prolonged duration of IV opioid (OR 0.84, 95% CI 0.73-0.98). GABAa use was significantly associated with decreased odds of prolonged IV opioid use (OR 0.63, 95% CI 0.53-0.75). Readmission rate at 30 days was 1.6% and most strongly associated with prolonged LOS.CONCLUSIONIn this national cohort of children with AIS undergoing PSF, patients who received postoperative ketorolac or GABAa were less likely to have prolonged IV opioid exposure. Given the rapid increase in use of adjuvant therapies without strong evidence, resources should be devoted to multicenter trials in order to optimize effectiveness and outcomes.LEVEL OF EVIDENCE3.

项与 L-1001BC 相关的新闻（医药）

2023-12-16

·生物制药小编

不孕症攻坚战，诱因PCOS的全靶点汇总

多囊卵巢综合征（PCOS）是生育年龄妇女常见的一种复杂的内分泌及代谢异常所致的疾病，以慢性无排卵（排卵功能紊乱或丧失）和高雄激素血症（妇女体内男性激素产生过剩）为特征，主要临床表现为月经周期不规律、不孕、多毛和/或痤疮，关键的病理变化包括神经内分泌失调、雄激素过度产生、胰岛素抵抗和脂肪组织生物学的变化，是最常见的女性内分泌疾病。除了众所周知的高雄激素血症和排卵功能障碍的临床表现外，多囊卵巢综合症患者还会增加不良心理健康后果、妊娠并发症和心脏代谢疾病的风险。现有治疗方式如避孕药，抗雄性激素药物，胰岛素增敏剂的效果仍然有限，一些药物也存在各类的副作用。核心原因在于对潜在病理和生理过程的不完全了解阻碍了药物开发，而随着近年来，遗传学、代谢组学和脂肪细胞生物学的等多方面的进展，对于PCOS靶点的开发也提上了日程。近日，著名医学期刊BMJ发表了了一篇关于PCOS的综述性文献，本文将对其列举靶点进行汇总和补充。（点击文末“阅读原文”可获得PCOS靶点临床药物汇总）KisspeptinKisspeptin是调节女性生殖功能重要的神经肽，由下丘脑神经元群表达，通过与KISS1R（G蛋白偶联受体）结合，刺激促性腺激素释放激素释放，进而调节下丘脑-垂体-性腺轴，在这一轴中具有重要作用，除下丘脑之外，卵巢、子宫内膜、滋养层等组织与细胞中也发现kisspeptin及其受体KISS1R的表达，局部表达的kisspeptin/KISS1R参与多种生理活动，对卵细胞成熟、胚胎着床等过程意义重大。虽然开始的研究着重于使用天然的Kisspeptin，KP54来诱导排卵。然而，使用KP54作为排卵诱导剂可能会受到快速免疫的限制。因为KP54比卵泡刺激素更优先刺激黄体生成素的分泌，也有人担心长期服用kisspeptin可能会加重多囊卵巢综合征患者卵泡刺激素的缺乏。在这种情况下PCOS中，Kisspeptin的作用似乎是矛盾的，这使得Kisspeptin激动剂和kisspeptin受体拮抗剂目前都被开发用于治疗多囊卵巢综合症。因为抑制剂又具有使黄体生成素的高分泌正常化、恢复卵泡生成和排卵以及改善卵巢雄激素过多的潜力。目前激动剂已经进入临床，疗效体现了上文所述的矛盾性，黄体生成素的分泌情况和KP54类似，而拮抗剂尚处于临床前研究阶段。神经激肽3受体同样位于下丘脑神经元群的还有神经激肽3受体（NK3R），同样也是PCOS的治疗靶点之一，通过拮抗NK3R，抑制剂可以阻断神经激肽B（NKB）与kisspeptin/神经激肽B/强啡肽（KNDy）神经元的结合，从而调节内分泌系统，有望恢复PCOS患者体内代谢和激素水平的平衡。目前，神经激肽3受体拮抗剂展现出了满足多囊卵巢综合征理想治疗的许多特性。MLE4901(也称为AZD4901)虽然因为肝毒性而停药，但是其他指标相当优秀，而肝毒性是MLE4901所独有的，其他NK3R拮抗剂中并没有观察到这一现象。另外一款神NK3R拮抗剂fezolinetant的疗效显著，不仅降低了睾酮水平，还降低了黄体生成素水平。临床前研究也强调了神经激肽3受体拮抗剂的潜在代谢益处。在双氢睾酮诱导的多囊卵巢综合征小鼠模型中，用神经激肽3受体拮抗剂治疗降低了体重和肥胖。强啡肽强啡肽是一种吗啡样活性肽，具有多种生理功能，包括镇痛、镇静、催眠和抗焦虑。当强啡肽与阿片受体结合时，kisspeptin向促性腺激素释放激素神经元的释放受到抑制，因此具有中枢作用的选择性阿片受体激动剂可能降低促性腺激素释放激素的脉动性。但是阿片受体激动剂本身具有成瘾性，相关药物的开发应当相当谨慎。而在美国，因为产业和政策相关原因，已有选择性κ受体激动剂上市，用于治疗瘙痒，而关于多囊卵巢综合症的适应症正在探索中。在多囊卵巢综合征的产前雄激素化小鼠模型中，difelikefalin降低了血清中促黄体生成激素和睾酮的水平，恢复了发情周期和排卵，并减少了下丘脑视前区KISS1 mRNA的过度表达。γ-氨基丁酸（GABA）GABA（γ-氨基丁酸）是一种抑制性神经递质，广泛存在于中枢神经系统中。GABA通过与其相应的受体结合而发挥作用。GABA对胰岛β细胞发挥保护和再生作用，并逆转糖尿病。在大脑之外，在胰岛、胃肠道、卵巢和肾上腺髓质中也有GAD和GABA受体的报道。在人体中，GABA受体分为多种类型，包括GABA A、GABA B和GABA C等。其中，GABA A受体是最主要的类型之一，也是最具有药理作用的一种。中枢作用的GABA A受体抑制剂可以抑制促性腺激素的分泌，从而减少雌激素的合成和释放。这种抑制作用有助于减轻多囊卵巢综合症患者的高雄激素血症和胰岛素抵抗等症状。（如果雌激素的水平降低，雄激素的水平也会相对降低，从而有助于改善高雄激素血症的症状）早先的研究表明，癫痫等神经疾病常见治疗方法之一的丙戊酸钠（一种GABAA激动剂）会增加中枢神经系统中的GABAA水平，这些患者会出现多囊卵巢综合症发病率提升的情况（尽管体重增加也可以部分解释其原因）。而外周GABA和中枢GABA的开发完全相反，并非采用中枢一样的拮抗作用，而是因为多囊卵巢综合征患者外周GABA水平降低，在临床前研究中，肠内给药GABAA降低了来曲唑诱导的多囊卵巢综合征大鼠模型中的体重指数和睾酮水平。抗缪勒管激素抗缪勒管激素（AMH）是一种由卵巢内窦前卵泡和小窦卵泡分泌的糖蛋白，能够反映卵巢内储备的卵泡数量，是近年来被认为能评估卵巢功能最有效和敏感的指标。抗缪勒管激素水平与卵巢储备功能的变化密切相关，可以预测女性的卵巢功能是否衰退。抗缪勒管激素途径的拮抗作用也可能是治疗上有用的；最近对抗缪勒管激素与抗缪勒管激素受体2型结合的结构基础的深入研究有助于合理设计抗缪勒管激素拮抗剂。靶向类固醇生成中的关键酶AKR1C3是醛酮还原酶家族的一员，能够催化多种类固醇激素和药物的还原反应。同时，它还在雄性激素的合成过程中起到了关键作用，可以转化雄烯二酮为睾酮，以及转化11-酮雄烯二酮为11-酮睾酮。这种转化过程对于经典的和11-氧化的雄激素合成来说非常重要。目前已经开发了各种AKR1C3抑制剂，其抗肿瘤作用和抑制去势抵抗性前列腺癌、急性髓细胞性白血病和雌激素受体阳性乳腺癌中前列腺素F合酶活性的能力结果不一。虽然基于类固醇的AKR1C3抑制剂正在开发中，但在多囊卵巢综合征的临床前模型中的治疗潜力尚未得到检验。在多囊卵巢综合征的啮齿动物模型中用BVT.2733选择性抑制11β-HSD1可改善胰岛素抵抗、生殖激素功能障碍和多囊卵巢形态学。这些初步疗效相当可观，但在AKR1C3和11β-HSD1抑制剂的潜在治疗益处可以在患者中测试之前，还需要进一步的临床前工作。GLP-1：司美格鲁肽又要跨界胰高血糖素样肽1 (GLP-1)受体激动剂通过体重减轻(通过刺激饱腹感)和抑制脂肪组织中的炎症，增加葡萄糖依赖性胰岛素分泌，抑制胰高血糖素分泌，并增加外周胰岛素敏感性。一些研究表明，GLP-1受体激动剂改善了月经的规律性或频率，并且月经频率的改善与体重的减轻相关。GLP-1受体激动剂也显示出降低雄激素水平和改善心血管风险的标志物。八项随机对照试验的荟萃分析得出结论，GLP-1激动剂在改善稳态模型评估方面比二甲双胍更有效——胰岛素抵抗(标准平均差0.40，95%可信区间0.74至0.06)、腹围(0.45，0.89至0.00)和体重指数(1.02，1.85至0.19)，但在改善月经频率(0.15，-0.24至0.54)或血清方面无效。而新型长效GLP-1类似物，如司美格鲁肽或度拉糖肽，或双重GLP-1-葡萄糖依赖性促胰岛素多肽激动剂，如替泽帕肽，则可以提供更多的治疗机会，具有更好的减肥效果、更长的作用持续时间和改善的依从性的潜在益处。司美格鲁肽是目前口服制剂中唯一可用的GLP-1激动剂，目前正在对患有多囊卵巢综合症和肥胖症的青春期女孩进行临床试验研究(用司美格鲁肽治疗PCOS与积极生活方式干预(TEAL)、NCT03919929)。钠-葡萄糖协同转运蛋白抑制剂（SGLT-2）钠-葡萄糖协同转运蛋白2（SGLT-2）主要分布在肾脏近曲小管，是一种低亲和力、高转运能力的转运体，其主要生理功能是在肾脏近曲小管重吸收肾小球滤过液中80%-90%的葡萄糖。SGLT-2抑制剂则减少了肾脏近曲小管对葡萄糖的重吸收，促进了尿葡萄糖的排泄，还减少了其他人群的体重和心血管事件。目前关于多囊卵巢综合征患者的数据仅限于四项小型随机对照试验。与二甲双胍相比，卡格列净对多囊卵巢综合征女性的体重指数(P=0.006)、基础代谢率(P=0.02)和脂肪量(P=0.02)有更大的改善，但在激素或代谢参数方面没有改善在超重和肥胖多囊卵巢综合征患者中，卡格列净-二甲双胍联合治疗3个月的总睾酮、葡萄糖曲线下面积、胰岛素和葡萄糖曲线下面积之比的降低幅度大于单用二甲双胍治疗，但在月经频率、体重指数、或体内平衡模型评估-治疗组之间的胰岛素抵抗却没有改善。利格列净是钠-葡萄糖共转运蛋白1 (SGLT1)和2 (SGLT2)的双重抑制剂。同时抑制SGLT1和SGLT2可提供更有效的减肥效果，因为单独抑制SGLT1可刺激肠道分泌GLP-1。在一项包含29例患者的2期随机对照试验中，利格列净可使多囊卵巢综合征女性的雄烯二酮水平降低19%，硫酸脱氢表雄酮水平降低24%，高胰岛素血症水平降低70%。最近完成的一项dapagliflozin对多囊卵巢综合征患者胰岛素抵抗和血清雄激素水平的随机对照试验(dapagliflozin Efficacy and Action in PCOS (DEAP)， NCT04213677)的结果正在等待中。总结总体来看，因为多囊卵巢综合征经常伴随各类因素，所以可能后续的研究会致力于排除肥胖，糖尿病等因素，或者是设定特殊人群而进行细分，未来的临床规划可能朝着这一方向迈进。参考来源：孙轶群,赵军招.Kisspeptin在辅助生殖过程中的研究进展[J].温州医科大学学报,2023,53(09):761-767.https://bmjmedicine.bmj.com/content/2/1/e000548

2023-09-04

·Firstwordpharma

Side effects appear to have thwarted FDA approval of Biogen, Sage's Zurzuvae in MDD

Newly-released documents from the FDA reveal the agency's safety concerns that led to the rejection of Biogen and Sage Therapeutics' application for Zurzuvae (zuranolone) in major depressive disorder (MDD). The regulator's review highlighted a signal for suicidal ideation and behaviour that was seen in MDD studies, but not in those for postpartum depression (PPD).The FDA approved the oral GABAA receptor positive allosteric modulator for PPD in adults last month, but denied its authorisation in the larger indication of MDD. Since the agency's split decision, Sage has been forced to undertake cost-cutting measures, including slashing 40% of its workforce, as it attempts to capitalise on the US launch of Zurzuvae for PPD in the fourth quarter.RBC Capital Markets analyst Brian Abrahams, who reviewed the new FDA documents, noted that one patient with MDD was unresponsive to stimuli for 50 minutes after receiving a high dose of Zurzuvae. That patient, given a dosage 30% to 50% higher than what is now approved, also lost consciousness twice, while another subject lost consciousness for nearly five hours.No signal in PPDThe FDA noted "there was no signal for suicidal ideation and behaviour in the PPD studies… However, because there was a signal in the MDD studies, and we cannot rule out an effect, we will include suicidal thought and behaviour warning language" in any potential label in this indication. Commenting on the safety issues, Sage spokesman Matthew Henson said that they involved patients given the oral solution of Zurzuvae, rather than the approved capsule formulation."It is inaccurate and misleading to extrapolate findings associated with the oral solution to the PPD population," Henson noted, adding that there were no reports of loss of consciousness in any of the participants in the PPD and MDD studies given the capsule version of Zurzuvae.Abrahams estimates that the drug will generate annual sales of $240 million in PPD, but he's not hopeful of approval in MDD, where its use would likely be chronic. In PPD, the analyst noted that the "FDA seemed comfortable (with effectiveness) and durability were rapid and clinically meaningful, and had slightly fewer concerns on safety given likelihood of one-time use and lower possible suicidality risk."

上市批准临床结果临床研究

2023-08-17

·BioSpace

Marinus Pharmaceuticals to Host Hybrid Investor & Analyst Event on Tuesday, September 19, 2023

RADNOR, Pa.--(BUSINESS WIRE)-- Marinus Pharmaceuticals, Inc. (Nasdaq: MRNS), a pharmaceutical company dedicated to the development of innovative therapeutics to treat seizure disorders, will host a hybrid Investor & Analyst Event on Tuesday, September 19 from 9:00 a.m. to 1:00 p.m. Eastern Time in New York. The event will feature presentations from Marinus management and Key Opinion Leaders to discuss the Company’s clinical pipeline progress, strategic initiatives and business outlook. In-person attendance is open to invited research analysts and institutional investors. All others are invited to watch the live video webcast. Live questions will be taken by in-person guests, and virtual participants may submit questions through the webcast platform. To register for the video webcast, please visit the Investor Relations section of the Company's website at . A replay of the webcast will be archived on the Investor Relations section of the Company's website following the event. About Marinus Pharmaceuticals Marinus is a commercial stage pharmaceutical company dedicated to the development of innovative therapeutics for seizure disorders. The Company’s commercial product, ZTALMY® (ganaxolone) oral suspension CV, has been approved by the U.S. FDA for the treatment of seizures associated with CDKL5 deficiency disorder in patients two years of age and older. The potential of ganaxolone is also being studied in other rare seizure disorders, including in Phase 3 trials in tuberous sclerosis complex and refractory status epilepticus. Ganaxolone is a neuroactive steroid GABAA receptor modulator that acts on a well-characterized target in the brain known to have anti-seizure effects. It is being developed in IV and oral formulations to maximize therapeutic reach for adult and pediatric patients in acute and chronic care settings. For more information visit .

上市批准临床3期

100 项与 L-1001BC 相关的药物交易

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