Evaluation of the Necessity of Long-term Pharmacological Treatment With Antipsychotics for the Prevention of Relapse in Long-term Stabilized Schizophrenic Patients: a Randomized, Single-blind, Longitudinal Trial

The main objective of the trial is to evaluate, how long an antipsychotic relapse-prevention should be continued and to which time a patient with schizophrenia is protected enough, so that a withdrawal or reduction of the medication seems appropriate. Relapse is defined as primary outcome.

开始日期2015-02-01

申办/合作机构

Technische Universität München

NCT02374567 / Terminated临床3期IIT

Pharmacovigilance in Gerontopsychiatric Patients

The purpose of this multicenter-study is to investigate safety of psychopharmacological treatment and rates of adverse drug reactions in gerontopsychiatric inpatients. Elderly people are at higher risk for developing side effects under pharmacological treatment due to an altered metabolic situation, higher comorbidity rates and often polypharmacy. Furthermore gerontopsychiatric patients can often not articulate their symptoms clearly, for example due to pronounced cognitive impairment.
The aim of the study is to gain valid data of possible adverse drug reaction rates, their potential risk factors and outcome, as well as medical prescription practises.
To assess these outcomes an intensive pharmacovigilance-monitoring will be conducted at the five participating study sites.
At Baseline demographic data, previous and present disorders, use of drugs, previous and present medication, quality of life, cognitive function, physical examination results, laboratory results and ECG will be assessed.
Afterwards patients are visited weekly and screened for possible adverse drug reactions. All adverse drug reactions will be coded in the MedDRA-system.
In case of a possible serious adverse drug reaction serum levels of all psychotropic substances applicated will be assessed. Drug combinations will be analysed using an established advanced bioinformatic tool (mediQ). Diagnosis, medication intake and possible adverse drug reactions are documented continually.
2 weeks after discharge from the ward, patients will be contacted by phone to assess catamnestic data.

开始日期2015-01-01

申办/合作机构

Hannover Medical School

NCT01498770 / CompletedN/A

An Observational Drug Utilization Study of SYCREST^® (Asenapine) in the United Kingdom

This study is designed to describe asenapine prescribing patterns in the United Kingdom (UK) during the post-approval period under conditions of usual practice. The use of asenapine in Bipolar Disorder and other indications will be described. To provide epidemiological and clinical perspective, use of aripiprazole and other comparator drugs will be described.

开始日期2013-04-01

申办/合作机构

Organon & Co.

100 项与舍吲哚相关的临床结果

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100 项与舍吲哚相关的转化医学

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100 项与舍吲哚相关的专利（医药）

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项与舍吲哚相关的文献（医药）

2024-06-01·JOURNAL OF MOLECULAR MODELING

Understanding the interactions between repurposed drugs sertindole and temoporfin with receptor for advanced glycation endproducts: Therapeutic implications in cancer and metabolic diseases

Article

作者: Shamsi, Anas ; Anwar, Saleha ; Shahwan, Moyad ; Ashames, Akram ; Khan, Mohd Shahnawaz ; Yadav, Dharmendra Kumar

CONTEXT:

In the pursuit of novel therapeutic possibilities, repurposing existing drugs has gained prominence as an efficient strategy. The findings from our study highlight the potential of repurposed drugs as promising candidates against receptor for advanced glycation endproducts (RAGE) that offer therapeutic implications in cancer, neurodegenerative conditions and metabolic syndromes. Through careful analyses of binding affinities and interaction patterns, we identified a few promising candidates, ultimately focusing on sertindole and temoporfin. These candidates exhibited exceptional binding affinities, efficacy, and specificity within the RAGE binding pocket. Notably, they displayed a pronounced propensity to interact with the active site of RAGE. Our investigation further revealed that sertindole and temoporfin possess desirable pharmacological properties that highlighted them as attractive candidates for targeted drug development. Overall, our integrated computational approach provides a comprehensive understanding of the interactions between repurposed drugs, sertindole and temoporfin and RAGE that pave the way for future experimental validation and drug development endeavors.

METHODS:

We present an integrated approach utilizing molecular docking and extensive molecular dynamics (MD) simulations to evaluate the potential of FDA-approved drugs, sourced from DrugBank, against RAGE. To gain deeper insights into the binding mechanisms of the elucidated candidate repurposed drugs, sertindole and temoporfin with RAGE, we conducted extensive all-atom MD simulations, spanning 500 nanoseconds (ns). These simulations elucidated the conformational dynamics and stability of the RAGE-sertindole and RAGE-temoporfin complexes.

2023-11-01·Schizophrenia research

The cellular mechanism of antipsychotic-induced myocarditis: A systematic review

Review

作者: Bousman, Chad A ; Vaziri, Nazanin ; Greenway, Steven C ; Marques, Diogo

Antipsychotic drug-induced myocarditis is a serious and potentially fatal adverse drug reaction characterized by inflammation of the heart muscle (myocardium) that typically develops within the first month after commencing an antipsychotic drug. Although the precise mechanism of this severe adverse drug reaction is unknown, multiple theories have been proposed with varying levels of support from cellular or animal studies. We conducted a systematic review, in accordance with PRISMA guidelines, of published preclinical and clinical studies investigating the cellular mechanism by which antipsychotic drugs induce myocarditis. A literature search including all studies available before December 10, 2022, yielded 15 studies that met our inclusion criteria. Antipsychotics examined in the included studies included clozapine (n = 13), ziprasidone (n = 1), amisulpride (n = 1), haloperidol (n = 1), levomepromazine (n = 1), olanzapine (n = 1), and sertindole (n = 1). The evidence suggests several overlapping mechanistic cascades involving: (1) increased levels of catecholamines, (2) increased proinflammatory cytokines, (3) increased reactive oxygen species (ROS), (4) reduced antioxidant levels and activity, and (5) mitochondrial damage. Notable limitations such as, a focus on clozapine, sample heterogeneity, and use of supratherapeutic doses will need to be addressed in future studies. Discovery of the mechanism by which antipsychotic drugs induce myocarditis will allow the development of clinically-useful biomarkers to identify those patients at increased risk prior to drug exposure. The development or repurposing of therapeutics to prevent or treat drug-induced myocarditis will also be possible and this will enable increased and safe use of antipsychotics for those patients in need.

2023-10-11·Molecules (Basel, Switzerland)

Naphthaleneoxypropargyl-Containing Piperazine as a Regulator of Effector Immune Cell Populations upon an Aseptic Inflammation.

Article

作者: Balabekova, Marina K ; Balapanova, Anar Kh ; Dembitsky, Valery M ; Sycheva, Yelena S ; Seilkhanov, Tulegen M ; Zharkynbek, Tolganay Y ; Tokusheva, Aliya N ; Kairanbayeva, Gulgul K ; Yu, Valentina K ; Tassibekov, Khaidar S

This study investigated the effects of aseptic inflammation and heavy metal exposure on immune responses, as well as the potential immunomodulatory properties of the newly synthesized 1-[1-(2,5-dimethoxyphenyl)-4-(naphthalene-1-yloxy)but-2-ynyl]-4-methylpiperazine complexed with β-cyclodextrin (β-CD). Aseptic inflammation was induced by a subcutaneous injection of turpentine in rats, while heavy metal exposure was achieved through a daily administration of cadmium chloride and lead acetate. The levels of immune cell populations, including cytotoxic T lymphocytes (CTL), monocytes, and granulocytes, were assessed in the spleen. The results showed that aseptic inflammation led to decreased levels of CTL, monocytes, and granulocytes on the 14th day, indicating an inflammatory response accompanied by a migration of effector cells to the inflamed tissues. The exposure to cadmium chloride and lead acetate resulted in systemic immunotoxic effects, with reduced levels of B cells, CD4⁺ Th cells, monocytes, and granulocytes in the spleen. Notably, piperazine complexed with β-CD (the complex) exhibited significant stimulatory effects on CD4⁺, CD8⁺, and myeloid cell populations during aseptic inflammation, even in the presence of heavy metal exposure. These findings suggest the potential immunomodulatory properties of the complex in the context of aseptic inflammation and heavy metal exposure.

项与舍吲哚相关的新闻（医药）

2024-10-25

·奇点网

改善认知看来不是抗精神病药物的长项。

*仅供医学专业人士阅读参考认知功能缺陷是精神分裂症谱系障碍（SSDs）的重要症状之一，涵盖注意力、专注力、记忆等多个方面，对疾病进程和患者生活质量有着深远影响。作为SSDs患者的关键治疗手段，抗精神病药物虽然不是专门用于改善认知功能的药物，但由于其受体结合特性，被认为可能对认知功能产生不同程度的影响。然而结果有些差强人意。德国慕尼黑工业大学的Stefan Leucht团队完成了迄今为止最全面的关于抗精神病药物与精神分裂症谱系障碍（SSDs）患者认知功能关系的网络荟萃分析，结果于近日发表在《JAMA·精神病学》期刊上。他们基于包含近千名SSD患者的68项试验数据进行分析后发现，抗精神病药物整体上对认知功能有轻微的改善效果，略胜于安慰剂，但不具有统计学意义。每种药物之间的效果差异不大，其中氯氮平、氟哌啶醇、氟奋乃静在认知功能的改善方面表现垫底，逊色于安慰剂。研究者们表示，抗精神病药物对认知功能的轻微改善可能更多是由于其减少了思维紊乱和其它阳性症状（比如激动、妄想、幻觉等），而非直接作用于认知功能本身。论文首页截图在这项研究中，Stefan Leucht等人通过系统回顾和随机效应网络荟萃分析，评估了抗精神病药物对精神分裂症谱系障碍（SSDs）患者认知功能的影响。研究的主要数据来源于Cochrane精神分裂症组试验注册库，截至2023年6月25日，共筛选并纳入68项随机对照试验，涉及9525名SSDs患者。这些患者的平均年龄为35.1岁，男性占70%。研究的主要结局是患者整体认知功能的变化，次要结局是患者具体认知领域（如处理速度、工作记忆、语言学习等）、生活质量和社会功能的变化。结果显示，整体上，抗精神病药物对认知功能的改善效果有限，虽然相比安慰剂表现出一定的优势，但效应值（SMD）较小，并且不同药物之间的差异不明显。具体来说，在改善认知的效果上，吗茚酮（Molindone，MOL）和盐酸硫利达嗪（Thioridazine，THIOR）分别排名第一和第二。不过这两种药物的分析结果都是基于单项小规模研究（15-22人数），且仅改善大脑处理速度这一个认知领域。同样，位列第五的氯丙嗪（Chlorpromazine，CPZ）也存在这个问题，但尽管相关研究数量多了些，总参与人数依然较少（N=101），且数据来源于二十世纪六七十年代的随机临床试验。相比之下，位列第三、第四的帕利哌酮（Paliperidone，PAL）和舍吲哚（Sertindole，SER），其分析结果基于近年来的研究数据，与安慰剂相比，表现出中等效果（SMD -0.43，95%CI -0.93至0.08 ；SMD -0.57，95%CI -1.03至 -0.11）。排名倒数的三位，则是氟奋乃静（Fluphenazine，FLU）（SMD = 0.15, 95% CI = -0.39至0.69）、氟哌啶醇（Haloperidol，HAL）（SMD 0.04，95%CI -0.25至0.33）、氯氮平（Clozapine，CLZ）（SMD 0.12，95%CI -0.23至0.48），落后于安慰剂。这一结果与它们的强效多巴胺型受体阻断作用相符。其他排名靠前的药物还有喹硫平（Quetiapine，QUE）、布瑞吡唑（Brexpiprazole，BRE）、利培酮（Risperidone，RIS）、唑吡坦（Zotepine，ZOT）、奥氮平（Olanzapine，OLA）、氨磺必利（Amisulpride，AMI）、鲁拉西酮（Lurasidone，LUR）、阿立哌唑（Aripiprazole，ARI）、齐拉西酮（Ziprasidone，ZIP）。排名（PLB-安慰剂）在额外的探索性事后分析中，研究按照抗精神病药物的结合受体将其分为四个组。结果显示，作用于肾上腺素能受体、5-羟色胺能药物、毒蕈碱型受体、多巴胺受体的四组药物，相比于安慰剂对患者认知功能都有改善的趋势。按作用受体分类时，每组抗精神病药物都有点小优但不明显某些药物在个别领域表现出较为积极的效果，比如刚才提到的吗茚酮和盐酸硫利达嗪对于SSD患者大脑处理速度的提高。相比于安慰剂，布瑞吡唑在视觉学习方面显示出小幅但显著的积极效果，帕利哌酮在语言学习和工作记忆方面有改善的趋势。研究还评估了患者的生活质量和社会功能，然而整体来看抗精神病药物在这些方面的表现同样有限，未能显著优于安慰剂，而且纳入分析的各项研究中认知评估工具所提供的证据也不明确。药物对具体认知功能的改善效果过去相关的荟萃分析和网络荟萃分析存在时效性不足、新药物的纳入有限、方法学质量较低等限制，并缺乏对抗精神病药物与安慰剂的直接比较。这项研究迄今为止最大的相关领域研究，表明尽管某些药物显示出小幅认知改善，但大多数抗精神病药物的效应较小，且部分药物的结果因样本小而不具备足够的意义，很难区分这些改善是否源于减少思维紊乱等症状。这些结果为临床实践中抗精神病药物的选择提供了有价值的最新见解，同时也强调了统一认知评估标准的重要性，以便未来研究能够更有效地比较不同药物的效果。另外，研究者们呼吁开发新的抗精神病药物，特别是那些针对认知缺陷的新型机制药物，以更好地满足SSDs患者的治疗需求。参考文献：[1]https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2825154本文作者丨张艾迪

临床研究

2024-03-05

·精准药物

含吲哚药物结构与靶点，药理与SAR 研究归纳

吲哚是一种芳香杂环分子，具有一个苯环和一个含氮吡咯环组成的双环结构。吲哚中的氮原子提供一对孤对电子，形成共轭体系，从而稳定了吲哚结构。这对孤电子使吲哚化合物呈现弱碱性(pKa=16.2和pK,=17.6)。由于吡咯环的电子密度相对较高以及氮原子的共轭效应，吲哚可以在其吡咯环的3位发生亲电取代反应(图la)。图 1 (a) 全球有超过70种含有吲哚的合成药物在市场上销售，并被证明具有良好的医疗效果(图1b)。用于治疗的疾病包括糖尿病、癌症、白血病、丙型肝炎、心理障碍和其他临床问题。自2015年起，美国(FDA)专门批准了14种含吲哚药物，其中3种是在2021年批准的(图2)。二氢麦角胺(DHE,1)的化学结构中含有吲哚支架，对头颅血管平滑肌中的5-HT1b受体具有激动活性，治疗偏头痛。昂丹司琼(2)是一种血清素5-HT3受体拮抗剂，用于预防癌症治疗期间和手术后的恶心和呕吐(图3a)。图 3 (a) 双氢麦角胺（1）和昂丹司琼（2）的结构。(b) 双氢麦角胺(1)与其靶点（左）和昂丹司琼(2)与其靶点（右）的关键靶点相互作用。替加色罗(3)在临床相关水平上被认为是5-HT(4)受体的激动剂和5-HT(2B)受体的拮抗剂，其作用之一是使受损的胃肠道运动恢复正常。多拉司琼(4)用于中度致吐的癌症化疗以及术后恶心和呕吐的治疗(图5)。它是一种高效、选择性的血清素5-HT3受体拮抗剂。 Tropisetron（5）可抑制5HT3受体上血清素的活性，从而抑制放疗和化疗引起的呕吐。 Vilazodone(6)是5HT-1A受体的部分激动剂，专门抑制中枢神经系统对血清素的再摄取。在治疗偏头痛急性发作方面，三苯氧胺药物(5-羟色胺受体激动剂)比其他药物更有效、更耐受。这类药物具有起效快、用药时间长、不良反应少等优点。Sumatriptan(7),zolmitriptan(8),naratriptan(9), rizatriptan(10), almotriptan (11), frovatriptan (12), eletriptan (13), 和 oxitriptan (14) 是国外已商业化的曲坦类药物的代表。(图7)。环氧化酶(COX)被称为前列腺素G/H合成酶，而吲哚美辛是一种非特异性的可逆性环氧化酶抑制剂。吲哚美辛(18)属于吲哚-3-乙酸类，其官能团包括对氯苯甲酰基、甲基和甲氧基。它是一种非甾体抗炎药(NSAID), 具有消炎、镇痛和解热的特点(图11a)。 Acemetacin(19)是另一种强效非甾体抗炎药物，由吲哚-3-乙酸衍生而来(图12)。它主要通过酯分解代谢为吲哚美辛。 Etodolac(20)是一种非甾体抗炎药，具有消炎、镇痛和解热作用(图13a)。以前被认为是一种非选择性COX抑制剂，但现在被认为对COX-2的选择性是COX-1的5-50倍。 Carprofen(21)是兽医用作缓解老年犬关节炎症状的辅助疗法的一种非甾体抗炎药，人们认为卡洛芬(21)的作用机制是抑制环氧化酶的活性。帕金森病的药物 Cabergoline(22)是一种长效多巴胺受体激动剂，与D2受体有很强的亲和力，用于治疗高催乳素血症和帕金森综合症(图14a)。 Lisuride(23)可能是某些血清素受体的激动剂,也可能是多巴胺D1受体的拮抗剂。可降低催乳素水平，适量服用可阻止偏头痛，从药理上讲，(23)是还是一种帕金森氏症药物。治疗子宫脱垂的药物甲基麦角新碱(26)是一种麦角生物碱，临床上用于预防和治疗产后和流产后出血(图17)。这种药物与多巴胺D1受体结合，作为一种拮抗剂发挥作用，可增强平滑肌的张力、节奏和节律性收缩的幅度。治疗精神疾病的药物 sertindole（27）是一种抗精神分裂症药物，也是一种苯基吲哚衍生物。临床试验证实，(27)对低水平的多巴胺D2占位具有疗效。治疗神经系统疾病的药物吲哚洛尔(28)是一种非选择性β肾上腺素受体拮抗剂，用于治疗心房颤动、水肿、高血压和室性心动过速。卡维地洛(29)通过阻断β肾上腺素受体防止运动引起的心动过速，它对α-1肾上腺素能受体的作用可使血管平滑肌放松，从而降低外周血管阻力和血压。尼麦角林(30)是一种半合成麦角衍生物，可用于治疗认知功能障碍。这种药剂作为一种选择性α-1A肾上腺素能受体抑制剂用于临床(图20)。治疗生殖系统疾病的药物麦角新碱(32)是一种麦角生物碱，可用于控制妇女的产后和流产后出血。结构与活性关系明确的药物 Tezacaftor(41)属于用于治疗囊性纤维化(CFTR)增效剂。美国食品及药物管理局批准该药与ivacaftor联合用于治疗囊性纤维化(图28a)。该药物可在2至4小时内达到血浆浓度峰值。 2015年2月23日，FDA批准口服去乙酰化酶(DAC)抑制剂Panobinostat(42)用于治疗多发性骨髓瘤(图29a)。(42)在体外与人体血浆蛋白的结合率约为90%,这与其浓度无关。其吲哚环可以通过与Asn645的氢键相互作用为SAR创造一个稳定的框架(图29b)。结构与活性关系不完全明确的药物 Metergoline(52)是一种麦角衍生物，用于治疗女性高催乳素闭经症(图39)。通过靶向钠通道而非5HT受体来抑制钠通道的活性，从而导致泌乳素分泌减少。 Lurbinectedin(53)是一种抗癌天然产物。该药物在化疗中用于治疗转移性小细胞肺癌。Lurbinectedin(53)在临床试验中的治疗反应率和持续时间在2020年获得了加速批准。总体而言，在FDA批准的药物中，含有吲哚环的药物数量在不断增加。在药物分子中引入吲哚砌块也已成为药物化学和药物设计中的一种常见策略。现有的含吲哚药物因其特殊的结构，在抗癌、抗炎和抗病毒等方面具有显著的临床价值。参考文献：DOI: 10.1039/d3md00677h 内容来源于网络，如有侵权，请联系删除。

上市批准放射疗法

100 项与舍吲哚相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D00561	舍吲哚	N05AE03	DB06144

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
精神分裂症	俄罗斯	H. Lundbeck A/S	2008-09-08

未上市

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适应症	最高研发状态	国家/地区	公司	日期
认知	临床3期	美国	H. Lundbeck A/S	2008-03-01

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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


NCT00654706 (Pubmed \| Eur Neuropsychopharmacol)	临床3期	精神分裂症	264	Sertindole	製蓋選築鏇遞夢醖夢選(淵窪積壓窪窪顧願鹽餘) = 選範鹽壓鏇鹹積蓋遞鬱網艱糧鹽艱範鹽築糧蓋 (築觸餘網鹹鏇觸鏇構艱 )	-	2015-03-01
				Quetiapine	製蓋選築鏇遞夢醖夢選(淵窪積壓窪窪顧願鹽餘) = 構鑰糧齋淵鬱繭範蓋選網艱糧鹽艱範鹽築糧蓋 (築觸餘網鹹鏇觸鏇構艱 )
NCT00856583 (SCoP, CTgov)	临床3期	精神分裂症	9,809	Sertindole (Sertindole)	繭範築壓願膚簾壓鬱積(顧衊廠膚製憲鑰膚鏇膚) = 夢鑰顧顧願餘顧鏇製範壓窪衊繭齋顧願鑰顧積 (襯鹽襯蓋襯構鑰範廠夢, 襯糧築簾構衊顧簾窪夢 ~ 繭觸膚鏇顧製淵蓋築獵) 更多	-	2011-08-01
				Risperidone (Risperidone)	繭範築壓願膚簾壓鬱積(顧衊廠膚製憲鑰膚鏇膚) = 鹹顧襯網鹹衊壓蓋壓築壓窪衊繭齋顧願鑰顧積 (襯鹽襯蓋襯構鑰範廠夢, 餘糧淵壓膚鬱願鬱鹽遞 ~ 衊鏇淵鬱餘糧艱製襯網) 更多
NCT00856583 (SCoP, Pubmed \| Eur Arch Psychiatry Clin Neurosci)	临床3期	精神分裂症	261	Sertindole	鏇淵艱顧製鹽鹽齋選窪(蓋鑰網壓構願願膚獵壓) = 願遞選鹽壓鑰簾膚餘鏇顧壓鏇築鏇鬱廠繭鏇積 (鑰艱獵廠願築顧壓顧願 ) 更多	-	2011-06-01
				Risperidone	鏇淵艱顧製鹽鹽齋選窪(蓋鑰網壓構願願膚獵壓) = 遞鏇鹽窪鬱簾糧製觸夢顧壓鏇築鏇鬱廠繭鏇積 (鑰艱獵廠願築顧壓顧願 ) 更多
NCT00856583 (SCoP, Pubmed \| Eur Neuropsychopharmacol)	临床3期	精神分裂症	9,809	Sertindole	餘糧鹹繭廠簾選夢餘糧(壓鏇築網觸簾壓顧壓鑰) = 鹽窪鹹網製廠衊壓餘繭糧顧積蓋廠觸遞夢顧選 (簾製選襯遞淵鹽鬱獵鬱 )	-	2010-12-01
				Risperidone	餘糧鹹繭廠簾選夢餘糧(壓鏇築網觸簾壓顧壓鑰) = 壓鑰壓鏇衊膚積網襯選糧顧積蓋廠觸遞夢顧選 (簾製選襯遞淵鹽鬱獵鬱 )
NCT00856583 (SCoP, Pubmed \| Acta Psychiatr Scand)	临床3期	精神分裂症	9,858	Sertindole	願鹹簾齋糧廠蓋壓選鹽(廠憲鑰鹹窪齋醖餘獵窪): HR = 2.84 (95% CI, 1.45 ~ 5.55), P-Value = 0.0022 更多	-	2010-11-01
				Risperidone