盐酸吗茚酮(Molindone hydrochloride) - 药物靶点：D2 receptor_在研适应症：精神分裂症_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Molindone、Molindone XR、Molindone hydrochloride (USP)

+ [7]

靶点

D2 receptor

作用机制

D2 receptor拮抗剂(多巴胺D2受体拮抗剂)

治疗领域

其他疾病

在研适应症

精神分裂症

非在研适应症

攻击注意缺陷障碍伴多动品行障碍

原研机构

Strides Pharma Global Pte Ltd.

在研机构

Epic Pharma LLC

非在研机构

Supernus Pharmaceuticals, Inc.CHARTWELL RX SCIENCES LLC

最高研发阶段批准上市

首次获批日期

美国 (1974-01-18),

精神分裂症

最高研发阶段(中国)-

特殊审评-

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结构

分子式C16H24N2O2

InChIKeyKLPWJLBORRMFGK-UHFFFAOYSA-N

CAS号7416-34-4

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关联

10

项与盐酸吗茚酮相关的临床试验

NCT03638466 / Terminated临床2期

Exploratory Neuroimaging Study to Evaluate the Effect on Brain Activity of SPN-810 for Impulsive Aggression (IA) in Patients With Attention-Deficit/Hyperactivity Disorder (ADHD) in Conjunction With Standard ADHD Treatment

The purpose of this study is to evaluate the effect of 4-week SPN-810 treatment on brain functioning in patients aged 8-12 years with ADHD and associated feature of impulsive aggression (IA). This will be achieved using functional magnetic resonance imaging (fMRI) in conjunction with the point subtraction aggression paradigm (PSAP) Task, a behavioral aggression paradigm in which subjects are provoked by having money indirectly taken from them by a fictitious opponent, simulating an aggression response.

开始日期2019-05-30

申办/合作机构

Supernus Pharmaceuticals, Inc.

NCT03597503 / Terminated临床3期

Assessment of Efficacy and Safety of SPN-810 for the Treatment of Impulsive Aggression (IA) in Adolescent Subjects With Attention Deficit/Hyperactivity Disorder (ADHD) in Conjunction With Standard ADHD Treatment

The purpose of this study was to evaluate the effect of SPN-810 for the treatment of impulsive aggression (IA) in adolescents diagnosed with ADHD when taken in conjunction with standard ADHD treatment.

开始日期2018-07-31

申办/合作机构

Supernus Pharmaceuticals, Inc.

NCT02691182 / Terminated临床3期

Open-Label Extension Study to Evaluate the Long-Term Safety of Molindone Hydrochloride Extended-Release Tablets for the Treatment of Impulsive Aggression in Pediatric and Adolescent Subjects With Attention Deficit/Hyperactivity Disorder (ADHD) in Conjunction With Standard ADHD Treatment

Children between the ages of 6-12 years who are diagnosed with impulsive aggression comorbid with ADHD and have participated in the 810P301 or 810P302 study were invited to participate in this study. This was a Phase 3 open-label extension (OLE) study to collect long-term safety data on the use of SPN-810 in treating impulsive aggression in pediatric subjects with ADHD when taken in conjunction with standard ADHD treatment. After confirmation of eligibility, all subjects were treated with SPN-810. Subjects were given a choice to extend participation in this study every 6 months for up to 36 months.

开始日期2016-04-01

申办/合作机构

Supernus Pharmaceuticals, Inc.

100 项与盐酸吗茚酮相关的临床结果

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100 项与盐酸吗茚酮相关的转化医学

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100 项与盐酸吗茚酮相关的专利（医药）

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25

项与盐酸吗茚酮相关的文献（医药）

2021-09-01·Journal of Attention Disorders2区 · 医学

A Double-Blind, Randomized Study of Extended-Release Molindone for Impulsive Aggression in ADHD

2区 · 医学

Article

作者: Findling, Robert L. ; Liranso, Tesfaye ; Schwabe, Stefan ; Xu, Jiahong ; Adewole, Toyin ; Nasser, Azmi ; Ceresoli-Borroni, Gianpiera

Objective: To evaluate efficacy and safety of SPN-810 (extended-release molindone) in a Phase-2b, randomized, double-blind, placebo-controlled, dose-ranging study of children (6–12 years) with ADHD and persistent impulsive aggression (IA). Method: After lead-in, children were randomized to (a) placebo ( N = 31); (b) low-dose ( N = 29, 12/18 mg/day); (c) medium-dose ( N = 30, 24/36 mg/day); and (4) high-dose ( N = 31, 36/54 mg/day) groups. Treatment included ~2.5-week titration, 3-week maintenance, and 1-week tapering/conversion, alongside existing monotherapy (stimulants/nonstimulants) and behavioral therapy. The primary endpoint was change in Retrospective-Modified Overt Aggression Scale (R-MOAS) score at end of study, with safety monitored. Results: A total of 95 (78.5%) children completed the study. Aggression (R-MOAS) improved with low and medium doses (low dose: p = .031; medium dose: p = .024; high dose: p = .740). The most common adverse events were headache (10.0%), sedation (8.9%), and increased appetite (7.8%). Conclusion: These results suggest SPN-810 may be effective in reducing residual IA behaviors in children with ADHD. Research is still needed to support the benefit–risk profile of SPN-810 in pediatric populations.

2017-06-13·Toxicology Mechanisms and Methods4区 · 医学

Toxicity assessment of molindone hydrochloride, a dopamine D2/D5 receptor antagonist in juvenile and adult rats

4区 · 医学

Article

作者: Gopalakrishnan, Gopa ; Krishna, Gopala ; Goel, Saryu

Neuroleptic drug molindone hydrochloride is a dopamine D2/D5 receptor antagonist and it is in late stage development for the treatment of impulsive aggression in children and adolescents who have attention deficient/hyperactivity disorder (ADHD). This new indication for this drug would expand the target population to include younger patients, and therefore, toxicity assessments in juvenile animals were undertaken in order to determine susceptibility differences, if any, between this age group and the adult rats. Adult rats were administered molindone by oral gavage for 13 weeks at dose levels of 0, 5, 20, or 60 mg/kg-bw/day. Juvenile rats were dosed for 8 weeks by oral gavage at dose levels of 0, 5, 25, 50, or 75 mg/kg-bw/day. Standard toxicological assessments were made using relevant study designs in consultation with FDA. Treatment-related elevation in serum cholesterol and triglycerides and decreases in glucose levels were observed in both the age groups. Organ weight changes included increases in liver, adrenal gland and seminal vesicles/prostate weights. Decreases in uterine weights were also observed in adult females exposed to the top two doses with sufficient exposure. In juveniles, sexual maturity parameters secondary to decreased body weights were observed, but, were reversed. In conclusion, the adverse effects noted in reproductive tissues of adults were attributed to hyperprolactinemia and these changes were not considered to be relevant to humans due to species differences in hormonal regulation of reproduction. On the whole, there were no remarkable differences in the toxicity profile of the drug between the two age groups.

2016-05-01·Environmental and Molecular Mutagenesis3区 · 环境科学与生态学

In vitro and in vivo genotoxicity assessment of the dopamine receptor antagonist molindone hydrochloride

3区 · 环境科学与生态学

Article

作者: Gopalakrishnan, Gopa ; Krishna, Gopala ; Goel, Saryu

Molindone hydrochloride is a dihydroindolone neuroleptic with dopamine D2 and D5 receptor antagonist activity. As an integral component of its preclinical safety evaluation, molindone hydrochloride was evaluated in a series of in vitro and in vivo genetic toxicology assays. In the bacterial reverse gene mutation assays employing four Salmonella tester strains (TA98, TA100, TA1535, and TA1537) and the E. coli tester strain WP2uvrA, molindone hydrochloride was negative in all strains, except TA100, in which it induced a positive response (up to 3‐fold) in the presence of rat liver S9. With human S9, a small (2‐fold), but nonreproducible, increase in revertants was observed in TA100 at the highest concentration of molindone tested (5,000 µg/plate). The mutagenicity was completely abrogated by the addition of glutathione and UDP‐glucuronic acid to rat liver S9, suggesting detoxification of the mutagenic metabolite(s) by Phase II conjugation reactions, pathways commonly operational in humans. Molindone hydrochloride did not induce chromosomal aberrations in human lymphocyte cultures, did not elicit a positive response in a rat bone marrow micronucleus test for clastogencity/aneugenicity, and did not give a positive response in the rat liver comet assay for DNA damage. Collectively, the weight of evidence from these studies, combined with a large margin of safety and efficient detoxification through Phase II conjugation supports the interpretation that molindone hydrochloride does not pose a genotoxic risk to humans at the anticipated clinical dose levels. Environ. Mol. Mutagen. 57:288–298, 2016. © 2016 Wiley Periodicals, Inc.

1

项与盐酸吗茚酮相关的新闻（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

100 项与盐酸吗茚酮相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D00796	盐酸吗茚酮	N05AE02	DB01618

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	美国	Epic Pharma LLC	2015-03-20

未上市

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适应症	最高研发状态	国家/地区	公司	日期
注意缺陷障碍伴多动	临床3期	美国	Supernus Pharmaceuticals, Inc.	2016-01-25
品行障碍	临床3期	美国	Supernus Pharmaceuticals, Inc.	2008-09-01
攻击	临床2期	美国	Supernus Pharmaceuticals, Inc.	2018-07-31
注意缺陷障碍伴多动	临床2期	美国	Supernus Pharmaceuticals, Inc.	2016-01-25

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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


NCT02691182 (CTgov)	临床3期	注意缺陷障碍伴多动	491	SPN-810 (<18 mg SPN-810)	獵醖築築網選遞築顧鑰(築鑰糧繭鑰願鹽蓋衊網) = 觸齋顧築鏇膚鬱鏇鬱餘繭積憲構遞積獵齋鬱衊 (簾積範製鬱夢願鹽簾積, 餘鑰遞鬱餘築鏇選衊衊 ~ 選遞遞製夢膚憲觸襯製) 更多	-	2024-05-16
				SPN-810 (18 mg to < 24 mg SPN-810)	獵醖築築網選遞築顧鑰(築鑰糧繭鑰願鹽蓋衊網) = 願選憲選鏇鬱築製鏇遞繭積憲構遞積獵齋鬱衊 (簾積範製鬱夢願鹽簾積, 糧積餘廠製鑰醖鏇廠願 ~ 膚蓋窪遞願願積憲構憲) 更多
NCT02618434 (CTgov)	临床3期	注意缺陷障碍伴多动	297	Placebo (Placebo)	淵顧衊憲選積壓簾膚積(積廠壓願艱鏇淵觸鬱製) = 遞廠鹹夢衊窪鏇繭衊鹹壓窪膚憲獵鬱衊構蓋襯 (築鹹衊鏇壓憲鹽廠構選, 顧遞繭鏇衊夢構簾顧蓋 ~ 網繭壓簾遞憲膚膚憲繭) 更多	-	2024-03-18
				SPN-810 (36 mg) (High Dose SPN-810 (36 mg))	淵顧衊憲選積壓簾膚積(積廠壓願艱鏇淵觸鬱製) = 願積衊構糧艱壓積顧襯壓窪膚憲獵鬱衊構蓋襯 (築鹹衊鏇壓憲鹽廠構選, 願鏇廠積積淵鹽艱遞齋 ~ 顧憲獵鹹遞蓋鑰遞襯鏇) 更多
NCT03597503 (CTgov)	临床3期	攻击 \| 注意缺陷障碍伴多动	41	Placebo (Placebo)	衊襯蓋鹽壓壓糧壓艱蓋(糧醖壓遞選簾願鬱築淵) = 鑰簾範鬱齋網鹽鑰遞蓋憲窪糧遞襯獵廠獵夢夢 (鹹觸積鹹醖觸積醖襯製, 繭積簾蓋積鏇鬱簾鹹鏇 ~ 憲顧鏇糧構構襯鏇憲繭) 更多	-	2024-02-20
				SPN-810 (Flexible Dose of SPN-810)	衊襯蓋鹽壓壓糧壓艱蓋(糧醖壓遞選簾願鬱築淵) = 築衊鏇艱觸衊醖壓構築憲窪糧遞襯獵廠獵夢夢 (鹹觸積鹹醖觸積醖襯製, 簾襯築齋獵築膚製繭製 ~ 鹽簾築製選夢顧鏇積艱) 更多
NCT02618408 (CTgov)	临床3期	注意缺陷障碍伴多动	333	Placebo (Placebo)	遞構簾獵齋憲壓鏇遞積(艱糧網鹽選壓廠網廠獵) = 齋範選蓋廠憲艱膚選憲選鹹蓋醖願築鏇築廠繭 (顧壓憲鹹襯繭憲廠築淵, 鏇衊齋鏇艱選廠襯鑰餘 ~ 齋鹹顧繭蓋衊糧顧網廠) 更多	-	2022-11-01
				SPN-810 (18 mg) (Low Dose SPN-810 (18 mg))	遞構簾獵齋憲壓鏇遞積(艱糧網鹽選壓廠網廠獵) = 製簾鹽糧醖鑰醖衊衊憲選鹹蓋醖願築鏇築廠繭 (顧壓憲鹹襯繭憲廠築淵, 網壓餘夢製鏇壓齋夢範 ~ 廠鑰衊簾鏇壓鬱構醖構) 更多
NCT00053703 (TEOSS, CTgov)	临床4期	精神分裂症	116	Olanzapine (enrollment closed in this treatment) (Olanzapine)	憲觸醖廠鹽廠範觸獵壓(遞遞壓製觸製襯簾餘遞) = 顧糧衊製鹽鏇積廠觸艱願憲鏇願鹹製獵憲憲糧 (蓋廠鹽鬱蓋選醖淵鏇壓, 餘製膚鏇夢衊憲鏇鹽願 ~ 壓醖鬱獵壓遞遞網夢壓) 更多	-	2014-03-26
				risperidone (Risperidone)	憲觸醖廠鹽廠範觸獵壓(遞遞壓製觸製襯簾餘遞) = 壓艱築願觸鏇齋顧齋鏇願憲鏇願鹹製獵憲憲糧 (蓋廠鹽鬱蓋選醖淵鏇壓, 齋鏇繭網網鏇製鏇憲憲 ~ 構顧齋鑰鏇願積獵獵鏇) 更多