更新于：2024-12-06

Flavoxate Hydrochloride

盐酸黄酮哌酯

更新于：2024-12-06

概要

概要

基本信息

药物类型

小分子化药

别名

2-(1-piperidinyl)ethyl 3-methyl-4-oxo-2-phenyl-4H-chromene-8-carboxylate、2-piperidinoethyl 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate、2-piperidinoethyl 3-methylflavone-8-carboxylate

+ [18]

靶点

ORAI1

作用机制

ORAI1抑制剂(钙离子释放激活钙通道蛋白-1抑制剂)

治疗领域

在研适应症

非在研适应症

原研机构

在研机构

非在研机构

Ortho-McNeil Pharmaceutical LLC

最高研发阶段批准上市

首次获批日期

美国 (1970-01-15),

排尿困难疼痛膀胱过度活动症+ [2]

最高研发阶段(中国)批准上市

特殊审评-

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结构

分子式C24H26ClNO4

InChIKeyXOEVKNFZUQEERE-UHFFFAOYSA-N

CAS号3717-88-2

关联

项与盐酸黄酮哌酯相关的临床试验

CTRI/2024/09/073950 / Not yet recruitingN/AIIT

Effect of oral flavoxate on postoperative catheter related bladder dysfunction in adult males undergoing transurethral resection of bladder tumors- A randomized controlled trial vs solifenacin and placebo - Nil

开始日期2024-09-17

申办/合作机构-

CTRI/2020/04/024700 / CompletedN/A

Single dose oral bioavailability pilot study of two test formulations ofFlavoxate XR Tablet 600 mg, once a day (T1) and Flavoxate XR Tablet800 mg, once a day (T2) and reference formulation of Flavoxate Tablet200 mg, thrice a day (R) in healthy adult male subjects under fastingconditions.

开始日期2020-04-20

申办/合作机构-

JPRN-UMIN000009999 / CompletedN/AIIT

Clinical evaluation of add-on administration of flavoxate hydrochloride in nocturia patients resistant to an anticholinergic agent - Clinical evaluation of add-on administration of flavoxate hydrochloride in nocturia patients

开始日期2013-02-12

申办/合作机构-

100 项与盐酸黄酮哌酯相关的临床结果

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100 项与盐酸黄酮哌酯相关的转化医学

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100 项与盐酸黄酮哌酯相关的专利（医药）

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201

项与盐酸黄酮哌酯相关的文献（医药）

2024-11-01·BMJ medicine

Risk of dementia associated with anticholinergic drugs for overactive bladder in adults aged ≥55 years: nested case-control study

Article

作者: Dening, Tom ; Ashcroft, Darren M ; Orrell, Martin William ; Iyen, Barbara ; Coupland, Carol ; Bell, Brian Gregory ; Bishara, Delia ; Avery, Anthony J

Objective:

To investigate whether different anticholinergic drug treatments for overactive bladder have differential risks for incident dementia, in a large representative population of older adults in England.

Design:

Nested case-control study.

Setting:

General practices in England providing data to the Clinical Practice Research Datalink (CPRD) GOLD database, with linked patient admission records from secondary care (Hospital Episode Statistics), 1 January 2006 and 16 February 2022

Participants:

170 742 patients aged ≥55 years, with a first reported diagnosis of dementia during the study period, matched by age, sex, and general practice with 804 385 individuals without dementia (controls).

Interventions:

Cumulative drug use (defined using total standardised daily dose) of different anticholinergic drugs used for the treatment of an overactive bladder, and a non-anticholinergic drug, mirabegron, in the period 3-16 years before a diagnosis of dementia (or equivalent date in matched controls).

Main outcome measures:

Odds ratios for onset of dementia associated with the different anticholinergic drugs used for the treatment of an overactive bladder, adjusted for sociodemographic characteristics, clinical comorbidities, and use of other anticholinergic drug treatments.

Results:

The study population comprised 62.6% women, and median age was 83 (interquartile range 77-87) years. 15 418 (9.0%) patients with dementia and 63 369 (7.9%) controls without dementia had used anticholinergic drugs for the treatment of an overactive bladder in the 3-16 years before diagnosis (or equivalent date for controls). The adjusted odds ratio for dementia associated with the use of any anticholinergic drug used to treat an overactive bladder was 1.18 (95% confidence interval (CI) 1.16 to 1.20), and was higher in men (1.22, 1.18 to 1.26) than women (1.16, 1.13 to 1.19). The risk of dementia was substantially increased with the use of oxybutynin hydrochloride (adjusted odds ratio 1.31, 95% CI 1.21 to 1.42 and 1.28, 1.15 to 1.43 for use of 366-1095 and >1095 total standardised daily doses, respectively), solifenacin succinate (1.18, 1.09 to 1.27 and 1.29, 1.19 to 1.39), and tolterodine tartrate (1.27, 1.19 to 1.37 and 1.25, 1.17 to 1.34). No significant increases in the risk of dementia associated with darifenacin, fesoterodine fumarate, flavoxate hydrochloride, propiverine hydrochloride, and trospium chloride were found. The association between mirabegron, a non-anticholinergic drug, and dementia was variable across the dose categories and might be caused by previous use of anticholinergic drugs for the treatment of an overactive bladder in these individuals.

Conclusions:

Of the different anticholinergic drugs used to treat an overactive bladder, oxybutynin hydrochloride, solifenacin succinate, and tolterodine tartrate were found to be most strongly associated with the risk of dementia in older adults. This finding emphasises the need for clinicians to take into account the possible long term risks and consequences of the available treatment options for an overactive bladder in older adults, and to consider prescribing alternative treatments that might be associated with a lower risk of dementia.

2024-09-01·Heliyon

Probing N-substituted 4-(5-mercapto-4-ethyl-4H-1,2,4-triazol-3-yl)-N-phenylpiperdine-1-carboxamides as potent 15-LOX inhibitors supported with ADME, DFT calculations and molecular docking studies

Article

作者: Muzaffar, Saima ; Riaz, Naheed ; Ashraf, Muhammad ; Bilal, Muhammad Sajjad ; Prabhala, Bala Krishna ; Nawaz, Zahid ; Saleem, Muhammad ; Sajid, Salvia ; Ejaz, Syeda Abida ; Bashir, Bushra ; Iqbal, Ambar ; Rehman, Aziz-ur ; Rehman, Aziz-Ur

In our continuous efforts to find out leads against the enzyme 15-lipoxygenase (15-LOX), the current study deals with the synthesis of a series of new N-alkyl/aralkyl/aryl derivatives of 2-(4-ethyl-5-(1-phenylcarbamoyl)piperidine-4H-1,2,4-triazol-3-ylthio)methylacetamide (7a-n) with anti-LOX activities. The synthesis was started by reacting phenylisocyanate with isonipecotate that sequentially converted into N-substituted ester (1), hydrazide (2), semicarbazide (3) and N-ethylated 5-(1-phenylcarbamoyl)piperidine-1,2,4-triazole (4). The final compounds, 7a-n, were obtained by reacting 4 with various N-alkyl/aralkyl/aryl electrophiles. Both the intermediates and target compounds were characterized by FTIR, ¹H, ¹³C NMR spectroscopy, EI-MS and HR-EI-MS spectrometry and screened against soybean 15-LOX by chemiluminescence method. The eight compounds 7e, 7j, 7h, 7a, 7g, 7b, 7n, 7c showed potent inhibitory activities against 15-LOX with values ranging from IC₅₀ 0.36 ± 0.15 μM (7e) to IC₅₀ 6.75 ± 0.17 μM (7c) compared with the reference quercetin (IC₅₀ 4.86 ± 0.14 μM) and baicalein (IC₅₀ 2.24 ± 0.13 μM). Two analogues (7l, 7f) had significantly outstanding inhibitory potential with IC₅₀ values 12.15 ± 0.23 μM and 15.54 ± 0.26 μM, whereas, the derivatives 7i, and 7d displayed IC₅₀ values of 21.56 ± 0.27 μM, 23.59 ± 0.24 μM and the compounds 7k, 7m were found inactive. All analogues exhibited blood mononuclear cells (MNCs) viability >75 % at 0.25 mM concentration as determined by MTT method. Calculated pharmacokinetic properties projected good lipophilicity, bioavailability and drug-likeness properties and did not violate Lipinski's/Veber rule. Molecular docking studies revealed lower binding free energies of all the derivatives than the reference compounds. The binding free energies were -9.8 kcal/mol, -9.70 k/mol and -9.20 kcal/mol for 7j, 7h and 7e, respectively, compared with the standard quercetin (-8.47 kcal/mol) and baicalein (-8.98 kcal/mol). The docked ligands formed hydrogen bonds with the amino acid residues Gln598 (7e), Arg260, Val 126 (7h), Gln762, Gln574, Thr443, Arg580 (7j) while other hydrophobic interactions observed therein further stabilized the complexes. The results of density functional theory (DFT) revealed that analogues with more stabilized lower unoccupied molecular orbital (LUMO) had significant enzyme inhibitory activity. The data collectively supports these molecules as leads against 15-LOX and demand further investigations as anti-inflammatory agents.

2024-03-01·European urology focus

Risks of Dementia After Treatment with an Anticholinergic, Beta-3 Agonist, or Combination of Both for an Overactive Bladder: A Korean National Cohort Study

Article

作者: Choi, Soo Beom ; Ham, Won Sik ; Kim, Jongchan ; Park, Jee Soo ; Jang, Won Sik

BACKGROUND AND OBJECTIVE:

An overactive bladder (OAB) is primarily managed with behavioural therapy and using anticholinergics and beta-3 agonists. Reports have shown that the use of anticholinergics by OAB patients was associated with an increased risk of new-onset dementia compared with those using beta-3 agonists. This study compares the risks of dementia among patients with an OAB starting on a beta-3 agonist alone, an anticholinergic alone, or a combination treatment.

METHODS:

Using data from the Korean National Health Insurance Service database, we studied a nationwide population cohort comprising patients newly diagnosed with an OAB who initiated their OAB medications between 2015 and 2020. The treatment types were categorised as anticholinergics (oxybutynin, solifenacin, tolterodine, trospium, fesoterodine, flavoxate, and propiverine) alone, a beta-3 agonist (mirabegron) alone, and combination therapy (an anticholinergic plus the beta-3 agonist). To evaluate the impact of cumulative drug exposure, we quantified the cumulative exposure to solifenacin and mirabegron as cumulative defined daily doses (cDDDs) using proportional hazards regression analyses, adjusted for factors known to be associated with dementia.

KEY FINDINGS AND LIMITATIONS:

Among the study's 3 452 705 patients, 671 974 were new users of a beta-3 agonist alone (19.5%), 1 943 414 new users of anticholinergics alone (56.3%), and 837 317 receiving combination therapy (24.3%). The most common anticholinergic used both alone and as part of a combination treatment was solifenacin (42.9% and 56.3%, respectively). There was an increased risk of dementia between the users of an anticholinergic alone (adjusted hazard ratio [aHR] = 1.213; 95% confidence interval [CI], 1.195-1.232) and those taking a combination treatment (aHR = 1.345; 95% CI, 1.323-1.366) compared with the users of beta-3 agonists alone after the adjustment of covariates. However, the incidence of dementia was also significantly higher, with an increase in the cumulative dose of mirabegron (aHR = 1.062 [1.021-1.106] for 28-120 cDDDs and aHR = 1.044 [1.004-1.084)] for patients who received >121 cDDDs compared with those who received <27 cDDDs). A marked increased risk of dementia was associated with the use of solifenacin, tolterodine, fesoterodine, and propiverine, both separately and in combination with mirabegron.

CONCLUSIONS AND CLINICAL IMPLICATIONS:

In this large Korean cohort, the use of anticholinergics with or without a beta-3 agonist increased the risk of new-onset dementia compared with the use of a beta-3 agonist alone. Given that the risk of dementia was most significantly elevated with combination treatments, care should be taken when considering combination treatment for OAB patients with risk factors for dementia. Furthermore, there could be a possible association between beta-3 agonists and dementia, although future studies are needed.

PATIENT SUMMARY:

This study investigated the risk of dementia induced by overactive bladder (OAB) treatment in a large Korean cohort. Two representative OAB treatment drugs, anticholinergics and beta-3 agonists, both increased the risk of new-onset dementia. Clinicians should be cautious in using OAB treatment drugs since no drugs could be concluded as safe.

项与盐酸黄酮哌酯相关的新闻（医药）

2024-04-10

·CPHI制药在线

勃林格殷格翰反常裁员背后的不安

关注并星标CPHI制药在线1. 勃林格殷格翰裁员背后的推手勃林格殷格翰裁员了。裁员在譬如朝露的制药行业本是稀松平常的事情，但勃林格殷格翰的裁员有些特别。收到裁员通知的不是最常见的研发人员，而是他们美国市场的销售人员，而且是负责修美乐生物类似药Cyltezo的销售人员，这背后透露出的信息就并非普通裁员本身那么简单了。勃林格殷格翰表示，计划在 6 月 30 日之前减少面向客户的销售团队，转而采用面对面和虚拟混合销售模式。勃林格殷格翰全球拥有53000名员工，但他们并没有提供裁员人数的详细信息，据称受到影响的人数达到70人以上。勃林格殷格翰下岗的那些销售人员，并非败在他们的能力之上，而是输给了修美乐坚不可摧的市场占有率。在美国市场上市二十年后，修美乐从2023年1月份开始陆续受到上市生物类似药的挑战。勃林格殷格翰的Cyltezo便是其中之一，而且是"特别的那个"。Cyltezo 是第一款获得"可互换性"头衔的修美乐生物类似药，无需医生许可即可在药房柜台替代修美乐，因此它比大多数其他生物类似药具有更好的竞争"段位"。生物类似药最受行业关注的热点，在于它们的问世是否能够有效降低品牌生物制剂的高昂价格。自 2003 年推出以来，修美乐的价格在 20 年内上涨了 470%，如今已经攀升到了每年达到 8.4万美元以上。相对而言，生物类似药的最低标价比其便宜85%。根据 IQVIA 的数据，勃林格殷格翰去年 7 月推出了 Cyltezo，但此后总共只销售了 1487 份处方药。而同期修美乐的处方量接近 280 万份。勃林格殷格翰的品牌和非品牌版本修美乐生物类似药的定价比修美乐每月6922美元的标价分别低5%和81%，但仍然乏人问津。瑞士制药商山德士的修美乐生物类似药Hyrimoz，其价格与勃林格殷格翰和安进（Amjevita）相当。美国最大的两家 PBM ，UnitedHealth Group 的 Optum Rx 和 Cigna 的 Express Scripts 去年选择将 Cyltezo 与 Humira、Hyrimoz 和 Amjevita 一起纳入其保险报销清单。 2. 修美乐生物类似药火不起来的原因尽管坐拥巨大的节约成本能力，但医疗保险计划提供者一直以来对这些修美乐类似药采取的都是"若即若离"的温吞水态度，既不拒绝也不敞开接受。根据 IQVIA 的数据，截至去年 11 月，生物类似药仅占阿达木单抗销售额的 1%（图1），而在各个适应症下的新患者中，生物仿制药占比约为2%。图1. 修美乐生物类似药市场占有率与其它生物类似药对比。（图片来源：IQVIA）制药行业将修美乐生物仿制药的不佳市场吸收度归咎于药品流通的中间环节。由于美国复杂的政策原因，药品福利管理者（PBM）从修美乐身上赚到的钱比生物类似药赚的钱更多，因此作为决定处方集的重要角色，药品福利管理者可以动用手腕，通过为品牌修美乐提供更好的处方集地位来实现它的长久不衰，而自己也可以"桃李不言，下自成蹊”，收获更多的回扣收入。勃林格殷格翰发言人对此表示："在很大程度上，由于复杂环境以及一些PBM仍将修美乐保留在处方集，修美乐生物类似药的大规模采用尚未达到预期的潜力。因此，我们决定在 2024 年 6 月 30 日之前精简面向客户的销售团队，转而采用面对面和虚拟混合模式。" PBM对于修美乐"本乐"和修美乐"类似乐"在处方集中的位置抉择，将对这个庞大的市场产生无比重要的作用，但问题处在这些决策者的地位上。作为能够裁决生物品牌药和生物类似药的"裁判员"，PBM同时参与了利润的瓜分，可想而知他们能否天下为公地做出决策。值得注意的是，2024 年，美国三大PBM：Caremark (CVS Health)、Express Scripts (Cigna) 和 OptumRx (United Health Group) 从其标准处方集中排除了 600 种以上的药物。但修美乐并不在名单整饬的行列内，相反，其段位得到了提高。目前美国市场上有 14 种阿达木单抗生物类似药版本。其中 7 种产品的WAC (批发采购成本，即标价)仅略低于修美乐的标价，而剩下的7 种的WAC 则比修美乐大幅降低（便宜55%到86%）。九家制造商中有四家提供高价和低价两种版本。图2系统显示了这些类似药的WAC和PBM处方集信息。图2. 修美乐生物类似药种类、WAC以及处方集信息。（图片来源：Drug Channels Institute）从图2中可以看出，不是所有的修美乐生物类似药都可以被PBM们列入他们敲定的处方集。在这种游戏中举步维艰的勃林格殷格翰其实已经算得上赢家了，但处方量和销售额仍然无法对修美乐产生实质性的威胁。图3显示了修美乐WAC (批发采购成本，6922美元/月) 和净价格（2192美元/月）相对于生物类似药的水平。可以看出，无论是WAC还是净价格，修美乐都明显比生物类似药高出很多。图3. 修美乐与其生物类似药WAC和净价格对比图。（图片来源：IQVIA）图4. 销售量前五名修美乐生物类似药的PBM覆盖情况对比图。（图片来源：IQVIA）从图4中可以看出，大多数销量最高的修美乐生物类似药都是由较小的PBM推动的，他们可以从低成本、无回扣的选择中获得更多收益。大型 PBM 更喜欢修美乐品牌生物制剂，背后的道理就是前面提到的高价格下的回扣。能否被大型PBM青睐并在其处方集中为其安排一个"体面"的位置，是这些修美乐生物类似药能否抢夺修美乐市场的关键因素。一个值得注意的现象是，在那些在首次尝试获得修美乐生物类似药处方的患者中，只有三分之一的人在30天内成功得到了药物。其漫漫求药路上的各种障碍（图5）也成为了阻滞修美乐生物类似药市场吸收的不可忽略的因素。图5. 修美乐处方无法获得药物的情况。（图片来源：IQVIA） 3. 拯救修美乐生物类似药的意义生物类似药无法大行其道，对于医疗保险领域和患者本人都将造成巨大的成本压力。自推出生物仿制药以来持续使用修美乐品牌生物制剂的行为，导致患者、雇主和健康计划每月花费高达约 7 亿美元（图6）。与低价（WAC每月约1000 美元，图3）修美乐生物类似药相比，每个修美乐处方的额外成本高达 1300 美元以上（图3）。自修美乐生物类似药2023年1月份推出以来的前 11 个月内，持续使用修美乐生物制剂已造成近 60 亿美元的成本损失（图6）。图6. 修美乐生物类似药无法占据市场所导致的成本损失走势图。（图片来源：IQVIA）图7最好地诠释了修美乐生物类似药市场占有率提高的最大赢家将是保险提供者和患者本身。专业药店： • 有利因素：生物类似药可以使其出售药品价格降低，降低DIR (直接和间接再定价) 费用。DIR是针对药品支付者（如药房）的费用。这些费用通常由药品计划或药品支付者收取，体现药房与制药商之间的交易和协商。DIR费用可以根据多种因素而变化，包括处方数量、药品的销售价格、药房的绩效等。这些费用可能会影响药品价格、药房的经营成本以及消费者的支付金额。 • 不利因素：降低药品报销。在这里药品报销指的是医疗保险公司或其他支付者为医疗保健服务中使用的药物提供支付的过程。涉及到支付者向药房提供资金，以覆盖药物的成本。药物报销通常根据医疗保险计划的政策和规定来进行，这可能包括对特定药物的限制、要求先获得预授权、药物价格限制等。 PBM • 有利因素：可以降低药品报销额度，降低支付专业药店的费用。 • 不利因素：回扣降低，由WAC和将价格之间差异导致的利润将大大流失。政府和雇主保险计划 • 有利因素：降低药物成本、缩减PBM盘剥。 • 不利因素：无患者 • 有利因素：降低共付款。患者在购买药物或接受医疗服务时需要支付的固定金额。共付款通常是根据医疗保险计划的规定和药物的定价来确定的，而且可能会因不同的药物或医疗服务而有所不同。共付款是医疗费用的一部分，患者在享受医疗保险计划的同时需要承担一部分费用。 • 不利因素：无图7. 生物类似药利益影响图。（图片来源：IQVIA） Ref. Boehringer to lay off salespeople as Humira biosimilar sales lag. Market Screener. 04. 04. 2024. Wilkerson, J. Boehringer Ingelheim layoffs are a sign of dysfunctional Humira biosimilar market. STAT. 04. 04. 2024. Fein, A. J. The Big Three PBMs' 2024 Formulary Exclusions: Biosimilar Humira Battles, CVS Health's Weird Strategy, and the Insulin Shakeup (rerun). Drug Channels Institute. 03. 04. 2024. Adalimumab Biosimilar Tracking Q1 Readout. IQVIA. 02. 04. 2024.【智药研习社近期课程预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

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100 项与盐酸黄酮哌酯相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D00718	盐酸黄酮哌酯	G04BD02	DB01148

研发状态

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
尿道疾病	中国	浙江康恩贝制药股份有限公司	1995-01-01
排尿困难	美国	Ortho-McNeil Pharmaceutical LLC	1970-01-15
疼痛	美国	Ortho-McNeil Pharmaceutical LLC	1970-01-15
膀胱过度活动症	美国	Ortho-McNeil Pharmaceutical LLC	1970-01-15
尿失禁	美国	Ortho-McNeil Pharmaceutical LLC	1970-01-15
急迫性尿失禁	美国	Ortho-McNeil Pharmaceutical LLC	1970-01-15