Pirenzepine Hydrochloride

关注并星标CPHI制药在线近视是一种屈光不正的现象，当眼在调节放松状态下，平行光线进入眼内，其聚焦在视网膜之前，导致视网膜上不能形成清晰像。目前，近视已成为全球关注的公共卫生问题，据统计目前全球近视人数约26亿，而我国近视人群人数多达7亿。预计到2050年，全球近视人群将达49.49亿人，患病率为52%。近视一旦发生便不可逆，若不加以控制，很多近视会发展成高度近视甚至超高度近视，从而增加近视相关性眼底疾病的风险，引起更严重的视力损害甚至失明。预防近视的发生、延缓近视的进展以及近视的治疗对改善全球近视现状非常重要。近视的预防近视的预防，可以从以下几点做起：（1）注意用眼时间和姿势；（2）进行适当的锻炼；（3）注意眼睛的营养；（4）增加户外运动时间。此外，低浓度的阿托品也可以用来预防近视。一项对于年龄在6-12岁等效球镜为+1.00D和-1.00D的儿童群体的回顾性队列研究中发现，经过12个月随访，接受0.025%阿托品治疗组中仅有21%的儿童发生了近视，而不接受阿托品的研究组中有54%的儿童发生了近视。近视进展的延缓目前，针对延缓近视进展的研究比较多，如角膜塑形镜（OK镜）、低浓度阿托品滴眼液、双焦或多焦眼镜、角膜接触镜、欠矫等。角膜塑形镜，全称塑形用硬性角膜接触镜，俗称OK镜，采用一种与角膜表面几何形态相逆反的特殊设计，通过戴镜产生的机械力学及流体力学作用，对角膜实施合理的、可调控的、可逆的程序化塑形，改变角膜的屈光力，从而达到矫正近视的作用。此外，大量国内外的学术和临床应用数据均显示OK镜可以有效延缓近视的发展。目前，OK镜已被列入国家卫健委2018年6月发布的《近视防控指南》和2019年10月发布的《儿童青少年近视防控适宜技术指南》。来自：爱博医疗招股书截至目前，国内已有十余款OK镜获批上市。据NMPA官网，国内获批准上市OK镜的国产厂家包括欧普康视、爱博医疗、天津视达佳、浙江天瞳以及北京博视顿，进口OK镜厂家包括亨泰光学、美国欧几里德、C&E、 Paragon、日本 Alpha、韩国 Lucid、荷兰 Procornea 和鹰视有限公司等厂商。其中欧普康视的梦戴维于2005年获批上市，是首款获批的国产OK镜产品。爱博医疗的普诺瞳于2019年正式上市。2021年3月，昊海生科以2500万元的投资总额总计取得亨泰视觉55%的股权，通过亨泰视觉获得高端角膜塑形镜产品“迈儿康myOK”在中国大陆地区10年的独家经销权（截至2030年12月31日）。据智研咨询发布的《2022-2028年中国角膜塑形镜（OK镜）行业运行态势分析及市场潜力报告》显示，2020年我国OK镜市场规模为106.62亿元，2021年市场规模增长至125.32亿元，2012年至2021年的市场规模年均复合增速达24.8%。市场格局上，据东莞证券数据，2021年国内OK镜销量约300万片出头，其中欧普康视销量为63.4万片（收入近7亿），排名国内第一，市占率约20％（2019年欧普的市占率约30％）；2021年，爱博医疗全年累计售出OK镜（含试戴片）超21.52万片，产生收入约1.07亿。然而，目前OK镜在国内的市场渗透率仅为1.80%，远低于美国的3.5%。而OK镜的低市场渗透率与其居高不下的价格有关。据悉，目前市面上一副国产OK镜的终端销售价格大概在6000元至1.5万元之间，进口品牌价格的再1万元至1.5万元之间，每1.5-2年更换一副。加上配套使用的冲洗液、护理液等，一年下来费用可达到2万元。但据国盛证券发布的研报，OK镜的出厂价格仅为终端价格的10%-20%。不过，OK镜高价局面即将被打破。10月26日，根据河北省医用药品器械采购中心文件，包括OK镜在内的20个品种将开展医用耗材集中带量采购。受此消息影响，10月27日开盘，欧普康视、爱尔眼科、爱博医疗三只概念股均大幅低开，截至27日中午收盘，欧普康视报价33.49元/股，跌20%；爱博医疗报价212.6元/股，跌4.66%；爱尔眼科报价26.31元/股，跌10.84%；昊海生科报价75.87元/股，涨1.93%。此外，抗毒蕈碱药物也可延缓近视进展。其中阿托品是非特异性毒蕈碱受体拮抗剂，可麻痹睫状肌及扩大瞳孔。哌仑西平是M1特异性毒蕈碱受体拮抗剂。由于M1受体高度分布于视网膜，较少表达于睫状体及虹膜，哌仑西平较少引起睫状肌麻痹及瞳孔扩大。1%的阿托品是很有效的近视控制药物，但因麻痹睫状肌及扩大瞳孔等作用导致畏光及视近障碍，使用率不佳。多焦眼镜也可延缓近视发展，但是极少数研究表明其有临床意义的延缓近视发展，即使是应用于有最佳适应症的调节滞后或者近点内隐斜的儿童。近视的治疗近视治疗包括非手术治疗和手术治疗，其中非手术治疗包括框架眼镜及角膜接触镜（软性及硬性角膜接触镜）的佩戴。手术治疗包括角膜激光手术及人工晶体植入术等，但因一定的手术风险性，存在一定的争议。而且手术治疗一般要求在18岁以后，近两年近视稳定，且眼部健康。其中角膜激光手术主要是通过改变角膜曲率来矫正近视，是目前被广泛认为是安全和有效的手术，尤其是对于低度到中度近视患者。而对于有角膜激光手术禁忌症或者角膜激光手术无法有效治疗的患者，可以选择眼内晶体植入术。阿托品在近视领域的进展阿托品是唯一经循证医学验证能有效延缓近视进展的药物，被称为是近视防控中的“神药”。阿托品近视控制效果呈现浓度依赖效应，高浓度阿托品滴眼液对近视的控制效果可高达60%~96%，但高浓度阿托品滴眼液存在严重畏光、近视力下降等不良反应以及停药后反弹效应。近期研究显示0.01%、0.02%和0.05%低浓度的阿托品滴眼液有防止眼轴变长、控制近视增长的效果。目前，我国尚未有阿托品滴眼液药品获批上市。但据不完全统计，目前国内约有13家企业或医疗机构获得低浓度阿托品医疗机构制剂（院内制剂）批件，其中兴齐眼科医院的硫酸阿托品滴眼液最早于2019年1月取得获得辽宁省药品监督管理局下发的《医疗机构制剂注册批件》（辽药制字H20190001），适应症为降低近距离工作引起的短暂性近视。不过院内制剂有着严格地域使用限制，按照规定只能在所申报的医疗机构内凭执业医师或者执业助理医师的处方使用。2019年12月，兴齐眼科医院开通互联网医院，借助互联网医院，将阿托品这款院内制剂销售到了全国市场。但在今年7月，兴齐眼药、欧普康视、何氏眼科齐齐宣布硫酸阿托品滴眼液已在互联网医院暂停销售。目前，低浓度阿托品滴眼液产品研发格局逐渐清晰。近日，Vyluma公司/兆科眼科开发的NVK002在一项为期3年的3期临床试验CHAMP中取得积极结果：与安慰剂组相比，0.01%阿托品剂量组患者在所有关键结果测量上，包括缓解者分析、平均等效球面度数（SER）、在第36个月时与基线相较的平均眼轴长度等，都显示出具统计与临床意义上的差异。0.02%阿托品剂量也在许多时间点上展现疗效，包括在第36个月时达成统计上显著的平均眼轴长度变化。缓解者分析结果在36个月时无统计显著性。NVK002是一款具有专利配方、试验性、低剂量兼不含防腐剂、每晚使用的阿托品滴眼液。Vyluma公司计划在2023年第1季度向FDA递交NDA，若顺利，NVK002有潜力成为首个经FDA批准治疗儿童近视进展的药物疗法。此外，目前全球还有多款针对近视的低浓度阿托品滴眼液进入3期临床，如兴齐眼药的0.01%硫酸阿托品滴眼液、Eyenovia公司/极目生物的AVRN002 (MicroPine)、Sydnexis公司/参天制药的SYD-101、欧康维视的OT-101（2021年4月7日，OT-101在美国已完成III期临床试验首例受试者入组）、恒瑞医药的HR19034。1）ARVN002是一种全新的阿托品微量给药近视疗法，突破性地将其与创新微量给药系统Optejet®结合，利用专利的微矩阵药膜（MAP™）技术将微量药液快速均匀给至眼表，每次给药量与传统滴眼液相比大幅降低，可减少因非必要过量给药带来的眼部和全身性安全风险，实现更为高效、精准、安全的药物递送。给药系统内置蓝牙模块还可连接手机设备，智能操作和个人化设置能够进一步提高患者用药体验和依从性。2）SYD-101是一种低剂量硫酸阿托品滴眼液，旨在达到治疗儿童近视疗效的同时，增强药理稳定性和减少不适，以改善治疗的连续性。SYD-101无需降低pH值，并能在室温下达到长达3年的有效期。3）OT-101使用独家设计的创新密闭式分体装置，对装置的可靠性、密封完整性及无菌条件均进行了诸多完善，使之最大程度地贴近低浓度阿托品目前院内制剂现配现用的用药环境，解决了低浓度阿托品溶液的稳定性问题，适宜的pH值也改善了患者用药的舒适度，提升了用药依从性。总结每天2小时以上的户外运动、OK镜、低浓度硫酸阿托品滴眼液被称为近视防控的“三驾马车”。COVID-19反弹引发的居家隔离，增加了人们在阅读、学习和使用数字设备上的时间，预计将进一步增加近视的发病率。期待随着低浓度阿托品滴眼液的获批上市，以及OK镜进入集采，近视防控可以取得显著进展。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~

Researchers have found that blocking certain acetylcholine receptors in the lateral habenula (LHb), an area of the brain that balances reward and aversion, made it harder to resist seeking cocaine in a rat model of impulsive behavior. These findings identify a new role for these receptors that may represent a future target for the development of treatments for cocaine use disorder. There are currently no approved medications to treat cocaine use disorder. Researchers have found that blocking certain acetylcholine receptors in the lateral habenula (LHb), an area of the brain that balances reward and aversion, made it harder to resist seeking cocaine in a rat model of impulsive behavior. These findings identify a new role for these receptors that may represent a future target for the development of treatments for cocaine use disorder. There are currently no approved medications to treat cocaine use disorder. Published in the Journal of Neuroscience, the study was supported by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health. In 2020, over 41,000 people died from drug overdoses involving stimulants, including cocaine and methamphetamine. Developing safe and effective medications that help treat addictions to cocaine and other stimulants is critical to expand the choices offered to people seeking treatment and to help sustain recovery. "This discovery gives researchers a new, specific target toward solving a problem that has long been elusive -- developing treatments for cocaine addiction," said NIDA Director, Nora Volkow, M.D. "As we have seen with medications to treat opioid use disorder, adding this tool to clinical care could save lives from overdose and drastically improve health and quality of life." Addiction science researchers are particularly interested in the LHb as a target for future treatment development because of its position as an interface between brain regions involved with reasoning and other higher order thought processes and those mediating emotion and reward -- factors known to be associated with substance use disorders as well as major depressive disorders. For instance, these areas are involved in regulating behaviors like abstaining from a reward when it is determined not to be "beneficial." Building on previous work that established the importance of the LHb and acetylcholine receptor signaling in impulsive cocaine-seeking, this study further defines the cellular mechanisms through which LHb neurons regulate this behavior. Researchers used a behavioral paradigm called the Go/NoGo model in rats. In this model, rats were trained to self-administer cocaine, where a lever press led to an injection of the drug. This was followed by specific training in the Go/NoGo task where cocaine was available when the lights were on (Go), but not when the lights were off (NoGo). Animals quickly learned to stop responding when cocaine was not available. The researchers then chemically manipulated the LHb, to assess the impact on the rats' ability to withhold their response to cocaine. They found that response inhibition for cocaine was impaired by blocking a specific type of muscarinic acetylcholine receptor, known as M2Rs, with an experimental drug called AFDX-116, and not with a drug called pirenzepine that blocks other muscarinic acetylcholine receptors known as M1Rs. Thus, when M2Rs were blocked in the LHb the rodents were no longer able to stop responding for cocaine even when it was not available (the "NoGo" condition), despite the training. This indicates that increasing LHb M2R function may represent a potential target for treating impulsive drug seeking and substance use disorders. The researchers also studied the cellular mechanisms by which M2Rs alter LHb neuronal activity by measuring changes in the electrical activity of these neurons in response to acetylcholine-like drugs. Although these drugs reduced both excitatory and inhibitory inputs onto LHb neurons, there was a net increase in inhibition, which may account for acetylcholine's ability to limit impulsive cocaine seeking. "The LHb acts like an interface between rational thought in the forebrain and the modulation of neurotransmitters like dopamine and serotonin that originate in the midbrain, which are important in regulating decision processes and emotions," said Carl Lupica, Ph.D., chief of the Electrophysiology Research Section of the Computational and Systems Neuroscience Branch of NIDA. "While the immediate results of this study are related to cocaine seeking, there are also greater implications for impulsivity as it relates to other drugs as well as to psychiatric conditions like obsessive-compulsive disorder. Our future studies will explore the relationship between LHb activity and impulsive behavior related to other drugs such as cannabis, and opioids such as heroin." Although targeting M2Rs is promising, there are challenges because the muscarinic acetylcholine system is involved in everything from regulating heart rate, affecting motion sickness, and controlling vasodilation, for example. These receptors are also located throughout the body, including many other regions of the brain. Further research is needed to develop ways to target the M2Rs in the LHb without causing a cascade of side effects, and as a first step these researchers are now trying to identify where in the brain the acetylcholine released in the LHb originates. The study was funded by the NIDA Intramural Research Program.