CN108348488A - 用于治疗女性对象不孕症的组合物 - Google Patents
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Abstract
用于治疗女性对象不孕症的药物组合物,基本上由以下组分构成:酰胺类局部麻醉剂如利多卡因,人白蛋白,选自重组透明质酸以及重组透明质酸与水溶性纤维素醚的组合的粘度控制剂,任选的柠檬酸盐,葡萄糖,和/或氨基酸,水,任选包含一种或多种选自钠,钾,镁,钙,乙酸根,氯离子,硫酸根的离子。还公开了通过将所述组合物给予需要的女性对象来治疗不孕症的方法。
Description
技术领域
本发明涉及用于治疗不孕症,例如子宫内膜异位相关性不孕症和不明原因的不孕症的药物组合物。本发明还涉及使用该组合物的治疗方法及其制备方法。
背景技术
造成不孕的生物学原因很多。例如,不孕症可能是由于女性激素水平异常或者排卵功能障碍导致的,或者男性精子生成功能障碍引起的。然而,大量夫妇被诊断为不明原因的不孕症。通常尝试人工授精作为患有不明原因的不孕症的夫妇的首次治疗,同时有许多夫妇仍在等待体外受精(IVF)。输卵管注通(perturbation),即法娄皮欧氏输卵管注通,已显示能够提高患有不明原因的不孕症的夫妇以及被诊断为早期子宫内膜异位症的患者成功怀孕的机会(Johnson等,(2005),Cochrane Database Syst Rev,18(2):CD003718)。
子宫内膜异位症是一种妇科疾病,其特征是在子宫腔外存在与子宫内膜组织学上相同的组织,即哺乳动物子宫内内衬的膜。子宫内膜异位症与不孕症有关,在许多患有不明原因的不孕症的妇女中,子宫内膜异位症可能是潜在的原因。
利多卡因是一种著名的局部麻醉剂,其化学式如下:
已知具有膜稳定性,抗心律失常和抗炎特性。在本申请中,术语“利多卡因”包括其药学上可接受的盐,例如盐酸盐,优选施用该形式。利多卡因具有膜稳定性,抗心律失常和抗炎特性。在人工授权之前采用低剂量的利多卡因进行输卵管注通已显示能够增加患有不明原因的不孕症的夫妇的妊娠率(Edelstam,G.等,(2008),Human Reproduction,第23卷,第4期,第852-856页)。
US 2002/00421132 A1公开了包含人白蛋白、发酵的透明质酸和柠檬酸盐中的一种或多种的用于培养哺乳动物配子和胚胎组织的水性补充培养基。
透明质酸,也被称为乙酰透明质酸,是N-乙酰葡糖胺和D-葡萄糖醛酸重复二糖单元的天然形成的聚合物。它广泛分布于整个身体,有助于细胞增殖和迁移。它也是A族链球菌胞外胶囊的组分。透明质酸已被发现用于各种医疗应用。
需要用于有效治疗不孕症,例如子宫内膜异位相关性不孕症的药物组合物和/或方法。
发明目的
本发明的一个目的是提供一种药物组合物,该组合物增强了生育能力并且可以用于治疗不孕症,例如不明原因的不孕症或者被诊断为患有子宫内膜异位症的患者的不孕症。
本发明的另一目的是通过将上述种类的组合物给予有需要的人来提供治疗不明原因的不孕症的方法和治疗被诊断为患有子宫内膜异位的患者的不孕症的方法。
本发明的其他目的将通过以下发明内容、描述其优选实施方式的多个实施例和所附权利要求书而显见。
发明内容
在所附权利要求中充分公开了本发明的各个方面。
根据本发明,公开了用于治疗不孕症(例如被诊断为患有子宫内膜异位的患者的不孕症)以及用于治疗不明原因的女性不孕症的组合物。本发明的组合物可注射或植入腹盆腔,特别是采用皮下注射器经输卵管通过宫颈注射,也称为输卵管注通。
在一个方面,本发明提供了药物组合物,其包含选自阿替卡因,布比卡因,辛可卡因,依替卡因,左布比卡因,利多卡因,甲哌卡因,奥昔卡因,丙胺卡因,罗哌卡因,托考卡因和三甲卡因的酰胺类局部麻醉剂或其药学上可接受的盐,人白蛋白和透明质酸,以及任选的柠檬酸盐,葡萄糖和/或氨基酸,在水性介质中,特别是水中,或者是用水性介质,特别是水重建的粉末形式。人白蛋白或透明质酸或两者都优选是重组来源的。药学上可接受的盐包括但不限于盐酸盐,氢溴酸盐和硫酸盐。利多卡因,特别是其盐酸盐形式,是本发明优选的局部麻醉剂。本发明另一种优选的局部麻醉剂是丙胺卡因。
本发明的药物组合物比过去已知的包含利多卡因或盐酸利多卡因和用于控制渗透压的无机盐和/或有机盐的水溶液,例如包含氯化钠的林格溶液的组合物更加有效。本发明的药物组合物提供了比上述种类的已知的利多卡因组合物更高的生育率。
本发明的药物组合物中,本发明的局部麻醉剂如利多卡因或盐酸利多卡因的优选浓度为0.1-2.5mg/ml,更优选0.3-1.5mg/ml,最优选约1.0mg/ml。
为了制备本发明的组合物,将本发明的局部麻醉剂,具体是利多卡因或盐酸利多卡因,与人白蛋白和透明质酸以及任选的柠檬酸盐、葡萄糖和/或氨基酸以任意顺序干法或湿法混合。
本发明的人白蛋白优选是重组来源。在本发明的药物组合物中,重组人白蛋白提供了优于天然来源的人血清白蛋白(HAS)的许多优点。通过使用重组人白蛋白而不是血浆/血液来源的HAS,消除了血源性组分或传染性颗粒污染药物组合物的潜在风险。而且,重组蛋白比从诸如血液等生物来源分离的蛋白质变化小。包含重组人白蛋白的药物组合物因此更容易标准化。重组人白蛋白的生产在本领域中是众所周知的。在一个实施方案中,重组人白蛋白得自遗传修饰的酵母,经改造以表达人白蛋白。
本发明的药物组合物中人白蛋白的优选浓度为0.1-20.0mg/ml,更优选0.5-10.0mg/ml。
根据本发明的优选方面,药物组合物包含粘度控制剂。本发明的粘度控制剂是对需要治疗的病症缺乏药理学作用的试剂。此外,本发明的粘度控制剂优选是可生物降解的。
本发明优选的粘度控制剂是透明质酸,该术语包括其药学上可接受的盐如钠盐、钾盐、镁盐或钙盐。最优选的是透明质酸的钠盐。透明质酸是高分子量的粘多糖。
本发明的透明质酸优选是重组来源。如同重组人白蛋白一样,使用重组透明质酸可实现标准化并提供更高的药物组合物的安全性和稳定性。
US 2002/0042132 A1公开了柠檬酸盐确实增强了重组人白蛋白的性质。对于本发明,可以使用本领域已知用于药物组合物和/或培养基的任何柠檬酸盐。有用的柠檬酸盐的实例包括柠檬酸钠,柠檬酸钙,柠檬酸及其组合。优选使用柠檬酸钠。任选柠檬酸盐在本发明药物组合物中的优选浓度为0.1-5.0mM/L,更优选0.1-1.0mM/L。
根据本发明的另一方面,组合物包含葡萄糖。在组合物中,葡萄糖控制渗透压并构成能量来源。葡萄糖含量优选最高约5重量%。如果希望组合物与血清等渗,则相应地考虑到其他组分对渗透压的贡献,选择葡萄糖的含量。
根据本发明的方法,组合物局部施用至需要其的组织而不是全身施用。
为了制备本发明的组合物,将酰胺类局部麻醉剂,特别是利多卡因或其药学上可接受的盐和其它组分溶于水中。
在一个实施方案中,本发明的药物组合物不含非重组大分子或动物或人源大分子。
本发明的药物组合物的另一个实施方案包含用于调节组合物粘度的除了透明质酸之外的粘度控制剂。与粘度较低的药物组合物相比,较高粘度的药物组合物具有延长药物组合物对被治疗组织的暴露的优点。可以使用本领域已知的任何药学上可接受的粘度调节剂。在一个优选的实施方案中,粘度调节剂是纤维素醚,特别是羟丙基甲基纤维素(HPMC)。
药物组合物的粘度优选调节到40cp(厘泊)至600cp,更优选100-400cp。当透明质酸用作本发明药物组合物中唯一的粘度调节剂时,透明质酸的优选浓度为0.02mg/ml至2mg/ml或3mg/ml或5mg/ml,更优选0.1mg/ml至1mg/ml或0.2mg/ml至0.8mg/ml。当透明质酸与纤维素醚,特别是HPMC一起用作粘度控制剂时,其浓度以及纤维素醚的浓度适于为组合物提供上述优选粘度。
另一方面,本发明提供治疗人不孕症的方法,包括提供根据本发明的药物组合物并将其一定的量施用于所述人,特别是腹腔或腹膜内。优选通过输卵管进行腹膜内给药。通过输卵管给药例如可以通过输卵管注通(perturbation),参见Edelstam,G.等,(2008),Human Reproduction,第23卷,第4期,第852-856页;K.等,(2012),HumanReproduction,第27卷,第3期,第695-701页)。施用的组合物的量为约1ml至约40ml,更优选2ml至25ml。例如,需要治疗的人可能已经被诊断患有不明原因的不孕症或子宫内膜异位症。
腹膜内给药可以例如通过注射器将本发明的组合物注射到腹腔中,通过导管输注入腹膜腔,通过手术沉积在腹腔中,通过经腹壁透皮吸收或通过皮下沉积。本领域已知的包含本发明药物组合物的持续或延迟释放制剂可以通过手术植入腹腔中或注入其中,例如以包含组合物或包含除其水组分之外的组合物的微粒形式,或它们可以在腹部皮下沉积。透皮吸收可以通过例如用本发明组合物覆盖的透皮棉垫来实现。与垫一起使用的本发明组合物的粘度可以例外地显著高于600cp,例如1000或2000cp或甚至更高。
所述组合物优选以5-10ml至20-40ml,特别是约10或20ml的体积施用至腹膜腔。
现在将通过参考大量优选实施例更详细地描述本发明。
具体实施方式
材料
如下制备在醋酸林格中的0.5mg/ml利多卡因的储备溶液:NaCl(8.5g),KCl(0.3g),CaCl2·H2O(0.33g)和利多卡因(0.5g)溶解在800ml注射级用水(WFI)中。用NaOH将pH调节至7.0并加水至1000ml。
如下制备在醋酸林格中的1.0mg/ml利多卡因的储备溶液:NaCl(8.6g),KCl(0.3g),CaCl2·H2O(0.33g)和利多卡因(1.0g)溶解在800ml WFI中。用NaOH将pH调节至7.0并加水至1,000ml。制备透明质酸储备溶液(凝胶),其在WFI中含有40mg/ml透明质酸。
实施例1
通过在玻璃小瓶中混合0.1ml透明质酸储备溶液与3.9ml 0.5mg/ml利多卡因或1.0mg/ml利多卡因储备溶液(上述)制备含有1mg/ml透明质酸的水溶液。溶液在室温下通过大量涡旋混合。涡旋30分钟之后,透明质酸储备溶液(凝胶)未完全溶解于利多卡因溶液,但仍以凝胶形式存在。
实施例2
在37℃重复实施例的过程,结果为阴性,因为可以看到透明质酸凝胶粘附于小瓶的玻璃上。用塑料小瓶进行相同的实验得到类似的结果。
实施例3
将3.9ml两种储备溶液移液到玻璃小瓶中,加热至约40℃。向溶液中加入0.1ml40mg/ml透明质酸,制成1mg/ml透明质酸的溶液。注意不要让透明质酸粘在玻璃上。小瓶剧烈涡旋2分钟。检查小瓶显示透明质酸完全溶解。
实施例4
制备含有0.5mg/ml利多卡因或1.0mg/ml利多卡因的储备溶液并加热至约40℃。向每个小瓶中加入表1中列出的量的透明质酸。当加入透明质酸时小心不要接触小瓶的壁。涡旋约5分钟后,所有小瓶中的凝胶已溶解。含有16mg/ml利多卡因的水溶液就像软胶状物,业已证明其难以通过皮下注射器压注。浓度为8mg/ml时,溶液粘稠但易于处理,并通过相同规格的皮下注射器进行压注。使用Fiske 210型微渗透仪测试溶液的渗透压。
表1.含有透明质酸的输卵管注通溶液的流体稠度。
储备溶液A和B制备的输卵管注通溶液
实施例5
将透明质酸替换为羟丙基-甲基纤维素(HPMC)作为粘度控制剂。如上所述,HPMC也可用于控制粘度,但需要更大的体积。制备WFI中5%HPMC的储备溶液。
表2.含有羟丙基甲基纤维素的输卵管注通溶液的流体稠度。
储备溶液C和D制备的输卵管注通溶液
实施例6
如下制备含有葡萄糖和白蛋白的输卵管注通溶液(50ml,表3)。
在无菌条件下,在玻璃烧杯中将NaCl(425mg),CaCl2·H2O(16.5mg),利多卡因(25mg)和葡萄糖(1.25g)溶解在35ml WFI中。将该溶液加热至约40℃。加入白蛋白(1ml50mg/ml HAS溶液),合并的溶液涡旋直到完全混合。所得澄清溶液通过0.4微米过滤器进行灭菌。然后无菌加入10ml无菌透明质酸储备溶液(凝胶),同时防止它粘附在壁上。溶液在40℃温和涡旋。当透明质酸储备溶液(凝胶)完全溶解在利多卡因溶液中时,用无菌1M NaOH将pH调节至7.0,并用WFI稀释溶液至50ml。测量渗透压并确定为295mOsm/kg。将溶液等分至5瓶,每瓶含10ml。将小瓶冷却并在4℃至8℃冷藏。使用前将小瓶置于室温。
表3.含有透明质酸的输卵管注通组合物
实施例7
在鼠手术诱导的同源子宫内膜异位症模型中将本发明的组合物与缺乏白蛋白的相应的现有技术组合物进行比较。
该研究的目的是评估在雌性C57BL/小鼠的子宫内膜自体移植模型中本发明组合物和相应的缺乏白蛋白的现有技术组合物(“现有技术组合物”)改善生育力的功效。研究中使用表4的本发明的组合物。
表4.研究中使用的本发明的组合物
组分 | 量(mg/ml) |
氯化钠 | 7.8 |
氯化钾 | 0.3 |
氯化钙二水合物 | 0.33 |
盐酸利多卡因 | 0.5 |
白蛋白 | 1.0 |
透明质酸 | 1.0 |
氢氧化钠 | 适量,pH 7.0 |
注射用水 | 加至(ad)1.0ml |
过程:该研究包括四组n=5的雌性C57BL小鼠。三组接受单侧子宫角切除术和邻近肠系膜的动脉级联的子宫内膜异位组织的自体移植,而一组仅接受单侧子宫角切除并作为假-对照。雌性动物的发情周期在手术过程之前和之后同步,并且视觉评估接受可能。所有雌性的生育力通过交配成功和随后的6至7周手术后窝产仔数确定进行评估。通过在交配之前将本发明组合物和现有技术组合物连续三天每天一次重复腹膜内注射给予两个子宫内膜自体移植组进行治疗。组合物以每次注射20ml/kg体重的剂量施用,即10mg利多卡因/kg体重的剂量。另两组在相同实验条件下注射缓冲对照溶液并作为对照组。临床观察动物持续最长达10周。没有发现治疗死亡。
结果。来自用本发明组合物治疗的组的雌性表现出比其他组更高的体重增加。仅考虑在体重增加期间观察到交配和/或疑似怀孕的动物时,差异甚至更高。结果示于表4。
表4.C57BL小鼠模型中本发明组合物的妊娠效率
显然,本发明的组合物和现有技术的组合物均优于安慰剂,而且本发明的组合物的效力显著高于现有技术的组合物。在假操作对照中,本发明的组合物甚至至少与安慰剂相当。因此,本发明的组合物能够在子宫内膜异位症的情况下将生育力恢复至正常水平。
Claims (25)
1.用于治疗女性对象不孕症的药物组合物,其包含以下组分或基本上由以下组分构成:
-酰胺类的局部麻醉剂,选自下组:阿替卡因,布比卡因,辛可卡因,依替卡因,左布比卡因,利多卡因,甲哌卡因,奥昔卡因,丙胺卡因,罗哌卡因,托考卡因和三甲卡因,
-人白蛋白;
-粘度控制剂,选自下组:重组透明质酸以及重组透明质酸和水溶性纤维素醚的组合;
-水,任选地包含一种或多种选自下组的离子:钠、钾、镁、钙、乙酸根、氯离子、硫酸根。
2.如权利要求1所述的组合物,额外地包含柠檬酸盐、葡萄糖和/或氨基酸。
3.如权利要求1或2所述的组合物,其中,所述人白蛋白是重组来源。
4.如权利要求1-3中任一项所述的组合物,其中,所述局部麻醉剂是其药学上可接受的盐的形式。
5.如权利要求4所述的组合物,其中,所述药学上可接受的盐选自:盐酸盐、氢溴酸盐、硫酸盐。
6.如权利要求1-5中任一项所述的组合物,其中,所述局部麻醉剂是利多卡因或盐酸利多卡因。
7.如权利要求1-6中任一项所述的组合物,包含0.1-2.5mg/ml,具体约1.0mg/ml的局部麻醉剂。
8.如权利要求1-7中任一项所述的组合物,包含0.1-20.0mg/ml重组白蛋白。
9.如权利要求1-8中任一项所述的组合物,包含0.02-5.0mg/ml透明质酸。
10.如权利要求2-9中任一项所述的组合物,包含0.1-5.0mM/L柠檬酸盐。
11.如权利要求2-10中任一项所述的组合物,包含最高约5mg/ml的葡萄糖。
12.如权利要求1-11中任一项所述的组合物,其中,所述纤维素醚是羟丙基-甲基纤维素(HPMC)。
13.如权利要求1-12中任一项所述的组合物在女性对象的输卵管注通中的应用。
14.如权利要求1-12中任一项所述的组合物在治疗女性对象不孕症中的应用。
15.一种治疗女性对象不孕症的方法,包括提供如权利要求1-12中任一项所述的组合物;给予女性对象的腹盆腔药理学有效量的所述组合物。
16.如权利要求15所述的方法,其中,所述女性对象已诊断患有不明原因的不孕症。
17.如权利要求15或16所述的方法,其中,所述女性对象已诊断患有子宫内膜异位症。
18.如权利要求15-17中任一项所述的方法,其中,通过输卵管注通实现给药。
19.如权利要求15-17中任一项所述的方法,其中,通过导管输注入腹膜腔实现给药。
20.如权利要求15-17中任一项所述的方法,其中,通过注射器注入腹膜腔实现给药。
21.如权利要求15-17中任一项所述的方法,其中,通过手术沉积在腹腔中实现给药。
22.如权利要求15-17中任一项所述的方法,其中,通过经腹壁透皮吸收实现给药。
23.如权利要求1-12中任一项所述的药物组合物,其是干粉形式,具体是冷沉淀形式,用于用水重建,其中,所述一种或多种离子选自下组:钠、钾、镁、钙、乙酸根、氯离子、硫酸根,以所述冷沉淀或所述重建用水的一部分的形式。
24.用于治疗女性对象不孕症的持续释放的组合物,包含如权利要求1-12中任一项所述的组合物,除去结合到可生物降解的多孔聚合物微粒或含有可生物降解的聚合物壳的微粒中的其水组分。
25.如权利要求24所述的组合物,其中,所述多孔聚合物或聚合物壳包含选自以下的可生物降解的聚合物:聚-丙交酯、聚-乙交酯、聚[丙交酯-共-乙交酯]。
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998035676A1 (en) * | 1997-02-15 | 1998-08-20 | Edelstam Inc. | A medicament against infertility and for increasing fertility |
CN1847393A (zh) * | 2000-06-09 | 2006-10-18 | 维特罗莱夫公司 | 添加剂,制剂和培养基 |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3449738B2 (ja) * | 1991-07-10 | 2003-09-22 | 武田薬品工業株式会社 | 水溶性組成物 |
US5700485A (en) | 1992-09-10 | 1997-12-23 | Children's Medical Center Corporation | Prolonged nerve blockade by the combination of local anesthetic and glucocorticoid |
ES2249250T3 (es) * | 1997-02-15 | 2006-04-01 | Edelstam Inc. | Medicamento contra la dismenorrea y el sindrome premenstrual que comprende lidocaina. |
EP1009390A4 (en) * | 1997-07-02 | 2004-05-06 | Euro Celtique Sa | LONG-EFFECT ANESTHESIA INJECTED IN JOINT AND BODY SPACES |
US6762053B2 (en) * | 2000-06-09 | 2004-07-13 | Vitrolife, Inc. | Mammalian gamete and embryo culture media and culture media supplements |
FR2815035B1 (fr) | 2000-10-05 | 2003-03-07 | Commissariat Energie Atomique | Procede de coprecipitation d'actinides et procede de preparation d'oxydes mixtes d'actinides |
AUPR803501A0 (en) * | 2001-10-02 | 2001-10-25 | Xeno Trans Ltd | Gene transfer composition and method |
US7998579B2 (en) | 2002-08-12 | 2011-08-16 | Exxonmobil Chemical Patents Inc. | Polypropylene based fibers and nonwovens |
CN1833026A (zh) | 2003-07-31 | 2006-09-13 | 东洋纺织株式会社 | 生产透明质酸的植物 |
JP2007174957A (ja) | 2005-12-27 | 2007-07-12 | Toyobo Co Ltd | ヒアルロン酸生産酵母 |
JP5561636B2 (ja) | 2009-03-03 | 2014-07-30 | 東洋紡株式会社 | 改良されたヒアルロン酸の製造方法 |
US20110280763A1 (en) * | 2010-05-17 | 2011-11-17 | Abbott Medical Optics Inc. | Light-activated disinfection system |
WO2011145993A1 (en) * | 2010-05-19 | 2011-11-24 | Isifer Ab | Treatment for reducing inflammation |
-
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- 2016-10-11 KR KR1020187013216A patent/KR20180066193A/ko not_active Application Discontinuation
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998035676A1 (en) * | 1997-02-15 | 1998-08-20 | Edelstam Inc. | A medicament against infertility and for increasing fertility |
CN1847393A (zh) * | 2000-06-09 | 2006-10-18 | 维特罗莱夫公司 | 添加剂,制剂和培养基 |
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CA3002515C (en) | 2024-01-02 |
BR112018007731A2 (pt) | 2018-10-23 |
DK3364959T3 (da) | 2022-10-17 |
PL3364959T3 (pl) | 2022-12-27 |
AU2016340769A1 (en) | 2018-04-19 |
KR20180066193A (ko) | 2018-06-18 |
SG10201912767WA (en) | 2020-02-27 |
IL258757A (en) | 2018-06-28 |
EP3364959A4 (en) | 2019-05-22 |
HK1256531A1 (zh) | 2019-09-27 |
IL258757B (en) | 2021-07-29 |
US20190240338A1 (en) | 2019-08-08 |
WO2017069672A1 (en) | 2017-04-27 |
BR112018007731B1 (pt) | 2023-11-14 |
MX2018004958A (es) | 2019-03-28 |
US11191839B2 (en) | 2021-12-07 |
EA201890714A1 (ru) | 2018-09-28 |
JP7276806B2 (ja) | 2023-05-18 |
ES2932213T3 (es) | 2023-01-16 |
AU2016340769B2 (en) | 2018-07-12 |
EP3364959A1 (en) | 2018-08-29 |
EP3364959B1 (en) | 2022-07-13 |
HUE061056T2 (hu) | 2023-05-28 |
JP2018535253A (ja) | 2018-11-29 |
CL2018001058A1 (es) | 2018-09-14 |
EA036687B1 (ru) | 2020-12-08 |
NZ740967A (en) | 2024-03-22 |
SA518391400B1 (ar) | 2022-09-19 |
MY196628A (en) | 2023-04-23 |
JP2021130688A (ja) | 2021-09-09 |
CA3002515A1 (en) | 2017-04-27 |
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