CN105030789B - 曲安奈德的新用途 - Google Patents
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Abstract
本发明提供了曲安奈德的新用途,玻璃体切除治疗PDR于术中适当时机向眼内注射曲安奈德可有效控制术中视网膜出血,使手术时间缩短,手术安全性提高,因此将曲安奈德应用于减轻视网膜出血的药物的制备将具有非常重要的临床应用价值。
Description
技术领域
本发明涉及药物新用途,尤其是曲安奈德的新用途。
背景技术
玻璃体切除手术是治疗增生性糖尿病视网膜病变(proliferative diabeticretinopathy,PDR)的安全有效方法。术中由于剥除增生膜或切除牵拉等原因导致视网膜、新生血管膜及牵拉处的小血管出血,是玻璃体切除手术治疗PDR的术中常见并发症,如果处理不当,会导致手术操作难度加大、术后出血容易复发、手术效果差。以往对于术中视网膜出血常采用眼内电凝、升高灌注压、灌注液中加入凝血酶或肾上腺素,以及其他填充物等方法,但各有利弊。眼内电凝的应用需要明确出血部位;升高灌注压常常需要等待数分钟,且可能需要反复多次操作。气-液交换适用于术中出血过多,玻璃体腔混浊明显,且无法操作的情况下,气-液交换后可使屈光间质清晰,但止血作用不明显。PDR患者术前玻璃体腔注射抗VEGF药物可有效减少术中、术后出血,然而由于其高昂的价格限制了其广泛应用。
曲安奈德TA(CAS号:76-25-5),分子式:C24H31FO6,是肾上腺皮质激素类药,属长效、不溶于水、白色混悬液。作用与去炎松相似,其抗炎和抗过敏作用较强且远较持久。以往用于辅助玻璃体切除手术中识别玻璃体和增生膜,以及减轻术后炎症反应、增殖及黄斑水肿(1.Martidis A,Duker JS,Greenberg PB,et al.Intravitreal triamcinolone forrefractory diabetic macular edema.Ophthalmology,2002,109:920-927;2.Scott IU,Ip MS,et al.SCORE Study Research Group.A randomized trial comparing theefficacy and safety of intravitreal triamcinolone with standard care to treatvision loss associated with macular edema secondary to branch retinal veinocclusion:the Standard Care vs Corticosteroid for Retinal Vein Occlusion(SCORE)study report 6.Arch Ophthalmol,2009,127:1115-1128;3.Matsumoto H,Yamanaka I,Hisatomi T,et al.Triamcinolone accetonide-assisted pars planavitrectomy improves residual posterior vitreous hyaloid removal.Retina,2007,27:174-179)。
发明内容
本发明所要解决的技术问题在于提供曲安奈德的新用途。
为解决上述技术问题,本发明的技术方案是:
曲安奈德在制备用于减轻视网膜出血的药物方面的用途。
优选的,上述曲安奈德在制备用于减轻手术中和/或手术后视网膜出血的药物方面的用途。
优选的,上述曲安奈德在制备用于减轻增生性糖尿病视网膜病变手术中和/或手术后视网膜出血的药物方面的用途。
优选的,上述曲安奈德的用途,所述手术为玻璃体切除术。
本发明的有益效果是:
对于曲安奈德的新用途,收集2012年1月至2013年12月于我院行玻璃体切除手术治疗严重PDR患者25人29只眼,术中首先进行玻璃体切除,并尽可能切除干净,将容易剥除的增生膜尽可能剥除干净。在剥除增生膜时发生视网膜出血或小血管出血,此时向眼内注入曲安奈德(4mg/0.1ml),然后继续切除残存的玻璃体和增生膜。记录患者术中及术后视网膜出血情况、最佳矫正视力、眼压及并发症。结果显示术中所有眼于曲安奈德注射后,视网膜颜色稍微变浅,视网膜渗血及小血管出血减轻或停止;术后1周及1个月分别观察到9只眼(31.03%)及4只眼(13.79%)有少量残存视网膜出血未被完全吸收;术后3个月,所有视网膜出血吸收(100%);末次随访,视力提高25只眼(86.21%),视力不变4只眼(13.79%),未观察到视力下降者;术后早期眼压升高8只眼(27.59%),其中7只眼经抗青光眼药物治疗,2周内眼压恢复正常;1只眼于术后1个月行小梁切除术,术后眼压得到控制;白内障进展加重3只眼(3/14,21.43%),随访期间未观察到视网膜再出血、眼内炎及其他并发症。由此可以说明,玻璃体切除治疗PDR于术中适当时机向眼内注射曲安奈德可有效控制术中视网膜出血,使手术时间缩短,手术安全性提高,因此将曲安奈德应用于减轻视网膜出血的药物的制备将具有非常重要的临床应用价值,有望成为玻璃体切除手术治疗严重PDR术中辅助用药。
附图说明
图1是增生性糖尿病视网膜病变玻璃体切除术中注入曲安奈德减少术中出血效果图。其中,
图1A、图1B:在剥除增生膜时,发生视网膜出血或小的血管出血(白色箭头);
图1C:眼内注入曲安奈德后,视网膜出血减轻或停止,视网膜表面可见白色曲安奈德颗粒和红细胞凝聚在一起的混合物覆盖在视网膜表面;
图1D:继续切除残存的玻璃体和增生膜,视网膜表面无活动性出血。
具体实施方式
为了使本领域的技术人员更好的理解本发明的技术方案,下面结合具体实施方式对本发明所述技术方案作进一步的详细说明。
实施例1
1资料与方法
1.1一般资料
收集2012年1月~2013年12月在天津医科大学总医院接受玻璃体切除手术的严重PDR患者25例(29只眼),男11例12只眼,女14例17只眼(表1)。年龄23~75岁,平均(55.05±13.08)岁。术前合并高血压病17例,冠状动脉性心脏病4例,慢性肾功能不全2例,既往有脑梗塞病史2例。术前行全视网膜激光治疗4只眼(13.79%),部分视网膜激光治疗7只眼(24.14%)。术前视力光感~0.08。术前有明显晶状体混浊15只眼(51.72%)。PDR分期均为VI期(术中观察增殖及视网膜脱离情况见表1)。所有患者术前均签署知情同意书,并经过医院伦理委员会批准。排除原则为眼内曾注射抗VEGF(血管内皮生长因子)药物、既往有眼部手术史、术前应用抗凝药物及凝血功能异常者。术后随访3~12个月,平均(6.40±2.69)个月。所有患者均由内分泌科确诊并符合1998年世界卫生组织制定的糖尿病诊断标准。PDR分期符合1985年我国糖尿病视网膜病变临床分期标准。
1.2术前处理及手术治疗
患者术前常规行最佳矫正视力、裂隙灯显微镜、检眼镜、角膜内皮镜、角膜曲率与眼轴长度、B型超声、超声生物显微镜及眼压等检查。全身检查包括心电图、血常规、尿常规、血压、肝肾功能及电解质检查。全身严重疾病术前处理在相关科室配合下进行。严重高血压、动脉硬化及冠状动脉供血不足患者,术前、术中血压控制在150/90mmHg以下,实行术中心电监护,术后注意止血和控制血压。糖尿病患者术前空腹血糖控制在8.3mmol/L以下,术后继续降血糖治疗。
手术均由同一医师完成,2%利多卡因3ml球后注射麻醉,采用非接触广角镜观察系统23G或25G标准三切口玻璃体切除手术治疗。伴有白内障者先行白内障超声乳化手术,全部保留晶状体后囊膜。将玻璃体尽可能切除干净后,将容易剥除的增生膜尽可能剥除干净。在剥除增生膜时,所有29只眼均发生不同程度视网膜出血或小的血管出血(图1A,1B),此时向眼内注入曲安奈德(4mg/0.1ml),然后继续切除残存的周边部玻璃体以及与增生膜粘连紧密的玻璃体。此时玻璃体腔逐渐清晰,未发现玻璃体腔出血漂浮,视网膜出血部位被曲安奈德颗粒覆盖,形成红白相间的小出血片或膜(图1C)。用高速玻璃体切除和低负压的方法切除严重增生并且僵硬的增生膜,同时将曲安奈德与出血混合的膜切除干净(图1D),再继续行视网膜光凝、眼内填充物及人工晶状体植入。本组术中行白内障超声乳化14例15眼,眼内硅油填充20例21眼,C3F8注入2例2眼(表1)。眼内有填充物者,术后严格俯卧位至少2周。术后常规抗生素、糖皮质激素滴眼液及复方托吡卡胺滴眼液点眼4次/d,持续1周~2周。
术后1d、3d、5d、7d、1月、3月、半年及1年进行常规检查,随访观察包括视力、眼压、眼部并发症。视力提高、不变、下降为最佳矫正视力变化,疗效判定以最后一次随访结果为准。
表1.患者一般资料
PDR,增生性糖尿病视网膜病变;VH,玻璃体积血;RD,视网膜脱离;FVP,纤维血管增生;PPV,扁平部玻璃体切除;IVTA,玻璃体腔曲安奈德注射;P,视网膜激光光凝;SI,硅油注入;Phaco,白内障超声乳化;IOL,人工晶状体植入。
*:此列病人数量与总病人数不一致是由于3例PDR患者双眼分别行不同的手术方式,故此列未统计其百分比。&:白内障进展加重并手术治疗者为玻璃体切除术后有晶状体患者14人14只眼中的3人3只眼(21.47%)。
2结果
2.1术中、术后视网膜出血情况
术中所有眼(100%)均观察到于曲安奈德注射后,视网膜颜色稍微变浅,视网膜渗血及小血管出血减轻或停止,术野迅速恢复清晰。术后1周及1个月分别观察到9只眼(31.03%)及4只眼(13.79%)有少量残存视网膜出血未被完全吸收。术后3个月,所有患眼视网膜出血吸收,视轴区保持透明。
2.2视力
术前视力0.05以上3只眼(10.34%),0.02~0.05为2只眼(6.90%),其余24只眼(82.76%)术前最佳矫正均低于0.02。术后视力提高25只眼(86.21%),不变4只眼(13.79%),未观察到视力下降者(表2)。
表2.术前术后最佳矫正视力
*此列病人数量超过总病人数,是由于双眼增生性糖尿病视网膜病变患者的双眼视力分别位于不同范围内,故此列未统计其百分比。
2.3术后视网膜复位情况
所有患眼术后视网膜复位良好,未观察到明显玻璃体腔炎症反应,无视网膜增生膜复发及牵拉性视网膜脱离。
2.4术后并发症
术后2~5天内眼压升高8只眼(27.59%),范围26~38mmHg,其中7只眼经抗青光眼药物治疗,包括甘露醇临时静脉点滴、卡替洛尔眼药水2次/d及布林佐胺眼药水3次/d点眼,眼压于2周内恢复正常。1只眼于术后1个月经药物治疗眼压仍维持在28~44mmHg,即行小梁切除术,术后眼压得到控制。
术后早期观察到角膜水肿6只眼(20.69%)、前房呈轻度~中度炎症反应9只眼(31.03%),均为联合白内障手术患眼,术后滴用抗生素、糖皮质激素滴眼液4次/d,1~2周均恢复。白内障进展加重有3只眼(3/14,21.43%),于术后6至9月行白内障超声乳化及人工晶状体植入手术。随访期间未观察到视网膜再出血、眼内炎及其他并发症(表1)。
由上可见,对玻璃体切除手术治疗严重PDR患者术中进行眼内曲安奈德注射,曲安奈德可明显减轻术中视网膜出血,迅速使手术视野清晰,使手术时间明显缩短,术后炎症反应减轻,并发症降低。
曲安奈德除了上述辅助玻璃体切除手术中识别玻璃体和增生膜、以及能抑制术后炎症反应等作用外,其另一个作用为止血。其可能机制为:1.曲安奈德颗粒覆盖视网膜表面渗血;2.曲安奈德不溶于水,悬浮作用(增加粘稠性),可吸附红细胞;3.曲安奈德可促使血小板和纤维蛋白原增加,使血液呈高凝状态;4.曲安奈德可下调VEGF,抑制炎症反应,减少血-视网膜屏障破坏。
另外需要说明的是,虽然曲安奈德具有上述的止血作用,但如果注药时机不恰当,仍然起不到止血作用。需要在尽可能切除玻璃体及剥除增生膜后注射曲安奈德,此时正是视网膜出血或小的血管出血容易发生的时机。此时为适时注药时机的理由:1.此时玻璃体腔均被液体填充,注入曲安奈德后,曲安奈德可以充分在玻璃体腔扩散,并与残存玻璃体、残存未剥离的增生膜、以及视网膜接触,使残存的玻璃体和未剥除的增生膜更容易辨别;2.曲安奈德可以充分与视网膜和小血管的出血接触达到止血目的;3.由于曲安奈德是颗粒状态,有一定的质量,在玻璃体腔与红细胞接触后下沉到视网膜表面,可以吸附红细胞并直接覆盖在出血表面,使视网膜出血减轻或停止;4.由于曲安奈德充分与视网膜接触,因此,当手术结束时仍然有部分微细颗粒未被彻底吸除干净,对于抑制术后视网膜表面膜增生以及炎症反应起到一定作用。
上述参照具体实施方式对该曲安奈德的新用途进行的详细描述,是说明性的而不是限定性的,可按照所限定范围列举出若干个实施例,因此在不脱离本发明总体构思下的变化和修改,应属本发明的保护范围之内。
Claims (2)
1.曲安奈德在制备用于减轻增生性糖尿病视网膜病变手术中视网膜出血的药物方面的用途。
2.根据权利要求1所述的曲安奈德的用途,其特征在于:所述手术为玻璃体切除术。
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