CN102872154B - Houttuynoid B在抗幽门螺杆菌药物中的应用 - Google Patents
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Abstract
体外活性实验表明Houttuynoid B具有很强的抗幽门螺旋杆菌(Helicobacter pylori，Hp)活性。Houttuynoid B可用于急、慢性胃炎、胃、十二脂肠溃疡等疾病的治疗及在制备治疗急、慢性胃炎、胃、十二脂肠溃疡药物中得到应用。本发明涉及的HouttuynoidB在制备治疗抗幽门螺杆菌药物中的用途属于首次公开，由于骨架类型属于全新的骨架类型，而且其对于幽门螺杆菌抑制活性强得意想不到，不存在由其他化合物给出任何启示的可能，具备突出的实质性特点，同时用于幽门螺杆菌感染的防治显然具有显著的进步。
Description
技术领域
本发明属于生物制药技术领域，尤其涉及Houttuynoid B在制备抗幽门螺杆菌药物中的应用。
背景技术
幽门螺杆菌(Helicobacter pylori，Hp)是一种革兰氏阴性螺旋状细菌。研究显示，幽门螺杆菌是急、慢性胃炎以及胃、十二指肠溃疡的主要致病原因,并可能与胃癌和胃粘膜相关性淋巴样组织(MALT)恶性淋巴瘤发病有关。最近，世界卫生组织将Hp归为I类致癌物，它在胃癌发展中起主导作用。目前流行的治疗Hp感染的方案是同时服用质子泵抑制剂（PPI）加两种抗生素（克拉霉素，阿莫西林、四环素、甲硝唑等选二种）的三联疗法。影响三联疗法的最主要因素被认为是Hp对抗菌剂的耐药性；另一严重问题是质子泵抑制剂会诱发消化不良，大量抗菌剂则导致消化道内菌群的严重毁灭。因此，寻找高效、安全的抗Hp活性一类新药物成为一个重要和迫切的任务。
本发明涉及的化合物Houttuynoid B是一个2012年发表（Chen, S. D. et al., 2012. Houttuynoid B_E, Anti-Herpes Simplex Virus Active Flavonoids with Novel Skeletons from Houttuynia cordata. Organic Letters 14 (7), 1772–1775.）的新骨架化合物，该化合物拥有全新的骨架类型，目前的用途仅仅涉及抗单纯疱疹病毒活性（Chen, S. D. et al., 2012. Houttuynoid B_E, Anti-Herpes Simplex Virus Active Flavonoids with Novel Skeletons from Houttuynia cordata. Organic Letters 14 (7), 1772–1775.），对于本发明涉及的Houttuynoid B在制备治疗抗幽门螺杆菌药物中的用途属于首次公开，由于骨架类型属于全新的骨架类型，而且其对于幽门螺杆菌抑制活性强得意想不到，不存在由其他化合物给出任何启示的可能，具备突出的实质性特点，同时用于幽门螺杆菌感染的防治显然具有显著的进步。
发明内容
本发明的目的是研究Houttuynoid B在抗幽门螺杆菌药物中的应用。
所述化合物Houttuynoid B结构如式（Ⅰ）所示：
Houttuynoid B的体外实验表明，Houttuynoid B具有很强的抗幽门螺旋杆菌活性，纸片法显示其抑菌圈直径为29 mm (ATCC43504)。用琼脂稀释法显示它能完全抑制5个随机的临床菌株（Hp001、Hp003、Hp004、Hp018和Hp036）和1个标准菌株 (ATCC43504)的生长，最小抑菌浓度（MIC）均为1.0 μg/ml。用氨苄西林作阳性对照，其对6株测试菌完全抑制的最小浓度（MIC）为2.0 μg/ml。
本研究结果显示，Houttuynoid B的抑制幽门螺旋杆菌活性的能力比氨苄西林强，说明对于与幽门螺旋杆菌密切相关的急、慢性胃炎、胃、十二脂肠溃疡等疾病来讲，Houttuynoid B是一个极具开发潜力的化合物。它可直接用于相应疾病的治疗以及相关药物的制备。
本发明涉及的Houttuynoid B在制备治疗抗幽门螺杆菌药物中的用途属于首次公开，由于骨架类型属于全新的骨架类型，而且其对于幽门螺杆菌抑制活性强得意想不到，不存在由其他化合物给出任何启示的可能，具备突出的实质性特点，同时用于幽门螺杆菌感染的防治显然具有显著的进步。
具体实施方式
本发明所涉及化合物Houttuynoid B的制备方法参见文献（Chen, S. D. et al., 2012. Houttuynoid B_E, Anti-Herpes Simplex Virus Active Flavonoids with Novel Skeletons from Houttuynia cordata. Organic Letters 14 (7), 1772–1775.）。
以下通过实施例对本发明作进一步详细的说明，但本发明的保护范围不受具体实施例的任何限制，而是由权利要求加以限定。
实施例1：本发明所涉及化合物Houttuynoid B片剂的制备：
取20克化合物Houttuynoid B，加入制备片剂的常规辅料180克，混匀，常规压片机制成1000片。
实施例2：本发明所涉及化合物Houttuynoid B胶囊剂的制备：
取20克化合物Houttuynoid B，加入制备胶囊剂的常规辅料如淀粉180克，混匀，装胶囊制成1000片。
下面通过药效学实验来进一步说明其药物活性。
Houttuynoid B的药理实验
1）供试菌株
幽门螺杆菌(Helicobacter pylori，Hp)标准菌株ATCC 43504购于美国菌种保存中心(American Type Culture Collection，ATCC)。15株Hp临床菌株采自江苏省人民医院消化科、江苏省中医院检验科和南京市儿童医院胃镜室接受胃镜检查的患者；在连续胃镜检查中对消化性溃疡、十二指肠球炎或疣状胃炎的患者，先经快速尿素酶实验确定为Hp阳性者，再取胃窦黏膜1-2块，切碎后接种于含8%马血清、三甲氧苄氨嘧啶（trimethropin, TMP）1.25 g/L、多粘菌素（polymyxin）B2500 U/L、万古霉素(vancomycin)10 mg/L的Columbia选择性琼脂培养基中，于37 °C在微氧环境下(5% O2, 10% CO2 和 85% N2)培养72小时。收集细菌，经涂片革兰氏染色，氧化酶、触酶和尿素酶鉴定为阳性后，传代纯培养，所得菌株作为实验菌株。
2）菌株培养
我们采用微需氧袋（购自上海医科大学）进行HP的菌株培养，它可通过化学反应产生Hp所需要的微需氧环境。
3）生物活性测定
采用纸片法（Microbiological paper method）测定化合物对幽门螺杆菌的抑制作用，用琼脂稀释法来测定供试样品的最低抑菌浓度(minimal inhibitory concentration, MIC)。
I. 纸片法实验
(A) 准备培养基 将配制好的Columbia培养基经高压蒸汽灭菌后，冷却至50-60℃，加8%马血清或绵羊血，混匀倾注于已经灭菌的培养皿中，每皿7-10 ml，培养基厚度为1.5 mm(无菌操作)。
(B) 转接实验菌（涂菌） 用微量取样器取稀释好的108CFU/ml (1OD660=108 CFU/ml)Hp的菌悬液0.1 ml均匀地涂抹在适宜的培养皿表面。倒置于37oC烘干箱中15 min后取出，目的使琼脂表面干燥，备用。
(C) 贴样品纸片 用微量取样器取6 μl待测样品 (质量浓度2 mg/ml) 注入已经灭菌的圆滤纸片上。用无菌镊子镊取含样品的纸片和对照空白纸片，按无菌操作分别纸片紧贴于含菌琼脂表面，每隔一定距离贴一张纸片。每种菌做3皿，所得结果求其平均值。
(D) 培养 将各平皿置于微需氧袋中，封口，打开气体发生器，再置于37oC培养箱中培养72h。
(E) 测抑菌圈直径 取出平板后，分别测量各纸片周围抑菌圈直径的大小。参照对照组的结果，可得出待测样品敏感实验的结果。重复三次。
II.琼脂稀释法测定MIC
(A) 药物平板的制备 首先将测试的化合物用二甲基亚砜（DMSO）溶液配制成0.5 mg/ml的母液，再用无菌水稀释，最终配成10.0，8.0，6.0，4.5，4.0，3.5，3.0，2.5，2.0，1.5，1.0，0.5和0.25 μg/ml的浓度系列，DMSO在介质中的浓度小于1%。将1 ml配制好的测试化合物溶液与保温于50°C 的9 ml哥伦比亚培养基另加1 ml保温于50 °C的马血清充分混匀，浇制入培养皿中冷却即成。
(B) 转接实验菌（涂菌） 用微量取样器吸取稀释好的1×108 CFU/ml Hp的菌悬液0.1 ml均匀地涂抹在培养皿表面，倒置于37oC烘干箱中15 min后取出，目的使琼脂表面干燥，备用。
(C) 确定MIC 将待测培养皿在微需氧袋(含：85% N2, 10% CO2和5% O2)中，保温37oC培养72小时，观察Hp生长情况，与空白组相对照，以完全没有菌生长的样品最低浓度为最低抑菌浓度(minimal inhibitory concentration, MIC)值。阳性对照为氨苄西林(Ampicillin)。
3、Houttuynoid B的药理实验结果
体外实验表明，Houttuynoid B具有很强的抗幽门螺旋杆菌活性，纸片法显示其抑菌圈直径为29 mm (ATCC43504)。用琼脂稀释法显示它能完全抑制5个随机的临床菌株（Hp001、Hp003、Hp004、Hp018和Hp036）和1个标准菌株 (ATCC43504)的生长，最小抑菌浓度（MIC）均为1.0 μg/ml。用氨苄西林作阳性对照，其对6株测试菌完全抑制的最小浓度（MIC）为2.0 μg/ml。
结论：Houttuynoid B抑制幽门螺旋杆菌活性的能力比氨苄西林强，说明对于与幽门螺旋杆菌密切相关的急、慢性胃炎、胃、十二脂肠溃疡等疾病来讲，Houttuynoid B是一个极具开发潜力的化合物。它可直接用于相应疾病的治疗以及相关药物的制备。
Claims (1)
1.Houttuynoid B在制备抗幽门螺杆菌药物中的应用，所述化合物Houttuynoid B结构如式（Ⅰ）所示：
式（Ⅰ）。
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