WO2011026362A1 - 眼镜蛇短链神经毒素在制备治疗关节炎药物中的用途 - Google Patents

眼镜蛇短链神经毒素在制备治疗关节炎药物中的用途 Download PDF

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WO2011026362A1
WO2011026362A1 PCT/CN2010/073878 CN2010073878W WO2011026362A1 WO 2011026362 A1 WO2011026362 A1 WO 2011026362A1 CN 2010073878 W CN2010073878 W CN 2010073878W WO 2011026362 A1 WO2011026362 A1 WO 2011026362A1
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cobrotoxin
cobra
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arthritis
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秦正红
刘艳丽
邹容
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Suzhou University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/58—Reptiles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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  • the invention relates to a cobra short-chain neurotoxin (Cobrotoxin) Use in the preparation of a medicament for treating arthritis.
  • Cobrotoxin cobra short-chain neurotoxin
  • Snake venom is a complex mixture of various components secreted by the snake's venom glands. 90% of the dry matter of snake venom The above are proteins, which are the main components of their toxicity and their biological activities. The traditional medicine of the motherland believes that the cobra and its toxic components can pass through the meridians, rheumatism, and have the effect of strengthening the body. As early as the beginning of the twentieth century, people began to use snake venom to alleviate malignant tumor pain, neuralgia and joint pain, and then appeared. A series of reports on morphine-like analgesic effects of snake venom. With the deepening of research, snake venom and its products have been used in clinical practice, in addition to analgesic effects, in the anti-rheumatic, anti-tumor and treatment of nervous system diseases have a good effect.
  • Cobra short-chain neurotoxin (Cobrotoxin) whose sequence is mktllltllv vtivcldlgy Tlechnqqss qtptttgcsg getncykkrw rdhrgyrter gcgcpsvkng ieinccttdr cnn
  • the purified cobratoxin contains 64-83 amino acids and has a molecular weight of about 6946.
  • cobra short-chain neurotoxin (Cobrotoxin)
  • the treatment of rheumatoid arthritis has not been reported yet. We first found that it has a good anti-rheumatic arthritis effect.
  • the object of the present invention is to provide a cobra short-chain neurotoxin (Cobrotoxin) Use in the preparation of a medicament for treating arthritis.
  • Cobrotoxin cobra short-chain neurotoxin
  • the technical scheme of the present invention is: a cobra short-chain neurotoxin (Cobrotoxin)
  • a cobra short-chain neurotoxin (Cobrotoxin)
  • the use in the preparation of a medicament for treating arthritis includes oral liquids, capsules, paints, cataplasms, sprays, injections and the like, and the medicaments also include various unilateral and combination preparations.
  • Cobra short-chain neurotoxin ( Cobrotoxin ) Not only can it improve joint swelling and pain, but also improve the pathological changes of bones and joints.
  • Cobratoxin is less in dosage and has a wide effective range from 1-600 ⁇ g/kg Both have a good effect on the treatment of rheumatoid arthritis.
  • Cobra short-chain neurotoxin ( Cobrotoxin )
  • routes of administration including dermal administration, oral administration, oral (nasal) mucosal spray, and injection are effective.
  • Cobra short-chain neurotoxin (Cobrotoxin, 1-100 ⁇ g/kg Intraperitoneal injection can reduce the circumference of the ankle joint of rats with primary adjuvant arthritis and increase the mechanical pain threshold of rats.
  • Cobra short-chain neurotoxin (Cobrotoxin, 1-100 ⁇ g/kg Intraperitoneal injection can reduce the circumference of the ankle joint in rats with secondary adjuvant arthritis and increase the mechanical pain threshold of rats.
  • Cobra short-chain neurotoxin (Cobrotoxin, 1-400 ⁇ g/kg Administration by intragastric administration can reduce the circumference of the ankle joint of rats with primary adjuvant arthritis and increase the mechanical pain threshold of rats.
  • Cobra short-chain neurotoxin (Cobrotoxin, 1-400 ⁇ g/kg Skin coating administration can reduce the circumference of the ankle joint in rats with secondary adjuvant arthritis and increase the mechanical pain threshold of rats.
  • Cobra short-chain neurotoxin (Cobrotoxin, 1-400 ⁇ g / kg Skin coating administration can reduce the circumference of the ankle joint in rats with secondary adjuvant arthritis and increase the mechanical pain threshold of rats.
  • Cobra short-chain neurotoxin Effect of intragastric or transdermal administration on the circumference of ankle joint caused by Freund's complete adjuvant in rats Joint circumference difference (mm) Group Dose ( ⁇ g / kg ) 6 h 18 h 42 h Gastrointestinal group 50 11.3 ⁇ 2.
  • Cobratoxin (9, 18 ⁇ g/kg) injection can significantly reduce the difference in circumferential circumference of primary rats, increase the pain threshold, and its analgesic effect is better than aspirin ( 100000 ⁇ g/kg).
  • the results are shown in Tables 3 and 4.
  • Cobratoxin significantly reduced the circumferential length difference and increased the pain threshold in secondary rats.
  • Cobra short-chain neurotoxin (18 ⁇ g/kg ) was significantly different from the blank control group on the 15th day after the injection of Freund's complete adjuvant . The results are shown in Table 5.

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Description

眼镜蛇短链神经毒素在制备治疗关节炎药物中的用途
技术领域
本发明涉及一种眼镜蛇短链神经毒素 （ Cobrotoxin ） 在制备治疗关节炎药物中的用途。
背景技术
蛇毒是由蛇的毒腺分泌的多种组分构成的复杂混合物。蛇毒的干物质中 90% 以上是蛋白质，是其毒性和其生物学活性的主要成分。祖国传统医学认为眼镜蛇及其毒性成分可通经络，祛风湿，并具有强身健体之功效，早在二十世纪初，人们就开始应用蛇毒来缓解恶性肿瘤疼痛、神经痛和关节痛，随后出现一系列关于蛇毒有类似吗啡样镇痛作用的报道。随着研究的不断深入，现在，蛇毒及其制品已应用于临床，除了镇痛作用外，在抗风湿、抗肿瘤以及在神经系统疾病治疗方面都有很好的疗效。
眼镜蛇短链神经毒素 (Cobrotoxin) 其序列是 mktllltllv vtivcldlgy tlechnqqss qtptttgcsg getncykkrw rdhrgyrter gcgcpsvkng ieinccttdr cnn ，所提纯的眼镜蛇短链神经毒素 (Cobrotoxin) 含 64-83 个氨基酸，其分子量为 6946 左右。 目前关于眼镜蛇短链神经毒素 (Cobrotoxin) 治疗风湿性关节炎的研究还没有报道，我们首先发现其有良好的抗风湿性关节炎的作用。
发明内容
本发明目的是：提供一种眼镜蛇短链神经毒素 （ Cobrotoxin ） 在制备治疗关节炎药物中的用途。
本发明的技术方案是：一种眼镜蛇短链神经毒素 （ Cobrotoxin ） 在制备治疗关节炎药物中的用途，所述药物包括口服液、胶囊、涂剂、巴布剂、喷雾剂和注射剂等，所述药物还包括各种单方和复方制剂。
尽管中华眼镜蛇蛇毒在临床上已用于治疗风湿和缓解恶性肿瘤疼痛、神经痛和关节痛等，但目前还没有文献报道中华眼镜蛇中提纯的短链神经毒素 （ Cobrotoxin ） 可通过口服、鼻（口）粘膜喷雾、透皮给药和注射给药能治疗风湿，尤其是类风湿的报道。我们研究发现眼镜蛇短链神经毒素 （ Cobrotoxin ） 对弗氏完全佐剂导致的实验动物类风湿性关节炎，包括原发性和继发性类风湿性关节炎都有很好的治疗作用。这一发现，将对风湿性关节炎的研究和药物开发产生重大的影响，并有临床实用价值，为眼镜蛇短链神经毒素 （ Cobrotoxin ） 开辟临床新的用途。
本发明的优点是：
1. 眼镜蛇短链神经毒素 （ Cobrotoxin ） 不仅能改善关节肿大和疼痛等症状，还能改善骨关节和滑膜病理改变。
2. 眼镜蛇短链神经毒素 （ Cobrotoxin ） 用量少，有效范围大，从 1-600µg/kg 都有很好的治疗风湿性关节炎的作用。
3. 眼镜蛇短链神经毒素 （ Cobrotoxin ） 多种给药途径包括皮肤给药、口服、口（鼻）粘膜喷雾和注射等均有效。
下面结合实施例对本发明作进一步描述：
具体实施方式
实施例 ：根据眼镜蛇短链神经毒素 （ Cobrotoxin ） 在治疗类风湿性关节炎中的动物实验结果，以及眼镜蛇短链神经毒素 （ Cobrotoxin ） 可制成巴布剂的情况。本发明在治疗关节炎时，可采用巴布剂， 0.1-10 毫克 / 贴，贴于患病关节处，二天一次。
支持本发明的研究结果：
1 、眼镜蛇短链神经毒素（ Cobrotoxin, 1-100µg/kg ）腹腔注射给药能降低原发性佐剂关节炎大鼠踝关节周长，提高大鼠机械痛阈。
2 、眼镜蛇短链神经毒素（ Cobrotoxin, 1-100µg/kg ）腹腔注射给药能降低继发性佐剂关节炎大鼠踝关节周长，提高大鼠机械痛阈。
3 、眼镜蛇短链神经毒素（ Cobrotoxin, 1-400µg/kg ）灌胃给药能降低原发性佐剂关节炎大鼠踝关节周长，提高大鼠机械痛阈。
4 、眼镜蛇短链神经毒素（ Cobrotoxin, 1-400µg/kg ）皮肤涂布给药能降低继发性佐剂关节炎大鼠踝关节周长，提高大鼠机械痛阈。
5 、眼镜蛇短链神经毒素（ Cobrotoxin, 1-400µg/kg ）皮肤涂布给药能降低继发性佐剂关节炎大鼠踝关节周长，提高大鼠机械痛阈。
支持本发明的部分实验结果（图表）如下：
表 1 眼镜蛇短链神经毒素 (Cobrotoxin) 灌胃或经皮肤给药对弗氏完全佐剂致大鼠原发性关节炎踝关节周长的影响
　 　 关节周长差（mm）
组别 剂量 （ µg/kg ） 6 h 18 h 42 h
灌胃组 50 11.3±2. 6 11.0±2.0 7.3±4.2
100 10.7 ±1.7* 10.7 ±1.4 5.0 ±3.6*
200 13.4±2.1 10.9±1.5 9.4±0.9*
皮肤涂布 40 13.1 ±2.7 12.4 ±2.2 12.0 ±2.5
空白对照 80
160
--		 15.8±2.7
9.5 ±4.7 *
13.8±1.7##		 10.0±1.2*
9.0 ±4.1*
12.5±1.4##		 9.3±1.5
8.6 ±3.7
11.9±1.8##
正常对照 -- 0.13±0.12 0.11±0.10 0.24±0.19
*P<0.05 ，与空白对照组相比 ; ##P<0.01, 与正常对照组相比
结果提示，与正常对照组相比，空白对照组大鼠在注射弗氏完全佐剂后， 6 ， 18 和 42 小时，踝关节周长明显增加。注射弗氏完全佐剂 6 小时，灌胃（ 100 µg/kg ）和皮肤涂剂（ 160µg/kg ）与空白对照组相比，大鼠踝关节周长明显降低； 18 小时，皮肤涂布（ 80 ， 160µg/kg ）与空白对照组相比，大鼠踝关节周长差明显降低； 42 小时，眼镜蛇短链神经毒素 (Cobrotoxin) 灌胃（ 100 ， 200 µg/kg ）与空白对照组相比，大鼠踝关节周长差明显降低。结果见表 1 。
原发性佐剂关节炎病变持续 3 天后逐渐减轻，继发性病变由迟发性超敏反应引起，于致炎 10 天后出现新一轮的肿胀。佐剂致炎后 11-19 天，与正常对照组相比，大鼠踝关节差明显升高。 13 天，皮肤涂剂组（ 40 ， 80µg/kg ）明显降低大鼠关节周长。 15 天，灌胃组（ 200µg/kg ）和皮肤涂布组（ 40 ， 80 µg/kg ）明显降低大鼠关节周长差， 17 天，皮肤涂布组（ 40 ， 80 ， 160µg/kg ）明显降低大鼠关节周长差。结果见表 2 。
另外，我们采用注射给药的方法，考察眼镜蛇短链神经毒素 (Cobrotoxin) 对佐剂关节炎大鼠的抗炎和镇痛作用，实验结果如下：
眼镜蛇短链神经毒素 （ Cobrotoxin, 9 ， 18µg/kg ）注射给药能明显降低原发性大鼠关节周长差，提高痛阈，其镇痛效果优于阿司匹林 ( 100000 µg/kg) 。结果见表 3 ， 4 。
表 2 眼镜蛇短链神经毒素 (Cobrotoxin) 对弗氏完全佐剂致大鼠继发性关节炎踝关节周长的影响
　 　 关节周长差（mm）
组别 剂量 （ µg/kg ） 11 天 13 天 15 天 17 天 19 天
灌胃组 50 7.86 ±2.34 6.86 ±1.77 6.33 ±2.16 7.67 ±1.89 7.17 ±1.60
100 8.88 ±3.52 8.28 ±2.87 6.71 ±2.43 8.28 ±2.19 6.86 ±2.54
200 9.4 ±1.9 6.8 ±2.2 4.4 ±3.1* 7.0 ±3.1 6.4 ±4.1
皮肤涂布 40 9.8 ±1.7 5.0 ±1.5* 4.4 ±1.9* 2.0 ±1.3* 4.5 ±1.6
80 8.0 ±3.2 6.3 ±3.0* 3.3 ±1.8* 1.6 ±1.8* 2.9 ±2.2
空白对照 160
--		 11.3 ±3.6
10.25 ±1.75###		 8.3 ±3.3
9.0 ±1.80###		 7.1 ±4.6
7.88 ±3.09###		 5.8 ±5.4*
10.12 ±3.18##		 3.0 ±3.3
8.25 ±4.1##
正常对照组 ―― 0.18 ±0.06 0.10 ±0.05 0.12 ±0.03 0.14 ±0.05 0.16 ±0.07
*P<0.05 ，与空白对照组相比 ; ##P<0.01, ###P<0.001, 与正常对照组相比
表 3 眼镜蛇短链神经毒素 (Cobrotoxin) 对弗氏完全佐剂致大鼠原发性关节炎踝关节周长的影响
　 　 关节周长差（mm）
组别 剂量 （ µg/kg ） 6 h 18 h 42 h
短链神经毒素 9 6.4±1.0* 6.4±0.9* 5.3±1.0***
18 8.1 ±0.6 7.1 ±0.6* 6.1 ±0.7***
阿司匹林 100000 6.7 ±0.6* 8.1 ±0.7 7.5 ±0.8**
空白对照组 -- 9.3 ±0.5## 10.0 ±0.7### 11.0 ±0.7###
正常对照 -- 0.13±0.12 0.11±0.10 0.24±0.19
*P<0.05, ， ***P<0.001 ，与空白对照组相比
表 4 眼镜蛇短链神经毒素 (Cobrotoxin) 对弗氏完全佐剂致大鼠原发性关节炎机械痛阈的影响
　 　 痛阈（g）
组别 剂量 （ µg/kg ） 6 h 18 h 42 h
眼镜蛇短链神经毒素 9 5.3 ±1.2 13.3 ±1.1* 35.7 ±6.3*
18 8.1 ±1.3 14.3 ±0.7* 50.3 ±6.3***
阿司匹林 100000 7.9 ±2.2 11.7 ±1.6 23.4 ±6.9
空白对照组 　-- 4.3 ±0.8 8.4 ±1.5 16.7 ±3.4
*P<0.05, ***P<0.001 ，与空白对照组相比
眼镜蛇短链神经毒素 (Cobrotoxin) 明显降低继发性大鼠关节周长差，提高痛阈。在注射弗氏完全佐剂后第 15 天，眼镜蛇短链神经毒素（ 18 µg/kg ）与空白对照组相比，有显著性差异。结果见表 5 。
在注射弗氏完全佐剂后第 15 和 17 天，眼镜蛇短链神经毒素（ 9 ， 18 µg/kg ）与空白对照组相比，有显著性差异，提示其能降低关节炎疼痛。结果见表 6 。
表 5 眼镜蛇短链神经毒素 (Cobrotoxin) 对弗氏完全佐剂致大鼠继发性关节炎踝关节周长的影响
　 　 关节周长差（mm）
组别 剂量 （ µg/kg ） 11 天 13 天 15 天 17 天 19 天
眼镜蛇短链神经毒素 9 5.6 ±1.1 5.8 ±1.0 6.5 ±0.8 6.2 ±1.2 5.8 ±1.0*
18 4.1 ±0.8 5.3 ±1.0 4.1 ±1.1*** 6.4 ±0.7 6.8 ±1.2
阿司匹林 100000 4.2 ±0.9 5.2 ±0.8 5.8 ±0.7* 4.3 ±0.9* 4.8 ±0.8*
空白对照组 -- 5.4 ±0.5### 7.3 ±0.7### 8.7 ±0.8### 6.9 ±0.8### 8.2 ±0.6###
正常对照 -- 0.4 ±0.2 0.2 ±0.2 0.5 ±0.2 0.8 ±0.4 5.8 ±1.0
*P<0.05, ***P<0.001 ，与空白对照组相比， ###P<0.001 ，与正常对照组相比
表 6 眼镜蛇短链神经毒素 (Cobrotoxin) 对弗氏完全佐剂致大鼠继发性关节炎机械痛阈的影响
　 　 痛阈（ g ）
组别 剂量 （ µg/kg ） 11 天 13 天 15 天 17 天 19 天
眼镜蛇短链神经毒素 9 20.6 ±3.4 19.3 ±8.7 39.7 ±9.6* 42.0 ±11.4* 37.7 ±10.3
18 15.5 ±3.5 12.7 ±4.3 54.3 ±5.7*** 60.0 ±0.0*** 45.0 ±15.0
阿司匹林 100000 20.5 ±2.5 13.8 ±3.0 60.0 ±0.0*** 48.7 ±7.2* 54.3 ±5.7
空白对照组 -- 14.2 ±2.9# 7.0 ±1.1# 16.0 ±3.6## 16.0 ±3.5# 33.7 ±8.6
正常对照组 -- 38.5 ±9.8 14.8 ±3.8 48.7 ±7.2 35.5 ±7.9 54.3 ±5.7
*P<0.05, ***P<0.001 ，与空白对照组相比， # P<0.05 ， ##P<0.01 ，与正常对照组相比。

Claims (1)

  1. 1 ．一种眼镜蛇短链神经毒素在制备治疗关节炎药物中的用途。
    2 ．根据权利要求 1 所述的眼镜蛇短链神经毒素在制备治疗关节炎药物中的用途，其特征在于：所述药物包括口服液、胶囊、涂剂、巴布剂、喷雾剂和注射剂等各种剂型。
    3 ．根据权利要求 1 所述的眼镜蛇短链神经毒素在制备治疗关节炎药物中的用途，其特征在于：所述药物还包括各种单方和复方制剂。
PCT/CN2010/073878 2009-09-07 2010-06-12 眼镜蛇短链神经毒素在制备治疗关节炎药物中的用途 Ceased WO2011026362A1 (zh)

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CN116889558A (zh) * 2023-08-28 2023-10-17 四川大学华西医院 阿戈美拉汀用于制备治疗关节炎的药物的用途

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CN101648000B (zh) * 2009-09-07 2012-11-07 苏州大学 眼镜蛇短链神经毒素在制备治疗关节炎药物中的用途
CN102139093A (zh) * 2011-03-24 2011-08-03 苏州大学 眼镜蛇短链神经毒素在制备鞘内给药镇痛药物中的应用
CN102178928B (zh) * 2011-04-13 2013-05-29 昆明茂博生物科技有限公司 眼镜蛇毒神经毒在屈光不正治疗药物中的应用
CN102406665A (zh) * 2011-11-16 2012-04-11 苏州人本药业有限公司 物理改性后的眼镜蛇蛇毒在制备治疗关节炎药物中的应用
CN111939179B (zh) * 2020-08-24 2022-08-19 苏州人本药业有限公司 眼镜蛇蛇毒或其提取物在制备降尿酸和/或抗痛风性关节炎的药物中的应用

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