WO2015106678A1 - 孕酮在预防或治疗低压缺氧引起的高原病中的应用 - Google Patents

孕酮在预防或治疗低压缺氧引起的高原病中的应用 Download PDF

Info

Publication number
WO2015106678A1
WO2015106678A1 PCT/CN2015/070654 CN2015070654W WO2015106678A1 WO 2015106678 A1 WO2015106678 A1 WO 2015106678A1 CN 2015070654 W CN2015070654 W CN 2015070654W WO 2015106678 A1 WO2015106678 A1 WO 2015106678A1
Authority
WO
WIPO (PCT)
Prior art keywords
progesterone
hypoxia
altitude
high altitude
hypobaric hypoxia
Prior art date
Application number
PCT/CN2015/070654
Other languages
English (en)
French (fr)
Inventor
银巍
陈婕思
颜光美
陆秉正
朱文博
胡海燕
邱鹏新
黄奕俊
张静夏
Original Assignee
中山大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中山大学 filed Critical 中山大学
Publication of WO2015106678A1 publication Critical patent/WO2015106678A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics

Definitions

  • the present invention relates to a novel pharmaceutical use of the compound progester-4-ene-3,20-dione, Progesterone.
  • hypobaric hypoxia occurs mainly in the special environment of the plateau, also known as high altitude hypoxia.
  • HASH Acute Hypobaric Hypoxia
  • AMS Acute mountain sickness
  • HACE high altitude cerebral edema
  • HAPE high-altitude pulmonary edema
  • the main drugs for AMS and HACE prevention and treatment are mainly acetazolamide and dexamethasone.
  • Acetazolamide can rapidly improve the body's ability to adapt. It is the only drug approved by the US FDA to prevent acute altitude sickness, but it is also used only for mild AMS prophylaxis (2). However, the improvement of the ability to adapt to and adapt to hypoxia has always been limited, and the hypoxic environment in the body has not improved. The damage to the nervous system will become more and more serious with the prolongation of time, showing various neurophysiological and psychological clinical conditions. symptom. And acetazolamide is a sulfonamide with a high incidence of allergic reactions (7-10%) (2). At the same time, liver and kidney dysfunction should be used with caution. In addition, it has been reported that acetazolamide causes damage to the fear memory of rats (3).
  • dexamethasone The side effects of dexamethasone are widely known (4), and the use of mountain disease prevention and treatment can generally not exceed 10 days to prevent glucocorticoid toxicity or adrenal suppression, and this drug is not used in pediatrics.
  • Dexamethasone does not promote the body's adaptive function, and withdrawal will lead to a rebound in the condition.
  • the improvement of symptoms in dexamethasone to prevent AMS may improve mood only because of reducing vomiting and nausea, but the objective physiological abnormalities of hypoxia response are not improved. Therefore, the prevention of AMS may only be masked by dexamethasone. Symptoms, there is no real protection for the body (5).
  • Progesterone synthetic analog medroxyprogesterone (17 ⁇ -hydroxy-6 ⁇ -methylprogesterone), 20mg / d dose can improve oxygen saturation (6); but it has been reported that even the use of 60mg / d dose of medroxyprogesterone Improving AMS has no effect (2).
  • Progesterone and medroxyprogesterone are only slightly different in the side chain group, but our study found that progesterone unexpectedly can significantly improve the neurological function score of hypobaric hypoxia, protect the brain caused by hypobaric hypoxia Pathological damage, thus effectively preventing high altitude hypoxia caused by altitude sickness.
  • the object of the present invention is to provide a prodrug for the preparation of a medicament for treating or preventing high altitude hypoxia caused by high altitude hypoxia, thereby providing a new drug for the prevention and treatment of altitude sickness.
  • Another aspect of the invention provides a method of treating or preventing a high altitude disease caused by hypobaric hypoxia, the method comprising administering to a subject in need thereof an effective amount of progesterone, such as a mammal, such as a human, other Primates, competitive animals, animals with commercial interests (such as cattle), farm animals (such as horses) or pets (such as dogs and cats).
  • the high altitude disease is an acute high altitude disease caused by high altitude hypobaric hypoxia, including but not limited to acute altitude sickness, acute altitude sickness, and acute high altitude cerebral edema.
  • the high altitude disease is a chronic high altitude disease caused by high altitude hypobaric hypoxia, including but not limited to chronic altitude sickness.
  • the medicament comprises an additional active ingredient for the treatment or prevention of high altitude hypoxia caused by high altitude hypoxia.
  • the animal model of non-human primate hypobaric hypoxia model showed that progesterone treatment can significantly improve the neurological function score of experimental animals under hypobaric hypoxia, and has significant protective effect on neurological damage caused by hypobaric hypoxia.
  • Progesterone has preventive and therapeutic effects on AMS and HACE.
  • progesterone significantly blocks the increase of brain water content caused by hypobaric hypoxia. Electron microscopic morphological analysis shows that progesterone can reduce cerebral vasogenic edema caused by hypobaric hypoxia. Morphological studies of HE staining indicate that low pressure The damage of the cortex and white matter caused by hypoxia, progesterone can significantly alleviate these pathological changes.
  • Figure 1 Progesterone improves neurological functional scores in male cynomolgus monkeys treated with hypobaric hypoxia.
  • NN normobaric normoxia control
  • HH plateau hypobaric hypoxia 7500 m 48-hour solvent control ((hypobaric hypoxia, HH));
  • PROG plateau hypobaric hypoxia 7500 m 48-hour progesterone pre- Processing group.
  • Figure 2 Progesterone in the right cerebral ventricle of male cynomolgus monkey treated with hypobaric hypoxia (7500m treatment for 48 hours) The impact of water volume.
  • Figure 3 Observation of progesterone pretreatment under electron microscopy reduces angioedema in the cerebral cortex of cynomolgus monkeys after hypobaric hypoxia.
  • NN plain control group;
  • HH plateau hypobaric hypoxia 7500 m 48-hour solvent control group;
  • PROG plateau hypobaric hypoxia 7500 m 48-hour progesterone pretreatment group.
  • the thick arrow refers to the capillaries of the frontal cortex of the brain, and the thin arrow shows the VRS of the perivascular space.
  • Figure 4 HE staining to observe progesterone reduced brain cortex and white matter damage in hypobaric hypoxia experiments.
  • NN plain control group;
  • HH plateau hypobaric hypoxia 7500 m 48-hour solvent control group;
  • PROG plateau hypobaric hypoxia 7500 m 48-hour progesterone pretreatment group.
  • Black arrows refer to capillaries.
  • A) brain frontal cortex area;
  • B) white matter area.
  • Animals 18 healthy male cynomolgus monkeys (Macaca fascicularis), 6 to 6.5 years old, weighing 6.8-7.5 Kg.
  • the use of experimental animals was approved by the Laboratory Animal Management and Use Committee of Sun Yat-sen University and the Experimental Animal Ethics Committee of Sun Yat-sen University.
  • the experimental protocol is in line with animal protection, animal welfare and ethical principles and regulations.
  • the plateau environment simulation low-pressure tank group is a simulated low-temperature and low-pressure experimental platform system for the plateau environment, which can automatically control the low temperature and low pressure environment at any altitude below 10,000 meters and any temperature above -30 °C.
  • the cynomolgus monkeys reared in the animal room were transferred to a low pressure chamber for 1 day to adapt to the experimental environment.
  • the cabin temperature was constant at 22 ° C and the average air flow rate was 150 m 3 /h.
  • Neurological function scores were assessed and recorded according to literature method (7). Stayed at a simulated low altitude of 7,500 meters in the low-pressure chamber for 24 hours (since the skill limit of the human body cannot be measured at 7500 meters, down to 6000 meters), and was evaluated by two trained observers who did not understand the grouping and did not participate in the administration. Neurological function scores were recorded.
  • Brain water content measurements were performed according to literature method (8).
  • the experimental monkey stayed in the low-pressure chamber at a simulated altitude of 7,500 meters for 48 hours.
  • the experimental monkey was sacrificed by anesthesia, and the monkey brain was quickly removed.
  • the left hemisphere was removed and the wet weight was weighed.
  • the left hemisphere was placed in a dry box, and the brain weight was weighed every day for a fixed time until the brain weight value no longer changed to the end of the experiment, and the end point brain weight was recorded.
  • Percentage of water content (left hemi-wet weight - left hemi-brain dry weight) / left hemi-brain wet weight ⁇ 100%.
  • the treated frontal cortex tissue was removed and cut into 1*1*1 mm and fixed in 2.5% glutaraldehyde electron microscopy fixative to prepare ultrathin sections.
  • the following items were observed by transmission electron microscopy: morphology and organelle status of neurons. , the structure of blood vessels, etc.
  • the treated frontal cortex tissue was removed and cut into 1*1*1 cm squares and fixed in 4% paraformaldehyde. Then, according to the conventional HE staining step, paraffin embedding, sectioning, and hematoxylin and eosin staining were observed under a microscope.
  • Fig. 1 The results indicate that progesterone can significantly improve the neurological work of male cynomolgus monkeys treated with hypobaric hypoxia Can learn to score.
  • the experimental monkeys in the hypobaric hypoxia treatment (HH) group showed significant inhibition of consciousness, behavioral activities were greatly reduced, and dysfunction of motor and sensory system, neurological function scores appeared. 30.5 ⁇ 5.3, compared with the plain group without hypobaric hypoxia treatment, hypobaric hypoxia treatment (HH) caused obvious neurological impairment in experimental animals (P ⁇ 0.05), while the progesterone prevention group could significantly improve experimental monkeys. Neurological function score.
  • Progesterone can reduce the increase in brain water content in hypobaric hypoxia experiments. Calculating and analyzing the percentage of brain water content (see Table 2), the brain water content of the experimental monkey was 76.71% ⁇ 0.26% after 48 hours of simulated altitude in the low pressure chamber. The brain water content of the experimental monkey was compared with that of the plain group. Significant difference, P ⁇ 0.05; the brain water content of the drug progesterone intervention group was reduced to 76.12% ⁇ 0.47%, and the progesterone group was also significantly different from the model group, P ⁇ 0.05 (Fig. 2), and the progesterone group There was no significant difference compared to the plain group.
  • Progesterone can reduce the cerebral vasogenic edema of hypobaric hypoxia monkeys.
  • the hypoxic hypoxia model of the solvent control group showed significant widening of the extracorporeal cortex.
  • the perivascular space (Virchow Robin Space, VRS) showed severe edema exudation and a significant improvement in edema after progesterone preconditioning (Figure 3).
  • Progesterone can alleviate the damage of the cortex and white matter of monkeys under hypobaric hypoxia.
  • HE staining compared with the normal group (NN)
  • the hypovolemic hypoxic treatment group HH
  • A frontal cortex
  • B white matter
  • progesterone can significantly alleviate these pathologies.
  • the progesterone injection used in the present embodiment is a commercially available product of Zhejiang Xianyi Pharmaceutical Co., Ltd., and the preparation of progesterone for preventing or treating low altitude hypoxia-induced high altitude disease includes, but is not limited to, injection, oral capsule (pill), Suppositories and subcutaneous implants and external plaster preparations.
  • the progesterone injection preparation preparation may be 10 mg progesterone and 0.1 ml benzene per ml of progesterone injection. Methanol and 0.9 ml sesame oil.
  • the preparation process comprises the steps of first heating 0.9L sesame oil to 150 ° C for 1 h, cooling to room temperature, and dissolving 10 g of progesterone in 0.6 L of sesame oil; adding 100 ml of benzoic acid to the above solution, and mixing uniformly; adding the remaining sesame oil So that the total volume reaches 1L, and mix evenly; filter, dispense into 1000 ampoules.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Toxicology (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hematology (AREA)
  • Steroid Compounds (AREA)

Abstract

孕酮在制备治疗或预防低压缺氧造成的高原病的药物中的应用。孕酮对急性高原病和高原脑水肿具有预防和治疗效果。

Description

孕酮在预防或治疗低压缺氧引起的高原病中的应用 技术领域
本发明涉及化合物孕甾-4-烯-3,20-二酮，即孕酮(Progesterone)的新的药物用途。
背景技术
随着海拔上升，大气压降低且氧分压降低，吸入气氧分压过低导致动脉血氧分压降低，氧含量减少，组织供氧不足。这种低压缺氧(hypobaric hypoxia,HH)主要发生在高原这一特殊环境，也被称作高原低氧(high altitude hypoxia)。
当个体近期到达超过海拔2500米以上地区，在急性低压缺氧(Acute Hypobaric Hypoxia)发生时，如果个体适应不了这种环境变化，会相继发生高原性头痛(High-altitude headache，HAH)、急性高原病(Acute mountain sickness，AMS)，并且AMS可进一步发展为高原脑水肿(High altitude cerebral edema，HACE)和高原肺水肿(High-altitude pulmonary edema,HAPE)。已有大量报道，高原病根据程度不同主要表现出头痛、多言、失眠、步态不稳、受损伤的心智能力、嗜睡、神情恍惚麻木以及共济失调等神经功能上的症状(1)。
针对AMS和HACE防治常用药物主要是乙酰唑胺和地塞米松。
乙酰唑胺可以迅速提高身体适应能力，是美国FDA批准的唯一用于预防急性高原反应的药物，但也只用于轻度的AMS预防类药物(2)。但是，对于习服与适应缺氧能力的提高始终是有限的，体内缺氧环境并没有改善，随着时间延长对神经系统的损伤会越来越严重，表现出各种神经生理、心理的临床症状。并且乙酰唑胺是磺胺类药物，有较高的过敏反应发生率(7-10％)(2)。同时，肝、肾功能不全者也要慎用。另外，还有报道乙酰唑胺对大鼠的恐惧记忆认知造成损伤(3)。
地塞米松的副作用广为人知(4)，在高山病防治的使用一般不能超过10天，以防糖皮质激素毒性或者肾上腺抑制的发生，并且此药不予儿科使用。地塞米松并不会促进机体的适应功能，撤药会导致病情的反弹。并且地塞米松预防AMS时症状的改善可能仅仅因为减少呕吐恶心反应而改善了情绪，但对缺氧反应的客观生理不正常现象没有改进，因此这种预防AMS作用可能仅仅是地塞米松掩盖了症状，对机体并无真正保护作用(5)。
孕酮人工合成类似物甲羟孕酮(17α-hydroxy-6α-methylprogesterone)，20mg/d剂量可以改善氧饱和度(6)；但是已有报道表明即使使用60mg/d剂量的甲羟孕酮对改善AMS并无作用(2)。
Figure PCTCN2015070654-appb-000001
孕酮与甲羟孕酮在侧链基团上仅存在于的微小差异，但是我们的研究发现孕酮出人意料的可以显著改善低压缺氧处理的神经功能学评分，保护低压缺氧造成的脑部病理损伤，从而有效防治低压缺氧引起的高原病。
发明内容
本发明的目的在于提供孕酮在制备治疗或预防低压缺氧造成的高原病的药物中的应用，从而为高原病的预防与治疗提供一种新药物。本发明的另一个方面提供一种治疗或预防低压缺氧造成的高原病的方法，所述方法包括向有需要的对象施用有效量的孕酮，所述对象例如是哺乳动物，如人类、其他灵长类、竞技动物、具有商业利益的动物(如牛)、农畜(如马)或宠物(如狗和猫)。
在本发明的一个实施方式中，所述高原病为由高原性急性低压缺氧引起的急性高原病，包括但不限于急性高原头痛、急性高原反应和急性高原脑水肿。
在本发明的另一个实施方式中，所述高原病为由高原性慢性低压缺氧引起的慢性高原病，包括但不限于慢性高原反应。
在本发明的另一个实施方式中，所述药物包含额外的用于治疗或预防低压缺氧造成的高原病的活性成分。
非人灵长类低压缺氧模型动物模型的研究表明，孕酮处理可以显著改善低压缺氧环境下的实验动物的神经功能学评分，对低压缺氧导致的神经功能损伤具有显著保护作用，表明孕酮对AMS和HACE具有预防和治疗效果。
进一步机制研究表明，孕酮显著阻断低压缺氧导致的脑含水量上升，电镜形态学分析表明，孕酮可以减少低压缺氧导致的脑血管源性水肿，HE染色的形态学研究表明，低压缺氧造成的脑皮层与白质的损伤，给予孕酮可以明显缓解这些病理改变。
附图说明
图1:孕酮改善低压缺氧处理的雄性食蟹猴神经功能学评分。NN：常压常氧平原对照组(normobaric normoxia control)；HH：高原低压缺氧7500米48小时溶剂对照组((hypobaric hypoxia,HH))；PROG：高原低压缺氧7500米48小时孕酮预处理组。*P<0.05,NN vs.HH,#P<0.05,HH vs.PROG。
图2：孕酮对低压缺氧(7500m处理48小时)处理的雄性食蟹猴右脑含 水量的影响。
图3：电镜下观察孕酮预处理减少低压缺氧处理后食蟹猴脑皮层组织的血管性水肿。NN：平原对照组；HH：高原低压缺氧7500米48小时溶剂对照组；PROG：高原低压缺氧7500米48小时孕酮预处理组。粗箭头所指为大脑额叶皮层毛细血管，细箭头显示血管周隙VRS。
图4：HE染色观察孕酮减轻低压缺氧实验猴脑皮层与白质的损伤。NN：平原对照组；HH：高原低压缺氧7500米48小时溶剂对照组；PROG：高原低压缺氧7500米48小时孕酮预处理组。黑色箭头所指为毛细血管。(A):脑额叶皮层区域；(B):白质部位。
具体实施方式
下面通过具体实施例进一步解释本发明，但是本发明不仅限于实施例中。
孕酮的新用途验证
1.动物：健康雄性食蟹猴(Macaca fascicularis)18只，6至6.5岁，体重6.8-7.5Kg。实验动物的使用经过中山大学实验动物管理与使用委员会和中山大学实验动物伦理委员会批准，实验方案符合动物保护、动物福利和伦理原则和规定。
食蟹猴随机分为3组(表1)：
表1.实验动物分组说明
组别 处理
1(n＝6) 平原低压缺氧对照组
2(n＝6) 高原低压缺氧模型组(模拟高度7500米，溶剂对照组)
3(n＝6) 高原低压缺氧孕酮处理组
2.主要仪器：高原环境模拟低压舱群是模拟高原环境低温低压实验平台体系，可以自动化控制模拟1万米以下任意海拔高度、-30℃以上任意温度的低温低压环境。
3.主要试剂：黄体酮注射液(20mg/ml)浙江仙琚制药股份有限公司(国药准字H33020828)；4％多聚甲醛缓冲液购自广州威佳科技有限公司；盐酸氯胺酮注射液购自沈阳市兽药厂。
4.低压舱模拟7500米致食蟹猴高原缺氧模型制作及给药：
将饲养于动物房的食蟹猴转移放入低压舱内饲养1天以适应实验环境，舱内温度恒定于22℃，平均空气流速：150m3/h。
通过调节低压舱内气压来模拟3000、4500、6000、7500米海拔高度，以3米/秒(0至7500米)上升，前三个高度到达后停留30分钟并给与药物处理。平 原对照组实验猴在动物房未作其他处理，麻醉后放血处死；高原低压缺氧模型组给予孕酮注射液溶剂大豆油对照；高原低压缺氧孕酮处理组在模拟海拔升高前12小时分五点骨骼肌肌肉注射实验猴10mg/kg孕酮，在海拔高度达到6000米并停留30分钟后，再次分五点骨骼肌肌肉注射实验猴10mg/kg孕酮，随后海拔高度继续上升到7500米24小时后，海拔高度降到6000米(下降速度为2米/秒)，在神经功能评分后分五点骨骼肌肌肉注射实验猴10mg/kg孕酮，随后海拔高度继续上升到7500米，在7500米处理48小时后，盐酸氯胺酮注射液麻醉、放血处死动物并解剖取样。
5.检测指标
5.1动物神经功能评分
根据文献方法(7)评估并记录神经功能评分。在低压舱模拟高度7500米停留24小时(由于人体的技能限制不能在7500米活动，降至6000米进行评分)，由两位不了解分组情况且未参与给药的经培训的观察者评估并记录神经功能评分。
5.2左半球脑含水量测量
根据文献方法(8)进行脑含水量测量。实验猴在低压舱模拟高度7500米停留48小时后，麻醉放血处死实验猴，迅速取出猴脑，切取左半脑，称取其湿重。然后将左半脑置于干燥箱，每天固定时间称取脑重，直至脑重数值不再变化为实验结束终点，记录终点脑重。含水量百分比＝(左半脑湿重－左半脑干重)/左半脑湿重×100％。
5.3大脑额叶皮层组织透射电镜分析(Transmission eletron microscope analysis)
处理后的大脑额叶皮层组织取出后切成1*1*1毫米后固定于2.5％戊二醛电镜固定液后制作超薄切片，用透射电镜观察分析以下项目：神经元的形态和细胞器状况，血管的结构等。
5.4大脑额叶组织HE染色
处理后的大脑额叶皮层组织取出切成1*1*1cm的方块后固定于4％多聚甲醛中。之后按照常规HE染色步骤，进行石蜡包埋，切片，苏木素伊红染色后在显微镜下观察。
5.5脑含水量百分比：首先进行正态性检验和方差齐性检验，计算每组mean±SD、最大最小值并绘制误差条图，然后进行t-test检验。P<0.05表示与溶剂对照组比较有显著的统计学差异。
6.全部统计由SPSS 15.0统计软件完成。
结果(图1)表明，孕酮可以显著改善低压缺氧处理的雄性食蟹猴神经功 能学评分。实验猴在低压舱模拟7500米环境下24小时后，低压低氧处理(HH)组的实验猴出现明显的意识抑制，行为活动大为减少，且出现运动、感觉系统的功能障碍，神经功能评分为30.5±5.3，与未经低压缺氧处理的平原组比较，低压低氧处理(HH)导致了实验动物明显的神经功能损伤(P<0.05)，而给予孕酮预防组可以明显改善实验猴的神经功能评分。与之相比，孕酮处理组动物的神经功能有一定程度的恢复，神经功能评分为20.2±7.3。两组间具有统计学意义的差异(P<0.05)(图1)。表明孕酮处理改善低压缺氧导致的食蟹猴神经功能损伤具有显著保护作用。
孕酮可以减少低压缺氧实验猴脑含水量的上升。计算并分析脑含水量百分比(见表2)后显示，在低压舱内模拟高度7500米处理48小时后，实验猴的脑含水量76.71％±0.26％，与平原组相比，脑含水量具有显著差异，P<0.05；，药物孕酮干预组其脑含水量减至76.12％±0.47％，孕酮组与模型组相比也具有显著差异，P<0.05(图2)，且孕酮组与平原组相比则没有显著差异。结果表明，在低压舱内模拟高度7500米处理48小时使实验猴脑含水量增加，造成了低压缺氧损伤；而孕酮显著阻断低压缺氧导致的脑含水量上升，通过脑保护作用对AMS和HACE具有预防治疗效果。
表2 孕酮对低压缺氧处理的雄性食蟹猴脑含水量变化
  脑含水量％
平原常氧组 76.15±0.30(n＝6)
低压缺氧组(溶剂组) 76.71±0.26(n＝6)
低压缺氧孕酮组 76.12±0.47(n＝6)
孕酮可以减少低压缺氧实验猴脑血管源性水肿,在透射电镜下观察，与平原组、孕酮处理组比较，低压缺氧模型溶剂对照组动物大脑额叶皮层毛细血管外出现明显加宽的血管周隙(Virchow Robin Space，VRS)，表明出现严重的水肿渗出，而孕酮预处理后水肿得到明显改善(图3)。
孕酮可以减轻低压缺氧实验猴脑皮层与白质的损伤。经HE染色后观察(图4)与正常组相比(NN)，低压缺氧处理组(HH)脑额叶皮层区域(A)出现围绕微血管的明显空泡状变化(箭头所示)，结构明显疏松，血管周围的水肿液压迫管腔；白质部位(B)也出现明显海绵样改变，给予孕酮可以明显缓解这些病理。
药物组合物
本实施例中使用的孕酮注射剂是市售浙江仙琚制药股份有限公司产品，在孕酮制备预防或治疗低压缺氧引起的高原病的药物剂型包括但不限于注射剂、口服胶囊(丸)、栓剂以及皮下埋植剂及外贴膏药型制剂等。
孕酮注射剂制备处方可以为每毫升孕酮注射液含有10mg孕酮、0.1ml苯 甲醇和0.9ml芝麻油。制备工艺步骤包括首先将0.9L芝麻油加热至150℃，保温1h，冷却至室温后将10g孕酮溶解在0.6L芝麻油中；向上述溶液中加入100ml苯甲酸，并混合均匀；将剩余的芝麻油加入，使总体积达到1L，并混合均匀；过滤，分装至1000支安瓿瓶中即可。
参考文献
(1)Maa EH.Hypobaric hypoxic cerebral insults:the neurological consequences of going higher.NeuroRehabilitation 2010；26(1):73-84.
(2)Imray C,Wright A,Subudhi A,Roach R.Acute mountain sickness:pathophysiology,prevention,and treatment.Prog Cardiovasc Dis 2010May；52(6):467-84.
(3)Yang MT,Chien WL,Lu DH,Liou HC,Fu WM.Acetazolamide impairs fear memory consolidation in rodents.Neuropharmacology 2012Dec 8；67C:412-8.
(4)Eide RP,III,Asplund CA.Altitude illness:update on prevention and treatment.Curr Sports Med Rep 2012May；11(3):124-30.
(5)Levine BD,Yoshimura K,Kobayashi T,Fukushima M,Shibamoto T,Ueda G.Dexamethasone in the treatment of acute mountain sickness.N Engl J Med 1989Dec 21；321(25):1707-13.
(6)叶任高：《内科学第六版》，人民卫生出版社，2002，P998
(7)朱华,卢珊,冯铭,李秦等，一种改进的非人灵长类神经功能缺损评价方法,中国比较医学杂志,2011,21(9):58-62.
(8)Patir H,Sarada SK,Singh S,Mathew T,Singh B,Bansal A.Quercetin as a prophylactic measure against high altitude cerebral edema.Free Radic Biol Med 2012Aug 15；53(4):659-68.

Claims (6)

  1. 孕酮在制备治疗或预防低压缺氧造成的高原病的药物中的应用。
  2. 根据权利要求1所述的应用，其中所述高原病为由高原性急性低压缺氧引起的急性高原病。
  3. 根据权利要求2所述的应用，其中由高原性急性低压缺氧引起的急性高原病选自急性高原头痛、急性高原反应和急性高原脑水肿。
  4. 根据权利要求1所述的应用，其中所述高原病为由高原性慢性低压缺氧引起的慢性高原病。
  5. 根据权利要求4所述的应用，其中所述由高原性慢性低压缺氧引起的慢性高原病为慢性高原反应。
  6. 根据权利要求1所述的应用，所述药物包含额外的用于治疗或预防低压缺氧造成的高原病的活性成分。
PCT/CN2015/070654 2014-01-17 2015-01-14 孕酮在预防或治疗低压缺氧引起的高原病中的应用 WO2015106678A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410021720.6A CN103768072A (zh) 2014-01-17 2014-01-17 孕酮在预防或治疗低压缺氧引起的高原病中的应用
CN201410021720.6 2014-01-17

Publications (1)

Publication Number Publication Date
WO2015106678A1 true WO2015106678A1 (zh) 2015-07-23

Family

ID=50561134

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/070654 WO2015106678A1 (zh) 2014-01-17 2015-01-14 孕酮在预防或治疗低压缺氧引起的高原病中的应用

Country Status (2)

Country Link
CN (1) CN103768072A (zh)
WO (1) WO2015106678A1 (zh)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USD874064S1 (en) 2018-05-18 2020-01-28 Trudell Medical International Mask
USD893806S1 (en) 2018-11-09 2020-08-18 Trudell Medical Internationl Mask and shroud
USD903097S1 (en) 2018-05-18 2020-11-24 Trudell Medical International Mask
US11439869B2 (en) 2017-05-19 2022-09-13 Trudell Medical International Positive expiratory pressure device

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108653292B (zh) * 2018-07-03 2019-05-24 中国人民解放军总医院 一种化合物在治疗或预防高原病中的用途
CN115997833B (zh) * 2022-12-01 2024-09-24 中国人民解放军陆军勤务学院 一种适用平原移居高原环境的女性冻干功能茶饮及其制备方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HONIGMAN, B. MD ET AL.: "Acute Mountain Sickness in a General Tourist Population at Moderate Altitudes", ANNALS OF INTERNAL MEDICINE, vol. 118, no. 8 , 99, 1 May 1993 (1993-05-01), pages 591, XP055213266 *
MOORE, L.G.: "Adaptation to high altitude", ANNUAL REVIEW OF ANTHROPOLOGY, vol. 12, pages 299 *
WANG, XIAOYIN ET AL.: "Protective Effect of Progesterone on Brain Edema in Newborn Rats with Hypoxic-ischemic Encephalopathy", JOURNAL OF APPLIED CLINICAL PEDIATRICS, vol. 20, no. 8 , 00, 1 August 2005 (2005-08-01), pages 758 - 759, XP055213267 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11439869B2 (en) 2017-05-19 2022-09-13 Trudell Medical International Positive expiratory pressure device
USD874064S1 (en) 2018-05-18 2020-01-28 Trudell Medical International Mask
USD890437S1 (en) 2018-05-18 2020-07-14 Trudell Medical International Mask
USD903097S1 (en) 2018-05-18 2020-11-24 Trudell Medical International Mask
USD893806S1 (en) 2018-11-09 2020-08-18 Trudell Medical Internationl Mask and shroud

Also Published As

Publication number Publication date
CN103768072A (zh) 2014-05-07

Similar Documents

Publication Publication Date Title
WO2015106678A1 (zh) 孕酮在预防或治疗低压缺氧引起的高原病中的应用
Theoharides et al. Mast cells, brain inflammation and autism
Hosseini et al. The beneficial effects of olibanum on memory deficit induced by hypothyroidism in adult rats tested in Morris water maze
Jasnow et al. Activation of GABAA receptors in the amygdala blocks the acquisition and expression of conditioned defeat in Syrian hamsters
Baculis et al. Third trimester-equivalent ethanol exposure increases anxiety-like behavior and glutamatergic transmission in the basolateral amygdala
Sarroca et al. Resveratrol confers neuroprotection against high-fat diet in a mouse model of Alzheimer's disease via modulation of proteolytic mechanisms
WO2015161747A1 (zh) 神经保护剂及其适应症
Kim et al. Agmatine attenuates brain edema and apoptotic cell death after traumatic brain injury
Kim et al. The synergic effect of regular exercise and resveratrol on kainate-induced oxidative stress and seizure activity in mice
Wu et al. Puerarin suppresses TRPV1, calcitonin gene-related peptide and substance P to prevent paclitaxel-induced peripheral neuropathic pain in rats
Barichello et al. Targets for adjunctive therapy in pneumococcal meningitis
Xu et al. Isoflurane postconditioning induces concentration-and timing-dependent neuroprotection partly mediated by the GluR2 AMPA receptor in neonatal rats after brain hypoxia–ischemia
Liu et al. Protective effects of estrogen combined with sevoflurane in an experimental model of cerebral infarction and focal cerebral ischemia-reperfusion injury.
Salah et al. Histopathological and some biochemical effects of platinum drug on the liver and kidney of pregnant mice Mus musculus and their embryos.
Luckett et al. The role of the nucleus accumbens in the acquisition and expression of conditioned defeat
Krepkova et al. Effects of a new thyrotropic drug isolated from Potentilla alba on the male reproductive system of rats and offspring development
RU2642961C1 (ru) Способ профилактики ишемии головного мозга
AU2020359294B2 (en) Compositions and methods for the treatment or prevention of traumatic brain injury
Tirapelli et al. Expression of HSP70 in cerebral ischemia and neuroprotetive action of hypothermia and ketoprofen
CA3123524C (en) Synergistic nutritional compositions for pain management
Hashemi et al. Morphometric study of the effect of Walnut (Juglans regia) leaf extract on cerebrum malformation in fetuses of diabetic rats
Aboutaleb et al. Low protein diet: its relevance to Manganese-induced neurotoxicity in rats treated with Coenzyme Q10 and/or Epigallocatechin-3-gallate.
US10835539B2 (en) Neuro-protective agents and uses thereof
Lacey et al. Neuropeptide Y impairs the acquisition of conditioned defeat in Syrian hamsters
Wang et al. Antidepressant-like effects of Ficus deltoidea aqueous extract on chronic unpredictable mild stress-treated rats

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15737531

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15737531

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 15737531

Country of ref document: EP

Kind code of ref document: A1