WO2020192378A1 - 丙二醇在制备用于预防肠型放射病及放射性肠炎的药物中的应用 - Google Patents

丙二醇在制备用于预防肠型放射病及放射性肠炎的药物中的应用 Download PDF

Info

Publication number
WO2020192378A1
WO2020192378A1 PCT/CN2020/077892 CN2020077892W WO2020192378A1 WO 2020192378 A1 WO2020192378 A1 WO 2020192378A1 CN 2020077892 W CN2020077892 W CN 2020077892W WO 2020192378 A1 WO2020192378 A1 WO 2020192378A1
Authority
WO
WIPO (PCT)
Prior art keywords
radiation
intestinal
propylene glycol
medicine
enteritis
Prior art date
Application number
PCT/CN2020/077892
Other languages
English (en)
French (fr)
Inventor
余祖胤
申星
邢爽
熊国林
Original Assignee
中国人民解放军军事科学院军事医学研究院
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 中国人民解放军军事科学院军事医学研究院 filed Critical 中国人民解放军军事科学院军事医学研究院
Publication of WO2020192378A1 publication Critical patent/WO2020192378A1/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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • the invention belongs to the technical field of medicine, and specifically relates to a method for preventing gastrointestinal tissue damage caused by ionizing radiation by propylene glycol. Specifically, the present invention relates to the use of propylene glycol, alone or in combination with other treatment methods, to prevent intestinal radiation sickness and radiation enteritis caused by tumor radiotherapy.
  • Acute radiation sickness is a systemic disease. Depending on the exposure dose, the main damaged organs are also different. When the body is exposed to more than 10 Gy of radiation in a single or short period of time (several days), the intestinal damage is Basic changes. Very serious radiation sickness with vomiting, diarrhea and bloody stools as the main symptoms is called intestinal radiation sickness. This type of acute radiation sickness has a rapid clinical course and the condition is extremely serious. After active comprehensive treatment, there is no living disease Case.
  • the clinical symptoms are acute diarrhea, abdominal pain, blood in the stool and mucous stools.
  • the late stage manifests as fistula, perforation, stenosis, fibrosis or cancer, manifested as rectal stenosis, difficulty defecation, and even bowel. obstruction.
  • Iatrogenic radiation enteritis on the one hand increases the economic burden of patients and seriously affects the quality of life of patients, on the other hand, it also limits the radiation dose used in radiotherapy. At present, there are no specific drugs or treatments for radiation enteritis clinically, and the focus is on prevention.
  • the traditional concept is that alcohol compounds have alcohol toxicity in large doses (greater than 100mM) and have never been used in human research, but after decades of application, people have a new understanding of the toxicity of alcohol .
  • the tolerable dose of alcohols for humans can be greatly improved.
  • propylene glycol is widely used as a carrier of flavor in the food industry and also in the pharmaceutical industry. Used as an excipient, the maximum safe injection dosage in injections can reach 60%, and it is relatively safe for clinical use.
  • propylene glycol is used to prevent gastrointestinal tissue damage caused by ionizing radiation or radiation enteritis caused by tumor radiotherapy.
  • the purpose of the present invention is to provide a new pharmaceutical use of propylene glycol.
  • the new drug use of propylene glycol provided by the present invention is its application in the preparation of products; the functions of the product are as follows (a1) and/or (a2) and/or (a3):
  • the intestinal radiation sickness may be: acute intestinal radiation sickness, subacute intestinal radiation sickness and/or chronic intestinal radiation sickness;
  • the radiation enteritis may be: radiation enteritis caused by tumor radiotherapy, radiation enteritis caused by radiation treatment by doctors or staff who perform radiotherapy, radiation enteritis caused by exposure to radiation, and radiation enteritis caused by excessive exposure of researchers.
  • the ionizing radiation is: ionizing radiation refers to rays with short wavelength, high frequency and high energy. It is the general term for all radiation that can cause the ionization of matter.
  • the types include high-speed charged particles ⁇ particles, ⁇ particles, and protons.
  • Uncharged particles include neutrons, X-rays and gamma rays.
  • the occurrence of intestinal radiation sickness and radiation enteritis involved in the present invention is only related to the absorbed dose of radiation from the intestine, and has nothing to do with the specific source of ionizing radiation.
  • the propylene glycol may be 1,2-propylene glycol and/or its isomer 1,3-propylene glycol.
  • the present invention also provides a medicine for preventing gastrointestinal tissue damage caused by ionizing radiation, a medicine for preventing radiation enteritis caused by tumor radiotherapy, or a medicine for preventing intestinal radiation sickness.
  • the medicine for preventing gastrointestinal tissue damage caused by ionizing radiation, the medicine for preventing radiation enteritis caused by tumor radiotherapy, or the medicine for preventing intestinal radiation sickness contains propylene glycol.
  • the present invention therefore also relates to a pharmaceutical composition containing an effective dose of propylene glycol as an active ingredient and conventional pharmaceutical excipients or adjuvants.
  • the pharmaceutical composition of the present invention contains 0.1-100% by weight of propylene glycol.
  • the pharmaceutical composition can be prepared according to methods known in the art. When used for this purpose, if necessary, propylene glycol can be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants to prepare an appropriate administration form or dosage form for human use.
  • Propylene glycol or a pharmaceutical composition containing it can be administered in a unit dosage form, and the route of administration can be enteral or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum, or rectum.
  • dosage forms for administration include capsules, aerosols, solutions, suspensions, emulsions, liposomes, transdermal agents, suppositories and the like. It can be ordinary preparations, sustained-release preparations, and various particle delivery systems.
  • Propylene glycol or a pharmaceutical composition containing it can be administered prophylactically before radiation exposure.
  • it can be administered within 12 hours before the radiation, or administered 1 hour before the radiation.
  • Propylene glycol can be administered in combination with other drugs.
  • the present invention uses propylene glycol in the field of radiation protection research for the first time, and it is found that the pre-exposure preventive application of propylene glycol has obvious experimental treatment effects on intestinal acute radiation injury, and the intestinal or parenteral administration has curative effect.
  • the radiation protection mechanism may be related to the effect of propylene glycol in scavenging hydroxyl free radicals and reducing DNA damage in intestinal cells.
  • Figure 1 shows that in vitro incubation with propylene glycol significantly reduces the IEC-6 apoptosis of rat small intestinal crypt epithelial cells caused by ⁇ -ray irradiation.
  • Figure 2 shows that 1,2-propanediol can improve the survival rate of small intestine organoids in mice after X-ray irradiation.
  • Figure 3 shows that prevention of intraperitoneal injection of 1,2-propanediol can prevent radiation damage to intestinal crypts in mice.
  • Figure 4 shows that prevention of intraperitoneal injection of 1,2-propanediol significantly improves the survival rate of mice with intestinal acute radiation sickness.
  • Figure 5 shows that oral 1,2-propanediol can prevent radiation damage to intestinal crypts in mice.
  • Figure 6 shows that oral 1,2-propanediol can significantly improve the survival rate of mice with intestinal acute radiation sickness.
  • Example 1 In vitro experiments show that in vitro incubation of propylene glycol significantly reduces the IEC-6 apoptosis of rat small intestinal crypt epithelial cells caused by ⁇ -ray irradiation
  • Propylene glycol pretreatment can significantly reduce the apoptotic rate of IEC-6 cells caused by radiation.
  • the early apoptotic rate of IEC-6 cells in the IR group is 27.1 ⁇ 1.8
  • pretreatment with 1,2-propanediol and 1,3-propanediol can reduce the early apoptosis rate to 19.3 ⁇ 1.1 and 17.9 ⁇ 0.7, respectively.
  • prophylactic administration of propylene glycol can reduce the intestinal cell damage caused by radiation.
  • Example 2 In vitro experiments show that 1,2-propanediol can improve the survival rate of small intestinal organoids in mice after X-ray irradiation
  • Small intestine organoids are an organoid model derived from small intestinal stem cells or precursor cells. Small intestinal organoids are highly similar to small intestinal epithelium in terms of tissue structure and physiological functions.
  • the irradiation control (IR) group was given the same A volume of normal saline was irradiated with 6.0Gy and 8.0Gy (1.325Gy/min) X-rays, and the complete medium was replaced after irradiation for 7 days.
  • the survival rate was obtained by microscopic observation and counting the number of surviving organoids.
  • the results are shown in Figure 2.
  • 1,2-propanediol pretreatment can increase the survival rate of intestinal organs 7 days after 6.0Gy X-ray irradiation from 41.9 ⁇ 4.4% to 69.2 ⁇ 5.1%, and make the intestinal organs 7 days after 8.0Gy X-ray irradiation
  • the survival rate increased from 0.32 ⁇ 0.6% to 18.0 ⁇ 3.1%. This result suggests that the prophylactic administration of propylene glycol has a protective effect on intestinal organoids derived from small intestinal stem cells or precursor cells from radiation damage.
  • BrdU is an analogue of thymidine. Like thymidine, BrdU can be incorporated into DNA synthesized by cells. By detecting the BrdU expression level in mice receiving BrdU infusion, it can reflect the state of cell proliferation.
  • C 57 BL6/J mice were divided into a solvent control group (IR) and a propylene glycol administration group at different times.
  • the propylene glycol administration group was treated with 15Gy X-rays before (-) 12h, 6h, 3h, 1h and after irradiation ( +) 1 hour intraperitoneal injection of 1,2-propanediol 6g/kg, the solvent control group was given an equal volume of normal saline 1 hour before irradiation, the mice were sacrificed 3.5 days after irradiation, and the small intestine was taken for the experiment; the mice were 1.5 before sacrifice All h were intraperitoneal BrdU 120mg/kg.
  • mice in the normal saline administration group died 5 days after the exposure, the 30-day survival rate of the 1,2-propanediol preventive administration group increased to 87.5%, and the body weight returned to normal. Subsequently, we irradiated the mice whole body with 16Gy 60Go gamma rays and performed bone marrow transplantation 6 hours after the irradiation.
  • Example 5 Oral 1,2-propanediol prevents radiation damage to intestinal crypts in mice, and significantly improves the survival rate of mice with intestinal acute radiation sickness
  • 1,2-Propanediol is widely used in food processing as a water solvent.
  • propylene glycol is widely used in pharmaceutical engineering as a solvent for poorly soluble or water-soluble stable drugs.
  • the drug has a safer way of absorption and dosage range.
  • Our further experimental studies have shown that oral 1,2-propanediol can also effectively reduce radiation damage to the intestinal crypts of mice. The results are shown in Figure 5, when the dose is 6g/kg, oral 1,2-propane 2 has the best effect 1h before the shot, and the oral 1,2-propanediol dose reaches 12g/kg 1h before the shot.
  • mice received 16.0Gy (1.325Gy/min) X-ray local intraperitoneal irradiation.
  • the 30-day survival rate of irradiated control group mice was 0.
  • the present invention uses propylene glycol in the field of radiation protection research for the first time, and it is found that the pre-exposure preventive application of propylene glycol has obvious experimental treatment effects on intestinal acute radiation injury, and the intestinal or parenteral administration has curative effect.
  • Its radiation protection mechanism may be related to the effect of propylene glycol in scavenging hydroxyl free radicals and reducing DNA damage in intestinal cells.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

本发明提供丙二醇在制备用于预防肠型放射病及放射性肠炎的药物中的应用。本发明首次将丙二醇用于辐射防护研究领域，发现丙二醇于照前预防应用对肠道急性放射损伤的实验治疗作用明显，并且腹腔注射和口服均有疗效。其辐射防护机制可能与丙二醇清除羟基自由基、减轻肠道细胞DNA损伤的作用有关。

Description

丙二醇在制备用于预防肠型放射病及放射性肠炎的药物中的应用 技术领域
本发明属于医药技术领域，具体涉及丙二醇在预防电离辐射所引起的胃肠组织损伤方法。明确来说，本发明关于单独地或结合其它治疗方法，应用丙二醇来预防肠型放射病以及肿瘤放射治疗所引起的放射性肠炎。
背景技术
核次生灾害(核电站、钻井事故)、涉核恐怖袭击、意外的放射性核事故以及针对肿瘤的医疗照射都可能导致急性放射病(Acute Radiation Sickness,ARS)。急性放射病是一种全身性疾病，根据受照剂量的不同，主要受损器官也不相同，当机体在一次或短时间(数日)内遭受大于10Gy的射线照射后引起的以肠道损伤为基本改变，以呕吐、腹泻和血水便为主要症状的极严重的放射病，称为肠型放射病，此型急性放射病，临床经过较快，病情及其严重，经积极综合治疗后尚无活存的病例。
在过去的几十年里，腹部放射治疗一直是肠道或盆腔癌症患者治疗和姑息治疗的重要组成部分，大约70％的癌症患者接受了放射治疗，而放疗对25％的肿瘤治疗起着关键的作用。尽管放射疗技术不断进步，但是射线在杀伤肿瘤细胞的同时对正常肠道组织也不可避免造成放射损伤。放射性肠炎是指盆腔、腹腔、腹膜后恶性肿瘤经放射治疗引起的肠道并发症，可分别累及小肠、结肠和直肠，故又称为放射性直肠、结肠、小肠炎。早期肠黏膜细胞可发生糜烂、溃疡或出血，其临床症状为急性腹泻、腹痛、便血和黏液便，晚期表现为瘘管、穿孔、狭窄、纤维化或者癌变，表现为直肠狭窄，排便困难，甚至肠梗阻。医源性的放射性肠炎一方面加重了患者的经济负担并严重影响患者的生存质量，另一方面也限制了放射治疗所用的放射剂量。目前临床上对放射性肠炎尚无特效药物或治疗方法，重在于预防。
传统的观念认为醇类化合物在大剂量下(大于100mM))都具有醇类毒性而从未将其用于人体研究，但是经过几十年的应用，人们对醇类的毒性有了新的认识，通过更改给药途径、降低醇类注射浓度以及改变醇的稀释方式能够大幅提升醇类用于人体的耐受剂量，例如丙二醇，作为香精的载体在食品行业中被广泛使用，在医药行业也作为辅料使用，在注射剂中的最大注射安全用量可达60％，临床使用相对安全。
目前尚未见有丙二醇用于预防电离辐射所引起的胃肠组织损伤或肿瘤放射治疗所引起的放射性肠炎的报道。
发明公开
本发明的目的是提供一种丙二醇的药物新用途。
本发明所提供的丙二醇的药物新用途是其在制备产品中的应用；所述产品的功能为如下(a1)和/或(a2)和/或(a3)：
(a1)预防电离辐射所引起的胃肠损伤；
(a2)预防肠型放射病；
(a3)预防放射性肠炎。
其中，所述肠型放射病可为：急性肠型放射病、亚急性肠型放射病和/或慢性肠型放射病；
所述放射性肠炎可为：由肿瘤放射治疗所引起的放射性肠炎、执行放射性治疗的医生或工作人员受到放射线辐射引起的放射性肠炎或接触放射线的工作和研究人员接触过量引起的放射性肠炎。
所述电离辐射为：电离辐射指波长短、频率高、能量高的射线，是一切能引起物质电离的辐射总称，种类包括高速带电粒子α粒子、β粒子、质子，不带电粒子有中子、X射线及γ射线。
本发明所涉及的肠型放射病及放射性肠炎的发生与否只与肠道的放射线吸收剂量有关，与具体来源的电离辐射射线种类无关。
上述应用中，所述丙二醇可为1,2-丙二醇和/或其同分异构体1,3-丙二醇。
本发明还提供一种预防电离辐射所引起的胃肠组织损伤的药物、预防肿瘤放射治疗所引起的放射性肠炎的药物或预防肠型放射病的药物。
所述预防电离辐射所引起的胃肠组织损伤的药物、预防肿瘤放射治疗所引起的放射性肠炎的药物或预防肠型放射病的药物含有丙二醇。
本发明因此还涉及含有作为活性成份的有效剂量的丙二醇以及常规药物赋形剂或辅剂的药物组合物。
通常本发明药物组合物含有0.1－100重量％的丙二醇。
药物组合物可根据本领域已知的方法制备。用于此目的时，如果需要，可将丙二醇与一种或多种固体或液体药物赋形剂和/或辅剂结合，制成可作为人用的适当的施用形式或剂量形式。
丙二醇或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠等。给药剂型例如胶 囊、气雾剂、溶液剂、混悬剂、乳剂、脂质体、透皮剂、栓剂等。可以是普通制剂、缓释制剂及各种微粒给药系统。
丙二醇或含有它的药物组合物可在射线照射前预防给药。
具体可为在射线照射前12h以内给药，或在照射前1h给药。
丙二醇可结合其它药物一起给药。
本发明首次将丙二醇用于辐射防护研究领域，发现丙二醇于照前预防应用对肠道急性放射损伤的实验治疗作用明显，并且肠道或非肠道给药均有疗效。其辐射防护机制可能与丙二醇清除羟基自由基、减轻肠道细胞DNA损伤的作用有关。
附图说明
图1表明丙二醇体外孵育显著减少γ射线照射引起的大鼠小肠隐窝上皮细胞IEC-6凋亡。
图2表明1,2-丙二醇能提高X射线照射后的小鼠小肠类器官存活率。
图3表明预防腹腔注射1,2-丙二醇能预防小鼠肠道隐窝辐射损伤。
图4表明预防腹腔注射1,2-丙二醇显著提高肠型急性放射病小鼠的存活率。
图5表明口服1,2-丙二醇能预防小鼠肠道隐窝辐射损伤。
图6表明口服1,2-丙二醇能显著提高肠型急性放射病小鼠存活率。
实施发明的最佳方式
下述实施例中的实验方法，如无特别说明，均为常规方法
下面结合实施例对本发明作进一步的说明，但不以任何方式对本发明加以限制，基于本发明教导所做的任何变更或改进，均属于本发明的保护范围。
下述实施例中所用的试剂、材料等，如无特殊说明，均可从商业途径得到。
实施例1、体外实验表明丙二醇体外孵育显著减少γ射线照射引起的大鼠小肠隐窝上皮细胞IEC-6凋亡
我们将1,2-丙二醇及其同分异构体1,3-丙二醇进行效应研究，以X射线照射大鼠小肠隐窝上皮细胞IEC-6为模型初步观察醇类化合物能够减轻上皮细胞的放射损伤。IEC-6细胞经过2％体积浓度的丙二醇预处理30min，IR组给以相同体积的生理盐水，以15.0Gy(1.325Gy/min)X射线照射并于照射后更换完全培养基培养48h，通过流式细 胞仪检测各组细胞的凋亡率，结果如图1所示，丙二醇预处理能显著减少辐射所致IEC-6细胞的凋亡率，IR组的IEC-6细胞早期凋亡率为27.1±1.8，经过1,2-丙二醇、1,3-丙二醇预处理能使早期凋亡率分别减少为19.3±1.1、17.9±0.7。这表明，丙二醇预防给药能够减轻放射引起的肠细胞损伤。为了进一步证明丙二醇对肠道辐射损伤的防治作用，我们以1,2-丙二醇为例进行实验。
实施例2、体外实验表明1,2-丙二醇能提高X射线照射后的小鼠小肠类器官存活率
小肠类器官是一种衍生于小肠干细胞或前体细胞的类器官模型，小肠类器官在组织架构及生理功能等方面与小肠上皮高度相似。我们将体外培养的小鼠小肠类器官以200个/孔于照射前1天种植于24孔板，经过2％体积浓度的1,2-丙二醇预处理1h，照射对照(IR)组给以相同体积的生理盐水，以6.0Gy和8.0Gy(1.325Gy/min)X射线分别照射并于照射后更换完全培养基培养7d，进行显微镜观察并计数存活的类器官数量得到存活率，结果如图2所示，1,2-丙二醇预处理能使6.0Gy X射线照射后7天肠类器官的存活率从41.9±4.4％提升至69.2±5.1％，使8.0Gy X射线照射后7天肠类器官的存活率从0.32±0.6％提升至18.0±3.1％。该结果提示，丙二醇预防给药对衍生于小肠干细胞或前体细胞的肠道类器官具有辐射损伤防护作用。
实施例3、预防腹腔注射1,2-丙二醇减轻小鼠肠道隐窝放射损伤
为了进一步证明丙二醇对肠道辐射损伤的防治作用，我们通过BrdU掺入实验在肠型急性放射病小鼠模型上进行研究。BrdU是一种胸腺嘧啶核苷的类似物，同胸腺嘧啶核苷一样可掺入到细胞合成的DNA中，通过检测接受BrdU输注的小鼠体内BrdU表达水平，可反映细胞增殖状态。
C 57BL6/J小鼠分为溶剂对照组(IR)和丙二醇不同时间给药组，丙二醇给药组分别于15Gy X-射线全身照射前(-)12h、6h、3h、1h和照射后(+)1h腹腔注射1,2-丙二醇6g/kg，溶剂对照组于照射前1h给等体积生理盐水，照射后3.5天处死小鼠，取小肠做病理组织切片用于实验；小鼠处死前1.5h均腹腔BrdU 120mg/kg。免疫组化法检测小鼠小肠隐窝细胞中BrdU的表达情况，并通过计数BrdU阳性隐窝细胞数(BrdU +细胞数>5个为1个隐窝)，比较各组小鼠肠隐窝细胞增殖差异。结果如图3所示，照射前12h以内腹腔注射1,2-丙二醇6g/kg能够增加增殖期肠隐窝数量，照前1h给药6g/kg疗效最佳，能使15Gy照射小鼠肠道BrdU阳性隐窝数达到56.3±4.0个/肠环。 这表明，丙二醇预防给药对肠型急性放射病小鼠的肠道隐窝有明显的保护作用。
实施例4、预防腹腔注射1,2-丙二醇显著提高肠型急性放射病小鼠的存活率
我们首先以X射线16.0Gy腹部局部照射C57BL/6J小鼠模拟放疗所致的肠损伤模型观察1,2-丙二醇预防给药的防护作用，健康C57BL/6J小鼠照前1h腹腔注射1,2-丙二醇6g/kg或相同体积生理盐水(IR)，每组8只，然后均接受16.0Gy(1.325Gy/min)X射线腹腔局部照射，观察小鼠30天的存活率并记录体重，结果如图4所示，生理盐水给药组于照后5d全部死亡，1,2-丙二醇预防给药组小鼠30d存活率提高至87.5％，并且体重恢复正常。随后，我们以16Gy 60Goγ射线全身照射小鼠，并于照后6h进行骨髓移植，结果表明，1,2-丙二醇预防给药可使16Gyγ射线全身照射骨髓移植小鼠30d存活率提高100％并且体重恢复至照前水平。
实施例5、口服1,2-丙二醇预防小鼠肠道隐窝辐射损伤，显著提高肠型急性放射病小鼠存活率
1,2-丙二醇作为水溶剂，被广泛用于食品加工，同时丙二醇在制药工程广泛应用，用作难溶性或水溶性稳定药物的溶媒，其小鼠口服毒性LD50＝32,000mg/kg，口服给药相比腹腔注射具有更加安全的吸收方式和给药剂量区间。我们进一步实验研究表明口服1,2-丙二醇同样能够有效的减轻小鼠肠道隐窝的放射损伤。结果如图5所示，当给药剂量为6g/kg时，照前1h口服1,2-丙二给药疗效最佳，当照前1h口服1,2-丙二醇给药剂量达到12g/kg时，能使15Gyγ射线全身照射小鼠肠道BrdU阳性隐窝数达到54.5±9.0个/肠环，与腹腔注射给药6g/kg的疗效基本相当，该结果说明口服1,2-丙二醇预防小鼠肠道隐窝辐射损伤同样有效。
健康C57BL/6J小鼠接受16.0Gy(1.325Gy/min)X射线局部腹腔照射，照射对照组小鼠30d的存活率为0，照前1h口服1,2-丙二醇12g/kg，可使小鼠活存明显时间延长，并显著提高其30天存活率(50％)，该结果说明口服1,2-丙二醇同样明显提高肠型放射病小鼠的存活率(图6)。
工业应用
本发明首次将丙二醇用于辐射防护研究领域，发现丙二醇于照前预防应用对肠道急性放射损伤的实验治疗作用明显，并且肠道或非肠道给药均有疗效。其辐射防护机 制可能与丙二醇清除羟基自由基、减轻肠道细胞DNA损伤的作用有关。

Claims (15)

  1. 丙二醇在制备产品中的应用；
    所述产品的功能为如下(a1)和/或(a2)和/或(a3)：
    (a1)预防电离辐射所引起的胃肠损伤；
    (a2)预防肠型放射病；
    (a3)预防放射性肠炎。
  2. 根据权利要求1所述的应用，其特征在于：所述肠型放射病为：急性肠型放射病、亚急性肠型放射病和/或慢性肠型放射病；
    所述放射性肠炎为：由肿瘤放射治疗所引起的放射性肠炎、执行放射性治疗的医生或工作人员受到放射线辐射引起的放射性肠炎或接触放射线的工作或研究人员接触过量引起的放射性肠炎。
  3. 根据权利要求1或2所述的应用，其特征在于：所述丙二醇为1,2-丙二醇和/或其同分异构体1,3-丙二醇。
  4. 根据权利要求1所述的应用，其特征在于：所述应用具体可为丙二醇在制备如下功能的产品中的应用：
    1)减少γ射线照射引起的小肠隐窝上皮细胞IEC-6凋亡的产品；
    2)减轻肠道隐窝放射损伤的产品。
  5. 一种预防电离辐射所引起的胃肠损伤的药物、预防放射性肠炎的药物或预防肠型放射病的药物，含有丙二醇。
  6. 一种预防电离辐射所引起的放射性肠炎的药物组合物或预防肠型放射病的药物组合物，含有有效剂量的丙二醇以及药物赋形剂或辅剂。
  7. 根据权利要求5所述的药物或权利要求6所述的药物组合物，其特征在于：所述药物或药物组合物的给药途径为肠道或非肠道给药，具体可为口服或腹腔注射给药。
  8. 根据权利要求5所述的药物或权利要求6所述的药物组合物，其特征在于：所述药物或药物组合物在射线照射前预防给药。
  9. 根据权利要求5所述的药物或权利要求6所述的药物组合物，其特征在于：所述药物或药物组合物在射线照射前12h以内给药。
  10. 根据权利要求5所述的药物或权利要求6所述的药物组合物，其特征在于：所述药物或药物组合物可结合其它药物一起给药。
  11. 一种预防电离辐射所引起的胃肠损伤、预防肠型放射病或预防放射性肠炎的 方法为：给予权利要求5所述的药物或给予权利要求6所述的药物组合物。
  12. 根据权利要求11所述的方法，其特征在于：所述肠型放射病为：急性肠型放射病、亚急性肠型放射病和/或慢性肠型放射病；
    所述放射性肠炎为：由肿瘤放射治疗所引起的放射性肠炎、执行放射性治疗的医生或工作人员受到放射线辐射引起的放射性肠炎或接触放射线的工作或研究人员接触过量引起的放射性肠炎。
  13. 根据权利要求11或12所述的方法，其特征在于：通过肠道或非肠道给药，具体可为通过口服或腹腔注射给药。
  14. 根据权利要求11或12所述的方法，其特征在于：在射线照射前预防给药。
  15. 根据权利要求11或12所述的方法，其特征在于：在射线照射前12h以内给药。
PCT/CN2020/077892 2019-03-26 2020-03-05 丙二醇在制备用于预防肠型放射病及放射性肠炎的药物中的应用 WO2020192378A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910230933.2 2019-03-26
CN201910230933.2A CN109806246A (zh) 2019-03-26 2019-03-26 丙二醇在制备用于预防肠型放射病及放射性肠炎的药物中的应用

Publications (1)

Publication Number Publication Date
WO2020192378A1 true WO2020192378A1 (zh) 2020-10-01

Family

ID=66610341

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/077892 WO2020192378A1 (zh) 2019-03-26 2020-03-05 丙二醇在制备用于预防肠型放射病及放射性肠炎的药物中的应用

Country Status (2)

Country Link
CN (1) CN109806246A (zh)
WO (1) WO2020192378A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109806246A (zh) * 2019-03-26 2019-05-28 中国人民解放军军事科学院军事医学研究院 丙二醇在制备用于预防肠型放射病及放射性肠炎的药物中的应用
CN115429777A (zh) * 2021-06-01 2022-12-06 中国人民解放军军事科学院军事医学研究院 二甲亚砜防护肠型急性放射病的用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109806246A (zh) * 2019-03-26 2019-05-28 中国人民解放军军事科学院军事医学研究院 丙二醇在制备用于预防肠型放射病及放射性肠炎的药物中的应用

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109806246A (zh) * 2019-03-26 2019-05-28 中国人民解放军军事科学院军事医学研究院 丙二醇在制备用于预防肠型放射病及放射性肠炎的药物中的应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
UJENO, Y.: "Nuclear Magnetic-Resonance Relaxation-Times for Tissues of Mice Given Radioprotective Compounds", PHYSIOLOGICAL CHEMISTRY AND PHYSICS., vol. 12, no. 3, 31 December 1980 (1980-12-31), DOI: 20200522160124X *
VACEK, A ET AL.: "Comparative Protection of Hematopoietic and Intestinal System in Mice by Environmental Hypoxia and Chemical Compounds", JAPANESE JOURNAL OF RADIOLOGICAL TECHNOLOGY, vol. 27, no. 8, 25 November 1967 (1967-11-25), DOI: 20200526102153X *
YI, LIRONG ET AL.: "A Preliminary Discussion on Preventive Effects of 1,2-propanediol against Injury Induced by 5.5 Gy 60Co γ Ray in Mice", CHINESE JOURNAL OF RADIOLOGICAL HEALTH, vol. 28, no. 1, 28 February 2019 (2019-02-28), DOI: 20200525113651X *

Also Published As

Publication number Publication date
CN109806246A (zh) 2019-05-28

Similar Documents

Publication Publication Date Title
Pinkel Actinomycin D in childhood cancer: A preliminary report
WO2020192378A1 (zh) 丙二醇在制备用于预防肠型放射病及放射性肠炎的药物中的应用
WO2019015279A1 (zh) Sirt1抑制剂在预防和治疗放射引起的肠道疾病中的应用
CN101484167A (zh) 吡啶酮类衍生物预防和治疗放射性肺损伤的用途
AU2017278299B2 (en) Novel benzenesulfonamide compositions for treatment of malignant pleural effusions
WO2019214723A1 (zh) 绿原酸及其组合物在制备治疗鳞状细胞癌的药物中的用途
JP6462147B2 (ja) Ｈｓｐ９０阻害ペプチド結合体及びその腫瘍治療における応用
WO2007140280A1 (en) Anti-cancer composition and method for using the same
US4384001A (en) Treatment of tumors with thiazolidine-4-carboxylic acid
CN117045687A (zh) 一种凝结芽孢杆菌在制备防治电离辐射致肠道损伤的药物中的应用
WO2014106473A1 (zh) 甘草次酸、甘草酸在制备预防或治疗放射性软组织损伤药物中的应用
AU2004201707B2 (en) Radioactive arsenic-containing compounds and their uses in the treatment of tumors
CN104815014A (zh) 虎杖在制备防治电离辐射诱导小肠损伤药物中的应用
CN111939159A (zh) Nsc 23766辅助肿瘤放射治疗的用途
CN111714483A (zh) 半胱氨酸衍生物作为辐射防护剂的应用
CN114081880B (zh) 木香内酯及其衍生物在制备预防和/或治疗肠损伤的药物中的用途
RU2763663C2 (ru) Способ лечения перевивной соединительнотканной саркомы м-1 крыс при комбинированном воздействии фотодинамической терапии и лучевой терапии
US7846901B2 (en) Method for inhibiting or treating intestinal damage caused by radiotherapy or chemotherapy comprising administering substance-P
US20080038376A1 (en) Anti-cancer composition and method for using the same
CN111407748B (zh) 酪醇在制备治疗脑胶质瘤的药物中的应用
RU2238091C2 (ru) Способ лечения туберкулеза у человека
CN102614180A (zh) 伊曲康唑在制备治疗多发性骨髓瘤药物中的应用
CN105816862A (zh) 乌司他丁在制备治疗前列腺癌药物中的用途
WO2012147834A1 (ja) 放射線増感剤
RU2065303C1 (ru) Способ лечения онкологических больных

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: 20779787

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: 20779787

Country of ref document: EP

Kind code of ref document: A1