WO2022241985A1 - H1组胺受体拮抗剂在制备治疗神经胶质瘤的药物中的应用 - Google Patents

H1组胺受体拮抗剂在制备治疗神经胶质瘤的药物中的应用 Download PDF

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WO2022241985A1
WO2022241985A1 PCT/CN2021/119087 CN2021119087W WO2022241985A1 WO 2022241985 A1 WO2022241985 A1 WO 2022241985A1 CN 2021119087 W CN2021119087 W CN 2021119087W WO 2022241985 A1 WO2022241985 A1 WO 2022241985A1
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glioma
receptor antagonist
histamine receptor
terfenadine
drug
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PCT/CN2021/119087
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French (fr)
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杨建静
诸葛启钏
王堪凯
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温州医科大学附属第一医院
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the invention relates to the technical field of biomedicine, in particular to the application of an H1 histamine receptor antagonist in the preparation of drugs for treating neuroglioma.
  • Glioma is a tumor that begins to grow from the glial cells of the brain or spine, accounting for 30% of all brain and central nervous system tumors and 80% of all malignant tumors. Mainly divided into astrocytoma, glioblastoma, oligodendroglioma, medulloblastoma, ependymoma and other types.
  • the WHO divides it into I-IV grades, in which the prognosis of high-grade glioma is extremely poor (1 year), even after complete surgical resection, it will always recur, while low-grade glioma can survive for a long time (5 -10 years). Symptoms of gliomas depend on where they grow and can cause headaches, vomiting, seizures, and cranial nerve dysfunction.
  • the treatment of brain glioma is mainly based on surgical resection, combined with comprehensive treatment methods such as radiotherapy and chemotherapy.
  • Surgery can relieve clinical symptoms, prolong survival, and obtain enough tumor samples for clear pathological diagnosis and molecular genetic testing.
  • the principle of surgical treatment is to safely remove tumors in the largest range, and new technologies such as conventional neuronavigation, functional neuronavigation, intraoperative neurophysiological monitoring, and intraoperative MRI real-time images can help achieve safe tumor removal in the largest range.
  • Radiotherapy can kill or inhibit tumor cells and prolong the survival period of patients.
  • Conventional fractionated external beam radiation is the standard treatment for glioma radiotherapy.
  • GBM Glioblastoma
  • TMZ temozolomide
  • Histamine is a messenger molecule released from mast cells, enterochromaffin-like cells and neurons. It acts on G protein-coupled receptors such as HRH1, HRH2, HRH3, and HRH4.
  • G protein-coupled receptors such as HRH1, HRH2, HRH3, and HRH4.
  • the currently known biological effects include mediating the contraction of smooth muscle, the increase of capillary permeability caused by the contraction of peripheral venules, and the release of catecholamines from the adrenal medulla. Mass release and neurotransmission in the central nervous system.
  • Terfenadine is an effective H1 histamine receptor antagonist, which is mainly used clinically for the treatment of seasonal and non-seasonal allergic rhinitis, urticaria and hay fever.
  • Literature (Terfenadine : A new drug for restoring sensitivity to multidrug resistant cancer cells[J].Biochemical Pharmacology, Vol.45, No.2.pp.401-406) discloses that terfenadine is a drug for restoring multidrug resistant tumor sensitivity medicine. Terfenadine has the same effect as trans-flupizoxol, which is one of the most active multidrug resistance modulators.
  • the invention provides a new pharmaceutical application of the H1 histamine receptor antagonist in the preparation of medicine for treating neuroglioma.
  • the invention provides the application of H1 histamine receptor antagonist, its optical isomer or its pharmaceutically acceptable salt in the preparation of medicine for treating or preventing neuroglioma.
  • H1 histamine receptor antagonist its optical isomer or its pharmaceutically acceptable salt as the only active ingredient in the preparation of a drug for treating or preventing neuroglioma.
  • the present invention also provides an application of a pharmaceutical preparation in the preparation of a drug for treating or preventing glioma, said pharmaceutical preparation comprising a therapeutically effective amount of an H1 histamine receptor antagonist, its optical isomer or Its pharmaceutically acceptable salt is used as an active ingredient and a pharmaceutically acceptable carrier or excipient.
  • the present invention also provides an application of a pharmaceutical composition in the preparation of a drug for treating or preventing glioma, said pharmaceutical composition comprising an H1 histamine receptor antagonist, an optical isomer thereof, or a pharmaceutically acceptable Accepted salts as well as conventional chemotherapy drugs for glioma.
  • the conventional chemotherapy drugs for glioma include but not limited to temozolomide, nimustine, carmustine, lomustine, procarbazine, methotrexate or formustine.
  • the conventional chemotherapy drug for glioma is preferably temozolomide.
  • H1 histamine receptor antagonist is terfenadine, terfenadine metabolite, desloratadine, hydroxyzine hydrochloride, clopiramide hydrochloride or chlorpheniramine maleate; Preferably Terfenadine.
  • Terfenadine is an antiallergic drug used in clinical practice, and its safety is guaranteed. Its adverse reactions include headache, gastrointestinal dysfunction and rash, and its sedative effect and dry mouth are not obvious. In addition, it has been verified by experiments that compared with other H1 histamine receptor antagonists, terfenadine can effectively inhibit the growth and migration of glioma cells in vivo and in vitro.
  • the metabolite of terfenadine is 4-[1-hydroxyl-4-(4-hydroxydiphenylmethyl-1-piperidinyl) butyl]- ⁇ , ⁇ -dimethylphenylacetate Compound, 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]- ⁇ , ⁇ -dimethylphenylacetic acid or 1-[p-(2-hydroxy Methyl-2-propyl)phenyl)-4-[4-( ⁇ -hydroxy- ⁇ -phenylbenzyl)-1-piperidinyl]butanol.
  • the glioma is astrocytoma, glioblastoma, oligodendroglioma, medulloblastoma or ependymoma.
  • the glioma is low-grade glioma or high-grade glioma.
  • the pharmaceutically acceptable carrier includes, but is not limited to: saline, buffer, glucose, water, glycerin, ethanol, diluent, lubricant, binder, disintegrant, sweetener, wetting agent.
  • the pharmaceutical composition containing the compound of the present invention can be prepared as a solid/liquid oral pharmaceutical preparation or intravenous injection according to conventional methods in the prior art.
  • compositions in solid oral form may include diluents, lubricants, binders, disintegrants, sweeteners, wetting agents, and inactive and pharmacologically inactive substances commonly used in pharmaceutical preparations.
  • These pharmaceutical preparations can be prepared by methods known in the art. For example, it can be prepared into capsules, granules, tablets or mixtures by mixing, granulating, tabletting, sugar coating or film coating.
  • Exemplary diluents may be, for example: lactose, dextrose, disaccharides, sucrose, cellulose, corn starch or potato starch; lubricants may be: silica, talc, stearic acid, magnesium or calcium stearate and/or or polyethylene glycol; the binder can be: starch, acacia, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; the disintegrant can be: starch, alginic acid, alginate or sodium starch glycolate; humectants can be: lecithin, polysorbate, lauryl sulfate.
  • compositions in liquid oral form may be syrups, emulsions or suspensions.
  • a syrup may contain a disaccharide as carrier, or a disaccharide and glycerol and/or mannitol and sorbitol.
  • Suspensions and emulsions may contain natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol as examples of carriers.
  • Intravenous injection forms are prepared by conventional methods using physiological saline or aqueous solutions containing dextrose and other adjuvants.
  • the therapeutically effective amount refers to the amount of the compound of the present invention that is sufficient to achieve the intended purpose of treatment, which is achieved according to the expected therapeutic effect before treatment. Determination of a therapeutically effective amount is a routine technique for those skilled in the art, and the effective amount depends on various factors, such as the body size of the individual to be treated and/or the degree of development of the individual's disease or undesired condition. The effective amount also depends on whether the pharmacological compound is in a single dose and the frequency of administration.
  • the medicaments of the present invention treat individuals, including mammals and non-mammals.
  • mammals include, but are not limited to: any member of the mammalian class, such as adults, children, non-human primate orangutans, and other apes and monkeys; farm animals such as cows, horses, sheep, goats, pigs; Livestock animals such as rabbits, dogs and cats; laboratory animals include rodents such as rats, mice and guinea pigs.
  • non-mammals include, but are not limited to, birds, fish, and the like.
  • the H1 histamine receptor antagonist provided by the present invention can effectively kill glioma cells, and compared with existing antiglioma drugs, it acts on a new drug target, that is, the H1 histamine receptor on the cell membrane , the mechanism of killing tumor cells is completely different from the previous drugs, and there is no drug resistance and drug resistance at present.
  • the target of the drug is different from the previous drugs, and it belongs to the new use of old drugs, which is expected to bring light to the treatment of glioma prospect.
  • the H1 histamine receptor antagonist provided by the present invention can be used alone, or combined with surgery, or with other chemotherapeutic drugs, and combined with radiotherapy to produce a comprehensive therapeutic effect.
  • the anti-tumor drug H1 histamine receptor antagonist provided by the present invention has the advantages of quick effect and good curative effect.
  • the results of cell experiments and animal experiments show that the selective H1 histamine receptor antagonist terfenadine can significantly inhibit glioma Cell proliferation and migration, terfenadine has an inhibitory effect on the growth and migration of glioma cells, and can effectively kill glioma cells at lower concentrations, so the compound terfenadine can be used to prepare glioma cells Drugs for glioma, improve the prognosis and survival rate of glioma patients, and reduce social burden.
  • Figure 1 shows the proliferation of HRH1 gene knockdown U87 and U251 glioma cell lines.
  • Fig. 2 is a dose-effect relationship curve of terfenadine's inhibitory effect on the proliferation of U87 and U251 glioma cell lines.
  • Fig. 3 is a light microscope image of the inhibitory effect of terfenadine on cell invasion of U87 and U251 glioma cell lines.
  • Fig. 4 is a statistical graph showing the inhibitory effect of terfenadine on cell invasion of U87 and U251 glioma cell lines.
  • Fig. 5 is a light microscope image of the effect of terfenadine on the migration distance of U87 and U251 glioma cell lines.
  • Fig. 6 is a statistical graph showing the effect of terfenadine on the migration distance of U87 and U251 glioma cell lines.
  • Fig. 7 is an in vivo imaging diagram of the inhibitory effect of terfenadine on intracranial glioma implantation in BALB/C-nu nude mice.
  • Fig. 8 is a statistical graph showing the inhibitory effect of terfenadine on intracranial glioma implantation in BALB/C-nu nude mice.
  • human glioma cell lines U87 and U251 were cultured with DMEM+10% fetal bovine serum, and the cells were seeded in 96-well plates at 5000 cells/well, and cultured in a 37°C incubator containing 5% carbon dioxide. .
  • a series of H1 histamine receptor antagonists of different concentrations were added every other day, and the cell viability was detected by MTT method after drug incubation for 3 days. The experimental results are shown in Table 1.
  • terfenadine can significantly inhibit the growth of tumor cells, and the dose-effect relationship of terfenadine inhibiting the growth of glioma cells is shown in Figure 2.
  • the IC50s of U251 are 4.12 ⁇ M. and 2.89 ⁇ M, respectively.
  • the cells were treated with 1/2 IC 50 concentration of terfenadine for Transwell invasion assay: add 100 ⁇ l of 2*105/ml cell suspension resuspended in serum-free medium to the transwell chamber after matrigel gel pretreatment (The blank serum-free medium was used for the control group, and the serum-free medium containing 1/2 IC50 concentration of terfenadine was used for the drug treatment group), and normal serum-containing cell culture medium was added in the lower chamber. After culturing for 48 hours in a 37°C incubator containing 5% carbon dioxide, the samples were fixed with 4% paraformaldehyde, then stained with crystal violet staining solution, observed under a microscope, photographed and counted. The results are shown in Figure 3.
  • Embodiment 2 in vivo animal experiments
  • Rat U87 glioma cells were cultured in high-glucose DMEM containing 10% fetal bovine serum, and placed in an incubator at 37°C with 5% CO 2 for passage. The cells in the logarithmic growth phase were taken, washed with PBS and digested with 0.25% trypsin, the cells were collected with PBS to make a cell suspension, and the cell concentration was adjusted to 1,000,000/ ⁇ l before planting into the brain of nude mice.
  • the bone window After determining the position, open the bone window, drill a small opening with a small cranium at this position, and then use a 10 ⁇ l micro-syringe to extract the U87 cell suspension (containing 500,000 cells), and slowly insert the needle vertically along the bone hole to 3 mm below the dura, slowly After 10 minutes of injection, the needle was retained for 5 minutes. After the needle was pulled out slowly, the bone hole was closed with bone wax, and the scalp was sutured.
  • U87 cell suspension containing 500,000 cells
  • Drug treatment and observation The experiment was divided into drug solvent treatment group and terfenadine treatment group. 5 nude mice in each group.
  • Terfenadine treatment group U87 cells began to receive terfenadine on the 7th day after implantation. The preparation method of terfenadine is to dissolve it with DMSO first, and then add PEG300, Tween80 and normal saline.
  • Drug solvent treatment group U87 cells began to receive solvent on the 7th day after planting. The drug solvent treatment group and the terfenadine treatment group each received 200 ⁇ l (5 mg/ml) of solvent and drug solution, once a day, and continued administration until the mice died.

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Abstract

H1组胺受体拮抗剂在制备治疗神经胶质瘤的药物中的应用，该H1组胺受体拮抗剂为特非那定、特非那定代谢产物、地氯雷他定、盐酸羟嗪、氯吡胺盐酸盐或马来酸氯苯那敏。H1组胺受体拮抗剂特非那定能够抑制胶质瘤细胞增殖和迁移，在较低浓度时就能有效杀死神经胶质瘤细胞。

Description

H1组胺受体拮抗剂在制备治疗神经胶质瘤的药物中的应用 技术领域
本发明涉及生物医药技术领域，具体涉及H1组胺受体拮抗剂在制备治疗神经胶质瘤的药物中的应用。
背景技术
神经胶质瘤是一种从大脑或脊柱的胶质细胞开始生长的肿瘤，占所有脑肿瘤和中枢神经系统肿瘤的30％，占所有恶性肿瘤的80％。主要分为星型细胞瘤、胶质母细胞瘤、少突胶质细胞瘤、髓母细胞瘤、室管膜瘤等类型。WHO将其分为Ⅰ-Ⅳ级，其中高级别胶质瘤预后极差(1年),即使在手术完全切除后,也总是会复发,而低级别胶质瘤可以生存较长时间(5-10年)。胶质瘤的症状取决于其生长部位，可引起头痛，呕吐，癫痫发作和颅神经功能紊乱。
脑部胶质瘤治疗以手术切除为主，结合放疗、化疗等综合治疗方法。手术可以缓解临床症状，延长生存期，并获得足够肿瘤标本用以明确病理学诊断和进行分子遗传学检测。手术治疗原则是最大范围安全切除肿瘤，而常规神经导航、功能神经导航、术中神经电生理监测和术中MRI实时影像等新技术有助于实现最大范围安全切除肿瘤。放疗可杀灭或抑制肿瘤细胞，延长患者生存期，常规分割外照射是脑胶质瘤放疗的标准治疗。胶质母细胞瘤(GBM)术后放疗联合替莫唑胺(TMZ)同步辅助化疗，是当前新诊断GBM的标准治疗方案(放射治疗合并替莫唑胺治疗多形性胶质母细胞瘤的研究[J].中国神经肿瘤杂志,2005(4):290-295.)，当其疗效仍不尽人意。有效的提高患者生存的 治疗手段是目前胶质瘤患者急切需要的。
组胺是从肥大细胞，肠嗜铬样细胞和神经元释放的信使分子。作用于HRH1、HRH2、HRH3和HRH4等G蛋白偶联受体，目前所知的生物学作用包括介导平滑肌的收缩，末梢小静脉的收缩引起的毛细血管通透性的增加，儿茶酚胺从肾上腺髓质的释放以及中枢神经系统的神经传递。
特非那定是一种有效的H1组胺受体拮抗剂，临床上主要用于季节性和非季节性过敏性鼻炎、荨麻疹及枯草热的治疗。文献(Terfenadine
Figure PCTCN2021119087-appb-000001
:A new drug for restoring sensitivity to multidrug resistant cancer cells[J].Biochemical Pharmacology,Vol.45，No.2.pp.401-406)公开了特非那定是一种恢复多药耐药肿瘤敏感性的药物。特非那定具有和反式氟哌唑吨一样的效用，其为活性最强的多药耐药调节剂之一。
Figure PCTCN2021119087-appb-000002
然而，现有技术中，关于H1组胺受体拮抗剂在制备治疗神经胶质瘤的药物中的应用，目前还未见报道。
发明内容
本发明提供了H1组胺受体拮抗剂在制备治疗神经胶质瘤的药物中的制药新用途。
本发明采用的技术方案如下：
本发明提供了H1组胺受体拮抗剂、其光学异构体或其药学上可接受的盐在制备治疗或预防神经胶质瘤的药物中的应用。
H1组胺受体拮抗剂、其光学异构体或其药学上可接受的盐作为唯一的活性成分在制备治疗或预防神经胶质瘤的药物中的应用。
另外，本发明还提供了一种药物制剂在制备治疗或预防神经胶质瘤的药物中的应用，所述的药物制剂包含治疗有效量的H1组胺受体拮抗剂、其光学异构体或其药学上可接受的盐作为活性成分以及药学上可接受的载体或赋形剂。
本发明还提供了一种药物组合物在制备治疗或预防神经胶质瘤的药物中的应用，所述的药物组合物包括H1组胺受体拮抗剂、其光学异构体或其药学上可接受的盐以及神经胶质瘤常规化疗药物。
所述的神经胶质瘤常规化疗药物包括但不限于替莫唑胺、尼莫斯汀、卡莫斯汀、洛莫斯汀、甲基苄肼、甲氨喋呤或福莫司汀。所述的神经胶质瘤常规化疗药物优选为替莫唑胺。
所述的H1组胺受体拮抗剂为特非那定、特非那定代谢产物、地氯雷他定、盐酸羟嗪、氯吡胺盐酸盐或马来酸氯苯那敏；优选为特非那定。
特非那定作为一种临床中使用的抗过敏药物，其安全性有保障，其不良反应包括有头痛，胃肠功能紊乱和皮疹，镇静作用和口干现象不明显。另外经实验验证，相比于其他H1组胺受体拮抗剂，特非那定能有效抑制胶质瘤细胞在体内和体外的生长和迁移。
所述的特非那定代谢产物为4-[1-羟基-4-(4-羟基二苯基甲基-1-哌啶基)丁基]-α,α-二甲基苯乙酸酯类化合物、4-[1-羟基-4-(4-羟基二苯基甲基-1-哌啶基)丁基]-α,α-二甲基苯乙酸或1-[对-(2-羟甲基-2-丙基)苯基)-4-[4-(α-羟基-α-苯基苄基)-1-哌啶基]丁醇。
所述的神经胶质瘤为星型细胞瘤、胶质母细胞瘤、少突胶质细胞瘤、髓母细胞瘤或室管膜瘤。
所述的神经胶质瘤为低级别胶质瘤或高级别胶质瘤。
所述药学上可接受的载体包括但并不限于：盐水、缓冲液、葡萄糖、水、甘油、乙醇、稀释剂、润滑剂、粘合剂、崩解剂、甜味剂、湿润剂。
由于特非那定口服以后，可以通过血脑屏障进入脑组织发挥作用，因此包含本发明化合物的药物组合物可以根据现有技术常规方法制备固/液体口服药物制剂或静脉注射液。
固体口服形式的药物制剂可以包括稀释剂、润滑剂、粘合剂、崩解剂、甜味剂、湿润剂以及药物制剂中常用的无活性且无药理活性的物质。这些药物制剂可以以现有技术已知的方法进行制备。例如，通过混合、制粒、制片、糖包衣或膜包衣处理的方法，制备成胶囊剂、颗粒剂、片剂或合剂。示例性的稀释剂例如可以是：乳糖、右旋糖、二糖、蔗糖、纤维素、玉米淀粉或马铃薯淀粉；润滑剂可以是：硅石、滑石、硬脂酸、硬脂酸镁或钙和/或聚乙二醇；粘合剂可以是：淀粉类、阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素或聚乙烯吡咯烷酮；崩解剂可以是：淀粉、海藻酸、海藻酸盐或淀粉羟乙酸钠；湿润剂可以是：卵磷脂、聚山梨酯、月桂硫酸盐(酯)。
液体口服形式的药物制剂可以是糖浆、乳剂或混悬液。糖浆可以包含作为载体的二糖，或者二糖和甘油和/或甘露醇和山梨糖醇。混悬液和乳剂可以包含作为载体例子的天然胶、琼脂、海藻酸钠、果胶、甲基纤维素、羧甲基纤维素或聚乙烯醇。
静脉注射剂形式，例如用生理盐水或含有葡萄糖和其他辅剂的水溶液通过常规方法进行制备。
所述治疗有效量，是指本发明化合物的施加量足以达到治疗预期目的量，其根据治疗前所期望的治疗效果实现。治疗有效量的确定是本领域技术人员 的常规技术手段，有效量取决于多种因素，例如接受治疗个体的体型和/或个体所患疾病或不希望有的病症的发展程度。有效量也取决于药效化合物是否以单一剂量及用药频率。
本发明中的药物治疗个体，包括哺乳动物和非哺乳动物。哺乳动物的例子包括但不限于：哺乳动物类的任何成员，例如成年人、儿童、非人的灵长类猩猩，以及其他猿和猴类；农场动物例如牛、马、羊、山羊、猪；家畜类动物例如兔、狗和猫；实验室动物包括啮齿类，例如大鼠、小鼠和豚鼠等。非哺乳动物的例子包括但不限于，鸟、鱼等。
与现有技术相比，本发明的有益效果体现在：
本发明提供的H1组胺受体拮抗剂能有效杀灭神经胶质瘤细胞，与现有的抗胶质瘤药物相比较，作用于全新的药物靶点，即细胞膜上的H1组胺受体，杀灭肿瘤细胞的机制与以往的药物完全不同，目前没有产生耐药性和抗药性，药物作用靶点与既往药物不同，属于老药新用，有望给神经胶质瘤的治疗带来光明前景。
在治疗神经胶质瘤的过程中，本发明提供的H1组胺受体拮抗剂可以单独使用，也可以与手术治疗合用，或与其他化疗药物合用，与放射性治疗方法合用，产生综合治疗效果。
本发明提供的抗肿瘤药物H1组胺受体拮抗剂具有见效快、疗效好的优点，细胞实验和动物实验结果显示：选择性H1组胺受体拮抗剂特非那定能够显著抑制胶质瘤细胞增殖和迁移，特非那定对神经胶质瘤细胞的生长迁移都有抑制作用，在较低浓度时就能有效杀死神经胶质瘤细胞，因此化合物特非那定可用于制备神经胶质瘤的药物，改善神经胶质瘤患者的预后和提高生存率，减轻社会负担。
附图说明
图1是HRH1基因敲低的U87，U251胶质瘤细胞系增殖情况。
图2是特非那定对U87，U251胶质瘤细胞系增殖抑制作用的量效关系曲线图。
图3是特非那定对U87，U251胶质瘤细胞系细胞侵袭抑制作用的光镜图。
图4是特非那定对U87，U251胶质瘤细胞系细胞侵袭抑制作用的统计图。
图5是特非那定对U87，U251胶质瘤细胞系迁移距离影响的光镜图。
图6是特非那定对U87，U251胶质瘤细胞系迁移距离影响的统计图。
图7是特非那定对BALB/C-nu裸鼠颅内种植胶质瘤抑制作用的活体成像图。
图8是特非那定对BALB/C-nu裸鼠颅内种植胶质瘤抑制作用的统计图。
具体实施方式
下面结合具体实施方式进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明记载的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
经过MTT实验，发现通过shRNA抑制HRH1表达能够显著抑制胶质瘤细胞增殖，如图1所示，进一步进行细胞实验以及体内动物实验。
实施例1 细胞实验
实验过程中，用DMEM+10％的胎牛血清培养人神经胶质瘤细胞系U87、U251，细胞以5000个/孔接种于96孔板，放入含有5％二氧化碳的37℃培养箱内培养。隔天加入一系列不同浓度的H1组胺受体拮抗剂，药物孵育3天后用MTT的方法检测细胞活性，实验结果如表1所示。
表1
药物 U87 IC 50(μM) U25 IC 50(μM)
特非那定 4.12 2.89
地氯雷他定 29.66 36.42
盐酸羟嗪 91.49 123.23
氯吡胺盐酸盐 85.62 122.14
马来酸氯苯那敏 255.72 321.98
结论：相比于其他H1组胺受体拮抗剂，特非那定能够显著抑制肿瘤细胞的生长，特非那定抑制胶质瘤细胞生长的剂量-效应关系如图2所示，对U87，U251的IC 50分别为4.12μM.和2.89μM。
使用1/2 IC 50浓度的特非那定对细胞进行处理进行了Transwell侵袭实验：在matrigel胶预处理后的transwell小室中加入无血清培养基重悬的2*105/ml的细胞悬液100μl(对照组用空白无血清培养基，药物治疗组用含有1/2 IC 50浓度的特非那定的无血清培养基)，下室中则加入正常的有血清细胞培养基。在含有5％二氧化碳的37℃培养箱内培养48h后取出，先用4％多聚甲醛固定，然后使用结晶紫染色液进行染色，显微镜下观察，拍照并且计数，结果如图3所示。
划痕实验：铺U87，U251细胞于六孔板中，隔天长满后换液(对照组用2％浓度的血清培养基，药物治疗组用含有1/2 IC 50浓度的特非那定的2％浓度的血清培养基)，并用200ul的黄色枪头进行划痕实验，接下来每隔24小时进行观察，拍照，并且对细胞的迁移举例进行统计。结果如图3-6所示，特非那定可以明显抑制U87,U251细胞的侵袭和迁移。
实施例2 体内动物实验
BALB/C-nu裸鼠U87神经胶质瘤细胞的培养和体内种植：
用含有10％胎牛血清的高糖DMEM培养大鼠U87神经胶质瘤细胞，置于37℃、含有5％CO 2的培养箱内传代生长。取对数生长期细胞，用PBS洗和0.25％胰酶消化，用PBS收集细胞制成细胞悬液，调整细胞浓度为1000000/μl后种植到裸鼠脑内。
裸鼠原位脑胶质瘤模型的建立：将带有luciferase的U87细胞种植到大鼠右侧矢状缝前方1mm，中线右方2mm位置的硬脑膜下3mm位置。采用SPF级BALB/C-nu裸鼠10只，每只25g，均为雄性，购自史莱克实验动物中心。裸鼠经异氟烷气体麻醉后，固定于立体定位仪上(型号68001，深圳瑞沃德生命科技有限公司)。剪去头顶部毛发，碘伏消毒，切开头皮，暴露颅骨。确定位置后，打开骨窗，在此位置用小型颅钻开一个小口，然后用10μl微量注射器抽取U87细胞悬液(含500000个细胞)，沿骨孔缓慢垂直进针至硬脑膜下3mm，缓慢注射10分钟后留针5分钟，缓慢拔针之后用骨腊封闭骨孔，缝合头皮。
药物治疗和观察：实验分为药物溶剂治疗组和特非那定治疗组。每组各5只裸鼠。
特非那定治疗组：U87细胞种植后第7天开始接受特非那定。特非那定配置方法是先用DMSO溶解，然后加入PEG300，Tween80以及生理盐水。药物溶剂治疗组：U87细胞种植后第7天开始接受溶剂。药物溶剂治疗组和特非那定治疗组各自接受溶剂和药物溶液200μl(5mg/ml)，每天一次，连续给药至老鼠死亡。
用PerkinElmer IVIS Lumina X5活体成像系统对肿瘤的生长进行监测，结果如图7～8所示。结果显示特非那定能明显的抑制裸鼠颅内胶质瘤的生长。

Claims (9)

  1. H1组胺受体拮抗剂、其光学异构体或其药学上可接受的盐在制备治疗或预防神经胶质瘤的药物中的应用。
  2. H1组胺受体拮抗剂、其光学异构体或其药学上可接受的盐作为唯一的活性成分在制备治疗或预防神经胶质瘤的药物中的应用。
  3. 一种药物制剂在制备治疗或预防神经胶质瘤的药物中的应用，其特征在于，所述的药物制剂包含治疗有效量的H1组胺受体拮抗剂、其光学异构体或其药学上可接受的盐作为活性成分以及药学上可接受的载体或赋形剂。
  4. 一种药物组合物在制备治疗或预防神经胶质瘤的药物中的应用，其特征在于，所述的药物组合物包括H1组胺受体拮抗剂、其光学异构体或其药学上可接受的盐以及神经胶质瘤常规化疗药物。
  5. 根据权利要求4所述的应用，其特征在于，所述的神经胶质瘤常规化疗药物为替莫唑胺、尼莫斯汀、卡莫斯汀、洛莫斯汀、甲基苄肼、甲氨喋呤或福莫司汀。
  6. 根据权利要求1～5任意一项所述的应用，其特征在于，所述的H1组胺受体拮抗剂为特非那定、特非那定代谢产物、地氯雷他定、盐酸羟嗪、氯吡胺盐酸盐或马来酸氯苯那敏。
  7. 根据权利要求1～5任意一项所述的应用，其特征在于，所述的特非那定代谢产物为4-[1-羟基-4-(4-羟基二苯基甲基-1-哌啶基)丁基]-α,α-二甲基苯乙酸酯类化合物、4-[1-羟基-4-(4-羟基二苯基甲基 -1-哌啶基)丁基]-α,α-二甲基苯乙酸或1-[对-(2-羟甲基-2-丙基)苯基)-4-[4-(α-羟基-α-苯基苄基)-1-哌啶基]丁醇。
  8. 根据权利要求1～5任意一项所述的应用，其特征在于，所述的神经胶质瘤为星型细胞瘤、胶质母细胞瘤、少突胶质细胞瘤、髓母细胞瘤或室管膜瘤。
  9. 根据权利要求1～5任意一项所述的应用，其特征在于，所述的神经胶质瘤为低级别胶质瘤或高级别胶质瘤。
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