The Blood-Brain Barrier Bottleneck in Brain Drug Development

众所周知，在大多数脑癌中，血脑屏障（BBB）的存在是药物输送的重要障碍[1]。

BBB 是内皮细胞，星形胶质细胞，周细胞，基底层和细胞外基质（ECM）之间的复杂相互作用。

这些成分与平滑肌细胞和神经元一起形成神经血管单位（NVU），进而调节脑血流量和BBB功能。

这种严格调节的屏障的结果是毒素和药物（包括化学疗法）不易穿过血脑屏障，给药物向大脑的输送带来了麻烦。

现有的药物递送方法并未导致恶性原发性脑肿瘤患者的存活率显着增加。

虽然由外科手术，放射疗法和化学疗法组成的常规疗法的组合可以改善某些类型的脑肿瘤（例如WNT 髓母细胞瘤）的存活率，但其他类型的脑部肿瘤（例如胶质母细胞瘤和弥漫性中线神经胶质瘤）的预后仍然很差。

目前已经开发了几种药物递送方法，例如纳米颗粒递送，对流增强递送，聚焦超声，鼻内递送和动脉内递送以克服原发性脑肿瘤中的血脑屏障。

结合诸如聚焦超声和纳米粒子等策略的药物递送可能是更成功的方法。

但是，需要更多的研究来优化和开发新的药物递送技术，以改善原发性脑肿瘤患者的生存率。

图1 当前用于治疗原发性脑肿瘤的药物递送方法的概述[2]第1组：鼻内药物输送药物以喷雾颗粒形式进行配制，这些喷雾颗粒通过神经上皮通过鼻腔进入大脑。

在这里，药物可以不受血脑屏障（BBB）干扰地进入。

药物通过从鼻腔神经上皮细胞到CNS的细胞旁，跨细胞和神经元运输而传递到大脑。

然而，并不是所有的药物都适合鼻内给药，因为特定的物理化学性质和配方决定了药物在大脑中的生物利用度。

一般来说，低分子量的亲脂性药物（例如脂质体、环糊精等）经鼻给药后比带电荷的亲水药物表现出更好的生物利用度[3]。

另外，药物通过鼻腔输送的优点是药物不会被首过代谢所代谢。

但是，缺点是可通过鼻内进行给药的体积很小。

第2组：纳米颗粒纳米颗粒包裹药物以延长血浆半衰期，并通过增强的通透性和保留（EPR）效应，内吞作用和受体介导的胞吞作用进入脑实质。

纳米颗粒渗出后，包封的药物可以缓慢释放到组织中。

JournalofChinaPharmaceuticalUniversity2022，53（3）：333-339

学报

SNP-9对Aβ25-35导致bEnd.3细胞损伤的作用及其机制

孟悦，姚思远，高向东，陈松*（中国药科大学生命科学与技术学院江苏省生物药物成药性研究重点实验室，南京211198）摘要为了研究来源于丝素蛋白水解物的神经保护活性多肽SNP-9对于阿尔茨海默病（Alzheimer′sdisease，AD）中血脑屏障损伤的作用，使用Aβ25-35损伤脑微血管内皮细胞bEnd.3建立AD损伤模型，并给药干预。通过MTT实验检测SNP-9和Aβ25-35

对细胞活力的影响；RT-qPCR法检测SNP-9和Aβ25-35对细胞紧密连接（tightjunctions，TJs）相关的ZO-1、occludin和claudin-5mRNA水平的影响；Westernblot检测SNP-9和Aβ25-35对细胞TNF-α、磷酸化NF-κB、NF-κB、IκBα和RAGE蛋白水平的影响。实

验结果显示，SNP-9给药减少了Aβ25-35诱导的bEnd.3细胞损伤，改善了模型细胞中ZO-1、occludin和claudin-5mRNA水平的异常情况，缓解了Aβ25-35导致的TNF-α、磷酸化NF-κB、IκBα和RAGE蛋白水平异常。研究结果表明，SNP-9可能通过影响RAGE/NF-κB通路，调控模型细胞炎症因子TNF-α水平，改善TJs相关指标异常，缓解Aβ25-35诱导的bEnd.3细胞损伤。

关键词SNP-9；阿尔茨海默病；血脑屏障；bEnd.3；Aβ25-35；NF-κB

中图分类号R965文献标志码A文章编号1000-5048（2022）03-0333-07doi：10.11665/j.issn.1000-5048.20220311

引用本文孟悦，姚思远，高向东，等.SNP-9对Aβ25-35导致bEnd.3细胞损伤的作用及其机制［J］.中国药科大学学报，2022，53（3）：333

盐酸氟桂利嗪胶囊（Flunarizine Hydrochloride Capsules）Brand name: Flunarizine Hydrochloride Capsules Flunarizine Hydrochloride Capsules manual]Generic name: Flunarizine Hydrochloride CapsulesEnglish Name: FlunarizineHydrochlorideCapsulesMain ingredients: This product is the main ingredients: flunarizine hydrochloride. Its chemical name is: (E) -1-[bis (4- fluoro phenyl) methyl]-4-2 (2- propylene group -3- phenyl) - piperazine two hydrochloride.Molecular formula: C26H26F2N2. 2HClMolecular weight: 477.42Properties: This product is capsule.Pharmacological action:This product is a calcium channel blocker. It can prevent the damage caused by ischemia and other pathological intracellular calcium overload. This product has: to alleviate vasospasm, vasoconstrictor persistent spasm caused a long-lasting inhibition, especially on the basilar artery and internal carotid artery significantly, the ratio of cinnarizine is 15 times stronger; inhibition of the vestibular cochlear arteriole, can increase blood flow, improve the circulation of the vestibular organ; epilepsy this product, can block the pathological calcium overload of nerve cells and preventparoxysmal depolarization, cell discharge, so as to avoid the seizure; the protection of myocardium, significantly reduce myocardial ischemic injury; the effect of flunarizine is renal function, can be used for chronic renal failure; in addition the products and antihistamine effects.Pharmacokinetics: the product reached the peak value of plasma 2~4 hours after oral administration, and the T1/2 ranged from 2.4 to 5.5 hours, mainly in the liver, lung, pancreas, and stored in the bone marrow and fat. Even for 5~6 weeks, the steady-state blood concentration, 90% and plasma protein binding, can pass through the blood-brain barrier, and can be secreted with milk. Most of them are metabolized by the liver and excreted by the digestive tract. Bile enters the intestines and is excreted through the stool.Indications / efficacy: (1) cerebral ischemia, vertebral artery ischemia, cerebral thrombosis and so on. (2) tinnitus, cerebral halo. (3) migraine prevention. (4) adjuvant treatment of epilepsy.Usage and dosage: (1) central vertigo and peripheral vertigo including vertebral base, basal artery insufficiency, 10 to 20mg per day, and 2~8 weeks for 1 courses. (2) idiopathic tinnitus patients, 10mg, 1 times a night, 10 days for a course of treatment. (3) intermittent claudication, 10 to 20mg per day.(4) migraine prevention, 5 ~ 10mg, 2 times a day. (5) cerebral arteriosclerosis, cerebral infarction; flunarizine daily 5 ~ 10mg.Adverse reactions / adverse effects:(1) in the central nervous system adverse reactions are: sleepiness and fatigue were the most common; the long-term use can appear in female patients with depression, more common; the extrapyramidal symptoms manifested as involuntary movement, jaw movement disorders, ankylosis. Most medications appeared after 3 weeks and disappeared after withdrawal. Among the elderly, it is easy to occur; a few patients can suffer from insomnia, anxiety and other symptoms.(2) the symptoms of digestive tract include burning sensation of stomach, appetite of stomach, increase of food intake and weight gain.(3) other: a small number of patients may have rash, dry mouth, diarrhea, muscle soreness and other symptoms. But most of them are transient, and withdrawal can relieve them.Contraindications: have a history of drug allergy, or have a history of depression, and acute hemorrhagic brain disease is prohibited.Note: (1) the symptoms of fatigue should be reduced or discontinued after medication. (2) strictly control the dosage of drugs. When the maintenance dose is not enough or the extrapyramidal symptoms occur for a long time, the dosage should be reduced or stopped. (3) when suffering from extrapyramidal diseases such as Parkinson's disease, the preparation should be used with caution. (4) drivers and mechanical operators are careful to avoid accidents.Interaction: (1) with alcohol, sedatives or hypnotics combination, increased sedation. (2) and phenytoin, combined with C Masi Bing, can reduce the blood concentration of flunarizine. (3) patients with radiotherapy combined with flunarizine, can improve the killing effect on tumor cells. (4) based on the application of antiepileptic drug therapy, combined with flunarizine can improve the anti epilepsy effect.Medication for pregnant women and lactating women: this drug can penetrate the placental barrier and secrete milk,Although there are no reports of teratogenic effects on embryonic development, pregnant women and lactating women are in principle not using this drug.Children: because the drug can penetrate the blood-brain barrier, there is a clear central nervous system adverse reactions and the central nervous system in children of drug sensitivity; metabolic function is relatively weak, there is no detailed information on medication for children, in principle, be careful not to use or the drug for children.Elderly medication: because elderly patients are more sensitive to the nervous system, metabolic capacity is weak, the dosage should be reduced as appropriateDosage form: capsuleStorage: shading, sealing and preservationSpecifications: 5mg (in C26H26F2N2), *20 granule / boxPeriod of validity: 4 yearsApproval number: national medicine quasi word H44021801 Manufacturer: Shenzhen Zhonglian Pharmaceutical Co., Ltd. Clinical study:In order to evaluate the clinical efficacy of Flunarizine Hydrochloride on vertebral basilar artery insufficiency vertigo. 120 patients with vertigo were randomly divided VBI into 2 groups, 60 cases in the control group treated with energy mixture combined with Compound Danshen Injection by intravenous drip for 1 times, the treatment group in the control group treated with flunarizine hydrochloride 10mg, every night for 1 times, 2 groups were treated for 10d. The results showed that the treatment group has a rapid onset, the total effective rate of 93%, control group slow onset, the total efficiency of 70%, there were significant differences between 2 groups, that of Flunarizine Hydrochloride for the treatment of vertebral basilar artery insufficiency vertigo curative effect.。

药理学名词解释归纳药理学是研究药物与机体之间相互作用规律及其机制的一门科学。

药物是能改变或查明机体的生理功能及病理状态，用以预防、治疗及诊断疾病的物质。

药动学研究机体对药物的处置过程，即药物在机体的作用下发生的动态变化规律。

药效学研究药物对机体的作用及作用机制，即机体在药物影响下发生的生理、生化变化及机制。

售后调研是在社会人群大范围内继续进行受试药物安全性和有效性评价，在广泛长期使用的条件下考查疗效和不良反应，该期对最终确定新药的临床价值有重要意义。

药效学中，药物作用指药物与组织细胞之间的初始作用，药理效应指继发于药物作用之后的组织细胞原有功能的改变。

兴奋是能使机体原有生理、生化功能加强的作用，抑制是能使机体原有生理、生化功能减弱的作用。

多数药物是通过化学反应而产生药理效应，这种化学反应的专一性使药物具有特异性。

药物只对某些组织器官发生明显作用，而对其他组织作用很小或无作用，称为选择性。

药物作用的结果有利于改变病人的生理生化功能或病理过程，使患病机体恢复正常，称为疗效。

如果用药目的在于消除原发致病因子，彻底治愈疾病称对因治疗，或称治本；如果用药目的在于改善疾病症状，减轻疾病的并发症称对症治疗，或称治标。

不良反应是凡不符合用药目的或给病人带来痛苦与危害的反应，多数不良反应是药物固有效应的延伸。

副反应是药物在治疗剂量时出现的与治疗目的无关的作用，亦称副作用。

副反应是药物本身固有的，是因药物选择性低而引起的，一般不严重，难避免。

药物在剂量过大、用药时间过长或机体敏感性过高时，会对机体产生危害性反应，称为毒性反应。

这种反应一般比较严重，但是可以通过预知和避免来降低风险。

停药后，药物在血液中的浓度已经降至阈浓度以下，但仍会残留药理效应，称为后遗效应。

另外，长期使用某些药物后突然停药，可能会导致原有病情加重，这种现象被称为停药反应或回跃反应。

过敏特质的病人对某些药物可能会引起异常免疫反应，这种反应被称为变态反应或过敏反应。