神经生长因子促周围神经生长的临床应用

目的：应用神经生长因子（NGF）于周围神经损伤注射。增加神经营养,可加快神经再生速度。方法：1995－2001年对26例,32条损伤神经手术中放置NGF2000U,术后每次局部注射100－1000U,每1－3d一次,结果：损伤神经再生速度明显加快,最快的平均每天生长6mm.32条神经半年内恢复正常或接近正常。结论：NGF局部应用具有明显的促神经再生作用, 临床观察感觉运动及交感神经功能恢复均较理想,是有效的促神经生长药物。     

神经生长因子对视网膜色素上皮细胞增殖、DNA合成及凋亡的影响

用培养的人胚胎视网膜色素上皮（Retinal pigment epithelium，RPE）细胞研究神经生长因子（Nerve growth factor，NGF）对其增殖、DNA合成及凋亡的影响。取传代培养的RPE细胞，分别用MTT（Methyl thiazolyl tetrazolium）法和核酸蛋白分析仪测定NGF对细胞增殖及DNA合成的影响；建立吲哚美辛（Indomethaein，IN）诱导细胞凋亡模型，用透射电镜（Transmission electron microsocpy，TEM）和吖啶橙（Acridine orange，AO）荧光染色研究NGF对RPE凋亡细胞的保护作用。结果表明，NGF能促进RPE细胞增殖和DNA合成，随着NGF浓度的升高而促进作用愈明显；NGF对IN诱导的RPE细胞凋亡有保护作用。     

神经生长因子对坐骨神经挤压伤后的促再生作用

目的:观察肌注神经生长因子(NGF)对大鼠坐骨神经挤压伤后的促再生作用。方法:40只大鼠随机分成NGF高、中、低剂量组,正常对照和模型对照组。距坐骨切迹远端6mm处钳夹坐骨神经,使产生-4mm宽的挤压伤。NGF高、中、低剂量组分别给予8,4和2μg·kg~(-1)(1.6×10~3,8×10~2和4×10~2IU·kg~(-1)NGF,im,qd,连续56d。手术后不同时间,检测运动神经传导速度(MNCV)、坐骨神经功能指数(SFI)以及进行组织形态学评价。结果:与模型对照组相比,高剂量组在d35和d56,中剂量组在d35的MNCV均显著加快;高、中、低3个剂量组在术后d14后的SFI与模型组相比,均有统计学意义,且高剂量组恢复较明显,至d56各剂量组SFI均无明显差异;组织形态学显示,NGF治疗组神经髓鞘、轴索与正常对照组相比,未见明显差异;而模型组髓鞘出现脱失,细微结构不清晰,许旺氏细胞变性坏死。结论:肌注神经生长因子能明显促进大鼠坐骨神经纤维的再生,促进其神经功能的恢复。     

神经生长因子促大鼠缺血后肢血管再生的实验研究

目的：通过制备大鼠后肢缺血模型,我们对神经生长因子（NGF）促大鼠缺血后肢血管再生的功能进行评价,为临床上治疗下肢缺血性疾病提供一些新的思路及实验依据。方法：通过结扎W istar大鼠一侧股动脉制备大鼠缺血后肢模型,通过EL ISA和免疫组化,观察缺血后肢的血管再生与NGF及其高亲和力受体在缺血组织中的表达与是否具有相关性的作用。结果：反复的缺血内收肌的NGF注射,可以增加毛细血管和小动脉的密度,减少血管内皮细胞及纤维细胞的凋亡,并在不改变血流动力学的前提下加速缺血再灌注。结论：结果表明NGF在血管的修复和新生血管的形成中起到很大的作用。此外,在组织缺血的条件下,NGF途径的正反馈作用,刺激了血管再生及动脉形成,从而加速了血液血流动力的恢复,NGF可以促进血管内皮生长因子（VEGF）在缺血肢体骨骼肌中的表达,从而可能促进缺血肢体的血管再生;通过增加一定剂量的NGF,可以明显改善缺血肢体的功能恢复。NFG促血管再生的机制可以做为缺血性血管疾病的治疗的一个科研方向。     

神经生长因子的研究

神经生长因子(NGF)在神经元的发育、轴突的生长、递质的合成及细胞的凋亡等阶段均起重要作用。NGF来源十分广泛,可以由不同来源的细胞分泌,其结构已得到证实,构效关系也已研究得较为清楚。NGF的作用主要通过与受体蛋白结合而发挥作用。NGF神经生物学的研究发展迅速,研究证明NGF能够促进神经细胞的再生,对中枢和周围神经的损伤均有保护和恢复的作用。     

神经生长因子的生物活性研究

用鸡胚背根培养法和新生大鼠皮层神经元原代分散培养法对制备的神经生长因子的生物活性进行了研究，实验结果证实了该神经生生因子确有促进神经细胞生长的活性，这为神经生长因子尽快过渡到临床，提供了实验依据。     

神经生长因子治疗脑梗塞的疗效观察

本文报告应用神经生长因子治疗10例脑梗塞的疗效观察结果，总有效率100％。以病程短、病情轻、范围小者疗效最佳。认为其治疗机理可能与神经生长因子在脑梗塞后促进神经纤维增生，预防神经坏死有关。结果表明：神经生长因子治疗脑梗塞疗效确切，且未发现不良反应，脑梗塞患者可广为试用。     

鼠神经生长因子致结膜充血

患者男,57岁。因右三叉神经痛,于2006年4月17日来我院镇痛科治疗。查体:T36.6℃,P70次/min,R20次/min,BP 129/76mmHg(1mmHg=0.133kPa),神志清楚,五官正常,颈无抵抗,心肺听诊无特殊。既往无药物过敏     

注射用鼠神经生长因子

[通用名称]mouse nerve growth factor for in-jection(简称NGF),注射用鼠神经生长因子[商品名]苏肽生[主要成分]小鼠颌下腺中提取的神经生长因子,是一种相对分子质量为2.65×104的生物活性蛋白。[药理作用]NGF是神经系统最重要的生物活性蛋白物质之一,是中枢及外周神经系统分化、发育及维持正常功能所必需的蛋白分子,能促进神经系统损伤后的修复。在神经系统遇物理、化学等多种损害时,外源性神经生长因子可以保护感觉神经元和交感神经元,减轻伤害的程度,促进再生神经纤维生长,有利于神经功能的恢复。[毒理研究]小鼠静注本品的半数致死量…     

蛇毒神经生长因子的稳定性研究

将来源于蛇毒的神经生长因子冻干粉剂分5组处理:4℃放置、室温放置、30℃放置、40℃放置和40℃加饱和湿度放置。在d1、10、30、60、90和180分别测定各自的活性。结果表明蛇毒神经生长因子冻干粉剂是稳定的。     

Neotrofin is transported out of brain by a saturable mechanism: possible involvement of multidrug resistance and monocarboxylic acid transporters.

Neotrofin (AIT-082; leteprinim potassium) is transported out of brain by a saturable mechanism and in this study the mechanisms mediating this efflux were evaluated. Intracerebroventricular coadministration of [(14)C]Neotrofin with verapamil, a P-glycoprotein inhibitor, probenecid, an organic anion transporter inhibitor, 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK571), a multidrug resistance-associated protein inhibitor, and salicylate or benzoate, both monocarboxylic acid transporter substrates, inhibited the efflux of [(14)C]Neotrofin. Additionally, Neotrofin inhibited the efflux of [(3)H]quinidine from brain. Compounds can diffuse from cerebrospinal fluid (CSF) into extracellular fluid of brain parenchyma and thus, efflux of [(14)C]Neotrofin after intracerebroventricular administration may indicate active transport across choroid plexus epithelium, brain capillary endothelium, or both. To determine whether [(14)C]Neotrofin efflux occurs at the brain capillary endothelium, experiments were performed in which [(14)C]Neotrofin was administered intraparenchymally. The t(1/2) for [(14)C]Neotrofin disappearance from brain after intraparenchymal administration was significantly lower than that for [(3)H]sucrose and the efflux of Neotrofin was inhibited by 600-fold excess of unlabeled Neotrofin, verapamil, MK571, and salicylate. Together, these data suggest that a saturable mechanism for the efflux of Neotrofin is located at the blood-brain barrier and possibly the blood-CSF barrier. It is likely that multiple transporters are involved in the efflux of Neotrofin and these may include multidrug resistance and monocarboxylic acid transporters. These data are discussed in detail with respect to the site of transporter expression, the recent identification of numerous multidrug resistance-associated protein and monocarboxylic acid transporter homologs, the existence of other potential brain efflux transporters, and the availability of specific pharmacological agents with which to distinguish these transporters.     

Reversal of cycloheximide-induced memory disruption by AIT-082 (Neotrofin) is modulated by,but not dependent on,adrenal hormones

Rationale. AIT-082 (Neotrofin), a hypoxanthine derivative, has been shown to improve memory in both animals and humans. In animals, adrenal hormones modulate the efficacy of many memory-enhancing compounds, including piracetam and tacrine (Cognex). Objective. To investigate the role of adrenal hormones in the memory-enhancing action of AIT-082. Methods. Plasma levels of adrenal hormones (corticosterone and aldosterone) in mice were significantly reduced by surgical or chemical (aminoglutethimide) adrenalectomy or significantly elevated by oral administration of corticosterone. The effects of these hormone level manipulations on the memory-enhancing activity of AIT-082 and piracetam were evaluated using a cycloheximide-induced amnesia/passive avoidance model. Results. As previously reported by others, the memory enhancing action of piracetam was abolished by adrenalectomy. In contrast, the memory enhancement by 60 mg/kg AIT-082 (IP) was unaffected. However, a sub-threshold dose of AIT-082 (0.1 mg/kg, IP) that did not improve memory in control animals did improve memory in adrenalectomized animals. These data suggested that, similar to piracetam and tacrine, the memory enhancing action of AIT-082 might be inhibited by high levels of adrenal hormones. As expected, corticosterone (30 and 100 mg/kg) inhibited the action of piracetam, however no dose up to 100 mg/kg corticosterone inhibited the activity of AIT-082. Conclusions. These data suggest that while AIT-082 function is not dependent on adrenal hormones, it is modulated by them. That memory enhancement by AIT-082 was not inhibited by high plasma corticosterone levels may have positive implications for its clinical utility, given that many Alzheimer's disease patients have elevated plasma cortisol levels. Electronic Publication     

β—CIT、β—FP—CIT及其前体nor—β—CIT的合成

2－β－甲酯基－3－β－（4－碘苯基）降托烷（nor－β－CIT）是多巴胺转运蛋白正电子显像剂[^11C]－2－β甲酯基－3－β－（4－碘苯基）托品烷（[^11C]-β-CIT）和[^18F]－N－3氟丙基－2－β－（4－碘苯基）降托烷([^18F]－β－FP－CIT）的前体。本实验以可卡因为原料,经水解、脱水、酯化、格氏化、碘化、脱甲基等步骤合成了nor-β－CIT,总产率为12．9％,并以nor-β-CIT为原料合成了β－CIT和β－FP－CIT,为进一步放射化学合成[^11C]-β－CIT和[^18F]-β-CIT提供了可靠的技术路线。     

α-甲氨基-苄基亚膦酸及其酯类化合物的合成

利用类似Arbuzov反应及Mannichd反应设计合成了12种α-（甲氨基）-苄基亚膦酸类化合物和2种α-（甲氨基-苄基亚膦酸酯类化合物,它们的结构均经MS或^1H-NMR证明,其中12种亚膦酸化合物由取代的苯甲醛、甲胺及亚膦酸为底物,以环丁砜为溶剂,TsOH为催化剂,缩合而成,此法的优点为易于纯化,另2种亚膦酸酯化合物以相应的芳醛、甲胺及亚膦酸二乙酯为底物,以无水乙醇为溶剂,经Mannich反应缩合而得,此法操作简便,收率高于前者。     

Synthesis of o-acylamino-beta-dimethylamino-propiophenones. 4. Synthesis of primary Mannich-bases

Synthesis of 2-Acylamino-β-amino-propiophenones 2-Acetamino-β-dibenzylamino-propiophenone (XXVII) and its derivatives, substituted in 5-position, can be synthetized by reaction of 2-acetamino-β-dimethylamino-propiophenone (IVb) with dibenzylamine. By hydrogenolysis in the presence of palladium charcoal it is possible to convert these compounds into primary Mannich-bases, exclusively acetylated in 2-N-position.     

莫吉司坦的合成

愈创木酚与2-溴代乙醛缩二甲醇发生亲核取代,再与半胱胺盐酸盐缩合闭环得到2-[(2-甲氧基苯氧基)甲基]噻唑烷,最后与氯甲酰乙酸乙酯反应得到外周非麻醉性镇咳药莫吉司坦,总收率约71%.     

法匹拉韦的合成

3-氨基吡嗪-2-甲酸经酯化、NBS溴代、重氮化及胺化得6-溴-3-羟基吡嗪-2-甲酰胺,再经三氯氧磷氯代、氟化钾氟代及水解制得抗病毒药法匹拉韦,总收率约22％.     

巴格列酮的合成

以1H-苯并[d][1,3]噁嗪-2,4-二酮与甲胺反应得到2-氨基-N-甲基苯甲酰胺,与氯乙酰氯环合后经醚化反应、Knoevenagel反应及催化氢化得到糖尿病治疗药巴格列酮,总收率约48%。     

普罗布考的合成

2,6-二叔丁基苯酚经二硫醚化和还原反应得到2,6-二叔丁基-4-巯基苯酚,无需分离,直接以2,2-二甲氧基丙烷为缩酮化试剂,在对甲苯磺酸一水合物作用下制得降血脂药普罗布考,总收率约78%.