粉防己碱对培养大鼠心肌细胞胞内游离钙的影响(英文)

目的:研究粉防己碱对心肌的作用。方法:采用Fura-2和AR-CM-MIC阳离子测定系统测定培养大鼠单个心肌细胞胞内游离钙。结果:外钙1.3mmol·L~(-1)时,细胞静息钙为90±12nmol·L~(-1)。粉防己碱不影响静息钙,但可明显抑制CaCl_2,KCl,哇巴因引起的胞内钙增高;对于去甲肾上腺素引起的胞内钙增高,粉防己碱只有在外钙存在时,方对其有抑制作用。结论;粉防己碱抑制钙离子的跨膜运动,但在心肌细胞,它并非是选择性的钙通道阻滞剂。     

普瑞巴林的临床应用与不良反应

普瑞巴林(pregabalin)是一种新型的神经递质γ-氨基丁酸(GABA)结构类似物,主要用于治疗成人癫痫症、带状疱疹后神经痛、糖尿病神经病变有关的神经性疼痛和纤维肌痛等。文中总结了普瑞巴林的临床应用和不良反应,建议普瑞巴林的维持剂量为300 mg.d-1,超过600 mg.d-1不会增强疗效,反而会增加普瑞巴林不良反应的发生率。     

红树林根泥真菌Aspergillus versicolor sp.PJX-9胞外多糖结构特征及抗氧化活性研究

目的对来源于红树林根泥真菌Aspergillus versicolor sp.PJX-9胞外多糖进行结构和抗氧化活性的研究。方法利用乙醇沉淀法、强阴离子交换色谱和凝胶渗透色谱对菌株发酵液中的胞外多糖进行分离纯化;通过高效凝胶渗透色谱(HPGPC)、PMP柱前衍生高效液相色谱(HPLC)、红外光谱(IR)及气质联用色谱(GC-MS)等方法,研究胞外多糖的化学组成和结构特征;通过测定DPPH、超氧阴离子和羟基自由基清除率,研究胞外多糖的抗氧化活性。结果从发酵液中分离得到的多糖组分Pw1-1的分子量为12.3kDa,其主要由甘露糖组成,少量葡萄糖和半乳糖;Pw1-1糖链中主要为(1→2)-Manp,还有少量(1→6)-Manp、(1→6)-Glcp和(1→2,6)-Manp及末端Manp和Gal f;Pw1-1具有良好的体外抗氧化活性,随着浓度的增加清除能力亦增强,对DPPH、超氧阴离子和羟基自由基清除的EC50分别为3.39、1.50和1.72mg/mL。结论首次从红树林根泥真菌Aspergillus versicolor sp.PJX-9中分离得到胞外多糖Pw1-1,它是1种具有良好体外抗氧化活性的结构新颖的杂多糖。     

新型外周镇痛药物作用靶点——辣椒素受体

辣椒素受体是表达于感受痛觉的中枢感觉神经元伤害性感受器上的阳离子通道,与人体对伤害性冲动的感受和痛觉的产生密切相关.实验条件下,辣椒素受体激动,机体会产生痛觉更应.而敲除辣椒素受体的动物则对某些伤害性刺激,如辣椒素、H+、热(＞43℃)极不敏感.随着研究的深入,外周伤害性感受器上的辣椒素受体VR1作为新型镇痛靶点的研究开始受到广泛关注.     

辣椒素受体在炎性疼痛中的作用

辣椒素受体（vanilloid receptor subtype1,VR1）是一个配体门控的非选择性阳离子通道,此结构与配体结合后,会引发了一系列生物学效应。辣椒素受体广泛分布于机体的伤害性感受器上,当机体受到伤害性化学、机械和热刺激时,VR1就被激活并产生痛觉。     

辣椒素抗疲劳作用研究进展

辣椒是一种在湖南、四川等地区广泛使用的药食两用植物。中医认为：辣椒具有通经活络、活血化瘀、驱风散寒、开胃健胃、补肝明目、温中下气、抑菌止痒和防腐驱虫的保健作用，被称为“红色药材”。辣椒素（capsaicinoids）是辣椒中的主要辛辣成分，可特异性作用于辣椒素敏感C类纤维的辣椒素受体（vanilloid receptor，VR1），继而配体操纵非选择性阳离子通道，引起一些活性物质释放，具有多种生物及药理活性，如止痛、减肥、降脂、扩张血管等作用。[第一段]     

血余炭纳米纤维膜抗菌活性的实验研究

目的:制备新型载药止血材料血余炭纳米纤维膜,并探讨其体内、体外的抗菌性能。方法:采用静电纺丝技术,将血余炭作为添加药物,以生物相容性较好的聚乳酸作为纳米纤维膜基体,制备了一种新型的载药止血材料。采用抑菌环实验法测定医用脱脂纱布、抗菌医用敷料、未载血余炭纳米纤维膜和载血余炭纳米纤维膜对金黄色葡萄球菌、大肠杆菌、铜绿假单胞菌的抑菌环直径;选用兔感染创面模型,使用材料对创面进行治疗,通过肉眼和组织病理学观察、组织内细菌计数等方法对各组材料的抗菌性能进行研究。结果:血余炭纳米纤维膜纤维直径相对较小,平均直径为400 nm,载入的血余炭与成纤维聚合物之间具有良好的相容性。血余炭纳米纤维膜在体外对金黄色葡萄球菌、大肠杆菌和铜绿假单胞菌均有一定的抑制效果;肉眼和组织学观察,血余炭纳米纤维膜治疗后的动物模型伤口炎症反应明显小于其他组;血余炭纳米纤维膜治疗后感染伤口细菌数量为(7.62±1.87)×104个.g-1组织,与空白对照组比较显著减少,差异具有统计学意义(P<0.01)。结论:血余炭纳米纤维膜具有良好的体内、体外抗菌性能。     

细胞外信号调节激酶在紫杉醇诱发神经痛中的作用机制

细胞外信号调节激酶（ extracellular signal-regulate kinase ，ERK）是一类丝／苏氨酸蛋白激酶，介导多种信号的胞内转导。糖尿病、神经损伤、化疗药物等引发的神经痛及炎性痛的发生发展都与ERK的磷酸化增加有关，继而认为紫杉醇诱发神经痛的发生发展也与ERK活化密切相关。这一新的发现为临床治疗紫杉醇诱发神经痛提供了新的思路和研究方向。本文主要从ERK的基本特性、紫杉醇诱发神经痛的可能机制及ERK参与其形成的可能机制以及影响ERK发挥作用的因素等方面进行了综述。     

浊度法与膜材测定法在评价脂质体柱回收率上的对比研究

目的研究浊度法与膜材测定法在评价脂质体柱回收率上的不同。方法采用改良乙醇注入法制备不同粒径的空白脂质体(liposome 1,L1;liposome 2,L2);建立高效液相色谱-蒸发光散射(HPLC-ELSD)法测定脂质体中胆固醇(cholesterol,CH)的含量;采用浊度法和膜材测定法对空白脂质体L1、L2于阳离子交换纤维柱,阳离子交换树脂柱及葡聚糖凝胶柱上的柱回收率进行测定,进而比较上述2种方法在评价相同脂质体于不同微柱回收率上的优劣;对洗脱过程中脂质体的粒径进行了检测。结果制备的空白脂质体L1、L2粒径分别为650.2nm和329.8nm;采用HPLC-ELSD法测定脂质体中CH的含量操作简便、结果准确、重现性好;采用浊度法测定柱回收率时,L1、L2在阳离子交换纤维柱,阳离子交换树脂柱及葡聚糖凝胶柱上回收率达到100%时对应的洗脱次数分别为3、4、4次和2、2、3次;采用膜材测定法测定脂质体柱回收率时,相应的洗脱次数分别为4、4、4次和3、3、3次。结论首次提出脂质体的"表观柱回收率"及"实际柱回收率"的概念,并用其进一步量化浊度法与膜材测定法在测定脂质体柱回收率的不同。浊度法与膜材测定法在评价脂质体柱回收率上存在很大差异,膜材测定法更为科学。     

杀菌/通透性增加蛋白23-人酸性成纤维细胞生长因子融合蛋白在CHO细胞中的表达及活性鉴定

<正>杀菌/通透性增加蛋白(BPI)是一种主要存在于中性粒细胞内的阳离子抗菌蛋白,具有杀菌、中和内毒素和抗真菌等作用,并且在发生生物学效应时,对机体不产生任何损害,在革兰阴性菌感染的治疗方面有很好的应用前景[1]。研究表明,     

VR1 receptor modulators as potential drugs for neuropathic pain

The involvement of VR(1) in the endogenous pain signalling has converted this receptor into a promising therapeutic target for the development of a new family of potent analgesics devoid of the shortcomings of other analgesics commonly used. The desensitisation induced after VR(1) activation points to the utility of VR(1) agonists for the treatment of various nociceptive disorders including mitigation of neuropathic pain, inhibition of neurogenic inflammation and suppression of urinary bladder hyperreflexia, whereas VR(1) antagonists have been described as valuable agents for the treatment of inflammatory hyperalgesia and pain. Structure of the main classes of VR(1) ligands developed to date, their molecular mechanisms of action and their promising utility for the management of diverse nociceptive alterations, specially neuropathic pain, are discussed in this review.     

Vanilloid receptor ligands: hopes and realities for the future

Neurons possessing C-fibers transmit nociceptive information into the central nervous system and participate in various reflex responses. These neurons carry receptors that bind capsaicin, recently identified as the vanilloid VR1 receptor. Excitation of these cells by capsaicin is followed by a lasting refractory state, termed desensitisation, in which the neurons fail to respond to a variety of noxious stimuli. Desensitisation to capsaicin has a clear therapeutic potential in relieving neuropathic pain and ameliorating urinary bladder overactivity, just to cite 2 important examples. Vanilloids may also be beneficial in the treatment of benign prostate hyperplasia (BPH). Since the majority of elderly patients have neuropathic pain co-existent with urinary incontinence and/or BPH, a drug that ameliorates pain and improves urinary symptoms at the same time promises to be of great clinical value in geriatric medicine. In fact, capsaicin has already been shown to have a role in the treatment of conditions that can arise in the elderly, including herpes zoster-related neuropathic pain, diabetic neuropathy, postmastectomy pain, uraemic itching associated with renal failure, and urinary incontinence. The potent VR1 agonist resiniferatoxin, now in phase II clinical trials, appears to be superior to capsaicin in terms of its tolerability profile. Recent discoveries enhance the therapeutic potential of vanilloids. The recognition that VR1 also functions as a principal receptor for protons and eicosanoids implies that VR1 antagonists may be of value in the treatment of inflammatory hyperalgesia and pain. Animal experimentation has already lent support to this assumption. The discovery of VR1-expressing cells in the brain as well as in non-neural tissues such as the kidney and urothelium places VR1 in a much broader perspective than peripheral pain perception, and is hoped to identify further, yet unsuspected, indications for vanilloid therapy. The realisation that VR1 and cannabinoid CB1 receptors have overlapping ligand recognition properties may also have far-reaching implications for vanilloid therapy. In fact, arvanil, a combined agonist of VR1 and CB1 receptors, has already proved to be a powerful analgesic drug in the mouse. From academic molecular biology laboratories to industrial drug discovery centres to the clinics, there is a steady flow of new data, forcing us to constantly revise the ways we are thinking about vanilloid receptor ligands and their hopes and realities for the future. This review covers the most promising current trends in vanilloid research with special emphasis on geriatric medicine.     

Identification and biological characterization of 6-aryl-7-isopropylquinazolinones as novel TRPV1 antagonists that are effective in models of chronic pain

Vanilloid receptor 1 (VR1, TRPV1) is a cation-selective ion channel that is expressed on primary afferent neurons and is upregulated following inflammation and nerve damage. Blockers of this channel may have utility in the treatment of chronic nociceptive and neuropathic pain. Here, we describe the optimization from a high throughput screening hit, of a series of 6-aryl-7-isopropylquinazolinones that are TRPV1 antagonists in vitro. We also demonstrate that one compound is active in vivo against capsaicin-induced hyperalgesia and in models of neuropathic and nociceptive pain in the rat.     

Current perspectives on the therapeutic utility of VR1 antagonists

This review gives a brief overview of the expression patterns, molecular pharmacology and physiological roles of the vanilloid receptor 1 (VR1). Particular emphasis is given to the therapeutic utility of VR1 modulators. Small molecule agonists of VR1, including capsaicin and RTX, are currently utilized for a number of clinical syndromes, including intractable neuropathic pain, spinal detrusor hyperreflexia, and bladder hypersensitivity; however, antagonists of VR1 have yet to reach the clinic. While the classic VR1 antagonist, capsazepine has proven a useful tool for unraveling the molecular pharmacology of VR1, in vivo studies with this compound have had limited success due to poor pharmacokinetic properties and species selectivity issues. With the cloning of VR1 in 1997, the pharmaceutical community has been provided a molecular target for high throughput screening and small molecule lead discovery and optimization. As a result, resurgence in the interest of VR1 antagonists has given way to many new pharmacological agents that may provide better tools to probe VR1 physiology, and ultimately yield promising therapeutic agents.     

Down-regulation of GFRalpha-1 expression by antisense oligodeoxynucleotide aggravates thermal hyperalgesia in a rat model of neuropathic pain

Glial cell line-derived neurotrophic factor (GDNF) has been hypothesized to play an important role in the modulation of nociceptive signals especially during neuropathic pain. The present study examined the expression of GDNF and GFRalpha-1 (the high-affinity receptor of GDNF) in dorsal root ganglions (DRG) in a rat model of neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve. In order to address the role of GDNF and GFRalpha-1 in neuropathic pain, antisense oligodeoxynucleotide (ODN) specifically against GFRalpha-1 was intrathecally administered to result in down-regulation of GFRalpha-1 expression. The results showed that both the protein and mRNA levels of GDNF and GFRalpha-1 were significantly increased after CCI, while the thermal hyperalgesia of neuropathic pain rats could be significantly aggravated by antisense ODN treatment, but not by normal saline (NS) or mismatch ODN treatment. The present study demonstrated that endogenous GDNF and GFRalpha-1 might play an anti-hyperalgesic role in neuropathic pain of rats. In addition, we found a down-regulation of somatostatin (SOM) in DRG and spinal dorsal horn after expression of GFRalpha-1 was knocked down, which suggested the possible relationship between the anti-hyperalgesic effect of GDNF and GFRalpha-1 on neuropathic pain and endogenous SOM.     

The effects of galanin on neuropathic pain in streptozotocin-induced diabetic rats

Diabetic neuropathy is a common complication associated with diabetes and is frequently painful. However, mechanisms responsible for diabetic neuropathic pain are still unclear. Experimental evidence has shown that the galanin and its receptor are involved in pain sensitization. The objective of the present study was to investigate the role of galanin and its receptor antagonist or agonist on neuropathic pain in streptozotocin-induced diabetic rats. The expression of galanin, galanin receptors 1 and 2 in dorsal root ganglion (DRG) and spinal dorsal horn (SDH) in diabetic rats were detected by Western blot assay. The effects of galanin, galanin receptor antagonist M35, galanin receptor 1 agonist M617, and galanin receptor 2 agonist AR-M1896 on neuropathic pain were evaluated by mechanical stimuli. The results showed that (1) the diabetic rats showed a significant mechanical hyperalgesia between 4 and 12weeks; (2) galanin receptor 1 expression decreased in SDH in diabetic rats; (3) galanin receptor 2 expression decreased in DRG and SDH in diabetic rats; (4) intrathecal administration of exogenous galanin attenuated diabetic neuropathic pain, this effect could be blocked by pre-treatment with galanin receptor antagonist M35; and (5) intrathecal administration of galanin receptor 1 agonist M617, but not galanin receptor 2 agonist AR-M1896, attenuated diabetic neuropathic pain. These results imply that galanin acts through receptor 1, but not galanin receptor 2, to exert analgesic effect in diabetic neuropathic pain and is one of the potential therapeutic targets on diabetic neuropathic pain sensitization.     

Design of potent, orally available antagonists of the transient receptor potential vanilloid 1. Structure-activity relationships of 2-piperazin-1-yl-1H-benzimidazoles

The vanilloid receptor-1 (VR1 or TRPV1) is a membrane-bound, nonselective cation channel that is predominantly expressed by peripheral neurons sensing painful stimuli. TRPV1 antagonists produce antihyperalgesic effects in animal models of inflammatory and neuropathic pain. Herein, we describe the synthesis and the structure-activity relationships of a series of 2-(4-pyridin-2-ylpiperazin-1-yl)-1H-benzo[d]imidazoles as novel TRPV1 antagonists. Compound 46ad was among the most potent analogues in this series. This compound was orally bioavailable in rats and was efficacious in blocking capsaicin-induced flinch in rats in a dose-dependent manner. Compound 46ad also reversed thermal hyperalgesia in a model of inflammatory pain, which was induced by complete Freund's adjuvant (CFA).     

Platelet-activating factor and pain

Platelet-activating factor (PAF) is a phospholipid mediator that regulates the functions of a variety of cells in the peripheral tissues and in the nervous system. Findings that injection of PAF exogenously at the skin or in the spinal cord induced pain hypersensitivity gave us much attention to its role in pain signaling. Studies using pharmacological and genetic tools to control the functions of the PAF receptor (PAFR) revealed that the PAF/PAFR system plays a role in tissue injury-induced pain, but not in the acute physiological pain evoked by thermal and mechanical stimuli. Recent investigations have focused on the roles of PAFR in pathological chronic pain such as the neuropathic pain that occurs after nerve injury for which there is currently no effective therapy. Nerve injury upregulated PAFRs in dorsal root ganglion (DRG) neurons. Studies using PAFR antagonists and PAFR-deficient mice indicated a crucial role of PAFR in production of tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β) in the DRG and in developing and maintaining neuropathic pain. Thus, blocking PAFRs may be a viable therapeutic strategy for treating neuropathic pain.     

Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness

Microglia play a crucial role in the maintenance of neuronal homeostasis in the central nervous system, and microglia production of immune factors is believed to play an important role in nociceptive transmission. There is increasing evidence that uncontrolled activation of microglial cells under neuropathic pain conditions induces the release of proinflammatory cytokines (interleukin - IL-1beta, IL-6, tumor necrosis factor - TNF-alpha), complement components (C1q, C3, C4, C5, C5a) and other substances that facilitate pain transmission. Additionally, microglia activation can lead to altered activity of opioid systems and neuropathic pain is characterized by resistance to morphine. Pharmacological attenuation of glial activation represents a novel approach for controlling neuropathic pain. It has been found that propentofylline, pentoxifylline, fluorocitrate and minocycline decrease microglial activation and inhibit proinflammatory cytokines, thereby suppressing the development of neuropathic pain. The results of many studies support the idea that modulation of glial and neuroimmune activation may be a potential therapeutic mechanism for enhancement of morphine analgesia. Researchers and pharmacological companies have embarked on a new approach to the control of microglial activity, which is to search for substances that activate anti-inflammatory cytokines like IL-10. IL-10 is very interesting since it reduces allodynia and hyperalgesia by suppressing the production and activity of TNF-alpha, IL-1beta and IL-6. Some glial inhibitors, which are safe and clinically well tolerated, are potential useful agents for treatment of neuropathic pain and for the prevention of tolerance to morphine analgesia. Targeting glial activation is a clinically promising method for treatment of neuropathic pain.     

辣椒素受体研究进展

辣椒素受体（vanilloid receptor subtypel，VR1）是机体的一个重要的伤害性感受分子，除了参与中枢和外周水平疼痛的形成外，还参与了多种生理活动和病理过程。激活神经纤维末端的辣椒素受体，可调节外周血管的舒缩，影响血压；对缺血心肌起到保护作用；辣椒素受体还参与哮喘的发生，调节胃酸的分泌，促进胃肠蠕动。另外，激活辣椒素受体，还可抑制毛干的增殖，并介导肿瘤细胞的凋亡。本文主要就辣椒素受体近几年的研究情况作一简要综述。