与功效和毒性相关的北豆根化学成分研究进展

目的 总结与北豆根的功效、毒性相关的化学成分研究现状,明确北豆根的有效成分和毒性成分,为进一步研究北豆根功效与毒性的相关性提供文献依据和研究思路.方法 对近20年发表的相关文献进行整理、分析、归纳.结果 生物碱既是北豆根的主要化学成分也是其发挥功效的主要物质基础;历代文献和药典均记载其有小毒,关于北豆根化学成分尤其是生物碱的规范毒性研究报道还不完善,对于功效和毒性物质基础的体内过程、药理特点、作用机制以及与临床应用的相关性尚属空白.针对药效物质基础和毒性物质基础的提取、分离工艺优化研究与质量控制研究也鲜有报道.结论 作为有小毒记载的中药北豆根,亟待需要进行基于功效和毒性相关的化学物质基础研究与质量的“保效、控毒”研究,为临床安全、可控、有效地使用北豆根提供试验依据和文献思路.     

北豆根化学成分及药理作用研究综述

通过对北豆根化学成分及药理作用研究的综述.为进一步开发北豆根资源提供可参考的资料.     

高效液相色谱法测定北豆根胶囊中蝙蝠葛含量

目的:北豆根胶囊为已上市销售纯中药制剂,为了更好地控制该产品质量.我们对处方中主药北豆根的蝙蝠葛含量测定方法进行了研究,采用高效液相法测定北豆根的蝙蝠葛含量,结果:线性、精密度、溶液稳定性、重现性、回收率、阴性等均符合要求,此方法可用于北豆根胶囊的含量测定和质量控制.通过本试验提高中药制剂的检验的准确性.为今后在生产中的检验提供依据.     

HPLC法对不同产地北豆根中蝙蝠葛碱的测定

目的　研究不同产地北豆根中蝙蝠葛碱含量的差异。方法　以北豆根饮片为分析对象,用phenomenexC18(4 . 6mm×15 0mm,5 μm)色谱柱,采用乙腈和0 . 2 %磷酸洗脱,流速1. 0ml·min-1,检测波长为2 84nm,对北豆根中的蝙蝠葛碱进行定性定量测定。结果　东北北豆根药材中生物碱含量最高,其次是山东产北豆根,河北产北豆根药材中蝙蝠葛碱含量较低。结论不同产地北豆根药材所含生物碱在质和量两方面均有较大差异。     

毒性导向下的北豆根中蝙蝠葛碱的质量控制方法学研究

目的 以北豆根不同组分的小鼠急毒研究为导向,进行北豆根毒性物质基础蝙蝠葛碱的质量控制方法学研究.方法 用高效液相色谱法测定北豆根全组分、水提组分、醇提组分中蝙蝠葛碱的含量.色谱条件:色谱柱用十八烷基硅烷键合硅胶为填充剂(250mm×4.6mm,5μm),流动相:乙腈- 0.05％三乙胺水溶液(40:60),流速:1.0mL/min,检测波长:282nm,柱温:25℃.结果蝙蝠葛碱在0.82～9.84g范围内与其峰面积呈良好的线性关系,平均回收率为98.7％.对北豆根不同组分中的蝙蝠葛碱的含量测定,发现蝙蝠葛碱的含量大小为:全组分＞水提组分＞醇提组分.结论 高效液相色谱法测定北豆根中蝙蝠葛碱的含量,方法线性关系良好,精密度、稳定性、重现性均较好,回收率较高.北豆根不同组分中蝙蝠葛碱的含量大小与急性毒性间均有一定的关系,但不完全一致.初步提示中药成分复杂,蝙蝠葛碱不是北豆根中的唯一毒性物质基础,因此寻找其他毒性成分进行多成分指标控制北豆根质量,对于北豆根的毒性研究具有重要作用.     

北豆根的现代研究概况

综述国内外学者对北豆根的研究情况，包括北豆根的生药学研究、化学成分的分析，着重阐述了有关北豆根的药理作用研究，同时概括介绍了其临床应用。     

北豆根抗炎镇痛作用的实验研究

目的 探讨北豆根提取物的抗炎镇痛作用,为新药开发和指导临床用药提供依据.方法 按不同工艺制备北豆根水煎液和流浸膏.采用二甲苯致小鼠耳肿胀模型和醋酸扭体实验研究北豆根不同提取物的抗炎镇痛作用.结果 与空白组比较,北豆根水煎液和流浸膏低剂量均能明显减轻小鼠耳炎性肿胀(P＜0.05),显示良好的抗炎作用;均明显减少小鼠扭体次数(P＜0.01),且扭体反应抑制率均大于50%,表明两个提取物在低剂量的镇痛作用显著.结论 北豆根水煎液和流浸膏低剂量均具明显的抗炎镇痛效果,且作用强于中、高剂量组.     

北豆根不同组分发挥抗炎作用的安全范围研究

目的研究北豆根水提、醇提组分发挥抗炎作用的治疗指数和安全范围。方法建立琼脂皮下注射致小鼠肉芽肿模型,给不同剂量的北豆根水提、醇提组分连续7天灌胃,观察北豆根不同组分抗炎作用,用Bliss法计算各组分发挥抗炎药效ED50、ED95;依据本实验室前文报道的北豆根不同组分急性毒性研究结果,用Bliss法计算各组分急性毒性的LD50,LD5,求得北豆根不同组分发挥抗炎作用的治疗指数(TI),安全系数(SF)。结果北豆根不同组分对炎症模型有明显的抗炎作用,呈现明显的量效关系,且醇提组分抗炎作用大于水提组分。北豆根水提、醇提组分对肉芽肿模型小鼠的抗炎安全范围TI、SF分别为57.532、17.4702和45.844、9.800。结论北豆根醇提组分对炎症模型的抗炎效果大于水提组分,但水提组分发挥抗炎作用的安全范围大于醇提组分。因此,在临床应用北豆根醇提组分时更应密切注意不良反应的发生并加强用药监测。     

北豆根总碱对环磷酰胺模型小鼠的免疫调节作用

从非特异性免疫功能及特异性免疫功能方面研究了北豆根总碱对环磷酰胺所致的免疫功能低下模型小鼠的免疫调节作用．实验结果表明,北豆根总碱２５ｍｇ／ｋｇ、５０ｍｇ／ｋｇ腹腔注射能显著增强模型小鼠单核巨噬细胞吞噬功能、迟发型超敏反应及增加其外周血淋巴细胞ＡＮＡＥ阳性百分率;北豆根总碱２５ｍｇ／ｋｇ腹腔注射能显著提高模型鼠血清溶血素生成能力．初步机理研究表明,北豆根总碱５０ｍｇ／ｋｇ腹腔注射能显著拮抗环磷酰胺对小鼠胸腺ＤＮＡ含量的抑制作用,提示北豆根总碱可能通过促进ＤＮＡ合成而达到增强免疫功能的作用．     

北豆根毒性研究进展

目的对北豆根的毒性及毒性与功效、毒性与物质基础之间的相关性进行综述。方法对近20年北豆根相关文献进行整理、分析、归纳。结果北豆根有小毒,临床大剂量使用会造成肾毒性损伤。其中蝙蝠葛碱、青藤碱等成分具有肝毒性。结论北豆根毒性物质基础、体内毒性过程、毒作用特点、毒性作用机制尚不完全明确,北豆根发挥功效和产生毒性的剂量范围尚不十分清晰,以功效和物质基础为背景的毒性研究尚处于起步阶段,仍需进行深入研究以期为临床合理用药提供实验数据和文献依据．     

Effect of valproic acid on mitochondrial epigenetics

Ceramides derived from sphingosine contribute to the apoptotic processes of neuronal cells in neurodegenerative disorders including Alzheimer's disease. This study investigates the potential neuroprotective effects of Asiatic acid, a triterpenoid derived from Centella asiatica, against C(2)-ceramides-induced cell death in primary cultured rat cortical neuronal cells. In primary neurons, Asiatic acid (0.01 to 1.0 μmol/l) reduced C(2)-ceramide-induced cell death and mitochondria membrane potential loss in a concentration-dependent manner. Furthermore, Asiatic acid decreased cellular production of reactive oxygen species following C(2)-ceramide treatment. At a maximal concentration of 1.0 μmol/l, Asiatic acid partly counteracted the pro-apoptotic effects of the C(2)-ceramide by reducing the cytosolic release of HtrA2/Omi, the upregulation of Bax and caspase 3, as well as the dephosphorlyation of ERK1/2. Taken together, these data suggest that Asiatic acid protects neurons from C(2)-ceramide-induced cell death by antagonizing mitochondria-dependent apoptosis.     

Asiatic acid,a non-detergent type spermicide: exploration of plausible pathway of spermicidal action

The spermicidal and microbicidal activity of Asiatic acid isolated from Shorea robusta resin was explored earlier using rat spermatozoa. The current investigation is aimed at examining the spermicidal efficacy of the molecule against human spermatozoa along with the plausible pathway involved in its spermicidal action. Spermicidal efficacy of Asiatic acid against human spermatozoa was evaluated in vitro by modified Sander-Cramer test and the subsequent mode of spermicidal action was assessed by (a) hypo-osmotic swelling test, (b) double fluoroprobe staining, (c) flow cytometric detection of apoptosis by fluorescein isothiocyanate-Annexin?V labelling and (d) JC-1 labelling. The minimum effective concentration of the molecule against human spermatozoa was found to be 500?µg/ml which is comparable to the standard spermicide nonoxynol-9 (minimum effective concentration 550?µg/ml). The mechanistic pathway of spermicidal action of the molecule involves apoptosis rather than general cell necrosis. The molecule Asiatic acid may be explored as an ingredient for the formulation of a new generation non-detergent type microbicidal contraceptive.     

Asiatic acid exerts anticancer potential in human ovarian cancer cells via suppression of PI3K/Akt/mTOR signalling

Context Asiatic acid, a triterpenoid compound extracted from the tropical medicinal plant Centella asiatica (Family: Apiaceae), has exhibited various biological activities.

Objective This study was performed to investigate the cytotoxic effects of asiatic acid on human ovarian cancer cells.

Materials and methods SKOV3 and OVCAR-3 ovarian cancer cells were exposed to different concentrations of asiatic acid (10–100?μg/mL) for 72 or 48?h. Cell viability, colony formation, cell cycle distribution, apoptotic response were examined. Involvement of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was tested.

Results At the concentration of 40?μg/mL, asiatic acid caused about 50% reduction in the viability of ovarian cancer cells, but had little effect on the viability of normal human ovarian epithelial cells. Asiatic acid at 10?μg/mL reduced colony formation of ovarian cancer cells by 25–30%. Asiatic acid-treated cells showed a cell cycle arrest at the G0/G1 phase and 7- to 10-fold increase in apoptosis. The phosphorylation levels of PI3K, Akt and mTOR were remarkably lower in asiatic acid-treated cells. Overexpression of constitutively active Akt partially reversed the cytotoxic effects of asiatic acid, as evidenced by increased cell viability and colony formation. Furthermore, knockdown of Akt mimicked the growth-suppressive activity of asiatic acid.

Discussion and conclusion These results provide first the evidence for the anticancer potential of asiatic acid in ovarian cancer cells, partially via inactivation of the PI3K/Akt/mTOR pathway. Asiatic acid may represent a potential therapeutic agent for ovarian cancer.     

Efficacy and safety of ticagrelor in patients with acute coronary syndrome: A meta‐analysis of randomized controlled trials

Acute coronary syndrome (ACS) is a dangerous and urgent clinical pattern of coronary artery disease. Aspirin and adenosine diphosphate P2Y₁₂ receptor antagonists are the standard dual anti‐platelet therapy for patients with ACS. Ticagrelor is a new oral antagonist of the adenosine diphosphate P2Y₁₂ receptor. Randomized controlled trials (RCTs) have evaluated the efficacy and safety of ticagrelor compared to clopidogrel or prasugrel in patients with ACS, obtaining conflicting results. Thus, we conducted a meta‐analysis of these RCTs to determine the efficacy and safety of ticagrelor in patients with ACS. Results of the meta‐analysis indicate that ticagrelor decreased the risk of major adverse cardiovascular events (MACE) and all‐cause death, but increased the risk of bleeding events. In Asiatic patients, analysis indicates that ticagrelor did not decrease the risk of MACE and all‐cause death, while increasing the risk of bleeding events. Together, this meta‐analysis suggests that ticagrelor was more effective, but less safe than clopidogrel and prasugrel in patients with ACS. Subgroup analysis indicates that ticagrelor was not more effective, although less safe than clopidogrel in Asiatic patients, thus more evidence is needed to further evaluate the efficacy and safety of ticagrelor in Asiatic patients.     

Asiatic acid inhibits LPS-induced inflammatory response in human gingival fibroblasts

Asiatic acid, a triterpenoid component isolated from Centella asiatica (L.) Urban, possesses antioxidative and anti-inflammatory activities. In this study, we aimed to investigate the anti-inflammatory effects of asiatic acid both in vivo and in vitro. HGFs or RAW264.7 cells were treated with asiatic acid 1 h before LPS treatment. Cell viability was measured by MTT assay. The levels of PGE2, NO, IL-6, and IL-8 were detected by ELISA. Protein expression levels were detected by western blot analysis. In vivo, asiatic acid significantly inhibited LPS-induced IL-6 and IL-8 expression levels in gingival tissues. In vitro, LPS-induced PGE2, NO, IL-6, and IL-8 production was significantly attenuated by asiatic acid. Asiatic acid also inhibited p65 NF-κB phosphorylation induced by LPS in HGFs. The expression of PPAR-γ was up-regulated by asiatic acid. Furthermore, GW9662, a PPAR-γ inhibitor, attenuated the inhibitory effect of asiatic acid on PGE2, NO, IL-6, and IL-8 production. Our results suggest that asiatic acid activates PPAR-γ, which subsequently inhibits LPS-induced NF-κB activation and inflammatory mediators production. Asiatic acid may offer therapeutic potential for the treatment of periodontitis.     

积雪草有效成分ADME的特性概述

积雪草酸及其衍生物是传统药用植物积雪草中含量较高并主要发挥活性的五环三萜类化合物,具有治疗皮肤损伤、抗癌、抗抑郁等多种药理活性,但口服生物利用度差。本研究通过查阅国内外相关文献,系统分析积雪草有效成分的吸收、分布、代谢和排泄(ADME)等药动学特点,探讨其口服生物利用度低的原因,并提出改善方法。     

Oxaliplatin-induced lung toxicity. Case report and review of the literature

Rapidly developing pulmonary fibrosis associated with the use of the anti-cancer drug oxaliplatin has been reported mainly by Asiatic literature as isolate case reports. This rare but potentially fatal side effect has neither identified risk factors nor established treatment guideline. We report here a new clinical case concerning a patient with advanced gastric cancer treated with the oxaliplatin-based FOLFOX regimen along with a review of the literature as well as a discussion of emerging experimental treatment mainly based on imatinib.     

积雪草酸C2、C3、C23、C28衍生物的合成及其体外抗肿瘤活性研究

目的设计并合成积雪草酸C2、C3、C23、C28衍生物,并对其体外抗肿瘤活性进行研究。方法以天然产物积雪草酸为先导化合物,对C2、C3、C23位羟基及C28位羧基进行结构改造,并采用SRB法对目标化合物进行初步的体外抗肿瘤活性研究。结果设计并合成了目标化合物,利用MS及1H-NMR确证了结构;体外实验中,积雪草酸衍生物的抗肿瘤活性明显高于积雪草酸,并优于对照药吉非替尼。结论积雪草酸衍生物具有良好的抗肿瘤活性,值得进一步研究。     

Agent-specific Shadoo Responses in Transmissible Encephalopathies

Transmissible spongiform encephalopathies (TSE) are neurodegenerative diseases caused by an infectious agent with viral properties. Host prion protein (PrP), a marker of late stage TSE pathology, is linked to a similar protein called Shadoo (Sho). Sho is reduced in mice infected with the RML scrapie agent, but has not been investigated in other TSEs. Although PrP is required for infection by TSE agents, it is not known if Sho is similarly required. Presumably Sho protects cells from toxic effects of misfolded PrP. We compared Sho and PrP changes after infection by very distinct TSE agents including sporadic CJD, Asiatic CJD, New Guinea kuru, vCJD (the UK epidemic bovine agent) and 22L sheep scrapie, all passaged in standard mice. We found that Sho reductions were agent-specific. Variable Sho reductions in standard mice could be partly explained by agent-specific differences in regional neuropathology. However, Sho did not follow PrP misfolding in any quantitative or consistent way. Tga20 mice with high murine PrP levels revealed additional agent-specific differences. Sho was unaffected by Asiatic CJD yet was markedly reduced by the kuru agent in Tga20 mice; in standard mice both agents induced the same Sho reductions. Analyses of neural GT1 cells demonstrated that Sho was not essential for TSE infections. Furthermore, because all infected GT1 cells appeared as healthy as uninfected controls, Sho was not needed to protect infected cells from their “toxic” burden of abundant abnormal PrP and intracellular amyloid.     

Venomous snakes of Saudi Arabia and the Middle East: a keynote for travellers

Geographically Saudi Arabia and the Middle East include Asian Turkey, Syria, Lebanon, Jordan, Israel, Palestine, the Arabian Peninsula, Iraq, Iran and the previous Southern Asiatic Soviet Republics. The snake fauna contains species in common with northern Africa, Europe and central Asia and towards the east there is infiltration of species characteristic of tropical Asia. A classification of the venomous snakes of this area together with their distribution in the different countries is presented. The epidemiology of snake bites, pathophysiology of toxicity and the clinical features of envenoming by the different species of snakes are discussed. Management of snake bite victims including first aid, treatment at the hospital, clues from signs and symptoms that can help in the identification of the causative snake and antivenom treatment is stressed. Traditional manipulations like local incision and suction, use of caustics, oxidizing agents and cryotherapy and the injudicious use of tourniquets are evaluated and criticized. Finally the preventive control of snake bites for travellers in areas infested with venomous snakes is presented and discussed.