齐墩果酸的药动学研究进展

齐墩果酸具有广泛的药理作用,包括抗炎、抗肿瘤、抗糖尿病、抗动脉粥样硬化,保肝、抗骨质疏松等。但是齐墩果酸口服的生物利用度低,通过被动扩散被肠道吸收,齐墩果酸的分散体制剂能提高溶出度和生物利用度,且能浓集于肝脏,有利于治疗肝部疾病。通过综述齐墩果酸药动学参数、体内过程、齐墩果酸分散体及其前药的药动学特征,总结齐墩果酸的药动学研究进展,为合理用药提供参考。     

茴三硫固体分散体的体内外评价

目的采用热熔挤出技术制备茴三硫固体分散体,用于提高其溶出度和口服生物利用度。方法以水溶性聚合物Plasdone S630为载体,用热熔挤出技术制备茴三硫固体分散体。采用差示扫描量热法和X射线粉末衍射法对固体分散体进行表征,并评价其溶出度及犬体内药动学行为。结果药物以无定形或分子状态存在于固体分散体中,溶出速率明显高于参比制剂与物理混合物,在40℃,湿度75%加速6个月,溶出曲线和固体分散体中茴三硫存在状态未发生变化。犬体内药动学研究结果表明,茴三硫固体分散体的Cmax和口服生物利用度是参比制剂的1.66倍和1.57倍。结论采用热熔挤出技术制备的茴三硫固体分散体为热力学稳定体系,能明显提高茴三硫的体外溶出度和口服生物利用度。     

芦丁药理作用与新剂型的研究进展

芦丁是一种天然的黄酮类化合物,在临床上常被用于治疗心血管类疾病,具有抗心肌损伤、抗炎、抗氧化、抗细胞凋亡、抗菌、抗病毒等药理活性,不良反应小。芦丁是治疗多种疾病的潜力药物,但因水溶性差和渗透性差导致口服生物利用度低,而在临床应用中受限。为了提高芦丁的水溶性和渗透性,改善生物利用度,多种新型芦丁制剂被研究。本文查阅国内外相关文献和报道,对芦丁的基本性质、药理作用、生物利用度和药动学研究现状进行归纳,并总结了芦丁的新剂型研究,阐述不同剂型对芦丁生物利用度和药动学参数的影响,为研发芦丁相关新药提供参考。     

给予盐酸氨基葡萄糖和硫酸氨基葡萄糖后的氨基葡萄糖药动学和生物利用度研究

目的观察盐酸氨基葡萄糖(glucosamine hydrochloride,GH)和硫酸氨基葡萄糖(glucosamine sulfate,GS)中氨基葡萄糖在大鼠体内药动学和生物利用度特征。方法大鼠经口服(ig)和静脉注射(iv)GH或GS后,LC-MS/MS检测血浆中氨基葡萄糖的血药浓度,采用DAS 3.0药动学处理软件,计算药动学参数及生物利用度。结果 GH和GS的T_(1/2)、Vz、绝对生物利用度等参数接近。口服GH的相对生物利用度大于GS,而GS的达峰时间早于GH。结论 GH和GS在药动学参数和生物利用度方面具有一定差异。     

热熔挤出技术制备普罗布考固体分散体及其大鼠体内药动学研究

以Soluplus为载体,采用热熔挤出技术制备普罗布考固体分散体,并评价其平衡溶解度、溶出度及大鼠体内药动学行为.结果表明,普罗布考-Soluplus比例为1:3(w/w)的固体分散体,在30 min时的体外累积溶出率为97％.差示扫描量热和粉末X-射线衍射分析表明药物主要以分子状态分散于固体分散体中.大鼠体内药动学研究表明,普罗布考固体分散体的cmax和口服生物利用度是原药的3.26倍和3.02倍.     

冷冻干燥法制备甲苯磺酸拉帕替尼固体分散体及其大鼠药动学评价

目的用冷冻干燥技术制备甲苯磺酸拉帕替尼固体分散体,以提高其生物利用度。方法以PVPS630和soluplus^■为载体,采用冷冻干燥法制备甲苯磺酸拉帕替尼固体分散体,通过SEM、DSC、XRPD等手段对固体分散体进行表征,通过表观溶解度、溶出度和大鼠体内药动学测定,评价固体分散体的增溶效果和生物利用度的改善情况。结果在相同药载比的条件下,PVPS630组的溶出度和表观溶解度均优于soluplus^■组。DSC、XRPD、SEM等表征结果显示,PVPS630为载体的固体分散体中,原料均以非晶态存在,而以soluplus^■为载体时,只有药载比为1∶3条件下,原料才呈现非晶态特征。大鼠药动学测定结果表明,固体分散体(甲苯磺酸拉帕替尼-PVPS630为1∶3)较上市药品AUC提高23.64%。结论载体PVPS630与甲苯磺酸拉帕替尼的相容性更理想;固体分散技术有助于本品提高生物利用度。     

熊果酸共晶在大鼠体内的药代动力学

目的建立基于高效液相色谱-质谱联用技术(HPLC-MS)的熊果酸血药浓度测定方法,考察熊果酸乙醇共晶在大鼠体内的相对生物利用度。方法采用口服灌胃方式给大鼠服用熊果酸及其乙醇共晶,分别于给药后0、0.25、0.50、1.00、1.50、2.00、3.00、4.00、5.00、6.00、8.00、10.00和12.00 h,大鼠眼眶后静脉丛取血。血浆经乙酸乙酯提取后,采用HPLC-MS测定血浆中熊果酸的浓度并绘制药代动力学曲线。方法的色谱条件为,固定相:Sino Pak-C18色谱柱(250 mm×4.6 mm,5.0μm),流动相:甲醇-纯净水(含体积分数为0.02%的三乙胺)(体积比为90∶10),流速:0.5 m L·min-1,柱温:25℃,进样量:10μL。质谱条件为:采集方式:多反应监测(multiple reaction monitoring,MRM),离子极性:负离子,离子源:电喷雾离子源,检测离子:熊果酸m/z=455.7、甘草次酸m/z=470.6,N2体积流量:35.0 L·min-1,加热温度:350℃。药动学数据处理采用中国药理学会编制的DAS 2.0药动学软件处理。结果熊果酸的线性为10~640μg·L-1,定量下限为10μg·L-1,日内、日间精密度(RSD)均小于10%,提取回收率为80.57%,熊果酸及其乙醇共晶在大鼠体内的血药浓度-时间过程均符合一室模型,其中熊果酸-乙醇共晶和熊果酸原料药经灌胃给药后,AUC0-12 h分别为(279.7±22.9)和(171.1±11.4)h·μg·L-1,AUC0-∞分别为(352.9±45.0)和(297.9±65.9)h·μg·L-1,ρmax分别为(83.5±4.1)和(44.01±2.79)μg·L-1。药动学参数经方差分析后均存在显著性差异(P<0.05)。结论该方法适用于熊果酸及其乙醇共晶在大鼠体内的血药浓度测定及药代动力学研究,熊果酸-乙醇共晶灌胃给药后明显提高其血药浓度,改善生物利用度。     

林可霉素溶液剂和片剂的生物利用度比较

本文采用微生物法测定了12名健康志愿者交叉口服750mg林可霉素溶液剂和片剂后的血药浓度,经IBM计算机药动学程序PKBP—NI的拟合和统计程序POMS分析,评价比较了这两种制剂的药动学参数和生物利用度。结果表明:溶液剂的口服吸收稍快于片剂,而片剂的吸收略优于溶液剂,但两者的药动学参数均无显著差异(p>0.05)。两者的生物利用度是相似的,其相对生物利用度F(AUC_(0→∞)溶液剂/AUC_(0→∞)片剂)为92.3%。     

抗低钠血症新药托伐普坦的药理学及临床评价

托伐普坦是2009年5月19日经FDA批准上市的抗低钠血症的新药,具有疗效显著、不良反应小和生物利用度高的特点。文中对其药理作用、药动学、临床研究以及不良反应等方面进行了简要综述。     

葛根素固体分散体的制备及大鼠体内生物利用度研究

本文采用新型的固体分散体技术,将葛根素,磷脂与PVP制成固体分散体,对其理化性质进行研究,考察固体分散体在大鼠体内的药一时曲线,计算其在大鼠体内的药动学参数,并与葛根素原料比较,研究固体分散体的相对生物利用度。结果表明以磷脂和PVP为载体制备的固体分散体（药物-磷脂-PVP,2：4：1）的表观油水分配系数最好,固体分散体相对生物利用度较纯葛根素提高了2．53倍。     

Ursolic acid enhances mouse liver regeneration after partial hepatectomy

Context: Ursolic acid is a pentacyclic triterpenoid which has hepatoprotective and antihepatotoxic activities.

Objective: This study investigated whether ursolic acid is able to stimulate liver regeneration in partially hepatectomized mice.

Materials and methods: Ursolic acid or the vehicle solution was orally administered to the experimental, sham-operated and vehicle-treated group mice for 7 days, positive control animal (mice) was treated with recombinant human hepatocyte growth factor (rhHGF), and then the 70% liver partial hepatectomy was performed. The liver mass recovery rate was estimated by measuring the ratios of mice liver weight to body weight. The liver cells undergoing DNA synthesis were identified by immunohistochemistry analysis using monoclonal anti-BrdU antibodies. The expression levels of cyclin D1, cyclin E and C/EBP proteins (C/EBPα and C/EBPβ) were detected by the Western blotting technique.

Results: Our results showed administration of ursolic acid significantly increased the ratio of the liver to body weight and BrdU labeling index at 36 and 48?h after partial hepatectomy, and the potency of UA is similar to rhHGF treated positive control mice. In addition, ursolic acid treatment significantly increased cyclin D1, cyclin E and C/EBPβ protein expression levels at 36?h after liver PHx compared with the vehicle-treated control mice.

Discussion and conclusion: All these results suggest that ursolic acid stimulates liver proliferation after partial hepatectomy, and this effect may be associated with the stimulation of C/EBPβ expression.     

枇杷叶中熊果酸的超声提取研究

目的用超声波辅助提取法考察不同处理方法对熊果酸的提取效果。方法将枇杷叶及不同方法处理后的药渣，以乙醇为介质，用超声波辅助提取;同时用HPLC测定提取液中熊果酸的含量。结果枇杷叶中熊果酸的含量为0.9%以上，不同方法处理后的药渣中熊果酸均有不同程度的残留。结论熊果酸在水和油中几乎不溶;乙醇回流法的提取效果欠理想，增加提取次数，其得率无明显提高;枇杷叶中的熊果酸主要以游离形式存在。     

熊果酸纳米制剂的研究进展

熊果酸是一种具有保肝、抗炎、抗癌等多种生物活性的五环三萜类化合物,药理活性广泛。但是,较低的水溶性和生物利用度等缺陷限制了其临床应用。因此,开发新剂型以提高熊果酸的生物利用度成为熊果酸研究的重要部分。纳米载体广泛应用于改善药物水溶性,提高药效、延长药物作用时间。本文总结了国内外熊果酸纳米制剂的相关研究,包括脂质体、胶束、纳米粒、纳米悬浮液和纳米乳,为其后续研究提供必要的思路和参考。     

熊果酸和齐墩果酸抗肝脂肪变和纤维化作用研究进展

熊果酸和齐墩果酸的抗氧化作用能对抗各种原因引起的氧化应激所致的肝组织脂质过氧化反应、炎性损伤、脂肪变和纤维化。熊果酸和齐墩果酸通过阻断两面神激酶2-信号传导及转录激活因子3（JAK2-STAT₃）信号转导,抑制还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOX）活化,阻止静息态肝星状细胞活化、增殖,促进活化态肝星状细胞凋亡,从而减少胶原生成、增加细胞外基质降解,产生防治肝纤维化的作用。熊果酸和齐墩果酸诱导肝脏去毒酶和外排转运体表达,降低胆汁淤积动物血清胆汁酸、胆红素水平和肝脏胆汁酸水平,减轻胆汁淤积性肝损伤和纤维化;还可通过降血脂作用抑制肝外脂质在肝脏沉积、抑制肝脏脂质生物合成和促进脂质代谢,阻滞肝脂肪变的发生和发展。     

Group IIA secretory PLA2 inhibition by ursolic acid: a potent anti-inflammatory molecule

Ursolic acid (3beta-hydroxy-urs-12-en-28-oic acid) isolated from many medicinal plants has diverse pharmacologically important properties, including strong anti-inflammatory activity. However its interaction with pro-inflammatory PLA2 is not known. Ursolic acid inhibited secretory PLA2 (sPLA2) enzymes purified from Vipera russelli, Naja naja venom and human pleural fluid and synovial fluid. IC50 values determined for these enzymes ranged from 12 to 18 microM. Group II secretory PLA2 from both venoms & human inflammatory source were found to be sensitive to inhibition in comparison with group I cobra venom sPLA2. Variation in Ca2+ concentration from 2.5-15 mM did not alter the level of inhibition. Similarly sPLA2 inhibition by ursolic acid is independent of substrate concentration. Ursolic acid interacts with purified venom sPLA2 enzymes and enhances relative fluorescence intensity in a dose dependent manner. In the presence of ursolic acid apparent shift in the far UV-CD spectra of sPLA2 was observed, indicating a direct interaction with the enzyme and formation of enzyme-ursolic acid complex. This complex results in irreversible inhibition of sPLA2 as evident by dialysis study. Inhibition of sPLA2 induced mouse paw edema and indirect hemolytic activity confirmed its sPLA2 inhibitory activity in vivo and in situ respectively. These studies revealed that the strong anti-inflammatory activity of ursolic acid is by inhibiting sPLA2 enzymes.     

Anti-lipase and lipolytic activities of ursolic acid isolated from the roots of <Emphasis Type="Italic">Actinidia arguta</Emphasis>

The aim of this study was to investigate the anti-obestic effects of ursolic acid isolated from the roots of Actinidia arguta, as well as the mechanism of action of this compound. This was conducted by testing whether ursolic acid inhibited the elevation of the rat plasma triacylglycerol levels after oral administration of a lipid emulsion containing corn oil in rats. Ursolic acid prevented the elevation of plasma triacylglycerol levels 2 h after oral administration of the lipid emulsion at a dose of 100 mg/kg. Furthermore, ursolic acid inhibited phosphodiesterase activity in vitro with an IC₅₀ of 51.21 μM and enhanced lipolysis in rat fat cells. We suggest that the inhibitory effects of ursolic acid, isolated from the roots of A. arguta, on obesity, might be attributable to the inhibition of lipid absorption through the inhibition of pancreatic lipase and by enhancing lipolysis in fat cells.     

Embelin reduces cutaneous TNF-α level and ameliorates skin edema in acute and chronic model of skin inflammation in mice

Ursolic acid is reported to have beneficial effects on the regulation of cardiovascular homeostasis. However, the effects of ursolic acid on cardiac hormone secretion are yet to be defined. The present study was designed to test the effects of ursolic acid on the secretory and contractile functions of the atria. Experiments were conducted in isolated perfused beating rabbit atria. We measured the changes in atrial dynamics, pulse pressure, stroke volume, cAMP efflux, as well as the secretion of atrial natriuretic peptide (ANP). Ursolic acid increased ANP secretion and mechanical dynamics in a concentration-dependent manner. The inhibition of L-type Ca(2+) channels with nifedipine attenuated the ursolic acid-induced increase in ANP secretion but not mechanical dynamics. The inhibition of K(+)(ATP) channels with glibenclamide attenuated the ursolic acid-induced increase in ANP secretion-but not atrial dynamics-in a concentration-dependent manner. The selective Na(+)-K(+)-ATPase inhibitor ouabain blocked the ursolic acid-induced increase in atrial dynamics but not ANP secretion. These findings show that ursolic acid increases ANP secretion via its activation of K(+)(ATP) channels and subsequent inhibition of Ca(2+) entry through L-type Ca(2+) channels in rabbit atria. These data also suggest that ursolic acid increases atrial dynamics via its inhibition of Na(+)-K(+)-ATPase activity.     

熊果酸平衡溶解度和油水分配系数的测定

目的测定熊果酸的平衡溶解度及其在正辛醇-水中的表观油水分配系数,为设计熊果酸新剂型提供基础。方法采用HPLC测定熊果酸在不同pH介质、不同溶剂中的溶解度及熊果酸在正辛醇-水中的表观油水分配系数。结果 25℃下熊果酸在水中的平衡溶解度为5.64 mg.L 1,在pH 2.0~7.4的缓冲体系中,熊果酸的溶解度不受pH的影响。熊果酸在油中溶解度不佳,在表面活性剂及半极性溶剂中溶解度相对较好,在正辛醇-水体系中的油水分配系数1gP=2.17。结论熊果酸为溶解度小的亲脂性药物。     

Induction of apoptotic cell death by ursolic acid through mitochondrial death pathway and extrinsic death receptor pathway in MDA-MB-231 cells

Ursolic acid (3-hydroxy-urs-12-en-28-oic acid) is a pentacyclic triterpenoid derived from leaves, berries, fruits, and flowers of medicinal plants, such as Rosemarinus officinalis. Ursolic acid has been shown to inhibit tumorigenesis, tumor promotion, and suppress angiogenesis. In our present study, we found that ursolic acid decreased cell proliferation rate and induce apoptosis in human breast cancer cell line, MDA-MB-231. When we checked the expression levels of proteins associated with apoptosis signal by using immunoblotting, we found that ursolic acid induces various apoptotic molecules related to either extrinsic or intrinsic apoptosis signal pathway in MDA-MB-231 cells. In our study, we found that ursolic acid induced the appearance of Fas receptor and cleavage of caspase-8, -3 and PARP. We also found that ursolic acid induced Bax up-regulation and Bcl-2 down-regulation and release of cytochrome C to the cytosol from mitochondria. Moreover, ursolic acid cleaved caspase-9 and decreased mitochondrial membrane potential (ΔΨm) as shown with JC-1 staining. These data indicate that ursolic acid induce apoptosis through both mitochondrial death pathway and extrinsic death receptor dependent pathway in MDA-MB-231 cells. Our data clearly indicate that ursolic acid could be used as a potential anticancer drug for breast cancer.     

熊果酸衍生物的合成及抗肿瘤活性的研究

以天然产物熊果酸为先导化合物,经过氧化、酰化、酯化(酰化)、水解等反应设计合成了16个熊果酸衍生物,其中包括11个新五环三萜化合物,以HeLa、SKOV3和BGC-823细胞为靶细胞,MTT法进行初步的体外抗肿瘤活性研究。结果表明,化合物7a对HeLa细胞的抑制活性、化合物8a对SKOV3细胞的抑制活性均明显强于熊果酸,值得进一步研究。