石杉碱甲鼻用原位凝胶的制备及其经鼻脑靶向性评价

目的探索利用鼻腔嗅觉区的鼻-脑通道开发经鼻脑靶向给药系统的可行性。方法用阳离子敏感性成胶辅料结冷胶，采用pH梯度沉淀法制备了石杉碱甲鼻用原位凝胶。以市售片剂和注射液为对照，用小脑延髓池插管法采集脑脊液，股动脉插管取血，测定其在大鼠脑脊液和血中药物动力学参数；用组织匀浆法，测定其在大鼠脑组织中的分布；用Morris水迷宫法、跳台法和避暗法试验其对大鼠和小鼠模型的药效。结果大鼠鼻腔给药血浆AUC_{0→6 h}为静注的0.94倍，但脑脊液AUC_{0→6 h}为静注和灌胃的1.3和2.3倍；大鼠鼻腔给药后大脑、海马、小脑、左右嗅球的AUC_{0→6 h}分别为静注的1.5，1.3，1.0，1.2和1.0倍，为灌胃的2.7，2.2，1.9，3.1和2.6倍。药效学研究表明以1/4～1/2口服剂量鼻腔给药与口服等效，与药动学结果相符。结论石杉碱甲原位凝胶鼻腔给药较静注和灌胃显著增加了药物在脑内，特别在其改善记忆障碍作用的靶部位——大脑和海马的分布，提高了药物的脑靶向性。     

榄香烯静脉输注浓缩液对G422小鼠神经胶质瘤疗效的实验研究

目的测定榄香烯静脉输注浓缩液小鼠体内实验抗肿瘤疗效。方法用CremophorEL作增溶剂配合丙二醇制成2%榄香烯静脉输注浓缩液。以静脉注射(40、20、10mg/kg)或腹腔注射(80、60、40mg/kg)途径给药,静脉给药组每天2次,腹腔给药组每天1次,连续给药5d进行榄香烯注射液动物脑瘤G422(颅内接种)模型抗肿瘤疗效实验。结果榄香烯静脉输注浓缩液体内对动物脑瘤G422(颅内接种)模型肿瘤生命延长率为:静脉给药方案:高剂量组为56·07%~59·16%,中剂量组为45·55%~47·98%,低剂量组为31·25%~38·22%,生命延长率比较明显;腹腔给药方案:高剂量组为12·0%~24·0%,中剂量组35·1%~37·0%,低剂量组为30·9%~36·1%。若以静脉给药80mg/kg,每天1次,连续10d给药,结果显示其生命延长率为52·60%~57·07%。结论榄香烯静脉输注浓缩液对小鼠神经胶质瘤G422(颅内接种)模型有一定的抑制作用。     

Tissue Distribution of Sex Steroids: Concentration of 17β-Oestradiol and Cyproterone Acetate in Selected Organs of Female Wistar Rats

Abstract: The tissue distribution of 17β-oeslradiol and cyproterone acetate was investigated after intravenous and intragastric administration to female Wistar rats by measuring the time course of the concentration of the sex steroids in plasma, liver, kidney, brain, and heart by radioimmunoassay. Test substances were administered intravenously in doses of 0.1 mg/kg each and intragastrically in doses of 10 mg/kg (17β-oestradiol) and 0.1 mg/kg (cyproterone acetate) corresponding to the expected oral bioavailability. Tissue distribution was assessed within each mode of administration by AUC_organ/ AUC_plasma-quotients (Q-values), and between both routes of administration by F-values representing (bio- and organ availability) and R-values, which express the organ load after intragastric compared to intravenous administration if the same amount of drug has been made bioavailable in the plasma after both routes (for explanation see next page). The absolute bioavailability of 17β-oestradiol after intragastric administration of 10 mg/kg was ca. 8%. The oestradiol liver load after intragastric administration was about 20 times higher than after intravenous administration, whereas the drug load of other organs was independent of the administration route. Cyproterone acetate was completely bioavailable after intragastric administration in a dose of 0.1 mg/kg. Cyproterone acetate levels and AUC-values in all organs investigated were higher when compared to the plasma with highest levels in the liver. The organ distribution of cyproterone acetate including the drug liver load was independent of the route of administration.     

榄香烯哌嗪对荷瘤小鼠免疫功能的影响

目的研究榄香烯哌嗪的抗肿瘤作用及其对免疫功能的影响。方法采用小鼠S180肉瘤移植性肿瘤动物模型,以抑瘤率为指标考察榄香烯哌嗪的体内抗肿瘤活性。并用四氮唑盐(MTT)法对荷瘤小鼠进行脾淋巴细胞增殖能力和自然杀伤(NK)细胞活性测定,考察其对荷瘤小鼠免疫功能的影响。结果榄香烯哌嗪对小鼠肉瘤S180的生长有明显的抑制作用(P<0.01),502、5 mg.kg-1剂量组抑瘤率分别为48.74%和37.60%。榄香烯哌嗪各种剂量对荷瘤小鼠的胸腺指数和脾指数无明显影响,但榄香烯哌嗪剂量为502、5 mg.kg-1可显著提高荷瘤小鼠脾淋巴细胞的增殖能力,对荷瘤小鼠NK细胞活性也有明显的提高作用。结论榄香烯哌嗪具有一定的抗肿瘤作用,其抗肿瘤作用可能与激活体内免疫系统有关。     

榄香烯乳对结肠癌Lovo细胞端粒酶活性、细胞凋亡及细胞周期的影响

目的：探讨榄香烯乳对结肠癌Lovo细胞的作用机制。方法：采用不用浓度的榄香烯乳处理结肠癌Lovo细胞后，分别应用四唑蓝比色试验、端粒重复扩增－微孔板杂交法、琼脂糖凝胶电泳方法及流式细胞仪研究榄香烯乳对结肠癌细胞生长、端粒酶活性、凋亡及细胞周期的影响。结果：榄香烯乳对结肠癌Lovo细胞增殖具有较强的抑制作用，能够抑制端粒酶活性，诱导细胞凋亡，且这种作用呈浓度及时间依赖；且细胞阻滞于G0/G1期。结论：榄香烯乳抑制结肠癌Lovo细胞恶性增殖与抑制端粒酶活性、诱导凋亡及细胞周期阻滞有关。     

Effect of Xiongbing compound on the pharmacokinetics and brain targeting of tetramethylpyrazine

Objectives To investigate the effect of the Xiongbing compound (XBC) on the pharmacokinetics and brain targeting of tetramethylpyrazine (TMP). Methods Three microemulsions containing the same TMP concentration were prepared. XBC microemulsions were made from Rhizoma ligustric Chuanxiong extracts, borneol and TMP. TMP microemulsions were made with TMP only. Borneol microemulsions contained borneol and TMP. Microdialysis with high performance liquid chromatography (HPLC) was used to measure the concentration of TMP in the blood and striatum after intravenous (i.v.) or intragastric (i.g.) administration of the three different microemulsions. Key findings The pharmacokinetics of free TMP concentration in the blood and the striatum fit a first‐order rate, open two‐compartment model after intravenous and intragastric microemulsion administration. The maximal concentration (C_max) and area under curve (AUC) values in the XBC microemulsion i.v. group were significantly higher than that in the TMP microemulsion and borneol microemulsion i.v. groups. After XBC microemulsion i.g. administration, the t_1/2, mean residence time (MRT) and AUC of TMP in both plasma and brain tissues were greater than those with TMP microemulsion and borneol microemulsion administration. The relative brain targeting efficiency of TMP for the XBC microemulsion i.v and i.g. groups relative to the TMP microemulsion and borneol microemulsion groups were greater than 1. Conclusion XBC microemulsion can enhance TMP oral bioavailability, brain targeting and tissue distribution, mainly through a synergistic action of Rhizoma ligustric Chuanxiong extracts and borneol.     

Whole-body autoradiographic studies in rats with gadolinium-diethylenetriaminepentaacetic acid, a new contrast agent for magnetic resonance imaging

The time course of the distribution of radiolabel in organs and tissues was investigated after intravenous administration of 0.5 mmol/kg of 14C-labelled gadolinium-diethylenetriaminepentaacetic acid (Gd-14C-DTPA) and of 153Gd-DTPA to pregnant rats (18th day p.c.) and after intragastric administration of 30 mumol/kg of Gd-14C-DTPA to male rats by whole-body autoradiographic technique. After intravenous administration Gd-DTPA was rapidly distributed within the organism. The distribution pattern was similar to that of classical X-ray contrast agents like diatrizoate and iotalamic acid. Gd-DTPA was not able to pass blood-brain and placental barriers. There was no indication of a dissociation of Gd-DTPA complex. 24 h after i.v. injection most of the radiolabel left the body. Only very small amounts were found in the kidney, the placenta and in the contents of the intestine. No specific and long-lasting retention of radioactivity was observed in any organ and tissue. After intragastric administration Gd-DTPA was not absorbed.     

Antineoplastic effect of β‐elemene on prostate cancer cells and other types of solid tumour cells

Objectives β‐Elemene, a natural compound extracted from over 50 different Chinese medicinal herbs and plants, has been effective in the treatment of hyperplastic and proliferative disorders such as prostatic hypertrophy, hysteromyoma and neoplasms. Our previous studies have demonstrated that β‐elemene exhibits strong inhibitory activity in ovarian cancer cells. The aim of the present study was to assess the effect of β‐elemene on prostate cancer cells as well as other types of tumour cells and to determine whether the effect of β‐elemene on prostate cancer cell death was mediated through the induction of apoptosis. Methods The MTT assay was used to evaluate the ability of β‐elemene to inhibit cellular proliferation in cancer cells. Cellular apoptosis was assessed by annexin V binding, TUNEL and ELISA‐based assays. Caspase activity was measured using a caspases assay kit. The protein levels of Bcl‐2, caspases, cytochrome c and poly(ADP‐ribose) polymerase (PARP) were analysed by Western blotting. Key findings Here, we showed that β‐elemene had an antiproliferative effect on androgen‐insensitive prostate carcinoma DU145 and PC‐3 cells. Treatment with β‐elemene also inhibited the growth of brain, breast, cervical, colon and lung carcinoma cells. The effect of β‐elemene on cancer cells was dose dependent, with IC50 values ranging from 47 to 95 µg/ml (230–465 µm ). TUNEL assay and flow cytometric analysis using annxin V/propidium iodide staining revealed that the percentage of apoptotic prostate cancer cells was increased by β‐elemene in a dose‐ and time‐dependent manner. Moreover, β‐elemene exposure resulted in a decreased Bcl‐2 protein level, increased cytochrome c release, and activated PARP and caspase‐3, ‐7, ‐9, and ‐10 in prostate cancer cells. Conclusions Overall, these findings suggest that β‐elemene exerts broad‐spectrum antitumour activity against many types of solid carcinoma and supports a proposal of β‐elemene as a new potentially therapeutic drug for castration‐resistant prostate cancer and other solid tumours.     

川芎对天麻苷元大鼠脑内药动学的影响

目的建立大鼠脑组织中天麻苷元的HPLC测定方法,并研究川芎对天麻苷元在大鼠脑内药动学的影响。方法 144只SD大鼠随机分为天麻单用组(灌胃给予天麻提取物0.945 mg.kg-1)和天麻-川芎配伍组(灌胃给予天麻提取物0.945 mg.kg-1和川芎提取物3.78 mg.kg-1),于给药后不同时间点取脑组织。采用HPLC法测定大鼠脑组织中天麻苷元的浓度,以DAS2.0药动学软件计算药动学参数。结果天麻苷元在0.125～8 mg.L-1(r=0.999 6)范围内线性关系良好,绝对回收率为86.54%～89.96%,日内及日间精密度均低于5%。天麻-川芎配伍组中天麻苷元脑内药物浓度曲线下面积为天麻单用组的1.66倍;平均滞留时间延长,清除率为天麻单用组的64.58%,与天麻单用组相比有显著差异(均P<0.05)。结论川芎可提高天麻苷元在大鼠脑内的生物利用度,减缓天麻苷元在大鼠脑内的消除速度。     

Pharmacokinetics and metabolism of gabapentin in rat, dog and man

This paper describes the pharmacokinetic studies of 1-(aminomethyl)-cyclohexane acetic acid (gabapentin, G? 3450, CI-945) conducted with the 14C-labelled substance following intravenous and intragastric administration to rats and dogs and oral administration to humans. Gabapentin is well absorbed in rats, dogs and in humans, with maximum blood levels, reached within 1-3 h after peroral administration. Following i.v. administration to rats, similar blood and brain levels of gabapentin are observed after a short distribution phase, whereby concentrations in cerebrum and cerebellum are comparable. The highest concentrations are found in the pancreas and kidneys and the lowest values in adipose tissue. No binding of gabapentin to human plasma proteins or human serum albumin is observed. The distribution coefficient (octanol/buffer pH 7.4) is 7.5 X 10(-2). In man, no biotransformation of gabapentin is observed. In rats, biotransformation is only minor. In dogs, however, a remarkable formation of N-methyl-gabapentin is found. Elimination half-lives range between 2-3 h in rats, 3-4 h in dogs, and 5-6 h in man. Gabapentin is nearly exclusively eliminated via the kidneys. Renal elimination was up to 99.8% in rats and approx. 80% in man following oral administration. The blood level-time course after i.v. administration to rats can well be described by a three-compartment open model. Experiments in rats and dogs demonstrate that pharmacokinetics are not sex-dependent and are not changed after multiple dosage. Pharmacokinetics are shown to be linear in the range tested of 4 to 500 mg/kg i.v. in rats.     

Intranasal mucoadhesive microemulsions of clonazepam: preliminary studies on brain targeting

The aim of this investigation was to prepare clonazepam microemulsions (CME) for rapid drug delivery to the brain to treat acute status epileptic patients and to characterize and evaluate the performance of CME in vitro and in vivo in rats. The CME were prepared by the titration method and were characterized for globule size and size distribution, zeta potential, and drug content. CME was radiolabeled with (99m)Tc (technetium) and biodistribution of drug in the brain was studied in Swiss albino rats after intranasal and intravenous administrations. Brain scintigraphy imaging in rabbits was also performed to ascertain the uptake of the drug into the brain. Pre and postCME formulation treated human nasal mucosa was subjected to transmission electron microscopy to investigate the mechanism of drug uptake across the nasal mucosa. CME were transparent and stable with mean globule size of 15 +/- 10 nm and zeta potential of -30 mV to -40 mV. (99m)Tc-labeled clonazepam solution ((99m)Tc CS)/ clonazepam microemulsion (CME)/clonazepam mucoadhesive microemulsion (CMME) were found to be stable and suitable for in vivo studies. Brain/blood uptake ratios at 0.50 hour (h) following intranasal CMME, CME, clonazepam solution (CS), and intravenous CME administrations were found to be 0.67, 0.50, 0.48, and 0.13, respectively indicating more effective targeting with intranasal administration and best targeting of the brain with intranasal CMME. Brain/blood ratio at all sampling points up to 8 h following intranasal administration of CMME compared to intravenous was found to be twofold higher indicating larger extent of distribution of the drug in brain. Rabbit brain scintigraphy also showed higher intranasal uptake of the drug into the brain. Transmission electron microscopy revealed significant accretion of CMME within interstitial spaces and paracellular mode of transport due to stretching of the tight junctions present in the nasal mucosa. This investigation demonstrates a more rapid and larger extent of transport of clonazepam into the rat brain with intranasal CMME, which may prove useful in treating acute status epileptics.     

β-榄香烯脂质体的制备及其在大鼠体内的组织分布

目的:研制β-榄香烯脂质体并考察其在大鼠体内的组织分布。方法:采用薄膜分散法制备β-榄香烯脂质体,考察其形态、粒径、Zeta电位、药物含量及包封率。并以榄香烯注射液为对照,大鼠尾静脉注射给药,考察β-榄香烯脂质体在血浆及心、肝、脾、肺、肾的分布特征。结果:制备的β-榄香烯脂质体均匀圆整,粒径为(158±s 37)nm,Zeta电位为(-67±4)mV,药物含量为(5.76±0.21)g·L~(-1),包封率为(45.08±0.15)%(n=3)。大鼠尾静脉注射β-榄香烯脂质体和榄香烯注射液后,2种制剂在心、肝、脾、肾中的AUC_(0-t)均有显著差异,其中β-榄香烯脂质体在肝、脾、肾组织中分布相对较多,在心脏中分布较少。结论:薄膜分散法制备β-榄香烯脂质体方法可行,β-榄香烯脂质体在大鼠体内的分布特性有不同程度的改变,可提高疗效,降低心脏毒性。     

Alkylglycerol opening of the blood-brain barrier to small and large fluorescence markers in normal and C6 glioma-bearing rats and isolated rat brain capillaries

1. The blood-brain barrier (BBB) represents the major impediment to successful delivery of therapeutic agents to target tissue within the central nervous system. Intracarotid alkylglycerols have been shown to increase the transfer of chemotherapeutics across the BBB. 2. We investigated the spatial distribution of intracarotid fluorescein sodium and intravenous lissamine-rhodamine B200 (RB 200)-albumin in the brain of normal and C6 glioma-bearing rats after intracarotid co-administration of 1-O-pentylglycerol (200 mm). To elucidate the mechanisms involved in the alkylglycerol-mediated BBB opening, intraluminal accumulation of fluorescein isothiocyanate (FITC)-dextran 40,000 was studied in freshly isolated rat brain capillaries using confocal microscopy during incubation with different alkylglycerols. Furthermore, 1-O-pentylglycerol-induced increase in delivery of methotrexate (MTX) to the brain was evaluated in nude mice. 3. Microscopic evaluation showed a marked 1-O-pentylglycerol-induced extravasation of fluorescein and RB 200-albumin in the ipsilateral normal brain. In glioma-bearing rats, increased tissue fluorescence was found in both tumor tissue and brain surrounding tumor. Confocal microscopy revealed a time- and concentration-dependent accumulation of FITC-dextran 40,000 within the lumina of isolated rat brain capillaries during incubation with 1-O-pentylglycerol and 2-O-hexyldiglycerol, indicating enhanced paracellular transfer via tight junctions. Intracarotid co-administration of MTX and 1-O-pentylglycerol (200 mm) in nude mice resulted in a significant increase in MTX concentrations in the ipsilateral brain as compared to controls without 1-O-pentylglycerol (P<0.005). 4. In conclusion, 1-O-pentylglycerol increases delivery of small and large compounds to normal brain and brain tumors and this effect is mediated at least in part by enhanced permeability of tight junctions.     

Influence of hydroxyurea on imatinib mesylate (gleevec) transport at the mouse blood-brain barrier.

The combination of imatinib mesylate and hydroxyurea provides a therapeutic benefit in patients with glioblastoma, although each drug is not effective when used alone. The increase of brain delivery of one or both drugs has been suggested to be a potential cause of this therapeutic benefit. The cross-influence of hydroxyurea and imatinib on their respective brain distribution was examined in mice and rats. We used in situ brain perfusion in mice to determine whether these two drugs have an influence on their respective initial transport across the blood-brain barrier. The brain penetration of hydroxyurea, assessed by its brain uptake clearance, Knet, was low in mice (approximately 0.10 microl/g/s) and not modified by coperfusion of imatinib (0.5-500 microM). Likewise, the brain penetration of imatinib was low (Knet, 1.39 +/- 0.17 microl/g/s) and not modified by direct coperfusion of hydroxyurea (0.2-1000 microM) or by intravenous pretreatment with 15 or 1000 mg/kg hydroxyurea. We also examined a potential time-dependent influence of hydroxyurea on imatinib brain distribution after sustained subcutaneous administration in rats using an implantable osmotic pump. The brain penetration of imatinib in rats increased with time, approximately 1.6-fold (p < 0.01) after 7 and 14 days' infusion of imatinib (3 mg/day) with or without hydroxyurea (15 mg/day), and was not influenced by hydroxyurea. The results of these two sets of experiments indicate that hydroxyurea has no significant influence on the brain distribution of imatinib in mice and rats.     

MEK信号通路活化在榄香烯致人源U87MG胶质瘤细胞增殖抑制及G0/G1细胞周期阻滞中的作用

目的探讨MKK3和MKK6在榄香烯致人U87MG胶质瘤细胞增殖抑制和细胞周期阻滞中的作用。方法以不同浓度榄香烯作用于人U87MG及U251胶质瘤细胞,应用噻唑蓝(MTT)法检测细胞活性。West-ern blot检测MEK信号通路中MKK3和MKK6的总蛋白及磷酸化蛋白含量。通过转染显性负突变质粒DN-MKK3和DN-MKK6,抑制MKK3和MKK6的活性。然后分别行MTT法和流式细胞术检测榄香烯对胶质瘤细胞的增殖抑制和细胞周期阻滞作用。结果榄香烯显著抑制了人胶质瘤细胞的增殖,呈时间和浓度依赖性,并可使细胞中MKK3和MKK6的磷酸化水平上调。抑制MKK3和MKK6的活性则可显著削弱榄香烯的抗胶质瘤增殖和G0/G1细胞周期阻滞作用。结论榄香烯可以通过将胶质瘤细胞的细胞周期阻滞于G0/G1期,进而有效地抑制肿瘤细胞增殖,且MKK3和MKK6信号通路的激活在其中发挥着不可或缺的作用。     

Pharmacokinetic interaction between puerarin and edaravone,and effect of borneol on the brain distribution kinetics of puerarin in rats

Objectives The aim was to investigate the pharmacokinetic interaction between puerarin and edaravone, and the effect of borneol on the brain distribution kinetics of puerarin in rats. Methods A reversed‐phase high performance liquid chromatography method was developed and validated for the simultaneous determination of puerarin and edaravone in rat plasma. The detection method was successfully applied to compare the pharmacokinetic interaction and brain distribution kinetics of puerarin and edaravone using in‐situ microdialysis sampling in rats after intravenous administration and co‐administration with a single dose. Key findings The method gave good linearity and no endogenous material interfered with the two target compounds and internal standard peaks. The limit of detection of puerarin and edaravone was 0.03 and 0.05 μg/ml, respectively. The average recovery of the two compounds from rat plasma was >94%. The precision of the test was determined to be within 10%. The combination of puerarin and edaravone reduced drug elimination rates, gave a wider distribution, and the disposition of both drugs in rats was optimized. The distribution of puerarin in brain tissues was significantly increased and its elimination was noticeably slower with borneol pretreatment. Conclusions The results provide important information for the improved combined use of puerarin and edaravone with borneol pretreatment in clinical practice.     

Transfer of morphine along the olfactory pathway to the central nervous system after nasal administration to rodents

The aim of this study was to investigate whether morphine can be transferred along the olfactory pathway to the CNS, thereby circumventing the blood–brain barrier, after nasal administration to rodents. Radiolabelled and unlabelled morphine were administered via the right nostril to mice and rats. Olfactory bulbs, brain tissue and blood samples were collected. Morphine-derived radioactivity was measured using liquid scintillation (LS) and the concentrations of morphine and its metabolite morphine-3-glucuronide (M3G) were also assessed with high-performance liquid chromatography. The location of morphine-derived radioactivity in the rat brain was visualised by autoradiography. Overall, the levels of morphine in the right olfactory bulbs (ROBs) significantly exceeded those in the left olfactory bulbs (LOBs) and brain tissue samples 15, 60 and 240 min after right-sided nasal administration. Fifteen minutes after intravenous administration, there were no significant differences between olfactory bulbs and the other brain areas. Five minutes after nasal administration, autoradiography revealed radioactivity surrounding the ROB and reaching one of the ventricles in the brain. After 60 min, radioactivity had reached the peripheral parts of the ROB. All the techniques used in this study demonstrate that morphine was transferred along the olfactory pathway to the CNS after nasal administration to rodents.     

Contribution of both olfactory and systemic pathways for brain targeting of nimodipine-loaded lipo-pluronics micelles: in vitro characterization and in vivo biodistribution study after intranasal and intravenous delivery

Nimodipine (NM) is the only FDA-approved drug for treating subarachnoid hemorrhage induced vasospasm. NM has poor oral bioavailability (5–13%) due to its low aqueous solubility, and extensive first pass metabolism. The objective of this study is to develop radiolabeled NM-loaded LPM and to test its ability prolong its circulation time, reduce its frequency of administration and eventually target it to the brain tissue. NM was radiolabeled with ^99mTc by direct labeling method using sodium dithionite. Different reaction conditions that affect the radiolabeling yield were studied. The in vivo pharmacokinetic behavior of the optimum NM-loaded LPM formulation in blood, heart, and brain tissue was compared with NM solution, after intravenous and intranasal administration. Results show that the radioactivity percentage (%ID/g) in the heart of mice following administration of ^99mTc-NM loaded LPM were lower compared with that following administration of ^99mTc-NM solution, which is greatly beneficial to minimize the cardiovascular side effects. Results also show that the %ID/g in the blood, and brain following intravenous administration of ^99mTc-NM-loaded LPM were higher at all sampling intervals compared with that following intravenous administration of ^99mTc-NM solution. This would be greatly beneficial for the treatment of neurovascular diseases. The drug-targeting efficiency of NM to the brain after intranasal administration was calculated to be 1872.82%. The significant increase in drug solubility, enhanced drug absorption and the long circulation time of the NM-loaded LPM could be promising to improve nasal and parenteral delivery of NM.     

波棱瓜子提取物在大鼠体内分布的初步研究

目的:初步了解波棱瓜子提取物在大鼠体内的组织分布情况,为进一步确定其药效成分及作用机制奠定基础。方法:大鼠单次灌胃给予一定剂量的波棱瓜子乙酸乙酯提取部位,分别在给药后1 h、2 h处死并解剖大鼠,取心、肝、脾、肺、肾、脑六个组织;采用高效液相色谱法(HPLC)对比空白组织、给药组织及体外样品,对各组织中移行成分进行确定,了解波棱瓜子提取物中各成分在大鼠体内的分布状态。结果:大鼠给药后,肺出现了4个移行成分,心、肝组织中出现了两个移行成分,脾、肾组织在2 h出现了一个移行成分,脑组织中未有移行成分出现。结论:波棱瓜子提取物口服给药后,多种成分均有吸收。给药后1 h~2 h间,各脏器分布广泛,其中在肺脏中原型成分积蓄最多,肝脏中出现代谢成分,且药物进入肝、肺脏的速度较快;心、脾、肾中原型成分的积蓄较小,脑组织中未出现任何移行成分,该药似不能通过血脑屏障。     

β-Elemene induces apoptosis as well as protective autophagy in human non-small-cell lung cancer A549 cells

Objectives β‐Elemene, a novel traditional Chinese medicine, has been shown to be effective against a wide range of tumours. In this study, the antitumour effect of β‐elemene on human non‐small‐cell lung cancer (NSCLC) A549 cells and the mechanism involved have been investigated. Methods Cell viability and apoptosis were measured by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. Protein expression was assayed by Western blotting. Autophagy was evaluated under fluorescence microscopy and transmission electron microscopy. Key findings β‐Elemene inhibited the viability of A549 cells in a dose‐dependent manner. This suppression of cell viability was due to the induction of apoptosis. Further study showed that β‐elemene inhibited the activity of the PI3K/Akt/mTOR/p70S6K1 signalling pathway, and at the same time it triggered a robust autophagy. The autophagy was characterized by the accumulation of punctate LC3 dots in the cytoplasm, morphological changes, and the increased levels of LC3‐II as well as Atg5‐Atg12 conjugated proteins. Inhibition of autophagy with chlorochine significantly enhanced the antitumour effect of β‐elemene. Conclusions Our data indicated that β‐elemene inhibited the activity of the PI3K/Akt/mTOR/p70S6K1 signalling pathway in human NSCLC A549 cells, which resulted in apoptosis as well as protective autophagy. A combination of β‐elemene with autophagy inhibitor might be an effective therapeutic option for advanced NSCLC.