吸收促进剂对芍药苷大鼠肠道吸收的促进作用研究

目的 考察不同吸收促进剂对芍药苷在大鼠十二指肠吸收过程的影响,筛选最佳吸收促进剂。方法 利用大鼠在体单向肠灌流模型,采用HPLC法测定灌流液中芍药苷含量,分别考察聚山梨酯80、羟丙基-β-环糊精、癸酸钠、去氧胆酸钠和当归提取物对吸收的促进作用。结果 羟丙基-β-环糊精和当归提取物能显著提高芍药苷的肠道吸收速率,其次是癸酸钠和聚山梨酯80,而去氧胆酸钠则没有作用。结论 羟丙基-β-环糊精和当归提取物可作为芍药苷口服制剂的吸收促进剂使用,中药当归配伍芍药使用是合理、有效的。     

原人参二醇纳米混悬剂的大鼠在体肠吸收研究

目的 考察原人参二醇纳米混悬剂的在体肠吸收特征。方法 采用溶剂蒸发法, 以白蛋白作为稳定剂制备原人参二醇纳米混悬剂。以酚红为标示物, 采用大鼠在体单向肠灌流法评价原人参二醇纳米混悬剂的大鼠在体肠吸收特性。结果 Zetasizer nano ZS仪测得原人参二醇纳米混悬剂平均粒径为(220±10)nm, Zeta电位为(-28±0.2)mV。肠吸收实验表明, 原人参二醇纳米混悬剂在整个肠段都有吸收, 且吸收速率常数(K_a)与渗透系数(P_eff)均大于原人参二醇原药(P<0.05), 原人参二醇纳米混悬剂在小肠段(十二指肠、空肠和回肠)的K_a与P_eff均大于结肠(P<0.05)。结论 原人参二醇纳米混悬剂能够有效促进原人参二醇的大鼠在体肠吸收, 其转运机制可能为主动转运或促进扩散。     

Effect of Polyethylene Glycol 400 on the Intestinal Permeability of Carbamazepine in the Rabbit

Because of the limited solubility of carbamazepine, aqueous solutions are usually prepared using glycols as cosolvents. This research focuses on the effect of varying the composition of polyethylene glycol 400 (PEG-400) in aqueous solutions on rabbit intestinal permeability of carbamazepine in the duodenojejunum and the ascending colon using an in situ perfusion technique. In both segments the intestinal permeability varied inversely with the percentage of PEG-400, when the concentration of carbamazepine in the perfusing solution was maintained constant. The decreased permeability may be explained by a reduction in the thermodynamic activity of carbamazepine with increased concentrations of PEG-400, as well as by reverse solvent drag because of the hyperosmolarity of the perfusing solutions.     

依托度酸大鼠在体肠吸收动力学

目的考察依托度酸在大鼠各肠段的吸收动力学特征。方法运用大鼠在体单向灌流技术考察依托度酸在大鼠各肠段的吸收动力学特征;采用高效液相色谱法(HPLC)测定灌流液中依托度酸的含量;从药物质量浓度、吸收部位、灌流速度、pH值4个方面对依托度酸的各肠段吸收特性进行考察;利用重量法计算动力学参数。结果灌流速度和一定范围内的pH值(5.4～7.4)对药物吸收速率常数(ka)和表观吸收系数(Papp)影响显著;一定范围内的药物浓度对ka和Papp无显著影响;十二指肠、空肠、回肠和结肠的ka值分别为(0.082 7±0.003 8)、(0.077 5±0.004 5)、(0.073 3±0.006 4)、(0.064±0.009 3)min-1。结论依托度酸在大鼠肠道的吸收呈现一级动力学特征,且吸收机制为被动扩散。依托度酸在整个肠道均有吸收。     

P-glycoprotein is responsible for the poor intestinal absorption and low toxicity of oral aconitine: In vitro, in situ, in vivo and in silico studies

Aconitine (AC) is a highly toxic alkaloid from bioactive plants of the genus Aconitum, some of which have been widely used as medicinal herbs for thousands of years. In this study, we systematically evaluated the potential role of P-glycoprotein (P-gp) in the mechanisms underlying the low and variable bioavailability of oral AC. First, the bidirectional transport of AC across Caco-2 and MDCKII-MDR1 cells was investigated. The efflux of AC across monolayers of these two cell lines was greater than its influx. Additionally, the P-gp inhibitors, verapamil and cyclosporin A, significantly decreased the efflux of AC. An in situ intestinal perfusion study in rats showed that verapamil co-perfusion caused a significant increase in the intestinal permeability of AC, from 0.22 × 10^− 5 to 2.85 × 10^− 5 cm/s. Then, the pharmacokinetic profile of orally administered AC with or without pre-treatment with verapamil was determined in rats. With pre-treatment of verapamil, the maximum plasma concentration (C_max) of AC increased sharply, from 39.43 to 1490.7 ng/ml. Accordingly, a 6.7-fold increase in the area under the plasma concentration–time curve (AUC_0–12 h) of AC was observed when co-administered with verapamil. In silico docking analyses suggested that AC and verapamil possess similar P-gp recognition mechanisms. This work demonstrated that P-gp is involved in limiting the intestinal absorption of AC and attenuating its toxicity to humans. Our data indicate that potential P-gp-mediated drug–drug interactions should be considered carefully in the clinical application of aconite and formulations containing AC.     

百草枯中毒的临床研究

目的 评估血液灌流联合血液透析治疗急性百草枯中毒的临床疗效并进行系统研究.方法 将本院自2008年1月至2012年12月确诊为急性百草枯中毒40例患者随机分为两组,其中观察组23例,对照组17例,对照组采用常规治疗措施如积极洗胃、导泻、抑酸、保肝、补液及利尿等对症及支持疗法;观察组在对照组的常规治疗措施的基础上再配合血液灌流联合血液透析治疗,观察两组疗效并系统比较.结果 观察组23例中显效10例、有效8例、无效6例、总有效率74%、病死率26%;对照组17例中显效1例、有效3例、无效13例、总有效率23.6%、病死率76.4%,两组总有效率和病死率比较有显著性差异(P<0.01).其中观察组在血液灌流和血液透析后出现血小板数量的减少,未进行治疗,2 d后自行恢复,所有病例均未见其他脏器的活动性出血及血滤管阻塞.结论 根据两组之间治疗急性百草枯中毒的总有效率的比较,不难得出血液灌流联合血液透析治疗较常规治疗不但能提高有效率,还能早期改善症状及其预后,降低肺间质纤维化及其他并发症的发生率,疗效肯定,副作用又小,能被患者接受,值得在临床上推广应用.     

Water extracts of Brassica oleracea var. costata potentiate paraquat toxicity to rat hepatocytes in vitro

Tronchuda cabbage extracts have been proven to have antioxidant potential against various oxidative species in cell free systems, though its antioxidant potential in cellular models remained to be demonstrated. In the present study, we used primary cultures of rat hepatocytes for the cellular assay system and paraquat PQ exposure as a pro-oxidant model agent, to test whether tronchuda cabbage hydrolysed water extracts provide protective or aggravating effects towards PQ-induced oxidative stress and cell death. For this purpose cellular parameters related to oxidative stress were measured, namely the generation of superoxide anion, glutathione oxidation, lipid peroxidation, intracellular ATP levels, activation of nuclear factor-κB (NF-κB), activity of antioxidant enzymes, and cell death.The obtained results demonstrated that the studied hydrolysed water extracts of tronchuda cabbage, especially rich in kaempferol (84%) and other polyphenols, namely hydroxycinnamic acids and traces of quercetin, can potentiate the toxicity of PQ in primary cultures of rat hepatocytes. These results highlight that prospective antioxidant effects of plant extracts, observed in vitro, using non-cellular systems, are not always confirmed in cellular models, in which the concentrations required to scavenge pro-oxidant species may be highly detrimental to the cells.     

胃肠道净化佐治口服百草枯中毒体会

目的 评价胃肠道净化疗法佐治口服百草枯中毒的疗效.方法 回顾性分析65例口服百草枯中毒患者,胃肠道净化传统方法与改良方法疗效观察.结果 两组服毒量、入院时间及治疗时间经比较差异无统计学意义(P＞0.05),改良组病死率、平均排便时间明显低于传统治疗组,差异有统计学意义(P＜0.05).结论 早期、快速、反复、彻底胃肠道净化对于百草枯中毒能否成功救治至关重要.     

Relative absorption and dermal loading of chemical substances: Consequences for risk assessment

Quantification of skin absorption is an essential step in reducing the uncertainty of dermal risk assessment. Data from literature indicate that the relative dermal absorption of substances is dependent on dermal loading. Therefore, an internal exposure calculated with absorption data determined at a dermal loading not comparable to the actual loading may lead to a wrong assessment of the actual health risk. To investigate the relationship between dermal loading and relative absorption in a quantitative manner, 138 dermal publicly available absorption experiments with 98 substances were evaluated (87 in vitro, 51 in vivo; molecular weight between 40 and 950, log P between −5 and 13), with dermal loading ranging mostly between 0.001 and 10 mg/cm². In 87 experiments (63%) an inverse relationship was observed between relative dermal absorption and dermal loading, with an average decrease of factor 33 ± 69. Known skin irritating and volatile substances less frequently showed an inverse relationship between dermal loading and relative absorption.     

尿百草枯与动脉血乳酸浓度对急性百草枯中毒的预后评估

目的：观察急性百草枯中毒（APP）患者入院时尿百草枯（PQ）浓度与动脉血乳酸（Lac）浓度变化,探讨APP 患者预后特异度和敏感度较高的监测指标。方法收集我院急诊内科2012年1月－2015年1月 APP 患者142例的临床资料,根据中毒后30 d 是否死亡分为死亡组与存活组,记录入院时尿 PQ 浓度和血 Lac 浓度,通过 ROC 曲线评估其对 APP 预后的诊断价值。结果死亡组患者入院时尿 PQ 浓度和血 Lac 浓度明显高于存活组（P ＜0．05）;两者对 APP 患者死亡预测的 ROC 曲线下面积（AUC）显示,尿 PQ 浓度的 AUC 为0．843,截断值为50．12 mg／L,敏感度为78．6％,特异度为88．5％,Youden 指数0．671;血 Lac 浓度的 AUC 为0．782,截断值为3．76 mmol／L,敏感度为85．4％,特异度为76．7％,Youden 指数0．621。结论入院时尿 PQ 浓度（≥50．12 mg／L）和（或）血 Lac 浓度（≥3．76 mmol／L）可作为预测 APP 患者预后的参考指标。     

Inhibitory effect of nicotinamide to paraquat toxicity and the reaction site on complex I

The inhibitory effect and mechanism of action of nicotinamide to paraquat toxicity were studied in male Sprague-Dawley rats. Proteins of submitochondrial particles (SMP), especially of mol. wt. 25–30 kDa, in rat lungs were destroyed by paraquat radicals, and aggregated protein bands ∼100 kDa were observed by polyacrylamide electrophoresis. The competitive inhibition effects were observed of nicotinamide on NADH oxidation by paraquat via SMP in rat lungs and the K _i was 9.3 mM. The inhibitory effects of nicotinamide on lipid peroxidation by paraquat with rat lung and liver SMP were verified. The times of occurrence of dyspnea and death in rats after paraquat exposure were delayed by nicotinamide administration. The activity of NADH: ubiquinone reaction of NADH:ubiquinone oxidoreductase (complex I) in rat lung was reduced 24 h after paraquat exposure, and was protected by nicotinamide. The activity of NADH:ferricyanide reaction of complex I was, however, reduced by administration not only of paraquat but also nicotinamide. These results imply that nicotinamide is inhibitory to paraquat toxicity. Nicotinamide, paraquat, and ferricyanide may react at overlapping sites on complex I. Received: 14 April 1997 / Accepted: 13 May 1997     

The influence of pH on rectal absorption of sodium benzoate studied in man by rectal lumen perfusion

The influence of pH on rectal absorption of sodium benzoate in man was studied by means of a rectal lumen perfusion method and compared with in vitromeasurements on diffusional transport of sodium benzoate across an octanol/water interface. For nonbuffered solutions of benzoate in vitro,it was shown that mass flux across an octanol/water interface occurs in agreement with the pH-partition model. In vivohowever, mass flux increases less with decreasing pH of unbuffered perfusate than is anticipated on the basis of the pH-partition model. Probably an alkaline flow across the rectal mucosa into the lumen is present as a physiological neutralization mechanism. In contrast, buffered solutions of benzoate show a linear relationship between mass flux and decreasing pH in vitroas well as in vivo.The effect of buffer on the concentration profile of benzoic acid is qualitatively explained. It is shown that an alkaline flow across the rectal mucosa only slightly influences absorption of benzoic acid from strongly buffered solutions in the rectal lumen. It is concluded that the use of strong buffers in rectal solutions induces a drastic effect on the pH of the boundary layer, an effect not seen for unbuffered solutions. This phenomenon does not invalidate the pH-partition hypothesis but can be explained by it.     

Effect of preinduction of metallothionein on paraquat toxicity in mice

The effect of pretreatment with metallothionein (MT)-inducing metals (Zn, Cu, Bi, Co, Cd or Hg) on paraquat (PQ) toxicity was investigated in mice. PQ lethality was remarkably reduced by pretreatment with the above MT-inducing metals. The protective effect of pretreatment with these metals on PQ lethality was significantly correlated with MT levels in the lung, a target tissue of PQ toxicity, in mice administered MT-inducing metals, but not with MT in the liver or kidney. The increase in pulmonary lipid peroxidation in mice treated with PQ was significantly inhibited by Zn pretreatment. Zn was the most effective of the MT-inducing metals used in this experiment in protecting mice against PQ lethality. Of those monitored, the only pulmonary free radical scavenging factor increased by Zn pretreatment was MT. Other free radical scavenging factors (activities of Superoxide dismutase, glutathione peroxidase and catalase, and concentration of non-protein thiols level) were not influenced by Zn treatment. These results indicate that the induction of pulmonary MT protects against the lethality and lung toxicity of PQ. Pulmonary MT may scavenge free radicals produced by PQ, thereby protecting against lethal pulmonary toxicity.     

血必净联合甲强龙治疗百草枯中毒患者肺损伤的研究

目的评价血必净联合甲强龙治疗百草枯中毒患者肺损伤的临床疗效。方法选择我院急诊2004年1月-2008年9月收治的急性百草枯中毒患者51例,随机分为对照组(24例)与治疗组(27例)。对照组给予常规治疗。治疗组在对照组的基础上应用血必净注射液50mL,2次/d,连用7d;甲强龙500mg,1次/d,连用5d。结果治疗组发生低氧血症、Ⅰ型呼吸衰竭、ALI、ARDS、机械通气例数少于对照组,P<0.05;治疗组肺纹理增强、点片状影、磨玻璃影、胸腔积液、纤维条索、网状影、结节影表现明显少于对照组,P<0.05;治疗组入院后发生MODS、死亡数少于对照组,P<0.05。结论血必净联合大剂量甲强龙治疗可减轻肺组织损伤程度,降低患者死亡率。     

贝那普利对百草枯中毒大鼠肺纤维化的干预作用

目的观察贝那普利对百草枯中毒大鼠肺纤维化过程的影响并探讨其可能的作用机制。方法72只SPF级SD雄性大鼠按随机数字表法分为对照组、百草枯染毒组（一次性百草枯60mg／kg灌胃）和贝那普利干预组[一次性百草枯60mg／kg灌胃并予贝那普利10mg／（kg·d）灌胃],每组24只。对照组用0．9％氯化钠注射液替代百草枯及贝那普利。各组于实验第3、7、14天分批随机处死8只动物,取肺组织行苏木素一伊红（HE）染色和Masson染色,观察大鼠肺泡炎、肺纤维化程度;免疫组织化学测胶原I、Ⅲ;定时定量聚合酶链反应检测血管紧张素转化酶（ACE）、血管紧张素Ⅱ1型受体（ATl）mRNA表达;酶联免疫吸附法检测肺组织血管紧张素Ⅱ（AngⅡ）蛋白表达。结果百草枯染毒组第3、7、14天大鼠肺组织ACEmRNA、AT1 mRNA及AngⅡ蛋白表达均较对照组增高[ACEmRNA分别为（3．15±0．13）比（1．02±0．01）、（3．88±0．21）比（1．05±0．02）、（4．16±0．12）比（1．03±0．01）,AT1 mRNA分别为（1．53±0．23）比（1．00±0．01）、（2．92±0．05）比（1．06±0．03）、（3．62±0．03）比（1．08±0．05）,Angll分另0为（10．55±0．24）μg／L比（3．00±0．12）斗g／L、（7．43±0．23）彬L比（3．05±0．16）彬L、（8．36±0．35）形L比（3．03±0．13）μg／L];贝习B普利干预组[第3、7、14天ACEmRNA分别为（2．20±0．22）、（2．95±0．08）、（2．80-t-O．16）,ATlmRNA分别为（1．32±0．01）、（2．05±0．17）、（2．53±0．22）,Angll分别为（5．85±0．32）、（6．21±0．16）、（6．13±0．33）μg／L]与百草枯染毒组比,表达下调（P〈0．05）。贝那普利干预组第7天始肺泡炎和纤维化程度积分及胶原I、Ⅲ含量低于百草枯染毒组（P〈0．05）。结论局部。肾素-血管紧张素系统的激活可能参与百草枯中毒致肺纤维化的发病过程。贝那普利对百草枯中毒大鼠肺纤维化有一定阻抑作用,可能与其抑制局部ACE,减少AngⅡ生成有关。     

不同纯度苦杏仁苷巴布剂的透皮吸收比较研究

目的:比较研究不同纯度的苦杏仁苷提取物制备的巴布剂对小鼠皮肤不同的透过吸收情况,以便确定合适纯度的苦杏仁苷作为经皮制剂给药原料.方法:采用Franz扩散池法,研究各种苦杏仁苷巴布剂中苦杏仁苷的透皮吸收情况;并采用高效液相色谱法检测透过小鼠皮肤的苦杏仁苷的透过量.结果:制得巴布剂中苦杏仁苷的透皮吸收符合Higuchi方程,累积渗透量(Q)与t1/2呈线性关系.纯度为38.7%、61.4%、86.7%的苦杏仁苷巴布剂,累积渗透量分别为2 121.339、1 597.441、1 614.173 μg·cm-2,透皮速率常数(J)分别为969.95、828.26、793.14 μg·cm-2·h-1.结论:苦杏仁苷巴布剂能较好地透过皮肤,且38.7%纯度的透皮效果最好,可以考虑选择该纯度的苦杏仁苷提取物制备巴布剂.     

Enhancing and sustaining the topical ocular delivery of fluconazole using chitosan solution and poloxamer/chitosan in situ forming gel

Fungal keratitis is a serious disease that can lead to loss of vision. Unfortunately, current therapeutic options often result in poor bioavailability of antifungal agents due to protective mechanisms of the eye. The aim of this work was to evaluate the potential of a chitosan solution as well as an in situ gel-forming system comprised of poloxamer/chitosan as vehicles for enhanced corneal permeation and sustained release of fluconazole (FLU). For this, in vitro release and ex vivo corneal permeation experiments were carried out as a function of chitosan concentration from formulation containing the chitosan alone and combined with the thermosensitive polymer, poloxamer. Microdialysis was employed in a rabbit model to evaluate the in vivo performance of the formulations. The in vitro release studies showed the sustained release of FLU from the poloxamer/chitosan formulation. Ex vivo permeation studies across porcine cornea demonstrated that the formulations studied have a permeation-enhancing effect that is independent of chitosan concentration in the range from 0.5 to 1.5% w/w. The chitosan solutions alone showed the greatest ex vivo drug permeation; however, the poloxamer/chitosan formulation presented similar in vivo performance than the chitosan solution at 1.0%; both formulations showed sustained release and about 3.5-fold greater total amount of FLU permeated when compared to simple aqueous solutions of the drug. In conclusion, it was demonstrated that both the in situ gelling formulation evaluated and the chitosan solution are viable alternatives to enhance ocular bioavailability in the treatment of fungal keratitis.     

何首乌吸收动力学研究进展

何首乌作为传统常用中药,被广泛应用于临床,在疾病治疗中发挥重要作用。临床上,何首乌饮片及制剂主要以口服为主,所含化学成分被吸收进入机体并与机体相互作用是其发挥药效的前提,因此,研究何首乌的吸收机制具有重要意义。本文通过查阅文献,对何首乌主要成分的吸收动力学研究进行综述,以期为评价何首乌的生物利用度、改善剂型、提高药效提供参考。     

前列地尔注射液对百草枯中毒患者肺损伤的影响

目的:观察前列地尔注射液对百草枯中毒患者炎症介质和肺损伤的影响,为临床治疗提供参考。方法:30例急性百草枯中毒患者随机分为常规治疗组(对照组)和常规治疗+前列地尔注射液组(试验组),每组15例。前列地尔注射液用法:10μg加入100mL生理盐水(NS)静脉滴注,1次/d,连用7d。分别于入院当天及入院后7d测定患者血浆IL-6、IL-8、基质金属蛋白酶-9(MMP-9)浓度,行动脉血气分析和胸部X线检查,并随访生存情况。结果:与对照组比较,入院后7d试验组患者IL-6、IL-8、MMP-9浓度降低,急性肺损伤(ALI)及全身炎症反应综合症发生率降低(P<0.05);两组患者病死率差异无统计学意义(P>0.05)。结论:前列地尔注射液可减轻百草枯中毒患者炎症反应和肺损伤。