125I-眼镜蛇神经毒素透鼻黏膜吸收及冰片的促进作用研究

目的：考察^125Ⅰ-(α-cobratoxin，Nt)透鼻黏膜吸收的情况及冰片的促进作用。方法：以大鼠、家兔、狗和羊为研究对象，以放射性活性(每分钟计数，count per minute，cpm)为指标，采用离体渗透鼻黏膜实验、在体渗透鼻黏膜重循环实验等方法，研究^125Ⅰ-Nt对不同动物透鼻黏膜吸收的情况及冰片的促进作用。结果：研究发现，Nt很难透过鼻黏膜吸收，但在冰片作用下吸收显著增加。结论：冰片对Nt透鼻黏膜吸收有显著促进作用。     

渗透促进剂对盐酸氯胺酮经鼻黏膜渗透的促进作用

目的研究渗透促进剂对盐酸氯胺酮 (KET·HCl)鼻黏膜透过性的影响。方法使用水平双室扩散池法 ,测定分别加入 5种不同的渗透促进剂后家兔离体鼻黏膜对KET·HCl透过量的变化。结果 5 g·L-1的乙二胺四乙酸二钠 (EDTA 2Na)、5 g·L-1的牛磺胆酸钠 (TC)和 0 5 g·L-1月桂氮卓酮 (Azone)分别使KET·HCl的表观透过系数增大 1 4 5 9、1 187和 1 179倍。KET·HCl家犬离体鼻黏膜的渗透系数约为家兔鼻黏膜的 2 5倍。结论EDTA、TC和Azone为有效的鼻用渗透促进剂。KET·HCl的不同动物鼻黏膜的渗透性存在显著性差异     

鼻黏膜给药的研究进展

鼻腔给药是传统的给药方式,在耳鼻喉科应用极为广泛,一般用来治疗各种鼻腔和鼻窦疾病,也可作为辅助用药用于与鼻病有关的邻近器官疾患。近年来随着对这一给药途径研究的深入,通过鼻黏膜吸收发挥全身性治疗作用的药剂受到人们的重视,尤其是肽和蛋白质类药物的鼻黏膜给药研究较多,很有希望替代传统的注射给药途径。1鼻黏膜给药的特点鼻黏膜给药简便易行,药物经鼻黏膜吸收后直接进入体循环,可免受胃肠道中酶的破坏和肝脏对药物的首过效应,有利于提高生物利用度,某些药物鼻内给药的生物利用度接近100%,这对胃肠道吸收不良的药物有实际意义。鼻黏膜给药的缺点是制剂对鼻黏膜的刺激,主要是纤毛毒性作用,包括药物、附加剂、渗透促进剂和防腐剂对纤毛活动的作用。2对药物的要求用于鼻黏膜给药的药物应符合以下条件:2.1分子量不能太大药物分子量的大小与其鼻黏膜吸收有着密切关系,分子量在4000以下能较好地透过鼻黏膜,生物利用度较高。较大的分子在有渗透促进剂的情况下,也能较好的吸收。常用的渗透促进剂有:合成的表面活性剂:聚氧乙烯-9-月桂醚、硫代月桂醇钠。②胆酸衍生物:牛黄胆酸钠、葡萄糖胆酸钠,脱氧胆酸钠和脱氧牛黄胆酸钠。③烷显著提高胰岛素、17β-雌二醇和黄...     

几种促透剂联合使用对双氯芬酸钠体外经裸小鼠皮肤吸收的影响

目的:研究几种促透剂联合使用对药物体外经皮渗透的影响。方法:在离体透皮吸收装置上,采用正交试验的设计方法研究不同浓度的氮酮、薄荷醇、冰片联用对双氯芬酸钠在离体裸小鼠背部皮肤上的透皮行为,以累积透过量、渗透速率和滞后时间为药效指标,运用Topsis法评价促透效果。结果:对双氯芬钠的促透作用,氮酮2%、薄荷醇2%、冰片1%联用促透效果最好,其中以氮酮的促透作用最为明显。结论:三种促透剂的联合使用能有效促进双氯芬酸钠的透皮吸收,Topsis法可客观、公正地评价促透剂的促透效果并选出最优方案。     

速效救心丸中冰片“引经”作用机制研究

为了明确速效救心丸中冰片“引经”作用机制,本研究首先建立外翻肠囊体外肠道吸收模型、小鼠在体药代模型和Caco-2细胞体外吸收模型,评价冰片促吸收作用。所有动物实验均符合南开大学伦理委员会的规定。结果显示,与不含冰片的速效救心丸组相比,含冰片的速效救心丸组的肠囊液中阿魏酸和藁本内酯的肠道累计吸收量和吸收渗透率显著增加;冰片可以增加阿魏酸和藁本内酯在血液及心脏等组织中的含量,显著降低Caco-2细胞的跨上皮电阻值,并显著增加辣根过氧化物酶透过量。为了进一步探究冰片促进药物肠道吸收的作用机制,本研究合成了冰片炔基光敏探针捕获其作用靶点,采用双荧光素酶报告系统评价其钙调控作用,发现冰片可以通过调控瞬时离子通道蛋白M8 (TrpM8)发挥升钙作用。通过质谱成像技术证明了冰片可以使阿魏酸在心脏的富集显著增加,进而显著增强大鼠胸主动脉的舒张效果。综上所述,速效救心丸中的冰片可以通过作用于TrpM8蛋白,扩大细胞间隙并增加肠道通透性,促进药物吸收和靶器官富集,最终实现药效增强的作用。     

川芎嗪和冰片对鼻腔生化指标及鼻黏膜形态的影响

目的观察不同浓度的川芎嗪、冰片在鼻腔灌流时,对鼻腔总蛋白(TP)和乳酸脱氢酶(LDH)释放,以及鼻黏膜形态的组织病理学影响。方法采用大鼠在体鼻腔重循环法,研究川芎嗪、冰片对鼻腔生化指标及鼻黏膜形态的影响。结果川芎嗪对TP、LDH的分泌无显著性影响。未见明显的鼻黏膜病理组织学形态的改变。冰片对总蛋白分泌无显著性影响,而对LDH的分泌则有极显著性的影响。鼻黏膜病理结果显示,纤毛有不同程度的丢失。结论川芎嗪在鼻腔灌流时对鼻黏膜无明显的毒性影响,而冰片在鼻腔灌流时对鼻黏膜则有显著性的毒性影响。     

黄芩苷脂质体、β-环糊精包合物及磷脂复合物鼻黏膜渗透性及毒性研究

为提高鼻腔给药后脑内药物浓度,本文探讨了以脂质体、β-环糊精包合物和磷脂复合物为黄芩苷载药体系的体外离体动物鼻黏膜渗透性及鼻腔毒性。采用猪、羊、兔鼻黏膜,以体外扩散池装置进行鼻黏膜渗透实验,HPLC法测定接受池中药物累积渗透量,以表观渗透系数为评价标准,考察脂质体、β-环糊精包合物及磷脂复合物载药系统对黄芩苷在离体动物鼻黏膜的透过性,从而筛选出黄芩苷经鼻给药最佳载药形式;采用在体法考察黄芩苷及其磷脂复合物对蟾蜍上颚黏膜纤毛运动的影响和大鼠鼻黏膜长期毒性。3种黄芩苷载药体系的表观渗透系数均明显高于黄芩苷（P<0.05）,滞后时间也比黄芩苷短,提示3种载药载体均可提高黄芩苷的鼻黏膜渗透性,同时磷脂复合物的表观渗透系数明显高于脂质体和环糊精包合物,表明黄芩苷磷脂复合物鼻黏膜渗透性明显优于另外两种载药体系（P<0.05）。黄芩苷磷脂复合物对纤毛运动无影响,对大鼠鼻黏膜也无明显刺激性。结果表明,磷脂复合物为黄芩苷经鼻给药最佳载药形式,能明显提高其鼻黏膜渗透性,对鼻黏膜无毒性,可用于鼻腔给药。

      

冰片β-环糊精包结物的制备与透皮吸收研究

目的 考察冰片经β-环糊精包结后对透皮吸收的影响。方法 用NIH系小鼠背部皮肤分别涂布含冰片β-环糊精（β-CD）包结的乳剂和含冰片不包结乳剂，进行透皮吸收试验，用薄层扫描法测定冰片在不同时间点的透过率。考察冰片经β-环糊精包结后对透皮吸收的影响。结果 冰片经β-环糊精包结后，透皮速度减慢，持续释药，可防止冰片的挥发，提高了药物稳定性。结论 冰片经β-环糊精包结后可透皮吸收，并有缓释作用。     

氢溴酸高乌甲素鼻用原位凝胶剂的制备及其处方评价

目的：制备氢溴酸高乌甲素（LH）鼻用原位凝胶剂,并进行处方考察以提高其鼻腔给药的镇痛效果。方法：采用在体蟾蜍上腭纤毛法考察不同LH处方对鼻黏膜纤毛的毒性、大鼠在体鼻腔循环实验考察处方中3种吸收促进剂（β-环糊精、吐温-80和冰片）对LH的鼻黏膜吸收的促进作用以及小鼠扭体法实验考察不同LH处方的镇痛药效,从而确定LH鼻用原位凝胶剂的最佳处方工艺。结果：处方中LH和所选用的辅料对鼻黏膜纤毛均无显著毒性;3种吸收促进剂对LH的鼻黏膜吸收速率常数无显著影响（P〉0．05）;在所有受试处方中,结冷胶和β-环糊精联用处方制剂的镇痛效果最佳,其药效与腹腔注射相同剂量的LH注射液无显著差异（P〉0．05）。结论：结冷胶和β-环糊精联用是制备LH鼻用原位凝胶剂的最佳处方组合。     

蛇床子挥发油、薄荷醇及冰片对甲硝唑促透作用的比较

目的对蛇床子挥发油、薄荷醇、冰片促透作用进行比较，为蛇床子挥发油的应用提供理论依据。方法在离体透皮实验装置上进行透皮吸收实验和储库效应的研究。结果蛇床子挥发油、冰片、薄荷醇单独应用时对甲硝唑经皮渗透均有促进作用，增渗倍数分别为2．21、2．19和2．66；当蛇床子挥发油与冰片或薄荷醇合用时，促透效应比单用蛇床子挥发油时显著增强（P〈0．01）。蛇床子挥发油和冰片合用时储库效应显著增加。结论蛇床子挥发油对甲硝唑的皮肤吸收有促透作用，与冰片、薄荷醇合用时效果明显增强。     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.     

Nachweis einiger Heilmittel in der Kniegelenksynovialflüssigkeit

Zusammenfassung Mittels Gaschromatographie und Dünschichtchromatographie wiesen die Autoren 11 Substanzen nach, welche durch Injektion oder nach Verabreichung per os in die Kniegelenksynovialflüssigkeit eindrangen. In ihrer Aufstellung konnten sie eine direkte Beziehung zwischen Struktur sowie chemischphysikalischen Eigenschaften der Substanz und ihrer Fähigkeit, aus dem Blut in die Kniegelenksynovialflüssigkeit einzudringen, nicht nachweisen, außer der Tatsache, daß Substanzen mit starker Affinität zu Eiweißstoffen erst in höheren Dosen nachweisbar waren.     

Biochemical and molecular characterisation of cubozoan protein toxins

Class Cubozoa includes several species of box jellyfish that are harmful to humans. The venoms of box jellyfish are stored and discharged by nematocysts and contain a variety of bioactive proteins that are cytolytic, cytotoxic, inflammatory or lethal. Although cubozoan venoms generally share similar biological activities, the diverse range and severity of effects caused by different species indicate that their venoms vary in protein composition, activity and potency. To date, few individual venom proteins have been thoroughly characterised, however, accumulating evidence suggests that cubozoan jellyfish produce at least one group of homologous bioactive proteins that are labile, basic, haemolytic and similar in molecular mass (42-46 kDa). The novel box jellyfish toxins are also potentially lethal and the cause of cutaneous pain, inflammation and necrosis, similar to that observed in envenomed humans. Secondary structure analysis and remote protein homology predictions suggest that the box jellyfish toxins may act as α-pore-forming toxins. However, more research is required to elucidate their structures and investigate their mechanism(s) of action. The biological, biochemical and molecular characteristics of cubozoan venoms and their bioactive protein components are reviewed, with particular focus on cubozoan cytolysins and the newly emerging family of box jellyfish toxins.     

Dose tolerability of chronically inhaled voriconazole solution in rodents

Invasive pulmonary aspergillosis (IPA) is a fungal disease of the lung associated with high mortality rates in immunosuppressed patients despite treatment. Targeted drug delivery of aqueous voriconazole solutions has been shown in previous studies to produce high tissue and plasma drug concentrations as well as improved survival in a murine model of IPA. In the present study, rats were exposed to 20 min nebulizations of normal saline (control group) or aerosolized aqueous solutions of voriconazole at 15.625 mg (low dose group) or 31.25 mg (high dose group). Peak voriconazole concentrations in rat lung tissue and plasma after 3 days of twice daily dosing in the high dose group were 0.85 ± 0.63 μg/g wet lung weight and 0.58 ± 0.30 μg/mL, with low dose group lung and plasma concentrations of 0.38 ± 0.01 μg/g wet lung weight and 0.09 ± 0.06 μg/mL, respectively. Trough plasma concentrations were low but demonstrated some drug accumulation over 21 days of inhaled voriconazole administered twice daily. Following multiple inhaled doses, statistically significant but clinically irrelevant abnormalities in laboratory values were observed. Histopathology also revealed an increase in the number of alveolar macrophages but without inflammation or ulceration of the airway, interstitial changes, or edema. Inhaled voriconazole was well tolerated in a rat model of drug inhalation.