增稠后的氯霉素滴眼液的兔泪液药物动力学

目的：了解加入新型增粘剂后氯霉素滴眼液在兔泪眼中的药物动力学差别。方法：采用uV测定法测定不同时间兔泪眼中氯霉素的浓度。采用药物动力学软件(PK—GRAPH)分析药物浓度-时间数据。结果：不同增粘剂处方的氯霉素滴眼液的药物动力学参数之间具有非常显著性的差异，表明增粘剂的种类和浓度对药物动力学参数有较大影响。结论：经医用几丁糖增稠后的氯霉素滴眼液可使泪眼中的药物浓度衰减变慢，从而使药物的利用度提高。     

氟康唑原位胶化滴眼液眼内药代动力学研究

目的　比较氟康唑滴眼液及其原位胶化滴眼液在兔眼内药代动力学。方法　两种制剂滴眼后,用气相色谱法测定不同时间的兔眼结膜囊内泪液和房水中氟康唑浓度,药动学参数用非线性最小二乘法进行计算机拟合求得。结果　用药后180 min内,原位胶化组各时间点结膜囊内泪液药物浓度均明显高于一般滴眼液组。原位胶化组的房水药物浓度-时间曲线下面积和消除半衰期明显高于对照组,达峰时间延迟,但达峰浓度与一般滴眼液组无明显差异。结论　氟康唑原位胶化滴眼液可明显延长药物在眼部的滞留时间,提高药物的生物利用度。     

洛索洛芬钠速释缓释双层片药动学及其体内外相关性研究

目的建立家兔血浆中洛索洛芬钠浓度的HPLC定量分析方法,测定其在家兔体内的血药浓度经时过程,评价速释缓释双层片和普通片剂的生物等效性。方法血浆中加入内标布洛芬,酸化后经乙酸乙酯5mL提取．进行HPLC测定。给药方案采用单剂量自身交叉,采用DAS软件拟合药物浓度-时间曲线。计是药代动力学参数。结果与普通片相比,速释缓释鼹层片的tmax,t1／2,Cmax降低．相对生物利用度为（105．74％±7．67）％。结论本方法专属性强。灵敏度高,准确性好。速释缓释双层片与普通片生物等效。具有明显的缓释特征。     

吗替麦考酚酯纳米混悬剂的制备及其兔眼内生物学性质研究

目的：研究吗替麦考酚酯纳米混悬剂在兔眼角膜黏附性、泪液和房水药物动力学特性。方法：以薄膜分散．高压乳匀法制备纳米混悬剂,测定其理化性质。HPLC法检测角膜黏附、泪液和房水中的吗替麦考酚酯和麦考酚酸的含量。结果：混悬剂滴眼液呈米黄色乳液状,纳米混悬剂药物粒子呈圆球状,粒径均一,纳米混悬剂平均粒径592nm,多分散系数Pdl为0．114,Zeta电位为-29．6mV。与普通混悬剂滴眼液相比,纳米混悬剂的角膜黏附性、泪液和房水中药物浓度明显提高。结论：纳米混悬剂可以促进和提高吗替麦考酚酯眼局部给药后角膜黏附和药物吸收。     

阿昔洛韦原位胶化滴眼液的眼内药物动力学研究

目的：考察阿昔洛韦原位胶化滴眼液滴入眼睛后在眼房水中的药物代谢动力学，并与市售阿昔洛韦滴眼液进行比较。方法：两种制剂滴眼后，采用反相高效液相色谱法测定不同时间点的兔眼房水中阿昔洛韦的浓度。结果：原位胶化滴眼液和市售滴眼液滴眼后，除0.25h时间点外，其余各时间点阿昔洛韦原位胶化滴眼液治疗组的房水药物浓度较市售阿昔洛韦滴眼液治疗组明显增高（P＜0．05）。原位胶化滴眼液的生物利用度是滴眼液的2．67倍。用胶化滴眼液后6.5h，房水中仍可测出阿昔洛韦的浓度，而用滴眼液后5.5h，房水中已测不出阿昔洛韦的浓度。结论：阿昔洛韦原位胶化滴眼液能提高药物的生物利用度，增强疗效，并减少给药频率。     

2种更昔洛韦滴眼液在家兔眼部的生物等效性比较

目的:比较更昔洛韦壳聚糖滴眼液与不含壳聚糖的相同处方更昔洛韦滴眼液的眼部药动学与相对生物利用度。方法:取日本大耳兔分为实验组(更昔洛韦壳聚糖滴眼液)与对照组(更昔洛韦滴眼液),双侧眼分别滴入相应的更昔洛韦滴眼液50μL,分别于不同时间取泪液、角膜、房水,采用高效液相色谱法测定药物浓度并计算药动学参数。结果:实验组与对照组给药后泪液药物t1/2分别为15.41、16.22min,角膜t1/2分别为45.21、32.55min,房水t1/2为59.43、48.53min,房水Cmax分别为2.03、1.22μg·mL-1,实验组泪液、角膜与房水中药物AUC0→240分别是对照组的1.66、1.89、2.77倍。结论:与不含壳聚糖滴眼液比较,更昔洛韦壳聚糖滴眼液生物利用度显著提高。     

尼群地平微丸家犬体内药动学研究

目的研究自制尼群地平速释、缓释微丸在家犬体内的药物动力学,并进行相对生物利用度评价。方法分别以尼群地平国产片和日本片为参比制剂,采用高效液相色谱法测定4个制剂的家犬体内血浆药物浓度并绘制平均血药浓度-时间曲线,计算药动学参数并进行方差分析,同时对自制制剂的生物利用度进行了评价。结果尼群地平速释微丸、缓释微丸、国产片和日本片的Tmax依次为0.92±0.14、5.0、1.83±0.29和1.08±0.38h;Cmax依次为187.01±21.23、85.25±13.80、88.31±8.65和160.22±24.34ng.mL-1;AUC0~t依次为665.54±109.07、606.47±130.68、472.44±89.44和659.16±100.05 ng.h.mL-1。以国产片为参比制剂时,自制速释微丸和缓释微丸的相对生物利用度分别为146.92%和135.92%;以日本片为参比制剂时,速释微丸和缓释微丸的相对生物利用度分别为101.04%和91.63%。结论自制速释微丸接近同类产品国外制剂,优于国内制剂;缓释微丸体内作用时间延长,但生物利用度偏低,需进一步改进处方或工艺。     

玻璃酸钠在氯霉素滴眼液中的作用

目的研究玻璃酸钠(SH)在氯霉素滴眼液中所起的作用。方法采用对比实验法,测定氯霉素滴眼液和含SH的氯霉素滴眼液的运动黏度。给家兔的2只眼结膜囊内分别滴入氯霉素滴眼液和含SH的氯霉素滴眼液各50μL,采集泪液测定药物浓度,对2种滴眼液做家兔眼刺激实验。结果含SH的氯霉素滴眼液比氯霉素滴眼液的运动黏度大,对眼部不引起刺激性,可以延长药物在泪液中的滞留时间。结论SH能增加氯霉素滴眼液的黏度,延长药物在泪液中的滞留时间,提高药物疗效。     

格尔德霉素滴眼液兔眼角膜吸收的研究

目的：制备格尔德霉素滴眼液．进行兔眼角膜吸收实验．检测角膜及房水中药物量。方法：以健康新西兰大白兔为实验对象．单剂量给药．在不同时间点取房水及角膜．用HPLC法分别测定药物在角膜及房水中药物吸收量．用3p87药动学程序进行房室模型模拟和参数拟合。并进行体内外相关性考察。结果：药物易被角膜吸收，但不易渗透进入房水．药物在体角膜吸收符合血管外给药一级吸收一室模型。药物在眼部滞留时间较长．平均滞留时间为3.07h．有一定的缓释作用．利于提高药物生物利用度。体内外实验具较好的相关性(r=0．9086)、结论:格尔德霉素滴眼液易被兔眼角膜吸收，且在角膜中达到较高浓度．在治疗单纯疱疹性病毒性角膜炎方面具有良好的前景。     

格列吡嗪缓释胶囊在兔体内的药物动力学及相对生物利用度

目的:探讨格列吡嗪缓释胶囊在兔体内的药物动力学及相对生物利用度。方法:12只成年家兔随机分成2组,分别口服5mg格列吡嗪缓释胶囊和普通胶囊后,采用HPLC法测定血浆中药物浓度。结果:缓释胶囊和普通胶囊血药浓度达峰时间分别为5.16±0.75h和1.66±0.26h,峰浓度分别为257.7±31.7ng/ml和481.9±46.4ng/ml,药时曲线下面积分别为2270.22±311.8ng/(h·ml)和2190.2±430.5ng/(h·ml),药时曲线符合一级吸收的单室模型。统计分析表明,缓释胶囊具有缓释效果,相对生物利用度为103.6％,与普通胶囊具有生物等效性(P>0.05)。结论:格列吡嗪缓释胶囊能达到缓慢释药、持久降糖的作用,可减少临床给药次数,方便病人。     

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.     

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.