磷酸奥司他韦胶囊在健康中国受试者的生物等效性研究

目的:评价磷酸奥司他韦胶囊受试制剂与参比制剂(达菲?)在健康受试者空腹和餐后状态下的生物等效性和安全性.方法:采用单中心、随机、开放、两周期、自身交叉、单次给药试验设计,健康受试者分别空腹(36例)和餐后(36例)服用75 mg磷酸奥司他韦胶囊受试制剂或参比制剂,采用高效液相色谱-串联质谱(UPLC-MS/MS)检测奥...     

环孢素软胶囊在中国健康受试者中的生物等效性研究

目的 研究受试者口服环孢素软胶囊受试制剂和参比制剂后的药代动力学,并评价两制剂的生物等效性.方法 采用单中心、开放、随机、两序列、四周期重复交叉空腹/餐后口服给药的试验设计.空腹及餐后生物等效性试验分别纳入8例健康受试者,并随机分为2组,每组4例;口服环孢素软胶囊受试制剂(T)和参比制剂(R)50 mg,第一组按照TR...     

拉莫三嗪片在中国健康受试者中的生物等效性的研究

目的 研究拉莫三嗪片在中国健康受试者中的药代动力学特征,并评价国产拉莫三嗪片受试制剂(T)和原研参比制剂(R)在空腹和餐后条件下的生物等效性及安全性。方法 空腹和餐后试验分别入组24例中国健康受试者,空腹试验男性18例,女性6例,餐后试验男性17例,女性7例,采用单中心、随机、开放、单剂量、两制剂两周期两序列交叉的试验设计,受试者单次口服拉莫三嗪片受试制剂或参比制剂50 mg后采集72 h血样,用液质联用法(LC-MS/MS)测定血浆中拉莫三嗪浓度,用WinNonLin 8.1计算主要药代动力学参数并评价2种拉莫三嗪片的生物等效性。结果 空腹单次给药拉莫三嗪片受试制剂和参比制剂的C_max分别为(910.93±248.02)和(855.87±214.36) ng·mL^-1,t_max分别为0.50(0.25,4.00)和1.00(0.25,3.50) h,t_1/2分别为(36.1±9.2)和(36.0±8.2) h, AUC_{0-72 h}分别为(27 402.40±4 752.00)...     

布瓦西坦片在健康受试者中的生物等效性研究

目的 研究布瓦西坦片在空腹和餐后给药状态下的生物等效性。方法 采用单中心、单剂量、随机、开放、两周期、交叉试验设计,空腹和餐后组28例受试者最终入组,分别单次给予布瓦西坦片受试制剂或参比制剂50 mg即1片,用240m L温水送服。采用HPLC-MS/MS法测定人血浆样本中布瓦西坦,使用PhoenixWinNonlin8.1软件计算药动学参数,SAS9.4软件进行统计分析。结果 布瓦西坦片两种制剂的主要药动学参数(AUC_0-∞、AUC_0-t和C_max)几何均值均在生物等效性80.00%～125.00%。结论 布瓦西坦受试制剂与参比制剂在健康受试者空腹和餐后给药状态下具有生物等效性。     

醋酸阿比特龙片在中国健康人体空腹及餐后药动学和生物等效性研究

目的:评价高变异药物醋酸阿比特龙片在中国健康受试者空腹及餐后条件下单剂量给药时的药物动力学特征,并评价受试制剂和参比制剂的人体生物等效性.方法:本研究分为空腹试验和餐后试验两个部分,均采用单中心、单剂量、随机、开放、两制剂、三序列、三周期、部分重复交叉的试验设计.共入组健康男性受试者81例,其中空腹组45例,餐后组36...     

高脂高热量饮食对坎地沙坦酯氨氯地平在中国健康人体内药代动力学的影响

目的 探索空腹和高脂高热量饮食情况下坎地沙坦酯氨氯地平片中两制剂在中国健康受试者中的药代动力学特征差异.方法 用单中心、随机、开放、两制剂、单次给药、双周期、交叉的试验设计.空腹或高脂饮食条件下各入组32例中国健康受试者,单次口服坎地沙坦酯氨氯地平片(8 mg/5 mg),给药前后按时间点采集静脉血样.用高效液相色谱串...     

阿莫西林胶囊在中国健康受试者的生物等效性研究

目的 评价阿莫西林胶囊受试制剂和参比制剂在中国健康受试者体内的生物等效性和安全性.方法 按单中心、随机、开放、单剂量、两周期、双交叉设计.空腹及餐后试验各纳入24例受试者,每周期单次空腹或餐后口服受试制剂或参比制剂250 mg,用液相色谱串联质谱联用法测定阿莫西林血药浓度,用Phoenix WinNolin 8.0版软...     

富马酸喹硫平缓释片在中国健康受试者中的生物等效性研究

目的研究富马酸喹硫平缓释片仿制药与原研药在中国健康受试者中单剂量空腹和餐后条件下给药的生物等效性。方法用单中心、开放、随机、单次给药、两制剂、两周期交叉设计,共纳入68例(空腹试验36例,餐后试验32例)成年男性和女性受试者随机交叉给药。分别单次口服受试制剂和参比制剂200 mg,用液相色谱-串联质谱(LC-MS/MS)法测定血浆中喹硫平的浓度。用SAS V9.4软件计算主要药代动力学参数。结果空腹组的富马酸喹硫平缓释片受试制剂和参比制剂主要药代动力学参数如下:AUC_0-t分别为(2432.45±859.54)和(2368.00±792.38)ng·mL^-1·h,AUC_0-∞分别为(2516.56±864.19)和(2461.20±803.72)ng·mL^-1·h,C_max分别为(206.88±92.00)和(207.16±109.88)ng·mL^-1,t_max分别为5.25和4.50 h,t1/2分别为(6.97±2.43)和(7.26±2.13)h。餐后组的富马酸喹硫平缓释片受试制剂和参比制剂主要药代动力学参数如下:AUC_0-t分别为(2774.99±1077.62)和(2856.20±1180.25)ng·mL^-1·h,AUC_0-∞分别为(2840.63±1076.46)和(2916.44±1174.10)ng·mL^-1·h,C_max分别为(398.78±142.90)和(373.15±142.99)ng·mL^-1,t_max分别为5.50和5.00 h,t1/2分别为(4.41±0.63)和(4.68±0.96)h。在空腹及餐后条件下,受试制剂与参比制剂主要药代动力学参数的90%置信区间均在80.00%~125.00%。结论在空腹及餐后条件下,中国健康成年受试者单次口服富马酸喹硫平缓释片仿制药与原研药具有生物等效性。     

地氯雷他定片在中国健康受试者的生物等效性研究

目的 评价地氯雷他定片仿制药与原研药在中国健康受试者中单剂量空腹和餐后条件下给药的生物等效性。方法 用单中心、随机、开放、单次给药、两制剂、两周期、双交叉试验设计,空腹和餐后试验各入组24例受试者。空腹或餐后条件下单次口服地氯雷他定片受试制剂和参比制剂5 mg,用液相色谱串联质谱法测定血浆中地氯雷他定的浓度。用Phoenix WinNonlin 8.0软件计算主要药代动力学(PK)参数。结果 空腹组的地氯雷他定片受试制剂和参比制剂主要PK参数：地氯雷他定C_max分别为(3.81±1.44)和(3.76±1.25)ng·mL^-1,AUC_0-t分别为(52.18±19.21)和(50.71±18.21)ng·mL^-1·h, AUC_0-∞分别为(54.52±19.71)和(53.19±19.07)ng·mL^-1·h。餐后组的地氯雷他定片受试制剂和参比制剂主要PK参数：地氯雷他定C_max分别为(3.52±1.20)和(3.55±1.10)ng...     

哌柏西利胶囊空腹和餐后给药人体生物等效性研究

目的 评价哌柏西利胶囊受试制剂(T)和参比制剂(R)在中国健康受试者空腹和餐后状态下的生物等效性和安全性。方法 采用单中心、随机、开放、两制剂、两序列、两周期的交叉试验设计,空腹试验和餐后试验分别入组32例和28例健康受试者,受试者随机分配到2个试验组(T-R组和R-T组),每周期给药1次,125 mg/次。采用HPLC-MS/MS法测定血浆中哌柏西利浓度,用Phoenix Win Nonlin 8.3软件得出PK参数集,由非房室模型计算各受试者体内哌柏西利胶囊的药动学参数,进行统计分析,并对受试者的临床观察指标进行安全性评价。结果 空腹试验和餐后试验分别有31例和28例受试者完成两个周期给药。受试者空腹和餐后状态下服用哌柏西利胶囊受试制剂和参比制剂的血浆药物最大浓度(C_max)、时间-浓度曲线下面积(AUC_0-t和AUC_0-∞)的几何均值比值的90%置信区间均在80.00%～125.00%范围内,两制剂生物等效。整个试验过程中未发生任何严重不良事件。结论 受试制剂和参比制剂在中国健康志愿者空腹和进食条件下均具有生物等效...     

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.     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

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.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.