鲑鱼降钙素喷鼻剂的人体生物等效性研究

目的:研究国产和进口鲑鱼降钙素鼻喷剂的生物等效性。方法:采用双周期自身随机交叉设计。用放射免疫法(RIA)测定22例健康志愿者喷鼻给药后的血药浓度。结果:国产制剂及进口鼻喷剂实测平均血药峰浓度C_(max)分别为(64.72±9.68)ng·L~(-1)和(65.61±8.46)ng·L~(-1);实测平均达峰时间t_(max)分别为(0.27±0.05)h和(0.27±0.05)h;国产制剂及进口制剂t_(1/2)(ke)分别为(0.68±0.23)h和(0.69±0.24)h;血药浓度-时间曲线下面积AUC_(0-8)h平均值分别为(61.70±15.53)ng·L~(-1)·h和(64.89±15.12)ng·L~(-1)·h;以进口制剂为参比制剂,试验制剂鲑鱼降钙素鼻喷剂的相对生物利用度为(95.95±15.21)%。结论:国产与进口鲑鱼降钙素鼻喷剂生物等效。     

注射用鲑鱼降钙素的人体生物利用度

目的:评价注射用鲑鱼降钙素人体生物利用度和生物等效性.方法:男性健康志愿者20名,采用自身交叉方式单剂量注射鲑鱼降钙素与密钙息20 μg,以放射免疫法测定其血药浓度.结果:试验制剂注射用鲑鱼降钙素与参比制剂密钙息的主要药动学参数:Cmax分别为(154.5±35.2)ng·L-1和(153.8±28.1)ng·L-1;Tmax为(0.52±0.19) h和(0.48±0.14) h;AUC0～10为(344.6±46.8)ng·h·L-1和(339.4±40.6)ng·h·L-1,AUC0～∞为(356.4±48.3)ng·h·L-1和(350.5±41.7) ng·h·L-1.两种制剂的主要药动学参数差异无显著性(P>0.05).注射用鲑鱼降钙素对密钙息的相对生物利用度为(102.0±7.6)%.结论:两种制剂具有生物等效性.     

国产与进口吲达帕胺片在中国健康人体的生物等效性

目的研究国产和进口吲达帕胺片(抗高血压药)在中国健康人体的药代动力学,并评价2种制剂的生物等效性。方法用随机交叉试验,22名健康男性单剂量空腹口服国产和进口吲达帕胺片2.5mg,采集72h内动态血标本;用液相色谱-串联质谱法测定全血中吲达帕胺的浓度,计算药代动力学参数,并进行生物等效性评价。结果国产和进口片剂的tmax分别为(2.0±0.8)和(2.6±1.2)h,Cmax分别为(121.9±22.3)和(118.5±22.3)μg·L-1,AUC0-72h分别为(2464.9±423.2)和(2317.0±455.2)μg·h·L-1,t1/2分别为(15.4±1.9)和(15.2±2.1)h。国产制剂的相对生物利用度为(107.5±12.7)%。结论2种制剂具有生物等效性。     

加替沙星片人体药代动力学及生物等效性研究

目的:在中国健康成年男性志愿者中比较研究国产和进口加替沙星片剂的药代动力学参数,评估两者的生物等效性。方法:24名健康男性志愿者随机自身前后交叉给药,分别单剂口服国产和进口加替沙星片400mg。以HPLC测定血药浓度,应用DAS软件计算两者的药代动力学并考察其生物等效性。结果:受试者分别应用国产片剂(试验制剂)和进口片剂(参比制剂)400mg后,两药药-时曲线均符合二房室模型,主要药代动力学参数:Tmax分别为(0.99±0.41)h和(1.11±0.60)h;Cmax分别为(4.11±0.76)μg/mL和(3.89±0.54)μg/mL;t1/2β分别为(7.75±0.81)h和(7.39±0.92)h;AUC0-36h分别为(29.81±5.70)μg·mL-1·h和(30.77±4.40)μg·mL-1·h;AUC0-∞分别为(30.97±6.01)μg·mL-1·h和(31.85±4.58)μg·mL-1·h;国产片剂对于进口片剂的相对生物利用度F0-36h为(97.63±19.15)%。结论:国产与进口加替沙星片剂为生物等效制剂。     

国产替米沙坦片健康人体生物等效性评价

目的:评价国产和进口替米沙坦片剂在健康人体的生物等效性.方法:采用高效液相色谱-荧光检测法测定18名健康志愿者单次、交叉口服替米沙坦片80 mg后血浆替米沙坦浓度.用3P97药动学软件进行药动学参数计算及生物等效性评价.结果:两种替米沙坦片的药-时曲线均符合二室模型,参比制剂、受试制剂的主要药动学参数为:Cmax分别为(931.0±367.7)μg·L-1和(894.2±421.7)μg·L-1;Tmax分别为(1.0±0.6)h和(1.4±0.8)h;T1/2β分别为(28.1±14.1)h和(27.0±10.8)h;AUC0-t分别为(4 085±2 313)μg·L-1·h和(3 920±2 199)μg·L-1·h;AUC0-∞分别为(4 751±2 742)μg·L-1·h和(4 352±2 569)μg·L-1·h.国产替米沙坦片的相对生物利用度F0-t为(97.5±15.6)%,F0-∞为(96.5±15.8)%.结论:方差分析和双单侧t检验证明两制剂具有生物等效性.     

盐酸依匹斯汀片在健康人体的药代动力学和相对生物利用度

目的研究国产和进口盐酸依匹斯汀片(抗组胺药)在健康人体的药代动力学和相对生物利用度,并进行生物等效性评价。方法20名男性健康志愿者随机交叉单剂量口服国产和进口盐酸依匹斯汀片40mg后,用反相高效液相色谱法测定血浆盐酸依匹斯汀浓度,用DAS软件计算其药代动力学参数。结果2种制剂在人体的药时曲线均符合二室开放模型,主要药代动力学参数:t1/2分别为(10.12±1.28)和(10.43±2.44)h;tmax分别为(2.18±0.47)和(2.03±0.41)h;Cmax分别为(65.90±16.45)和(68.17±13.25)μg·L-1;AUC0-36分别为(591.63±88.22)和(600.90±93.74)μg·L-1.h;AUC0-∞分别为(647.04±101.58)和(657.96±87.56)μg·L-1.h。与进口制剂比较,国产制剂的相对生物利用度F0-36为(99.40±12.77)%;F0-36为(98.85±13.72)%。结论国产和进口制剂具有生物等效性。     

国产与进口富马酸奎的平片的药动学比较及相对生物利用度

目的:研究富马酸奎的平片的药动学及相对生物利用度.方法:受试者交叉口服单剂量(100mg)国产片与进口片,用高效液相色谱法测定血药浓度.结果:两种片剂的主要药动学参数:Tmax分别为(1.7±0.8)h与(1.6±0.7)h,Cmax分别为(100.4±18 9)μg·L-1与(100.0±17.8)μg·L-1,AUC0-t分别为(246.8±29.4)μg·L-1·h与(244.7±28.8)μg·L-1·h,AUC0-∞分别为(250.7±30.2)μg·L-1·h与(248.9±29.6)μg·L-1·h,T1/2分别为(1.8±0.5)h与(1.8±0.4)h,国产片相对于进口片的生物利用度为(101.9±7.4)%.结论:两种制剂具有生物等效性.     

非那雄胺片在健康志愿者的生物等效性研究

目的:比较国产与进口非那雄胺片的人体生物等效性.方法:18例健康男性单次随机交叉口服非那雄胺10mg后,用HPLC法测定血清中各时的药物浓度,计算两者的药物动力学参数和相对生物利用度,进行生物等效性评价.结果:国产及进口非那雄胺片的主要药动学参数如下:AUC0-t分别为(1039.13±272.37)和(1008.60±244.77)μg·h·L-1,Cmax分别为(128.72±26.69)和(117.32±25.20)μg·L-1,Tmax分别为(2.69±0.39)和(2.69±0.49)h,供试制剂相对于参比制剂的人体生物利用度为(106.58±27.79)%.结论:国产与进口非那雄胺片具有生物等效性.     

国产与进口奥氮平片的人体药动学及生物等效性

目的:考察健康受试者口服奥氮平片的药动学,比较国产制剂与进口制剂的生物等效性.方法:采用双周期两制剂交叉试验设计,22例男性健康志愿者随机分为2组,交叉单次剂量口服国产或进口奥氮平片10mg,用高效液相色谱电化学检测法测定给药后不同时间点血浆中奥氮平的浓度,采用3P97非房室模型法生物等效性计算程序进行统计分析.结果:国产和进口奥氮平片单次口服后的血药浓度时间曲线相似,主要药动学参数Cmax分别为(20.77±4.86)和(19.31±4.80)μg·L-1;Tmax分别为(2.91±0.68)和(3.73±1.24)h;AUC0～144h分别为(643.94±156.35)和(636.53±187.19)μg·h·L1;AUC0～∞分别为(688.42±156.19)和(684.85±192.66)μg·h·L-1.国产奥氮平片对进口奥氮平片的相对生物利用度F-AUC0～144h为(105.2±25.0)%,F-AUC0～∞为(104.8±27.9)%.除Tmax外(P＜0.05),主要药动学参数Cmax,AUC0～144h和AUC0～∞均无显著性差异(P＞0.05).结论:国产和进口奥氮平片具有生物等效性.     

奥硝唑血药浓度的高效液相色谱法测定及其国产和进口片剂的药动学和生物等效性研究

目的建立血浆中奥硝唑浓度的反相高效液相色谱分析方法,并用此法研究了国产和进口奥硝唑片剂在健康人体内的药动学及生物等效性.方法用甲醇/异丙醇(50/50)提取样本,采用Kromasil C18色谱柱,以甲醇:0.4%HAc(50∶50)为流动相,流速0.8mL·min-1,紫外检测波长316nm.18名健康男性志愿者随机交叉口服国产及进口奥硝唑片1.5g,测定其药动学参数,评价两种制剂的生物等效性.结果奥硝唑在2.0～20.0μg·mL-1范围内呈线性,r=0.9997,最低检测限0.2μg·mL-1.低、中、高浓度(2.0,10.0,20.0μg·mL-1)的方法回收率分别为100.36%,98.21%和97.42%,日间及日内RSD分别＜6%和＜7%.药动学研究表明,口服奥硝唑国产与进口制剂的药-时曲线符合有滞后时间的二室模型.其主要药动学参数如下:t1/2(β) 分别为(16.29±2.20)h 和(15.85±2.26)h ;Tmax 分别为(1.67±0.49)h 和(1.75±0.48)h; Cmax 分别为(22.03±3.53)mg·L-1 和(22.58±5.94)mg·L-1 ;AUC0～72 分别为(444.56±55.87)mg·h·L-1 和(433.31±58.52)mg·h·L-1 ;AUC0～∞分别为(462.95±55.35)mg·h·L-1 和(451.67±57.97)mg·h·L-1 .两种制剂主要药动学参数均无显著性差异(P＞0.05).国产奥硝唑片的相对生物利用度为(102.91±8.93)%.结论本法准确可靠,操作简便,适用于临床药动学研究及常规血药浓度监测.统计学检验结果提示,国产和进口奥硝唑片具有生物等效性.     

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.     

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.     

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.