富马酸异丙吡仑片的人体生物等效性

目的:研究富马酸异丙吡仑片的人体相对生物利用度。方法:健康志愿者20名,随机双交叉单剂量口服富马酸异丙吡仑试验和参比制剂,用高效液相色谱法测定血浆中异丙吡仑的浓度。用3p97药动学程序计算相对生物利用度和评价生物等效性。AUC0-36,AUC0-inf和Cm ax经方差分析和双单侧t检验,tm ax进行秩和检验。结果:单剂量口服试验制剂和参比制剂后血浆中的异丙吡仑的Cm ax分别为(1.10±0.14)mg.L-1和(1.09±0.15)mg.L-1;tm ax分别为(1.8±0.5)h和(1.9±0.6)h;AUC0-36分别为(9.1±1.9)mg.h.L-1和(9.2±2.3)mg.h.L-1;AUC0-inf分别为(9.6±2.0)mg.h.L-1和(9.9±2.4)mg.h.L-1;Cm ax、AUC0-36、AUC0-inf的90%可信区间分别为94.6%~107.1%、92.1%~106.1%、90.0%~106.2%。结论:试验制剂与参比制剂的人体相对生物利用度为(100.4±17.8)%,试验制剂和参比制剂具有生物等效性。     

国产左氧氟沙星片的人体生物等效性研究

目的评价国内不同厂家左氧氟沙星片的相对生物利用度和生物等效性。方法18名男性健康受试者采用随机、自身对照、交叉法单剂量口服两个不同厂家的左氧氟沙星片后,采用荧光检测器RP-HPLC测定血浆中左氧氟沙星浓度。结果单剂量口服200 mg左氧氟沙星受试和比对制剂后的达峰时间Tm ax分别为(1.03±0.67)和(0.93±0.38)h;峰值血药浓度Cm ax分别为(2363.29±552.13)和(2499.25±573.31)ng/m l;T1/2β分别为(5.57±0.92)和(6.04±0.55)h;MRT分别为(7.77±1.14)和(8.02±0.68)h;药时曲线下面积AUC(0→t)分别为(13790.96±2171.28)和(13894.83±1873.47)ng.h.m l-1。受试制剂的相对生物利用度F为(99.40±9.70)%。两种片剂Cm ax及AUC(0→t)通过双单侧t检验,药物动力学参数均无显著性差异(P>0.05),且均落在等效范围。结论两种制剂生物等效。     

茴三硫片剂人体生物等效性研究

目的:比较两种茴三硫制剂药动学及人体生物等效性。方法:19例健康男性受试者随机交叉口服茴三硫受试片剂和参比片剂75 mg,采用液相质谱-串联质谱(LC-MS/MS)的方法测定血清中茴三硫代谢物对羟基苯基三硫酮的浓度,经DAS2.0软件统计,进行相对生物利用度和生物等效性分析。结果:健康受试者口服茴三硫受试制剂和参比制剂75 mg后,血清中对羟基苯基三硫酮的Cm ax分别为(296±92.7)和(295±103)μg.L-1;Tm ax分别为(2.24±1.44)和(1.79±0.73)h;AUC0~t分别为(2 562±671)和(2 189±669)μg.L-1.h;AUC0~∞分别为(2 677±713)和(2 356±688)μg.L-1.h;t1/2分别为(12.5±4.43)和(11.8±4.40)h。以AUC0~t计算相对生物利用度,平均为(118.8±16.4)%。结论:采用双单侧t检验及置信区间法进行的生物等效性检验结果表明,两种茴三硫片制剂具有生物等效性。     

HPLC-MS法测定人血浆中的阿奇霉素及其人体药动学研究

目的:建立高效液相-质谱法(HPLC-MS)测定人血浆中阿奇霉素的浓度,用于研究阿奇霉素片的人体药动学。方法:采用HPLC-MS法测定18名健康志愿者单剂量口服阿奇霉素片受试和参比制剂各500 mg后的血药浓度,计算药动学参数,以判定生物等效性。结果:阿奇霉素的线性范围为10~1 000μg.L-1,日内、日间精密度均<10%。受试制剂和参比制剂的Cm ax分别为(594.9±195.7)和(586.3±186.5)μg.L-1;Tm ax为(2.02±0.91)和(1.70±0.80)h;T1/2为(29.20±8.38)和(27.28±7.62)h;AUC0~t为(4 736±1 317)和(4 567±1 129)μg.h.L-1。受试制剂的相对生物利用度为(104.0±14.6)%。结论:本研究建立的方法快速灵敏,适用于阿奇霉素人体药动学研究,统计学结果表明2种制剂具有生物等效性。     

左氧氟沙星分散片在健康志愿者体内的生物等效性评价

目的评价乳酸左氧氟沙星分散片在健康人体内的生物等效性.方法健康男性志愿者共20例随机分为两组,分别单次交叉口服乳酸左氧氟沙星分散片的试验制剂及参比制剂200 mg.采用HPLC法测定血药浓度,计算药动学参数及相对生物利用度,并计算两种制剂的生物等效性.结果受试者口服左氧氟沙星试验制剂或参比制剂的药动学参数t1/2β分别为(6.89±2.11)和(6.62±1.55)h;Tmax分别为(0.74±0.30)和(1.11±0.59)h;Cmax分别为(2.83 ±0.75)和(2.46±0.73)mg·L-1;AUC0～24h分别为(15.64±3.54)和(15.19±3.43)mg·L～·h;AUC0～∞分别为(17.15±4.34)和(16.75±4.29)mg·L-1·h.试验制剂对于参比制剂的平均相对生物利用度以AUC0～24h舢计算为(104.20 ±16.01)％,以AUC0～∞计算为(104.25 ±18.83)％.两种制剂的AUC0～24hAUC0～∞及max经对数转换后双单侧t检验,结果两种制剂生物等效.受试者均未发生药物不良反应.结论左氧氟沙星两种制剂生物等效.     

氟康唑两种分散片与胶囊在健康人体的相对生物利用度

目的研究氟康唑两种分散片与胶囊的人体生物利用度和药动学特征。方法18名健康男性志愿者随机分成六组,每组3人,采用三周期随机交叉试验设计,分别单剂量口服氟康唑分散片(T1:50mg/片,T2:150mg/片)或氟康唑胶囊(50mg/粒,R)后不同时间点采血,血样中氟康唑浓度以HPLC-UV测定。结果T1,T2与R的主要药动学参数分别为:tm ax(1.4±0.5),(1.4±0.4)和(1.6±0.3)h;Cm ax(7.949±1.653),(8.294±2.160)和(7.882±1.816)mg.L-1;AUC0→96(242.5±69.8),(262.8±88.0)和(242.1±67.2)mg.h.L-1;t1/2(28.1±7.9),(28.8±11.1)和(28.5±7.9)h。以胶囊剂为参比制剂,2种分散片的相对生物利用度分别为(101.2±16.4)%(T1)和(108.0±14.2)%(T2)。药动学参数经多因数方差分析显示周期间与制剂间差异均无显著意义(P>0.05),双单侧t检验表明接受T1,T2与R生物等效的假设,经计算90%置信区间均在规定值内。结论:分散片与胶囊剂体内规律无明显差异,T1,T2与R为生物等效制剂。     

盐酸左氧氟沙星胶囊的人体生物等效性研究

目的研究2种盐酸左氧氟沙星胶囊的人体生物等效性。方法18名健康男性受试者随机交叉单剂量口服盐酸左氧氟沙星胶囊受试制剂或参比试剂,采用反相高效液相色谱法测定血药浓度,计算其药动学参数和相对生物利用度,评价其生物等效性。结果受试制剂和参比制剂的tm ax分别为(1.0±0.1)h和(1.0±0.1)h,Cm ax分别为(3.1±0.7)μg.mL-1和(3.3±0.9)μg.mL-1,t1/2分别为(6.8±1.4)h和(6.9±1.7)h,AUC0-t分别为(20.7±6.1)μg.h.mL-1和(20.1±5.4)μg.h.mL-1,AUC0-∞分别为(22.1±6.1)μg.h.mL-1和(21.6±5.5)μg.h.mL-1,受试制剂的相对生物利用度为(103.0±8.2)%。结论盐酸左氧氟沙星2种制剂具有生物等效性。     

烟酸缓释胶囊在Beagle犬体内的药动学及生物等效性

目的 6只Beagle犬双周期双交叉单剂量口服烟酸受试制剂和参比制剂。方法用LC-MS/MS法检测血浆中药物浓度,计算两种制剂的药动学参数并进行等效性评价。结果受试胶囊和参比片剂的主要药动学参数为:Tmax(3.00±0.80)和(3.08±0.90)h,Cmax(5.13±0.52)和(4.85±0.64)mg·L-1,AUC0-t(43.85±7.41)和(51.30±6.50)mg·L-1.h-1,AUC0-∞(47.25±5.35)和(49.19±4.21)mg·L-1.h-1。受试制剂的相对生物利用度F为(96.0±6.7)%。结论表明两种制剂生物等效。     

复方氯唑沙宗胶囊人体药物动力学研究

目的建立同时测定复方氯唑沙宗胶囊中两种成分血药浓度的方法,并进行其在健康人体药物动力学研究。方法20名男性健康志愿者单剂量口服复方氯唑沙宗胶囊2粒,高效液相色谱法同时测定复方氯唑沙宗中氯唑沙宗和对乙酰氨基酚的血药浓度。结果和结论复方氯唑沙宗胶囊中的氯唑沙宗和对乙酰氨基酚主要药物动力学参数分别为:t1/21.629±2.218 h和3.82±1.222 h;Tm ax1.333±0.636 h和0.958±0.724 h;Cm ax4.995±2.11 mg.L-1和1.85±0.409 mg.L-1;AUC0~15 h12.16±4.192 mg.h-1.L-1和8.661±2.844 mg.h-1.L-1;AUC0~∞12.34±4.328和9.927±3.644 mg.h-1.L-1。     

莫雷西嗪在人体内的药动学及其生物等效性研究

目的观察18名健康志愿者单剂量po两种莫雷西嗪片后血药浓度的经时过程,并评价其生物等效性。方法采用HPLC法测定受试者血浆中莫雷西嗪的浓度,计算其药物动学参数和相对生物利用度,评价两制剂的生物等效性。结果采用3p97计算两制剂的主要药动学参数,Cm ax分别为1.499±0.173、1.537±0.174 mg.L-1;Tm ax分别为1.417±0.192、1.333±0.243 h;t1/2分别为2.671±0.677、2.653±0.625 h;用梯形法计算,AUC0→t分别为6.081±0.995、6.130±0.918 mg.h.L-1;AUC0→∞分别为6.991±1.947、7.210±1.604 mg.h.L-1。结论两种莫雷西嗪片剂具有生物等效性。     

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.

---

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.