马来酸依那普利片的药动学及相对生物利用度

目的研究马来酸依那普利片在健康人体内的药动学及相对生物利用度。方法用双周期交叉实验设计,采用液相色谱-质谱-质谱联用法测定18名健康男性受试者口服马来酸依那普利片(受试制剂)和悦宁定(参比制剂)后不同时刻血浆中依那普利和其活性代谢物依那普利拉的浓度,绘制血药浓度-时间曲线并计算主要药动学参数。结果18名受试者口服含马来酸依那普利20 mg的受试制剂和参比制剂后血浆中依那普利的tm ax分别为(0.83±0.44)和(0.93±0.37)h,ρm ax分别为(70.54±26.84)和(67.01±23.75)μg.L-1,t1/2分别为(2.13±0.52)和(2.14±0.42)h,AUC0t-分别为(122.82±45.31)和(121.45±43.06)μg.h.L-1,AUC0-∞分别为(123.77±45.36)和(122.55±43.32)μg.h.L-1;依那普利拉的tm ax分别为(3.72±1.18)和(3.61±0.92)h,ρm ax分别为(33.14±9.72)和(34.15±10.98)μg.L-1,t1/2分别为(8.88±1.35)和(8.99±1.09)h,AUC0-t分别为(301.64±82.71)和(316.47±99.09)μg.h.L-1,AUC0-∞分别为(307.32±83.54)和(322.70±100.67)μg.h.L-1,以AUC0-t计算,马来酸依那普利的平均相对生物利用度为(103.0±20.1)%,依那普利拉的平均相对生物利用度为(98.4±22.4)%。结论根据双单侧检验表明2种制剂具有生物等效性。     

氢溴酸加兰他敏口腔崩解片的人体药代动力学和生物等效性研究

目的建立人血浆中加兰他敏的高效液相色谱-质谱测定方法,用于研究氢溴酸加兰他敏口腔崩解片的人体药代动力学和生物等效性。方法20名男性健康志愿者随机交叉给药,分别单剂量口服国产的氢溴酸加兰他敏口腔崩解片(受试制剂)及氢溴酸加兰他敏口腔分散片(参比制剂),采用高效液相色谱-质谱法,电喷雾电离源选择性正离子检测受试者血浆中加兰他敏的浓度。结果计算两者主要药动学参数:Cmax分别为(51.883±14.185)和(53.500±13.478)μg.L-1,tmax分别为(1.092±1.014)和(1.150±0.528)h,AUC(0→30)分别为(501.679±136.094)和(464.010±100.890)μg.h.L-1。结论受试制剂对参比制剂的相对生物利用度为106.2%,两制剂在人体内具有生物等效性。     

HPLC/MS法测定人血浆中氯雷他定的浓度及人体生物等效性

目的建立测定人血浆中氯雷他定的LC/MS方法,并应用于药物制剂生物等效性研究。方法18名健康受试者单剂量口服氯雷他定20 mg后,血浆样品经液液萃取,通过液相色谱质谱联用法测定其质量浓度,并计算药动学参数。结果氯雷他定测定方法的线性为0.5~20.0μg.L-1,定量下限为0.5μg.L-1;参比制剂的主要药动学参数tmax为(0.94±0.21)h,ρmax为(16.41±2.83)μg.L-1,t1/2为(9.56±4.21)h,用梯形法计算,AUC0~t为(38.70±6.93)μg.h.L-1;受试制剂的主要药动学参数tmax为(0.94±0.21)h,ρmax为(16.45±2.42)μg.L-1,t1/2为(8.89±4.06)h,用梯形法计算,AUC0~t为(43.67±9.55)μg.h.L-1,以AUC0-t计算,受试制剂相对生物利用度为(113.4±19.0)%。结论该法适用于氯雷他定制剂的生物等效性评价。     

2种盐酸舍曲林制剂人体生物等效性研究

目的研究2种盐酸舍曲林制剂的人体生物等效性。方法采用双周期随机交叉设计试验,22名健康男性志愿者单剂量口服盐酸舍曲林口服液(受试制剂)或盐酸舍曲林片(参比制剂)50mg,以高效液相色谱-质谱联用法测定血药浓度。结果受试制剂与参比制剂的t1/2分别为(27.3±5.2)、(26.3±3.0)h,Cmax分别为(9.56±2.49)、(9.43±2.91)μg·L-1,tmax分别为(5.18±1.47)、(6.00±1.07)h,AUC0～108分别为(329±112)、(297±111)μg.h·L-1,AUC0～∞分别为(354±127)、(316±122)μg.h.L-1。经方差分析和双单侧t检验,主要药动学参数无差异,但tmax存在差异;受试制剂的相对生物利用度为(115.5±26.7)%。结论2种盐酸舍曲林制剂具有生物等效性。     

氢溴酸西酞普兰咀嚼片人体生物利用度和生物等效性研究

目的比较国产氢溴酸西酞普兰咀嚼片与进口氢溴酸西酞普兰片的人体药动学参数及生物利用度,评价二者的生物等效性。方法 24名健康男性受试者随机交叉单剂量服用20 mg受试制剂和参比制剂,受试制剂空腹咀嚼30～60 s后直接吞咽,参比制剂空腹用200 mL温开水送服。血浆样品采用高效液相色谱-串联质谱法检测。结果受试制剂及参比制剂的主要药代动力学参数:Cmax分别为(16.56±4.12)、(18.30±4.72)μg/L;Tmax分别为(4.42±2.41)、(5.00±2.87)h;t1/2分别为(47.44±7.74)、(48.43±14.56)h;AUC0-tn分别为(819.74±261.18)、(885.38±216.22)μg.h/L;AUC0-∞分别为(939.00±336.16)、(1 016.04±315.32)μg.h/L;受试制剂的相对生物利用度F0-tn、F0-∞分别为91.92%±15.10%、92.09%±15.52%。结论受试制剂和参比制剂具有生物等效性。     

卵磷脂络合碘片的人体生物等效性考察

目的评价卵磷脂络合碘片的药物动力学特征。方法用催化光度法测定血药质量浓度;采用双周期交叉试验设计,18名受试者单剂量口服4.5 mg受试制剂与参比制剂,用Das 2.0软件计算两者的药物动力学参数。结果受试制剂与参比制剂中卵磷脂络合碘的主要药物动力学参数tm ax、mρax、t1/2、AUC0-48、AUC0-∞分别为(1.3±0.4)、(1.2±0.3)h,(34.5±9.5)、(34.6±12.7)μg.L-1,(5.8±3.2)、(5.7±3.8)h,(176.7±34.9)、(171.9±49.4)μg.h.L-1,(188.2±37.6)、(194.4±60.2)μg.h.L-1;主要药物动力学参数无显著性差异;受试制剂的相对生物利用度(F)为(107.4±23.3)%。结论受试制剂与参比制剂具有生物等效性。     

替米沙坦片的人体生物等效性研究

目的:研究两种替米沙坦片的人体生物等效性。方法:20名健康男性受试者按照两制剂两周期的随机交叉试验设计,分别单剂量口服受试制剂和参比制剂80 mg,用HPLC-荧光法测定血浆中替米沙坦的浓度,用DAS1.0软件对所得药动学参数进行统计分析。结果:受试制剂和参比制剂在受试者体内的药动学参数如下:cm ax分别为(0.92±0.62)和(1.04±0.61)μg/m l;tm ax分别为(0.97±0.61)和(1.03±0.65)h;AUC0-96 h分别为(4.32±2.86)和(4.41±2.51)μg.h.m l-1;AUC0-∞分别为(4.60±3.08)和(4.59±2.64)μg.h.m l-1;t1/2分别为(24.38±10.50)和(21.31±6.81)h。tm ax、cm ax、AUC0-96 h、AUC0-∞在两制剂间均无显著性差异,双单侧t检验结果表明受试制剂cm ax的90%置信区间落在参比制剂70%~143%之间,受试制剂AUC的90%置信区间落在参比制剂80%~125%之间;受试制剂的相对生物利用度为(109.2±31.9)%。结论:两制剂具有生物等效性。     

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。     

氢溴酸加兰他敏口服液及片剂的人体生物等效性研究

目的:采用HPLC-RF检测法测定氢溴酸加兰他敏的血药浓度,研究其在人体内的药动学和生物等效性。方法:24例健康男性志愿者单剂量随机交叉口服5 mg加兰他敏口服液(受试制剂)和片剂(参比制剂)。血浆样品经碱化后用乙醚提取,采用反相HPLC-RF法测定血浆中加兰他敏浓度,检测波长:激发波长290 nm,发射波长320 nm。采用3P97药动学软件计算药动学参数和相对生物利用度,并对参数进行方差分析和双单侧t检验。结果:加兰他敏口服液和片剂的主要药动学参数:Cmax分别为(31．53±5．59)和(33．44±5．72)μg·L-1;Tmax分别为(1．66±0．79)和(1．51±0．72)h;t1/2分别为(7．06±2．16)和(6．64±2．30)h;AUC0～∞分别为(340．6±77．2)和(325．5±77．7)μg·h·L-1。氢溴酸加兰他敏口服液相对生物利用度为105．6％。结论:加兰他敏口服液和片剂生物等效。     

人血浆中氟康唑的HPLC-MS测定及其相对生物利用度

目的建立人体血浆中氟康唑浓度的HPLC-M S测定方法,评价氟康唑胶囊在健康人体内的药动学及生物等效性。方法以甲硝唑为内标,血浆样品用甲醇直接沉淀去除蛋白,采用HPLC-M S法,测定20名健康受试者随机双交叉口服150m g氟康唑受试胶囊或参比胶囊后不同时间点的血药浓度,计算其主要药动学参数及相对生物利用度,评价两种制剂的生物等效性。结果氟康唑受试胶囊和参比胶囊的主要药动学参数分别为:AUC0-120(121.59±12.79)、(115.01±13.44)μg.h.mL-1;Cm ax(3.09±0.29)、(3.18±0.33)μg.h.mL-1;Tm ax(2.6±1.1)、(2.3±1.0)h、t1/2(31.67±4.33)、(30.99±4.95)h。以AUC0-120计算的受试胶囊的相对生物利用度为(106.4±11.8)%。结论该测定方法灵敏、准确、简便、快速;2种制剂具有生物等效性。     

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.

     

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.     

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.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

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.