反相高效液相色谱法测定左羟丙哌嗪含片中左羟丙哌嗪的含量

目的建立反相高效液相色谱法测定左羟丙哌嗪含片中左羟丙哌嗪含量的方法。方法色谱柱为Diamonsil—C18（250mm×4．6mm,5μm）,流动相为甲醇-0.4％磷酸溶液（用三乙胺调pH至3．0）（25：75）,检测波长为237nm,流速为1．0mL·min^-1,柱温为室温,进样量为10μL。结果左羟丙哌嗪检测浓度的线性范围为10-80μg·mL^-1,r=0．9999,平均回收率为99．7％,RSD=0．32％。结论本法简便、快速,结果准确、可靠,可用于该制剂的质量控制。     

高效液相色谱法测定左羟丙哌嗪中右旋异构体的含量

目的 建立高效液相色谱法测定左羟丙哌嗪中右旋异构体的含量.方法 色谱柱为CHIRALCEL-OD-H手性柱,流动相为正己烷-异丙醇-二乙胺(90∶10∶0.1),检测波长为250 nm,流速为1.0 mL·min-1,柱温为30℃,进样量为20 μL.结果 右羟丙哌嗪检测浓度的线性范围为2.0～40.0 μg·mL-1,r=0.999 7,平均回收率为99.1％,RSD为0.72％.结论 本法操作简便、灵敏、准确、专属性强,可用于左羟丙哌嗪质量控制.     

左羟丙哌嗪缓释片体外释放度测定

目的:建立左羟丙哌嗪缓释片体外释放度测定方法,并对其释放度影响因素及释药机制进行考察。方法:采用单因素考察方法,研究处方、工艺及释放方法学因素对左羟丙哌嗪缓释片释放度的影响。结果:左羟丙哌嗪在237nm波长有最大吸收,辅料对药物测定无干扰。左羟丙哌嗪在2.56-20.48 mg·L-1浓度范围内线性关系良好。羟丙甲基纤维素的种类、用量、黏度、片剂的比表面积以及不同释放条件对药物的释放特性有一定影响。结论:左羟丙哌嗪缓释片的释放表现为药物扩散和凝胶溶蚀的协同作用,许多因素可以影响药物释放行为。     

HPLC法测定市售左羟丙哌嗪制剂中左羟丙哌嗪含量

目的建立HPLC法测定市售左羟丙哌嗪制剂中左羟丙哌嗪含量。方法色谱柱为Dia-monsil(钻石)C18(150mm4.6mm,5μm),流动相为甲醇-0.4%磷酸溶液(三乙胺调pH=3.0)(20:80),检测波长237nm。结果在22.3～223μg/ml线性范围内呈良好线性,r=0.9998,回收率为100.0%,RSD=0.84%。结论本方法简便、快速,可用于市售左羟丙哌嗪制剂的含量测定。     

左羟丙哌嗪口腔崩解片的制备与质量控制

目的 制备左羟丙哌嗪口腔崩解片并建立其质量控制方法 . 方法 采用直接压片法制备,高效液相色谱（HPLC）法测定其含量. 结果 制备的左羟丙哌嗪口腔崩解片外观光洁,硬度为3.5 kg,崩解时间<30 s; 检测浓度线性范围为8.48～42.4 μg.mL^-1（r＝0.999 9）,平均回收率为99.85%,RSD为0.71%（n＝9）. 结论 该制备方法 简单,含量测定方法 简便、准确,可用于左羟丙哌嗪口崩片的制备及含量测定.     

LC/MS/MS法测定血浆中左羟丙哌嗪浓度及其药代动力学

目的建立测定血浆中左羟丙哌嗪的液相色谱-串联质谱法，考察左羟丙哌嗪在中国健康志愿者体内的药代动力学行为。方法血浆样品经液-液提取后，进行色谱分离，在三重四极杆串联质谱仪上，以多重反应离子监测(MRM)方式进行定量分析，用于监测的离子为m/z 237 → m/z 120（左羟丙哌嗪）和m/z 288 → m/z 58(佐米曲普坦，内标)。结果左羟丙哌嗪的最低定量浓度为0.25 μg·L^-1，线性范围为0.25-500.0 μg·L^-1，精密度与准确度符合生物样品分析要求。结论该法操作简便、快速、灵敏度高。可检测出健康志愿者po左羟丙哌嗪60 mg,其24 h后的血药浓度，适于临床药代动力学研究。     

左羟丙哌嗪片剂人体生物等效性研究

目的:建立人血清左羟丙哌嗪浓度的HPLC荧光检测方法,并评价片剂与口服液体制剂的生物等效性。方法:18例健康男性志愿者随机交叉自身对照,分别口服单剂量左羟丙哌嗪片剂或口服液体制剂60 mg,测定血清药物浓度,并计算其药动学参数。以1-苯基哌嗪作内标物,色谱柱为HiQSil-C18(250 mm×4．6 mm,5μm);流动相为甲醇-0．1 mol·L-1磷酸盐缓冲液(pH 2．5)(25:75);荧光激发波长240 nm,发射波长350 nm。结果:血清药物测定线性范围2．54～1016．00μg·L-1,最低定量浓度2．54μg·L-1;方法精密度的日内、日间RSD 1．5％-7．8％;萃取回收率>85％,方法回收率>98％。片剂和口服液剂的AUC,Cmax和t1/2β无显著性差异(P<0．05),片剂的相对生物利用度为(99．65±22．61)％,AUC和Cmax经可信区间法检验生物等效。结论:本法适合人血清中左羟丙哌嗪药物浓度的测定,2种制剂生物等效。     

左羟丙哌嗪β-环糊精包合物的处方工艺优化及鉴定

目的:优化左羟丙哌嗪β-环糊精包合物的处方工艺,并对包合物进行鉴定。方法:采用饱和水溶液法制备包合物,以左羟丙哌嗪与β-环糊精摩尔比、包合温度、包合时间为考察因素,以收率和包合率为指标,采用正交设计优化处方。比较溶出5 min时所制包合物、左羟丙哌嗪和β-环糊精的物理混合物、左羟丙哌嗪原料药的溶出度,采用差示热分析法(DTA)和X-射线衍射法(XRD)对所制包合物进行鉴定,并比较包合物和物理混合物的口感。结果:最优处方工艺为左羟丙哌嗪与β-环糊精摩尔比为1∶1,包合温度为65℃,包合时间为0.5 h;所得包合物的平均收率为95.3%,平均包合率为82.3%;溶出5 min时包合物、物理混合物、左羟丙哌嗪原料药的溶出度分别为98.37%、61.62%、92.59%;DTA和XRD图谱确证已形成了包合物;包合物较物理混合物苦味明显降低。结论:成功制得左羟丙哌嗪β-环糊精包合物,其可较好掩盖药物的苦味。     

反相高效液相色谱法和薄层色谱法检查左羟丙哌嗪的有关物质

目的建立2种检测方法对左羟丙哌嗪的有关物质进行检测.方法反相高效液相色谱法色谱柱为Hypersil-ODS2(200mm×4.6mm,10μm),流动相为甲醇-0.05mol@L-1磷酸二氢钾溶液(3070),用磷酸调pH3.0;检测波长为242nm.薄层色谱法以硅胶G为吸附剂,乙酸乙酯-乙醇-氯仿-浓氨水(15880.5)为展开剂,碘蒸气显色.结果反相HPLC法左羟丙哌嗪与苯基哌嗪的tR值分别为5.7与8.5min;最低检出限量为0.1μg@mL-1.TLC法左羟丙哌嗪与苯基哌嗪的Rf值分别为0.62与0.46;最低检出限量为15μg@mL-1.结论2种方法均可用于左羟丙哌嗪有关物质的检查.反相HPLC法灵敏度高,检出限量低;TLC法方便、快速.     

(R)-3-氯-1,2-丙二醇及镇咳药左羟丙哌嗪的合成

目的制备高光学纯度的（R）-3-氯-1，2-丙二醇，并以此为原料改进镇咳药左羟丙哌嗪的合成工艺。方法以自制手性Salen—CoⅢ催化剂水解外消旋环氧氯丙烷得高光学纯度的中间体（R）-3-氯-1，2-丙二醇，该中间体再与N-苯基哌嗪反应合成镇咳药左羟丙哌嗪。结果与结论以手性Salen-CoⅢ催化剂水解环氧氯丙烷得到的（R）-3-氯-1，2-丙二醇光学纯度为99％；以此为原料合成的左旋羟丙哌嗪光学纯度为99％以上，收率为56．3％。目标产物经核磁共振氢谱、质谱确证。     

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.