伏立康唑对映体的手性高效液相色谱分离

目的:采用氨基酸衍生物基团键合硅胶手性分离柱Chiralcel OD-RH(150×4．6 mm,5μm)对伏立康唑手性对映体进行分离。方法:以Chiralcel OD-RH(150×4．6 mm,5μm)手性色谱柱为分析色谱柱,流动相为0．2 mol·L-1磷酸二氢钾溶液-乙腈(68:32),柱温25℃,检测波长为256 nm,流速为0．5 ml·min-1。结果:伏立康唑手性对映体在Chiralcel OD-RH柱上能够达到基线分离。结论:Chiralcel OD-RH对伏立康唑手性对映体有良好的拆分能力,可用于伏立康唑原料中右旋异构体的限度控制。     

手性固定相高效液相色谱法拆分雌马酚对映体

目的:建立手性固定相拆分雌马酚的高效液相色谱方法。方法:采用Daicel公司Chiralcel OJ-H(250 mm×4.6 mm,5.0μm,)手性色谱柱拆分雌马酚对映体,考察流动相中异丙醇比例、柱温、流速对分离效果的影响。确定了较佳的拆分条件:以正己烷-异丙醇(75∶25)为流动相,流速为1.0 mL.min-1,检测波长280 nm,柱温30℃。结果:Chiralcel OJ-H色谱柱能使雌马酚对映体达到基线分离,分离度达3.26,(S)-对映体先于(R)-对映体出峰。结论:本法操作简便,重复性好,可用于雌马酚对映体的分离和质量控制。     

手性固定相高效液相色谱法拆分佐米曲普坦对映体

目的 以纤维素氨基甲酸脂作为手性固定相,研究佐米曲普坦的高效液相色谱手性拆分方法.方法 对流动相的比例、柱温以及流速等进行了优化.采用Chiralcel OD柱(250mm×4.6mm,5μm),以正已烷-异丙醇-三乙胺(85∶15:0.2,v/v)为流动相,流速为0.7ml·min-1,检测波长280nm,柱温30℃.结果 用Chiralcel OD手性柱在拟定的色谱条件下可实现佐米曲普坦对映体的完全分离,分离度为1.6.R-(-)型先于S-( )型出峰.结论 流动相中异丙醇的含量由低向高变化时,有降低分离度的趋势;在流动相中增大三乙胺的比例对拆分较为有利;温度较高时,有利于对映体的分离;较低的流速可改善分离度,但会延长对映体的出峰时间.     

甲磺酸罗哌卡因对映体在纤维素衍生物固定相上的拆分

目的:研究甲磺酸罗哌卡因对映体在纤维素衍生物固定相上的保留行为,优化色谱条件。方法:色谱柱为纤维素三-3,5-二甲基苯基氨基甲酸酯(Chiralcel OD-RH,150mm×4．6mm,5μm),流动相为10mmol·L~(-1)磷酸盐缓冲液(10%氢氧化钾溶液调pH到5．0)-乙腈(64:36),流速0．5mL·min~(-1),检测波长210nm,并考察了影响分离的因素。结果:采用Chiralcel OD-RH色谱柱分离甲磺酸罗哌卡因对映体,分离度(Rs)为3．8。结论:所建立的方法可方便地分离和测定甲磺酸罗哌卡因异构体。     

3-环己烯-1-甲酸的手性拆分研究

目的 研究外消旋3-环己烯-1-甲酸的手性拆分,获得单一构型异构体.方法 通过化学拆分法中的生成非对映异构体拆分法来拆分外消旋3-环己烯-1-甲酸,以手性苯乙胺为手性拆分剂,外消旋3-环己烯-1-甲酸在丙酮中形成非对映体异构体并利用它们的溶解度差别来进行拆分.结果 拆分为(R)-(+)-3-环己烯-1-甲酸(收率28.3％)和(S)-(-)-3-环己烯-1-甲酸(收率28.7％),光学纯度均大于99％.结论 获得外消旋3-环己烯-1-甲酸的单一构型异构体.     

萘普生对映体的手性分离和纯度检查

目的:建立萘普生手性分离和光学纯度检查的高效液相色谱方法。方法:采用Chiralpak AD-H(4.6 mm×250 mm,5μm,Daicel公司)手性色谱柱在正相条件下拆分萘普生对映体,考察了固定相种类、流动相组成、柱温及流速等对萘普生对映体分离的影响,流动相为正己烷-异丙醇(30∶70,v/v),检测波长272 nm,流速0.5 mL.min-1,柱温20℃。结果:在此条件下,萘普生及其(R)-(-)-构型体达到基线分离,分离度为3.3。结论:该法简单快速,重现性好,能够用于萘普生对映体的分离和纯度考察。     

手性Chiralcel OD-RH柱拆分3种质子泵抑制剂对映体

目的建立了以纤维素-三(3,5-二甲基苯基氨基甲酸酯)为手性固定相拆分兰索拉唑、雷贝拉唑和泮托拉唑对映体的高效液相色谱法(HPLC)。方法考察了流动相中有机改性剂的种类和比例、pH、流速和柱温等对对映体分离的影响。结果拆分兰索拉唑、雷贝拉唑的流动相为水-甲醇(15:85);拆分泮托拉唑的流动相为磷酸盐缓冲液(pH6.0,20mmol.L-1)-乙腈(70:30)。结论兰索拉唑、雷贝拉唑和泮托拉唑对映体均可以在Chiralcel OD-RH手性柱上实现完全分离。     

高效液相色谱法测定左旋奥硝唑原料药中右旋异构体

目的:采用高效液相色谱法拆分奥硝唑对映体,并对左旋奥硝唑原料药进行其右旋异构体的检查。方法:使用Daicel Chiralcel OB-H手性固定相色谱柱,流动相为正己烷-异丙醇-甲醇(95∶1∶4),进样体积5μL,柱温30℃;流速0.8mL·min~(-1),检测波长311nm,并考察了流动相的组成、流速等色谱条件对分离的影响。结果:在上述色谱条件下,奥硝唑对映体的分离度大于1.86,原料药中未检出右旋体杂质。结论:本方法可以实现奥硝唑的手性分离,并能应用于左旋奥硝唑原料药中的右旋体杂质的控制。     

柱前衍生化RP-HPLC荧光色谱法分离肌肽的光学异构体

目的 采用柱前衍生化反相高效液相荧光色谱法拆分肌肽的对映体.方法 采用邻苯二甲醛和N-乙酰-L-半胱氨酸为柱前手性衍生化试剂,反相液相色谱法分离肌肽的光学异构体.考察衍生化反应条件对肌肽衍生化反应、不同色谱条件下对肌肽光学异构体分离的影响.通过光学异构体分离过程中的热力学参数的计算,探讨光学异构体分离过程的驱动力.结果 邻苯二甲醛和N-乙酰-L-半胱氨酸的摩尔比为1∶2时,以无水乙醇与硼酸缓冲液(pH9.8)为溶剂溶解,作为衍生化试剂,于室温下避光反应5 min,肌肽转化成异吲哚产物;在柱温35℃时,肌肽光学异构体的衍生化产物分离因子(α)和分离度(R)分别为1.533、3.947.其光学异构体-衍生产物的拆分过程主要是一个焓驱动的过程.结论 所用方法简单快速、灵敏度高、重复性好,适用于肌肽的手性拆分.     

手性异构体的色谱分离

在大多情况下,对映体(Enantiomers)的差别为:(1)生物活性——这是由于与受体(实质上是蛋白质,也具有手性中心)相互作用的强度不同;(2)转运机制;(3)可能的代谢途径。据统计,常用的200种处方用药中,有114种药物具有至少一个不对称中心,因此,开始试验一个药物时,就有必要将对映体拆分,以确定其效价、毒性和/或不良反应。对映体的拆分有两种基本方法:(1)采用能够区分对映体分子的色谱系统;(2)利用对映体分子中的反应基团与某一光学纯试剂反应产生非对映光学异构体混合物。由于非对映体(Diastereoisomers)之间有较大的物理性质差异,使有可能用非手性色谱系统将其分离,其程     

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.

     

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.     

2-(Acetoxyphenyl)-(Z)-styryl sulfides as cyclooxygenase inhibitors

2-(Acetoxyphenyl)-(Z)-styryl sulfides are described as selective cyclooxygenase-2 (COX-2) inhibitors, useful for treating inflammation and COX-2-mediated disorders including neoplasia. 2-(Acetoxyphenyl)-(Z)-styryl sulfide is claimed to be the most potent COX inhibitor in the series with a COX-2 selectivity ratio of 33. This compound is also claimed to be superior to celecoxib (Celebrex^®, Pfizer) in inhibiting cell growth of colorectal carcinoma cells. In this evaluation, the COX inhibitory activity of this compound is compared to that previously disclosed for diarylheterocycles and 2-(acetoxyphenyl)alkyl sulfides. The validity of the DLD-1 cell line in the growth inhibition studies is questioned based on recent literature reports indicating the lack of COX-2 expression in this cell line.     

Sleep-disordered breathing with chronic opioid use

Chronic opioid use for pain relief or as substitution therapy for illicit drug abuse is prevalent in our societies. In the US, retail distribution of methadone and oxycodone has increased by 824 and 660%, respectively, between 1997 and 2003. μ-Opioids depress respiration and deaths related to illicit and non illicit chronic opioid use are not uncommon. Since 2001 there has been an emerging literature that suggests that chronic opioid use is related to central sleep apnoea of both periodic and non-periodic breathing types, and occurs in ～ 30% of these subjects. The clinical significance of these sleep-related abnormalities are unknown. This review addresses the present knowledge of control of ventilation mechanisms during wakefulness and sleep, the effects of opioids on ventilatory control mechanisms, the sleep-disordered breathing found with chronic opioid use and a discussion regarding the future research directions in this area.     

Drug targets for cognitive enhancement in neuropsychiatric disorders

The investigation of novel drug targets for treating cognitive impairments associated with neurological and psychiatric disorders remains a primary focus of study in central nervous system (CNS) research. Many promising new therapies are progressing through preclinical and clinical development, and offer the potential of improved treatment options for neurodegenerative diseases such as Alzheimer's disease (AD) as well as other disorders that have not been particularly well treated to date like the cognitive impairments associated with schizophrenia (CIAS). Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABA_A α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population.