基于毒理学软件和细菌回复突变试验的大黄素型蒽醌基因突变风险评价

目的 使用毒理学软件和细菌回复突变（Ames）试验评价大黄素型蒽醌类化合物的致突变风险，分析不同取代基及所在位置对大黄素型蒽醌致突变风险的影响。方法 使用Toxtree、Derek Nexus和Sarah Nexus毒性预测软件对大黄素、羟基大黄素、芦荟大黄素、大黄素甲醚、大黄酚、大黄酸、大黄素-8-O-β-D-葡萄糖苷、芦荟大黄素-8-O-β-D-葡萄糖苷、大黄素-1-O-β-D-葡萄糖苷、大黄素甲醚-8-O-β-D-葡萄糖苷的致突变风险进行预测，并使用鼠伤寒沙门氏菌TA97、TA98、TA100、TA102、TA1535和TA1537及大肠杆菌WP2 uvrA开展基于6孔板的Ames试验，评价10种大黄素型蒽醌的致突变性。结果 基于蒽醌母核结构，Toxtree、Derek Nexus和Sarah Nexus毒性预测软件提示所有大黄素型蒽醌均存在致突变风险。在非S9代谢活化状态下，芦荟大黄素导致TA98和WP2 uvrA Ames菌落数增加，大黄酚、大黄酸导致WP2 uvrA Ames菌落数增加。在大鼠肝S9代谢活化状态下，大黄素和大黄酸导致TA98和TA1537 Ames菌落数增加，羟基大黄素导致TA97、TA98、TA1537和WP2 uvrA Ames菌落数增加，芦荟大黄素导致TA98、TA1537和WP2 uvrA Ames菌落数增加，大黄素甲醚导致TA1537 Ames菌落数增加，大黄酚导致TA1537和WP2 uvrA回复菌落突变数增加，大黄素-8-O-β-D-葡萄糖苷可引起TA1537回复突变菌落数增加。结论 大黄素型蒽醌类化合物在大黄素母核的基础引入羟基后其诱变能力显著升高，较大葡萄糖苷基团的引入反而使受试物诱变能力降低。     

染料溶剂红207的体外致突变风险评价

目的 使用基于鼠伤寒沙门氏菌的Ames波动试验和小鼠淋巴瘤细胞（L5178Y）的体外Pig-a基因突变试验评价新型染料溶剂红207的碱基突变风险。方法 不同质量浓度的溶剂红207（0.625~10.000 μg/mL）分别与TA98和TA100混合于96孔培养板,在37℃条件下作用72 h后判断其对突变菌落数的影响。在优化后的体外L5178Y细胞Pig-a基因突变实验中,溶剂红207（2.5~20.0 μg/mL）分别与L5178Y细胞在有或无S9代谢活化条件下作用24 h或4 h,于给药后第8天评价其是否可诱导哺乳动物细胞Pig-a基因的突变频率增加。结果 无和有S9代谢活化条件下,溶剂红207可导致TA98和TA100回复性突变孔数显著增加（P<0.05、0.01、0.001）,且存在浓度效应相关性,代谢活化后增加更为明显。在非S9代谢活化条件下,溶剂红207各浓度组Pig-a基因突变率与阴性对照组比较无显著性差异;在S9代谢活化条件下,溶剂红207质量浓度范围为2.5~20 μg/mL时,可导致Pig-a基因突变率显著增加（P<0.01、0.001）,且存在浓度效应关系。结论 首次使用体外高通量试验方法评价溶剂红207的致突变风险,发现其存在体外致突变性且经I相代谢活化后致突变性进一步增强。     

染料苏丹红的高通量致突变性筛选

目的 初步建立Ames波动试验酶标仪结果判定标准,并对染料苏丹红I~IV的DNA碱基突变风险进行评价。方法 不同浓度的阳性对照2-（2-呋喃基）-3-（5-硝基-2-呋喃基）丙烯酰胺（AF-2）、2-氨基蒽（2-AA）分别作用于鼠伤寒沙门氏菌TA98和TA100后,分别经人工识别或用酶标仪在492和623 nm波长下进行读数,确立基于吸光度的阳性孔判定标准。无或有代谢活化（-S₉）条件下使用鼠伤寒沙门氏菌TA98和TA100开展基于96孔液态培养法的细菌回复性突变试验,苏丹红I~IV终浓度分别为0.625、1.250、2.500、5.000和10.000 μg/mL。结果 非S₉代谢条件下酶标仪读板结果与人工计数结果一致性达98.1%,S₉代谢条件下酶标仪读数与菌落生长情况无法建立良好关联。在非代谢活化条件下,苏丹红I与IV对TA98的致突变性作用相对较弱;苏丹红I~IV对TA100存在明显的致突变性作用,并呈一定的浓度相关性。在S₉代谢活化条件下,苏丹红III对TA98和TA100均未见致突变作用;苏丹红I在最高浓度10 μg/mL时对2者均有明显的致突变作用,苏丹红IV浓度高于2.5 μg/mL、苏丹红II浓度高于5 μg/mL时,对2者致突变作用均显著。结论 首次使用Ames波动试验检出苏丹红I~IV的基因突变风险,吸光度读数可在非S₉代谢条件下准确判断Ames波动试验结果,为染料的高通量遗传毒性筛选奠定基础。     

雷公藤内酯醇的遗传毒性评价

目的 观察雷公藤的主要有效成分之一雷公藤内酯醇的遗传毒性。方法 采用鼠伤寒沙门氏菌回复突变试验(Ames试验)、体外培养CHO细胞染色体畸变试验和小鼠骨髓微核试验检测雷公藤内酯醇的遗传毒性。结果 Ames试验提示在每皿1.6~1000 μg受试剂量下,在加或不加S9代谢活化系统时,受试物对组氨酸缺陷型鼠伤寒沙门氏菌TA97、TA98、TA100、TA102及TA1535所诱发的回复突变菌落数均与溶媒对照的突变菌落数相近。体外培养CHO细胞染色体畸变试验结果显示0.01、0.02和0.04 μg/ml 3个剂量的受试物,对加与不加S9代谢活化系统培养的CHO细胞的染色体畸变率无明显影响。小鼠骨髓微核试验设180、360、720 μg/kg 3个剂量,在720 μg/kg剂量时,雷公藤内酯醇有诱发骨髓嗜多染红细胞微核率增高的效应。结论 在本实验条件下,雷公藤内酯醇对鼠伤寒沙门氏菌无致突变性,对哺乳动物培养细胞染色体无致畸变作用,720 μg/kg剂量下对ICR小鼠有诱发骨髓嗜多染红细胞微核率增高的效应。提示雷公藤内酯醇对人体可能具有潜在的遗传毒性。     

微型细菌回复突变试验方法的建立及验证

目的 建立高通量评价药物遗传毒性的微型细菌回复突变（Ames）试验。方法 采用平皿掺入法进行标准Ames试验,采用6孔板掺入法进行微型Ames试验,两试验均设置阴性对照组和阳性对照组,2组又分别分为代谢活化和非活化2个亚组,各组培养基中分别加入菌液（鼠伤寒沙门菌组氨酸缺陷型菌株：TA97、TA98、TA100、TA102和TA1535）,活化组加大鼠肝微粒体酶（S9）混合液,阳性对照组再加入阳性诱变剂：Dexon（-S9）,应用于TA97、TA98和TA102;NaN₃（-S9）,应用于TA100和TA1535;2-AA（+S9）,应用于TA97、TA98、TA100、TA102和TA1535。凝固后37℃温箱培养约48 h,计数各组回变菌落数。结果 在标准Ames试验中,阴性对照组各个菌株回变菌落数均在本实验室自发回变菌落数正常值范围内。在两试验中,阳性对照组所诱导的回变菌落数均是阴性对照组的2倍以上,标准试验细菌回变菌落数约为微型试验的5倍。结论 在6孔板上进行微型细菌回复突变试验,大大减少了受试物的用量,提高了筛选速度。本实验室建立的微型细菌回复突变试验背景数据,用于遗传毒理的检测是高效可靠的。     

金橙II及金胺O的体外遗传毒性评价

目的 使用基于鼠伤寒沙门氏菌的Ames波动试验和小鼠淋巴瘤细胞（L5178Y）的体外微核试验评价2种染料金橙Ⅱ和金胺O的遗传毒性风险。方法 在-/+S9处理下,不同质量浓度的金橙Ⅱ和金胺O（0.625~10.000 μg·mL^-1）分别与鼠伤寒沙门氏菌组氨酸营养缺陷型菌株TA98和TA100混合后接种于96孔板中,37℃下孵育72 h后判断其对细菌回复突变的影响;在体外微核试验中,在-/+S9处理下,金橙Ⅱ（10~50 μg·mL^-1）和金胺O（0.6~1.2 μg·mL^-1）分别与L5178Y细胞作用4 h或24 h,并在给药后24 h收集细胞进行流式细胞术检测。结果 金橙II自2.50 μg·mL^-1起可引起-S9和+S9处理组的TA98回复性突变孔数显著增加（P<0.05、0.01）,代谢活化后增加幅度更为明显;自5 μg·mL^-1起可引起-S9处理组的TA100回复性突变孔数显著性增加（P<0.01）,作用均呈浓度相关性。10 μg·mL^-1金胺O可引起-S9处理组的TA98回复性突变孔数显著增加（P<0.01）;自0.625 μg·mL^-1起即可引起+S9处理组的TA98回复性突变孔数显著增加（P<0.05、0.01）,且存在浓度相关性;自2.5 μg·mL^-1起可引起+S9处理组的TA100回复性突变孔数显著性增加（P<0.05、0.01）,且存在浓度相关性。在-S9处理组中,30~50 μg·mL^-1金橙Ⅱ可引起L5178Y细胞微核率显著增加（P<0.01）,且存在浓度相关性; 0.9~1.2 μg·mL^-1金胺O可引起L5178Y细胞微核率显著增加（P<0.01）,且存在浓度相关性。在+S9处理组中,10~50 μg·mL^-1金橙Ⅱ可导致L5178Y细胞微核率显著增加（P<0.05、0.01）。30~50 μg·mL^-1金橙Ⅱ可导致S期的L5178Y细胞比例增加;金胺O自0.6 μg·mL^-1起即可导致L5178Y细胞亚二倍体细胞核率增加。结论 金橙Ⅱ和金胺O均存在一定的遗传毒性风险。     

补血益母丸遗传毒性研究

目的 对补血益母丸干膏粉进行遗传毒性试验,为临床安全用药提供依据。方法 采用组氨酸营养缺陷型鼠伤寒沙门氏菌TA97a、TA98、TA100、TA102、TA1535进行细菌回复突变（Ames）试验,采用中国仓鼠肺成纤维（CHL）细胞进行体外染色体畸变试验,采用ICR小鼠进行骨髓细胞微核试验综合评估补血益母丸干膏粉的遗传毒性。其中,Ames试验设50、150、500、1 500、5 000 μg·皿^-1 5个剂量;体外细胞染色体畸变试验设125、250、500 μg·mL^-1 3个剂量;小鼠骨髓细胞微核试验设500、1 000、2 000 mg·kg^-1 3个剂量,每天给药1次,连续给药3 d。结果 在代谢及非代谢活化条件下（＋S9/-S9）,Ames试验结果 显示,补血益母丸干膏粉对各菌株均无明显或可重复的诱变性及抑菌性;体外CHL细胞染色体畸变试验结果显示,补血益母丸干膏粉对CHL细胞染色体结构畸变率未见有意义的升高;小鼠骨髓细胞微核试验结果显示,补血益母丸干膏粉对ICR小鼠骨髓细胞微核率无明显影响。结论 补血益母丸干膏粉未见潜在的遗传毒性。     

人源HepaRG肝细胞毒性与遗传毒性高通量筛选方法的初步建立

目的 利用正常人源肝细胞（HepaRG）和高内涵技术检测肝毒性标志物,并结合微核试验和单细胞凝胶电泳试验建立体外细胞毒性和遗传毒性的快速筛选平台。方法 选取适当的荧光探针Hoechst33342、DCFH-DA、Fluo4-AM、MitoTracker^® Red CMX Ros联合高内涵技术研究不同大黄蒽醌类单体（AQs）对HepaRG细胞活性氧簇（ROS）、胞内Ca²⁺含量及线粒体膜完整性等肝毒性标志物的影响,并开展高内涵法胞质分裂阻断法微核试验和高通量彗星电泳试验,综合评价AQs致肝细胞毒性及染色体、DNA损伤情况。结果 与对照组比较,HepaRG细胞经25.0 μg/mL大黄素、12.5和25.0 μg/mL芦荟大黄素、50和25.0 μg/mL大黄酚处理24 h后,胞内ROS含量显著增多;12.5和25.0 μg/mL芦荟大黄素和50.0 μg/mL大黄酸可引起胞内Ca²⁺含量显著增多;大黄素25.0 μg/mL、芦荟大黄素25.0 μg/mL、大黄酚50.0和25.0 μg/mL、大黄酸50.0和25.0 μg/mL组导致线粒体明显损伤（P<0.05、0.01）。与对照组比较,25.0 μg/mL大黄素诱导微核率、尾DNA含量和彗星尾距（OTM）数值均显著升高（P<0.05、0.01）;50.0 μg/mL大黄酚给药72 h后微核率显著升高（P<0.01）。结论 AQs的研究结果与现有文献报道基本相符。本研究成功建立肝细胞毒性和遗传毒性的联合快速筛选模型,有助于药物研发早期的毒性筛选。     

基于体外Pig-a基因突变试验的大黄素型蒽醌致突变风险评价

目的 对相同母核结构的8种大黄素型蒽醌类化合物开展体外Pig-a基因突变试验，分析不同大黄素型蒽醌结构与致突变性的关联。方法 L1578Y细胞分别与系列浓度的大黄素、芦荟大黄素、大黄素甲醚、大黄酚、大黄酸、羟基大黄素、大黄素-8-O-β-D-葡萄糖苷和芦荟大黄素-8-O-β-D-葡萄糖苷作用4 h（有S9）或24 h（无S9），给药24 h后应用细胞计数板进行计数，计算细胞相对倍增速率（RPD）评价受试物细胞毒性；细胞表达8 d后经APC-anti-CD45和PE-anti-CD90.2标定后，使用流式细胞仪检测突变细胞（CD45^＋CD90^－）发生率。结果 所有受试物在有或无S9代谢活化条件下所设浓度组RPD均大于50%，未见明显细胞毒性作用，可排除试验中假阳性结果。在非S9代谢活化条件下芦荟大黄素25 μg·mL^-1组Pig-a基因突变率与溶媒对照组比较显著升高（P<0.001）； S9代谢活化条件下，与溶剂对照组比较，大黄素50 μg·mL^-1组，羟基大黄素6.25、12.5、25 μg·mL^-1组，大黄酚25、50、100 μg·mL^-1组和大黄酸12.5、25、50 μg·mL^-1组Pig-a基因突变率显著升高（P<0.05、0.01、0.001）。结论 羟基取代基的多寡及所在位点是蒽醌类化合物致突变性强弱的决定性因素，其体内致突变性及致癌性作用仍需进行大量体内研究证实。     

鼠尾草酸的遗传毒性研究

目的 研究鼠尾草酸(carnosic acid,CA)的遗传毒性。方法 选用鼠伤寒沙门杆菌回复突变(Ames 试验)、体内哺乳动物红细胞微核、精子畸形以及单细胞凝胶电泳(彗星试验)四项致突变生物学试验进行筛选评价。结果 在6.25～50μg/mL 的剂量水平,CA 对鼠伤寒沙门菌株TA97、TA98、TA100、TA102 和TA1535 均无诱变性;此外,在受试剂量下小鼠骨髓嗜多染红细胞微核、小鼠精子畸形以及体内彗星试验的结果均为阴性(与溶剂对照比较,P> 0.05)。结论 在本实验条件下,CA 未见明显遗传毒性。     

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.

     

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.