复方蒿甲醚对Beagle犬的长期毒性

给 Beagle犬 po复方蒿甲醚 (蒿甲醚∶本芴醇 1∶ 6,W/W) 1 1 2 ,556,1 0 0 0 mg· kg-1· d-1,每天 1次 ,连服 1 4d.给药结束后 ,各组活杀 2 /3,留 1 /3继续观察 2 8d.观测了临床症状和生理指标 ,血液学 ,血生化 ,尿 ,心电图 ,眼底及病理组织学 .主要毒性反应为 1 0 0 0 mg·kg-1·d-1组给药早期出现网织红细胞降低 ,骨髓红系细胞的中幼红与早幼红比值降低 ,心电图 Q- T间期延长 ,生化检查谷草转氨酶 ,碱性磷酸酶轻度升高 .组织学检查可见肝 ,肾轻度损伤 .所有上述变化停药后均可恢复正常 . 556mg· kg-1· d-1及以下剂量组未见明显毒副作用 ,可视为基本安全剂量 .     

氯替泼诺家犬长期毒性研究

目的　观察长期重复口服给予氯替泼诺对家犬所产生的毒性反应。方法　取健康杂种家犬 2 4只 ,随机分为对照组、低 (5mg·kg-1)、中 (15mg·kg-1)和高剂量组 (30mg·kg-1) ,连续口服给药 18wk ,停药恢复 2wk ,进行常规毒理学观察和指标检测。结果　 (1)氯替泼诺 5mg·kg-1,未见明显异常发生。 (2 )氯替泼诺 15mg·kg-1给药 3wk后 ,动物体重增长减慢 ;给药4个月血液学检查 ,单核细胞比例高于对照组。 (3)氯替泼诺 30mg·kg-1,给药第 8d时一雄性犬死亡。其它 5只家犬给药期间体重增长明显低于对照组。给药结束时 ,尿蛋白升高 ,单核细胞比例升高 ,TP、Crea、TC降低 ,ALP升高。病理组织学检查 ,一只动物肝汇管区慢性炎症 ,肝细胞变性 ,胞浆空泡状 ,核固缩。停药结束 ,除高、中剂量组体重增长未完全恢复仍低于对照组外 ,其它各剂量组各项指标均未见明显异常。结论　氯替泼诺家犬长毒试验无毒反应剂量为 5mg·kg-1。     

淫羊藿总黄酮与雌激素合用对去卵巢大鼠骨质疏松的影响

目的　研究淫羊藿总黄酮 (EF)与己烯雌酚 (DES)合用对去卵巢大鼠骨质疏松的影响。方法　大鼠双侧卵巢去除术后预防用药 90d ,用骨组织形态计量学等方法 ,测定大鼠胫骨近端松质骨静态参数和动态参数 ,并观察血清生化指标和子宫内膜厚度。结果　DES 2 2 5 μg·kg-1·d-1可对抗去卵巢大鼠体重增加、血清总胆固醇增加、骨转换增高和骨丢失 ,但是使子宫内膜厚度增加。单用EF 30 0mg·kg-1·d-1对骨丢失没有对抗作用 ,DES 2 2 5 μg·kg-1·d-1和EF30 0mg·kg-1·d-1联合用药效应超过DES单独应用 ,而且不刺激子宫内膜增加。结论　EF与DES联合用药对去卵巢大鼠骨丢失的骨量增加有协同作用 ,而且没有刺激子宫的副作用。     

褪黑素对多柔比星所致肾病的保护作用

本研究旨在观察褪黑素 ( MT)对大鼠“阿霉素肾病”的保护作用 .将所有受试动物分为 5组 ,即正常组 ,MT( d0 - d7,5mg·kg-1·d-1,ig)组 ,多柔比星模型组 ( d 1 ,Dox,5mg· kg-1,iv)组和MT( d 0 - d 7,0 .5,5mg· kg-1· d-1) + Dox( d 1 ,5mg· kg-1,iv)组 .检测大鼠 d7,d1 4,d2 1和 d2 8时尿蛋白 ,尿丙二醛排泄量和 d 2 8时血浆生化指标 .结果显示 ,Dox组大鼠呈典型的肾病综合征 ,MT+ Dox组大鼠尿蛋白减少 ,血浆蛋白明显回升 ,血脂降低 ;同时 ,Dox组动物尿丙二醛显著增加 ,MT+ Dox组丙二醛降低 .这些结果表明 ,MT可减轻“阿霉素肾病”大鼠肾损害 .     

沙尔威辛治疗恶性肿瘤Ⅰ期临床耐受性试验

目的观察沙尔威辛治疗恶性肿瘤的安全性,毒副反应与剂量的关系,确定推荐Ⅱ期临床研究的剂量.方法共入选29例患者,沙尔威辛分为9个剂量组,由初始剂量15 mg·m-2·d-1开始逐渐增加至30,45,60,75,90,105 mg·m-2·d-1,加入生理氯化钠溶液500 mL静脉点滴2 h,连续3 d,其中第7剂量组为90 mg·m-2·d-1连续4 d,第8剂量组为90 mg·m-2·d-1连续5 d,第9剂量组为105 mg·m-2·d-1连续5 d,21 d为一周期,每剂量组3或4例.观察药物对人体各系统的影响及毒性反应.结果沙尔威辛的毒副反应比较轻微,除了血管刺激疼痛外主要还包括Ⅰ/Ⅱ度的骨髓抑制、消化道反应、发热及皮肤潮红等,所有的毒副反应均在停药2周内恢复.没有出现剂量限制性毒性.爬坡最高剂量为105 mg·m-2·d-1连续5 d.结论沙尔威辛对恶性肿瘤患者的耐受性良好,建议Ⅱ期临床研究推荐剂量为90 mg·m-2·d-1连续5 d,21 d为一周期.     

香椿叶总黄酮对糖尿病小鼠血糖的影响

目的研究香椿叶总黄酮对糖尿病小鼠血糖的影响。方法采用链脲佐菌素腹腔注射制备糖尿病小鼠模型,造模成功小鼠随机分为模型组、香椿叶总黄酮大剂量(800 mg·kg-1·d-1)、中剂量(400 mg·kg-1·d-1)和小剂量组(100 mg·kg-1·d-1),优降糖组(60mg·kg-1·d-1),连续给药30 d后,观察血糖的变化。结果香椿总黄酮可明显降低糖尿病小鼠的血糖。结论香椿叶总黄酮有明显的降糖作用,为临床上防治糖尿病提供了理论依据。     

姜黄素对大鼠环孢素慢性肾毒性防治作用研究

目的 观察姜黄素对环孢素(CSA)肾毒性的防治作用。方法 将30只大鼠随机分为4组，即正常组6只，模型组、治疗组和预防组各8只。正常组给予橄榄油30 mg·kg-1·d-1灌胃4周；模型组以CSA30 mg·kg-1·d-1灌胃4周；治疗组以CSA30 mg·kg-1·d-1灌胃2周后,再给予姜黄素200 mg·kg-1·d-1灌胃2周；预防组给予CSA30 mg·kg-1·d-1与姜黄素200 mg·kg-1·d-1联合灌胃4周。观察给药前后各组大鼠的体重变化，以及给药后24 h尿量、血肌酐、尿素氮和肾脏病理变化。用免疫组织化学和RT-PCR法检测各组大鼠肾组织HO-1和bFGF表达情况。结果 与正常组相比，模型组大鼠给予CSA后体重下降（P＜0.05＝，尿量增多（P＜0.05＝，尿素氮、肌酐上升（均P＜0.05＝，肾脏组织出现较典型的病理变化，HO 1表达显著下降（P＜0.01＝，bFGF表达增加（P＜0.01＝。与模型组相比，治疗组和预防组HO-1表达增加（均P＜0.01＝，bFGF表达下降（均P＜0.01＝。结论姜 黄素可改善CSA所导致的肾毒性，可能是通过增加HO-1、降低bFGF的表达发挥抗CSA肾毒性的作用。     

甲基汞对大鼠脑谷氨酸能神经元的免疫组化影响

【目的】　研究甲基汞亚急性染毒诱导大鼠脑内谷氨酸能神经元免疫组化改变 ,探讨其毒性机制。【方法】　免疫组织化学方法。【结果】　在低剂量组 (2mg·kg-1·d-1× 7d)大鼠脑内谷氨酸免疫反应阳性细胞 (Glu IRPC)数目、积分光密度、阳性面积比在给药 14d时下降有显著性意义 (P <0 0 5 )。在高剂量组 (10mg·kg-1·d-1× 7d) ,各时点大鼠各脑区Glu IRPC的数目下降 ,积分光密度降低 ,阳性面积比下降均有显著性意义 (P <0 0 5 ) ,且Glu IRPC的分支突起明显减少 ,有些细胞仅见胞体 ,未见突起。【结论】　甲基汞亚急性染毒可使大鼠脑内谷氨酸能神经元中谷氨酸水平降低     

用蒙特卡洛模拟优化耐甲氧西林金黄色葡萄球菌感染的肾功能不全低龄患儿万古霉素的给药方案

目的 应用蒙特卡洛模拟评价万古霉素在肾功能正常与不全低龄耐甲氧西林金黄色葡萄球菌(MRSA)感染患儿中的给药方案.方法 收集2013—2014年成都地区万古霉素对MRSA菌株的最低抑菌浓度值(MIC)和其在2个月 ～2岁中国低龄患儿中药动学资料,经Crystal Ball软件模拟5000例次得到相应目标获得概率(PTA)与累计反应分数(CFR).结果 万古霉素对MRSA的MIC分布频率,MIC为0.03、0.06、0.12、0.25、0.50 mg·L-1时各占12.79％,MIC为1、2 mg·L-1时各占29.07％ 、6.98％.万古霉素达满意抗菌活性的最低剂量:肾功能正常者(A组),MIC为0.03～0.06、0.12和0.25 mg·L-1时分别予30、37.5和80 mg·kg-1·d-1,MIC为0.5～2 mg·L-1时即使80 mg·kg-1·d-1也不能达满意抗菌活性;肾功能轻度不全者[B组,估算的肾小球滤过率(eGFR)为60～89 mL·min-1·1.73 m-2],MIC为0.03～0.12、0.25和0.5 mg·L-1时分别予30、40和80 mg·kg-1·d-1,MIC为1～2 mg·L-1时即使80 mg·kg-1·d-1也不能达满意抗菌活性;肾功能中度不全者(C组,eGFR为30～59 mL·min-1·1.73 m-2),MIC为0.03～0.25、0.5 mg·L-1时分别予30、50 mg·kg-1·d-1,MIC为1～2 mg·L-1时即使80 mg·kg-1·d-1也不能达满意抗菌活性.各方案下A、B组对MRSA的CFR均<90％.结论 感染MR-SA的肾功能正常与轻度不全低龄患儿经验性应用万古霉素时可考虑联合用药,结合各MIC分布频率和达满意抗菌活性的最低剂量可知,大多数肾功能正常低龄患儿按40 mg·kg-1·d-1给药剂量偏低,绝大多数肾功能中度不全者应用50～80 mg·kg-1·d-1可获得满意抗菌活性.     

西布曲明对谷氨酸钠诱导的肥胖动物模型的影响

目的　评价西布曲明 (Sibutramine ,Meridia ,MR)对肥胖动物的减肥作用。方法　取刚出生d 1的大鼠 ,♀♂兼用 ,皮下注射谷氨酸钠 (MSG) 3mg·g-1·d-1,连续 5d ;以诱导动物产生肥胖。在造型后 2 1d ,将肥胖动物按体重随机均分为 5组 ,分别灌胃MR 2 0、4 0和 8 0mg·kg-1·d-1;安菲拉酮 6 0mg·kg-1·d-1,模型组和对照组则均给 0 5 %CMC10ml·kg-1·d-1,连续 2 8d。在实验结束时 ,取样检测各指标。结果　研究显示 ,MR可使MSG诱导的肥胖大鼠体重增加减慢 ,使其脂肪垫重量及其Lees指数减少 ,脂肪细胞直径变小 ,脂肪细胞数 (一个视野内 )增加 ,使MSG大鼠血清甘油三酯降低 ,使其在禁食状态下降低的血糖及胰岛素水平恢复正常。MR对MSG的作用主要是降低其TG水平 ,而对TC无明显作用。结论　试验结果显示MR具有调节和改善脂质代谢及明显的减肥作用     

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.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

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.     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.     

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.