盐酸格拉司琼鼻喷剂对顺铂引起比格犬呕吐的对抗作用

目的:观察盐酸格拉司琼鼻喷剂对顺铂引起比格犬呕吐的对抗作用.方法:在顺铂致比格犬呕吐模型上,分别在给予顺铂3.0 mg·kg-1(iv)前或后30 min,对动物鼻腔喷雾盐酸格拉司琼鼻喷剂作为预防和治疗给药方法,测定呕吐次数、潜伏期和持续时间,并与口服和静脉给药途径进行比较.结果:顺铂对照组5只动物全部出现反复的呕吐发作,平均呕吐次数为(19.4±11.6),呕吐潜伏期31～114 min,呕吐持续时间151～290 min,5 h后呕吐基本停止.盐酸格拉司琼鼻喷剂0.5和1.0 mg·kg-1组预防给药时呕吐动物发生比率分别为0/4和1/5,与顺铂对照组相比显著降低(P＜0.01);治疗给药时呕吐动物发生比率均为1/4,与顺铂对照组相比也均显著降低(P＜0.05).鼻喷剂组无论是预防给药还是治疗给药出现呕吐的动物,除潜伏期未见改变外,其呕吐次数和呕吐持续时间均明显减少;而与盐酸格拉司琼注射液0.5 mg·kg-1(iv)和片剂1.0 mg·kg-1(po)预防和治疗的效果相当.结论:盐酸格拉司琼鼻喷剂对顺铂致比格犬呕吐有明显的对抗作用,与静脉和口服给药剂量的效果相当.     

非洛地平-美托洛尔复方经皮给药系统设计及其降压有效性评价

目的:设计制备非洛地平-美托洛尔复方经皮给药系统,评价其对自发性高血压大鼠的降压作用.方法:50只3月龄自发性高血压大鼠随机分为5组进行长期给药治疗试验:空白贴剂对照组、非洛地平(FEL)-美托洛尔(MET)口服混悬液组(FEL 1 mg·kg-1,MET 10 mg·kg-1,qd)及FEL-MET透皮贴剂低、中、高剂量组[剂量分别为:FEL 1 mg·kg-,MET 10 mg·kg-1;FEL 3 mg·kg-1,MET 30 mg·kg-1;FEL 9 mg·kg-1,MET90 mg·kg-,每隔2 d给药1次],共持续44 d.另设同月龄正常血压Wistar大鼠为正常对照组.以无创性尾套法测定给药后大鼠血压和心率,评价经皮给药系统的降压作用.结果:FEL-MET透皮贴剂降压作用起效快、持续时间长,无耐药趋势,强度具有剂量依赖性.FEL-MET透皮贴剂低、中、高剂量分别使收缩压下降27.3-39.2mmHg(14.78%～21.22%),34.2～49.7 mmHg(18.59%～27.01%)和50.8～68.6 mmHg(27.34%～36.92%);使舒张压下降19.8～32.6 mmHg(12.90%～21.24%),22.7～34.9 mmHg(15.30%～23.52%)和33.7～52.8mmHg(22.74%～35.63%);降压效果显著优于FEL和MET长期口服联用(P＜0.05).结论:FEL-MET经皮给药系统降压效果确切,作用平稳,持效时间长,使用方便,安全性高,适于高血压的长期药物治疗.     

咪达唑仑对猫注射顺铂引起的恶心呕吐及十二指肠5-HT含量的影响

目的：通过基础研究评价咪达唑仑预防恶心呕吐的作用,以探讨其镇静遗忘作用以外的药理作用。方法：健康杂种家猫39只：随机抽取3只作为正常对照组（N组）,其余36只均分为顺铂组（C组）、格拉斯琼组（G组）、咪达唑仑组（M组）和氟马西尼组（F组）。各组随机抽取3只用于取材,其余6只用于观察行为学指标。C、G、M组猫分别静脉注射0.9%氯化钠溶液3ml、格拉斯琼0.15mg/kg和咪达唑仑0.50mg/kg,20min后顺铂3mg/kgip,F组在给予咪达唑仑前10min氟马西尼0.2mg/kgiv,其后给药方式同M组。观察动物镇静程度和10h内恶心呕吐情况。取材组各猫在给顺铂后2h取3cm长小肠,免疫组化染色,并应用图像分析仪测十二指肠5-HT表达平均灰度值。相应数据行统计学分析。结果：与对照组相比,顺铂能诱发猫产生严重的恶心呕吐反应（P〈0.05,P〈0.01）,十二指肠5-HT的含量显著增加;与顺铂组比较,格拉斯琼和咪达唑仑能使猫干呕潜伏期延长,恶心呕吐次数减少,十二指肠黏膜5-HT含量降低（P〈0.05）;氟马西尼组恶心呕吐发生率和严重程度以及5-HT的表达情况与顺铂组相似（P〉0.05）。结论：猫静注咪达唑仑0.5mg/kg能降低腹腔注射3mg/kg顺铂诱发的恶心呕吐发生次数,延长干呕潜伏期,减轻严重程度。咪达唑仑能减少猫肠道5-HT含量,预防恶心呕吐部分机制与中枢镇静有关。     

妥洛特罗两种透皮贴剂临床药动学特性及其对临床疗效的可能影响

目的 评价妥洛特罗两种透皮贴剂和口服片剂的临床药动学特性及其对临床疗效的影响.方法 健康受试者分别单次接受2 mg妥洛特罗透皮贴剂A、贴剂B或口服1 mg盐酸妥洛特罗片剂,采血测试受试者不同时间点的血药浓度,并计算药动学参数.结果 贴剂A、贴剂B和片剂达峰时间(T<,max>)分别为(9.5±2.1)、(24.7±5.4)和(1.5±0.6)h;峰浓度(C<,max>)分别为(1.13±0.4)、(0.271±0.262)和(1.70±0.56) ng/mL.结论 两种贴剂药动学参数存在差异,有可能对临床疗效产生影响.预期贴剂A具有良好的临床疗效.     

楷木枝叶提取物抗水貂呕吐的药效及机制研究

目的 探讨楷木枝叶提取物(楷木提取物)抗水貂呕吐的药效及机制.方法 采用水貂作为模式动物,应用顺铂和1-苯基双胍盐酸盐(PBG)制造呕吐模型,记录水貂呕吐潜伏期、干呕及呕吐次数,同时用高效液相电化学法测水貂回肠5-羟色胺含量,全面观察和评价楷木枝叶提取物抗水貂呕吐的药效及其机制.结果 楷木枝叶提取物及组合物(楷木枝叶提取物与姜辣素按1:1混合)可抑制顺铂和1-苯基双胍盐酸盐所致的水貂呕吐行为,延长呕吐潜伏期,减少干呕次数(P<0.05);楷木枝叶提取物及组合物均可抑制顺铂和1-苯基双胍盐酸盐引起的5-羟色胺释放(P<0.05).结论 楷木枝叶提取物可以有效抑制呕吐反应,其机制涉及5-羟色胺系统.     

辣椒提取物对3种异嗜高岭土模型大鼠的止呕作用

目的研究辣椒提取物(extract of capsicum,以下简称EC,含辣椒素10mg·mL-1)对大鼠的止呕作用.方法大鼠分别给予顺铂、阿朴吗啡及接受旋转刺激,建立大鼠异嗜高岭土的3种呕吐模型,观察EC预防给药对3种模型大鼠的止呕作用.结果顺铂(3 mg·kg-1,ip)、阿朴吗啡(3.2 mg·kg-1,sc)以及旋转刺激(100 r·min-1,1 h)均能引起大鼠的异嗜呕吐行为,可作为建立大鼠异嗜高岭土模型的致呕最适剂量.EC 30,20,1O mg·kg-1三个剂量组可抑制顺铂、阿朴吗啡、旋转所致的大鼠异嗜高岭土的量(P＜O.05),并呈现一定的量效关系.结论EC在大鼠异嗜呕吐模型上具有止呕作用,其机制可能与P物质及抑制呕吐中枢有关.     

新型铂类化合物LLC-0601与舒铂对SD大鼠的肝毒性

目的观察新型铂类化合物LLC-0601与舒铂对SD大鼠的肝毒性,探讨其可能的毒性作用机制。方法 雄性SD大鼠尾静脉iv给予顺铂2mg.kg-1(阳性对照)、舒铂40mg.kg-1、LLC-060140和70mg.kg-1,连续2d,间隔5d,共6次,末次给药后恢复期28d,观察动物一般状况,并于给药末期和恢复28d后检测血清谷丙转氨酶(GPT),谷草转氨酶(GOT),碱性磷酸酶(ALP),总蛋白(TP),白蛋白(ALB)和总胆红素(T-Bil),肝质量与系数,组织匀浆谷胱甘肽过氧化物酶(GSH-Px),超氧化物歧化酶(T-SOD),微量丙二醛(MDA)及光学显微镜进行病理组织学检查。结果与正常对照组相比,LLC-060140mg.kg-1组各项检测指标未见明显异常,其余给药组动物均出现精神差、少食、少动、竖毛、毛发无光泽以及体质量下降;给药末期血清生化检测舒铂组GPT升高,TP和ALB降低(P<0.05);与正常对照组相比,顺铂、舒铂和LLC-060170mg.kg-1组肝质量明显降低(P<0.05),顺铂和舒铂组肝系数明显降低(P<0.05);顺铂、舒铂和LLC-060170mg.kg-1组肝组织匀浆中GSH-Px和T-SOD降低,各给药组MDA均升高(P<0.05);顺铂、舒铂和LLC-060170mg.kg-1组肝病理组织学均出现不同程度肝细胞点灶状坏死,肝窦内淋巴细胞浸润,以舒铂组病变程度最重。恢复期顺铂组病理组织学病变较给药末期重,出现延迟性毒性反应,其余各给药组各项检测指标均基本恢复。结论顺铂、舒铂和LLC-0601均可引起大鼠肝损伤,其机制与药物引起的组织过氧化损伤有关。     

盐酸奥昔布宁透皮贴剂的制备及体内外评价

采用溶媒挥发法制备了盐酸奥昔布宁骨架型透皮贴剂.体外透裸鼠皮肤试验表明,该贴剂能维持72 h稳定释药,透皮速率与上市产品Oxytrol(R)相比无显著性差异.测得制品中药物含量为(36.0±0.7)mg,在pH 5.8磷酸盐缓冲液中于24 h内基本释放完全,并且具有较好的含量均匀度和黏附性能.以Oxytro1(R)为参比制剂,考察了自制贴剂在大鼠体内的药动学行为.结果表明自制贴剂给药后能在72h内维持较恒定的血药浓度,平均相对生物利用度为102.7％.     

盐酸川芎嗪透皮贴剂体外透皮速率测定和体外释放研究

目的研究盐酸川芎嗪透皮贴剂的经皮吸收的可行性。方法采用高效液相色谱法测定透皮接受液和释放接受液中盐酸川芎嗪的浓度。结果体外透皮实验和体外释放实验结果表明：盐酸川芎嗪在24h内以一定的速率（0．1014mg／cm^2h^1恒速渗透,其释放符合Higuchi方程。此外,该贴剂的体外释放速率为0．1332mg／cm^2h^1/2。结论盐酸川芎嗪透皮贴剂为皮肤限速型的骨架控释透皮给药系统。     

丁螺环酮贴剂透皮吸收的药物动力学研究

目的:研究丁螺环酮透皮贴剂给药的药物动力学及生物利用度。方法:以丁螺环酮片剂为对照,采用HPLC法测定家兔随机交叉使用丁螺环酮贴剂和片剂在相同单剂量给药后的血药浓度,采用3p97软件处理数据,进行药物动力学及生物利用度的研究。结果:与片剂比较,贴剂达峰时间较长,但可维持较长时间平稳的血药浓度,在1.5～8 h内血药浓度保持在34.190±3.382 ng·ml~(-1)左右;贴剂和片剂的AUC_(0→∞)分别为(40.741±108.828)和(102.031±39.570)h·ng·ml~(-1),二者有极显著性盖异(P<0.01),贴剂相对生物利用度是片剂生物利用度的3.96倍。结论:外用贴剂相对口服片剂而言,有较高的生物利用度。     

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.     

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.     

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.     

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.