几种药物不同部位与不同途径给药对动物LD_(50)的影响

盐酸普魯卡因与硫酸阿託品注射于小白鼠前肢腕部內側正中线深部时其LD_(50)值显著低于同一药物后肢肌內或背部皮下注射。氰化鉀注射于小白鼠或大白鼠的上述部位其毒性显著低于后肢肌內注射与背部皮下注射。亚硝酸鈉LD_(50)值于小白鼠中未見有上述的差别。实驗論証上述毒性差別主要不是因药物自注射部位吸收差別所致。盐酸普魯卡因不論肌內或腕內侧正中线深部注射都能有效地減低氰化鉀的毒性。大白鼠一側臂神經纵切除后一周,再注射氰化鉀于此側的腕內侧正中线深部,其毒性即显著低于正常动物同部位的給药組,故认为氰化鉀毒性的发生可能与神經机制有关。     

猪毛菜(茨蓬)浸膏对实验动物的药理研究

猪毛菜浸膏对麻醉动物有明显持久降压作用,无明显快速耐受現象。猪毛菜对乙酰胆碱及刺激迷走神經离中端所致降压作用无影响,阿託品不阻断猪毛菜的降压作用。双側迷走神經切断后,猪毛菜降压作用略減弱。猪毛菜不阻断頸上交感神經传导,亦无明显抗腎上腺素作用。猪毛菜抑制因压迫頸总动脉及刺激坐骨神經向中端所致的升压反射,二側竇神經切除亦不影响其降压作用。在猪毛菜引起降压作用时,带神經离体兔耳血管反射性扩张,因此推测猪毛菜对血管运动中枢或交感中枢有抑制作用。猪毛菜5,10克/公斤皮下注射能显著减少小白鼠自由活动。20克/公斤延长戊巴比妥鈉(35毫克/公斤)催眠作用的时間,并使非催眠剂量的水合氯醛(200毫克/公斤)产生催眠作用。但不能对抗中枢惊厥药(戊四氮及士的宁)的惊厥及致死作用。在小白鼠防御运动条件反射实驗中,皮下注射猪毛菜3克/公斤,对条件反射活动无明显影响。5克/公斤,10克/公斤时能使条件反射时延长,強化次数增加,分化相无变化。20克/公斤时条件反射显著抑制。5,10克/公斤皮下注射均能加速阳性条件反射消褪过程。小白鼠皮下注射猪毛菜LD₅₀为56克/公斤,大白鼠腹腔注射8克/公斤卽死亡。家兔口服(灌胃)40克/公斤未見毒性反应,80克/公斤时可見死亡。     

硫辛酸对酒石酸锑钾解毒作用的研究

本文研究了国产硫辛酸对酒石酸锑钾的解毒作用.结果证明硫辛酸对酒石酸锑钾的急性及亚急性毒性均有非常显著的解毒作用.小白鼠腹腔注射酒石酸锑钾后,立即以130毫克/公斤的硫辛酸灌胃或皮下注射,可分别使酒石酸锑钾的急性LD₅₀提高1.6和1.9倍.在急性试验中,酒石酸锑钾为LD₉₅时,2-3分子硫辛酸可对抗1分子酒石酸锑钾;在亚急性试验中,酒石酸锑钾为LD₅₀时,1分子硫辛酸即可对抗1分子酒石酸锑钾.腹腔注射酒石酸锑钾LD₅₀后3小时皮下注射硫辛酸,可完全保护小白鼠免于死亡.硫辛酸性质稳定,口服吸收良好,在锑剂中毒出现症状后仍然有效,值得在临床试用.     

四环素叉向异构体及其脱水物的毒性探讨

本文比较了四环素,脱水四环素,叉向四环素及脫水叉向四环素的毒性。急性毒性以叉向四环素为最大,小白鼠靜脉LD₅₀为85.8毫克/公斤,而四环素,脫水四环素及脫水叉向四环素的LD₅₀分別为160.7毫克/公斤,134.2毫克/公斤及193毫克/公斤。亚急性毒性则以脫水叉向四环素为最大,小白鼠不论靜脉注射1毫克/0.5毫升或口服12毫克/0.2毫升,均能出现较重的糖尿及蛋白尿,肾曲管发生较重的病变,可能是临床引起Fanconi症候羣的主要物质。     

氯丙嗪裂环类似物的神经药理作用

本文报导了18个氯丙嗪裂环类似物的神经药理作用。試驗結果表明:按(Ⅰ)所示虛线剖裂吩噻嗪(即苯噻嗪,phenothiazine)环系后,它們的鎮靜鎮定作用消失,抗組織胺作用明显減弱,局部麻醉作用有所增强。其中N-(β-对-氯苯硫乙基)N-(β-哌啶基丙酰基)-苯胺盐酸盐(NM-568)的局部麻醉效能更为明显,用多种方法与沙夫卡因和普魯卡因比較試驗,获得它們的局部麻醉效价比例如下:(1)家兔角膜試驗:NM-568的表面麻醉效力約接近沙夫卡因,較普魯卡因强1060倍。(2)豚鼠皮內丘样試驗:普魯卡因的效价为1;NM-568,27.5;沙夫卡因,22。(3)小白鼠坐骨神經传导阻滞試驗:如以普魯卡因的效价为1;NM-568,16;沙夫卡因,39.(4)蟾蜍脊髓麻醉:普魯卡因的效价为1;NM-568,9;沙夫卡因,8。对小白鼠的急性毒性,NM-568較沙夫卡因約小1倍,比普魯卡因約大3倍;它对家兔皮內注射和角膜的刺激作用較普魯卡因和沙夫卡因大。氯丙嗪按上列方式裂环后,发現N-(β-对-氯苯硫乙基)N-(γ-嗎啉基)-苯胺盐酸盐(NM-572),N-(β-对-氯苯硫乙基)N-(γ-哌啶基丙基)-苯胺盐酸盐(NM-578)在較大剂量时有抗电休克作用,但作用持續时间仅2小时。     

新利胆药亮菌甲素的药理和毒性研究

亮菌甲素是从假蜜环菌(亮菌)中提取的、对胆道系统具有活性的成分之一。麻醉犬静脉注射本品后能松弛总胆管末端括约肌的紧张度,同时能使肝脏分泌胆汁量明显增加。麻醉大白鼠十二指肠给药或肌内注射本品后,均能促进肝脏分泌胆汁。麻醉犬静脉注射本品后还能引起十二指肠松弛、血压降低、心率减慢,作用均轻度而短暂。小白鼠腹腔注射和口服本品的急性LD₅₀分别为980mg/kg和>5000mg/kg。以人用每天最高剂量的25～125倍分别肌内注射于大白鼠和狗,每天一次,连续三个月,结果未见到明显的毒副作用。     

四种苯骈二氧六环化合物的腎上腺素能阻断作用

四种苯駢二氧六环化合物的結构式为: 小白鼠腹腔注射BD-3,933F,BD-1和BD-5的LD₅₀分別为0.1,0.20,0.26和0.22克/公斤,BD-3和933F組死亡多在1—3小时內,而BD-1和BD-5組死亡多在1—3天內。BD-5在小鼠能显著減低腎上腺素的毒性,而其他3药则不能。麻醉大白鼠和猫靜脉注射4药后均可引起降压,但4药间差异均不显著。BD-3,933F和BD-1使麻醉猫靜脉注射腎上腺素的升压引起反轉作用,而BD-5仅具抑制作用。对酪胺及去甲腎上腺素的升压,4药均可抑制。麻醉猫靜脉注射10毫克/公斤的933F有增血糖作用,BD-5注射20毫克/公斤才增高血糖。933F和BD-5对腎上腺素所引起的血糖及乳酸均无明显的抑制作用。因为BD-5同时阻断收縮和舒张血管的作用,但不引起腎上腺素的反轉作用,因此在治疗血管痙攣性疾患中可能比933F效果更好。     

国产乙酰普马嗪的药理作用研究——加强作用及对交感神经末梢介质释放的影响

(1)采用热水刺激小白鼠尾巴法試驗鎮痛作用,乙酰普馬嗪0.5毫克/公斤可使“疼痛”反应出現时間延迟,較盐酸嗎啡(2毫克/公斤)为弱;二者均以半量合并应用,鎮痛作用强度虽未見加强,但鎮痛时間則延长。(2)脑室內注射乙鮂振R嗪,可立即引起小白鼠安靜,并使其体溫明显下降;皮下注射同剂量时,安靜及降溫作用均不显著,但可明显加强安替比林及水合氯醛的降溫作用。(3)乙酰普馬嗪局部滴药及皮下注射均可产生角膜麻醉,并可加强普魯卡因的表面麻醉作用,尤以皮下注射法为强。(4)乙酰普馬嗪2.5微克/公斤即可減弱腎上腺素的升压作用;5微克/公斤时,使后者作用翻轉,并使电刺激交感神經节前纤維及注射腎上腺素所引起的瞬膜收縮反应減弱。(5)在离体兔神經——迴腸标本,电刺激交感神經节后纤維引起腸张力下降,运动減弱,乙酰普馬嗪及氯丙嗪均可加强此交感反应。     

华山参对中枢神经系统的药理作用

作者研究了华山参(Physochlaina infundibularis Kuang)对中枢神经系统的药理作用.华山参煎剂腹腔注射对小白鼠的LD₅₀为43(28.7-64.5)克/公斤;腹腔注射1克/公斤使大白鼠防御运动性条件反射潜伏期延长,部分动物条件反射破坏及分化抑制有解除现象;灌胃给药(2克/公斤)仅使条件反射潜伏期延长.腹腔注射1-4克/公斤显著降低大、小白鼠和家兔的自由活动,维持3-6小时,但不降低小白鼠的被动活动.腹腔注射4克/公斤,能协同硫喷妥钠及水合氯醛对小白鼠的催眠、麻醉作用;降低苯丙胺、咖啡因对小白鼠的兴奋活动,但在10克/公斤时对本丙胺的毒性作用及士的宁,戊四唑性惊厥无影响.给狗灌胃2-5克/公斤,有明显的镇静作用,但不能对抗去水吗啡的催吐效果.     

防治血吸虫病药物的研究 ⅩⅩⅧ.敌百虫的毒性及其对日本血吸虫病的实验治疗

敌百虫是有机磷杀虫剂,又是胆碱酯酶抑制剂。本文試驗动物內用敌百虫的毒性和对日本血吸虫病的疗效,以及阿託品和PAM对敌百虫毒性与疗效的影响。小白鼠灌胃和皮下注射敌百虫1次的LD₅₀分別为0.8和0.6克/公斤。小白鼠在服敌百虫前30分钟注射阿託品和PAM的解毒效能比单用阿託品或单用PAM为佳。家兔每天灌胃30或60毫克/公斤共2周,抑制血浆胆碱酯酶活力70%左右。猴子灌胃剂量从4毫克/公斤开始,逐日递增4毫克/公斤,至第6天不食,胆碱酯酶活力也明显受到抑制,第7天躺臥不动,停药5天后恢复。小白鼠每天灌胃敌百虫200毫克/公斤,經2周后平均每鼠余存虫13±5条,和对照组24±6条相差非常显著.兔每天灌胃30毫克/公斤或皮下注射40毫克/公斤历2周后虫数也有减少.狗口服敌百虫2周后粪便转为阴性.然后停药2周解剖,平均每狗余存虫8±9条,比对照组6狗平均47±29条显著减少。在病狗治程中,血清磺溴酞钠存留率与血象无明显改变,血浆胆碱酯酶活力降为原来水平的25%左右.停药2周后恢复至原来水平的75%左右。敌百虫与吐酒石合并使用比单独应用一药治疗的效果要更好。阿品及PAM并不减弱敌百虫的疗效。敌百虫对动物的日本血吸虫病确有疗效,价格低廉,且可口服,为找寻有效的非锑剂开辟了新的途径。     

The treatment of experimental cyanide poisoning by hemiglobin formation

Summary Following the observation that some aminophenols produce hemiglobin rather rapidly in vivo and in vitro and with regard to the need of rapid hemiglobin formation in the treatment of cyanide poisoning, o-aminophenol hydrochloride was tried in cyanide poisoning of mice and dogs.In mice o-aminophenol was found to produce hemiglobin more rapidly than an equally effective dose of nitrite.The injection of o-aminophenol hydrochloride saved 95% of the mice injected subcutaneously with two DL₅₀ of potassium cyanide. Only 60% of these mice survived if an optimal dose of sodium nitrite was injected.Dogs which had received four DL₅₀ of potassium cyanide were kept alive if the treatment with o-aminophenol began at the moment the corneal reflex disappeared.Whereas the intravenous injection of nitrite was found to lower the arterial pressure quickly for a long time, o-aminophenol did not affect the blood pressure in dogs.Briefly presented at a meeting of the Deutsche Pharmakologische Gesellschaft in Bad Nauheim on Oct. 8, 1964 (Kiese andWeger).     

荭草苷对缺氧模型小鼠的抗缺氧作用研究

目的:研究荭草苷对缺氧模型小鼠的抗缺氧作用。方法:通过常压耐缺氧、亚硝酸钠中毒、氰化钾中毒、利多卡因中毒、夹闭气管及断头等建立小鼠缺氧模型,于造模前20min给予相应药物,观察药物的抗缺氧作用。结果:与生理盐水空白对照组比较,荭草苷可明显延长模型小鼠在常压缺氧、亚硝酸钠中毒、氰化钾中毒、利多卡因中毒时的存活时间,延长夹闭气管后的心电图消失时间及断头后的喘气时间。结论:荭草苷对缺氧模型小鼠具有抗缺氧作用。     

Cyanide intoxication: protection with cobaltous chloride

Protection against the lethal effects of cyanide can be elicited by administration of cobaltous chloride, either alone or in combination with sodium nitrite and/or sodium thiosulfate. Potency ratios derived from the LD50 values were compared in groups of mice premedicated with cobaltous chloride and/or sodium thiosulfate and/or sodium nitrite. Under the conditions of our experiment cobaltous chloride alone is slightly more effective than sodium nitrite; when it is combined with sodium nitrite, an additive effect is obtained. When cobaltous chloride is administered in combination with sodium thiosulfate, a dramatic antagonism of the lethal effects of potassium cyanide is observed. The synergistic antidotal effect of cobaltous chloride may be related to the physiological disposition of the cobaltous ion and its ability to chelate both cyanide and thiocyanate ions.     

高效液相色谱法测定盐酸普鲁卡因及其注射液的含量

目的采用高效液相色谱（HPLC）法测定盐酸普鲁卡因及其注射液的含量。方法色谱柱为Diamonsail C18（200mmx4．6mm,5μm）,以32：68的甲醇-磷酸盐缓冲液（0．05mol／L磷酸二氢钾,0．1％庚烷磺酸钠,用磷酸调pH至3．0）为流动相,检测波长290nm,流速1．0mL／min。结果盐酸普鲁卡因质量浓度在40～2000μg／mL范围内与峰面积线性关系良好,r=0．9999（n=10）,平均回收率为100．32％,RSD为0．28％（n=9）。结论HPLC法灵敏、专属、快速方便,可以更好地控制产品质量。     

一种检测药物镇痛作用和局部麻醉作用的简便方法

４－氨基吡啶（４－ＡＰ）２．６ｍｍｏｌ·Ｌ－１０．０２ｍＬｓｃ于小鼠颈背部可引起用后足爪搔抓注射部位的反应．以４－ＡＰｓｃ后５ｍｉｎ内发生搔抓鼠数为指标，观察不同药物对它的抑制作用．麻醉性镇痛药吗啡，哌替啶和芬太尼能明显抑制这一反应；弱镇痛药罗通定，安乃近，水杨酸钠和非镇痛药无效．局部麻醉药普鲁卡因，利多卡因或丁卡因与４－ＡＰ混合ｓｃ也可取消搔抓反应．结果表明这一方法可用于检测麻醉性镇痛药的镇痛作用和局麻药的局部麻醉作用．     

Ifenprodil: Protective effect in experimental cyanide poisoning

In in vivo experiments, dose-dependent protection against the lethality of cyanide was elicited by im pretreatment with ifenprodil in rats, guinea pigs, rabbits, and mice. The decline in respiration rate, blood pressure, and heart rate, and the flat electroencephalogram induced by iv administration of sodium cyanide was also reversed by previous administration of ifenprodil in these species. Methemoglobinemia was not observed after protective doses of ifenprodil in rats and ifenprodil did not affect thiocyanate formation induced by sodium cyanide and sodium thiosulfate in rats. In vitro, ifenprodil exhibited a stimulative effect on respiration of mitochondria isolated from guinea-pig liver, this effect being the most prominent with succinate as substrate and in the presence of phosphate. In addition, the inhibitory effect of potassium cyanide on the respiration was completely abolished by ifenprodil. These protective effects of ifenprodil on cyanide intoxication were also observed with both ifenprodil tartrate and hydrochloride, and tartaric acid did not exert this action. Experiments using ultraviolet absorption and proton nuclear magnetic resonance spectra did not show that ifenprodil reacts directly with free cyanide ion to trap it. The results suggest that ifenprodil prevents the signs and lethality of cyanide, and a part of the mechanism can be ascribed to antagonism at the mitochondrial level, though the mechanism is not clear at present.     

Formation of cyanide from o-chlorobenzylidene malononitrile and its toxicological significance

Mice received o-chlorobenzylidene malononitrile (CS) by i.p. injection (0.5 LD₅₀) or by aerosol exposure (20,000 mg min^–1 m^–3). Increased excretion of thiocyanate in the urine was observed, indicating a transformation of CS to cyanide in vivo. Determinations of cyanide in whole blood after i.p. administration of CS verified a rapid transformation of the agent to cyanide. A correlation between the time course of cyanide levels and symptoms was observed. Toxicity of injected CS was significantly reduced by pretreatment with thiosulfate, slightly reduced by nitrite and not affected by Co₂EDTA.Thiocyanate excretion, blood cyanide levels and protective effect of antidotes were also evaluated after administration of 0.5 LD₅₀ of malononitrile and potassium cyanide. The importance of cyanide formation for the toxicity of CS is discussed.     

萃取除扰鲎试验检查盐酸普鲁卡因注射液细菌内毒素

目的:建立盐酸普鲁卡因注射液的细菌内毒素检查法,探讨萃取法排除鲎试剂与细菌内毒素凝集反应干扰因素的可行性。方法:利用普鲁卡因的脂溶性将普鲁卡因排除后行细菌内毒素检查法。结果:15批盐酸普鲁卡因注射液中细菌内毒素均低于0.5EU·mL~(-1),真实地反映普鲁卡因注射液中细菌内毒素的污染程 度。结论:萃取法去除鲎试验干扰因素可扩大细菌内毒素检查法的应用范围。     

The role of cyanide liberation in the acute toxicity of aliphatic nitriles

The acute ip LD50 values for a series of six aliphatic nitriles were determined in mice and compared with acetone cyanohydrin and sodium cyanide. When sodium thiosulfate was given in multiple injections, it protected mice against death by acetonitrile, propionitrile, n-butyronitrile, malononitrile, or succinonitrile. In contrast, multiple injections of sodium nitrite protected mice against death by acrylonitrile, n-butyronitrile, and malononitrile, but not against acetonitrile, propionitrile, or succinonitrile. Single prophylactic doses of either thiosulfate or nitrite protected mice against death by either acetone cyanohydrin or sodium cyanide. Only sodium cyanide and acetone cyanohydrin predictably produced death within 5 min. All other nitriles produced death at widely varying intervals from a few minutes to many hours. Only acetone cyanohydrin and cyanide inhibited the activity of purified preparations of cytochrome c oxidase in vitro and in equimolar concentrations. Pretreatment of mice with carbon tetrachloride protected them against death from all nitriles except acetone cyanohydrin. Elevated concentrations of cyanide were found in the livers and brains of mice given lethal doses of all of the nitriles, acetone cyanohydrin, or sodium cyanide. The tissue concentrations of cyanide were substantially reduced in all cases when thiosulfate was also given or when nitriles were given to carbon tetrachloride-pretreated mice. Cyanide was liberated when n-butyronitrile or succinonitrile were incubated with mouse liver slices or NADPH-fortified mouse hepatic microsomal preparations. This reaction was inhibited when the livers were taken from mice pretreated with carbon tetrachloride or when SKF-525A was added in vitro to normal liver slices. Acetone cyanohydrin in all systems tested behaved qualitatively and quantitatively like its molar equivalent in cyanide. The results suggested that the other nitriles examined here possess little, if any, acute toxicity in the absence of normal hepatic function and that these nitriles were activated by hepatic mechanisms to release cyanide which can account for their major acute toxic effects.     

Stereospecific effect of naloxone hydrochloride on cyanide intoxication

Cyanide intoxication in mice can be antagonized by the opiate antagonist, (-)naloxone HCl, alone or in combination with sodium thiosulfate and/or sodium nitrite. Potency ratios, derived from LD50 values, were compared in groups of mice pretreated with sodium nitrite (sc, 100 mg/kg), sodium thiosulfate (ip, 1 g/kg), and (-)naloxone HCl (sc, 10 mg/kg) either alone or in various combinations. These results indicate that naloxone HCl provides a significant protection against the lethal effects of potassium cyanide. The protective effect of sodium thiosulfate, but not sodium nitrite, was enhanced with (-)naloxone HCl. The combined administration of sodium nitrite and sodium thiosulfate was further enhanced with (-)naloxone HCl. This protective effect of naloxone HCl against the lethal effect of cyanide appears to be restricted to the (-)stereoisomer, as the (+)stereoisomer, the inactive opiate antagonist, is also inactive in protecting against the lethal effects of cyanide. The mechanism of antagonism is discussed.