Protective effects of aerosolized scopolamine against soman-induced acute respiratory toxicity in guinea pigs

The protective efficacy of the antimuscarinic agent scopolamine was evaluated against soman (o-pinacolyl methylphosphonofluoridate [GD])-induced respiratory toxicity in guinea pigs. Anesthetized animals were exposed to GD (841 mg/m(3)) by microinstillation inhalation exposure and treated 30 seconds later with endotracheally aerosolized scopolamine (0.25 mg/kg) and allowed to recover for 24 hours. Treatment with scopolamine significantly increased survival and reduced clinical signs of toxicity and body weight loss in GD-exposed animals. Analysis of bronchoalveolar lavage (BAL) fluid showed normalization of GD-induced increased cell death, total cell count, and protein following scopolamine treatment. The BAL fluid acetylcholinesterase and butyrylcholinesterase levels were also increased by scopolamine treatment. Respiratory dynamics parameters were normalized at 4 and 24 hours post-GD exposure in scopolamine-treated animals. Lung histology showed that scopolamine treatment reduced bronchial epithelial and subepithelial inflammation and multifocal alveolar septal edema. These results suggest that aerosolized scopolamine considerably protects against GD-induced respiratory toxicity.     

The effects of inhibiting choline dehydrogenase on choline metabolism in mice

3,3-Dimethylbutanol (Dimbunol), a competitive inhibitor of choline dehydrogenase (CDH), and ethylcholine mustard aziridinium (ECMA), an effective irreversible inhibitor of both CDH and choline transport, were investigated for their effects upon the uptake and metabolism of [3H]choline in mice. Thirty minutes after Dimbunol administration (i.p. 0.5 mmoles/kg) a reduction in the rate of choline oxidation was accompanied by an inhibition of choline phosphorylation in the kidney. Choline had accumulated to 5-fold the control level. After ECMA (i.v. 4 mumoles/kg), kidney choline was elevated 18-fold and both oxidation and phosphorylation rates were severely inhibited. In the liver Dimbunol inhibited oxidation and phosphorylation of choline and generated a 2-fold rise in tissue choline. Ethylcholine mustard aziridinium inhibited both oxidation and phosphorylation in the liver to the same extent as in the kidney but produced only a 3-fold elevation of choline. Dimbunol failed to elevate serum choline 30 min after administration and brain choline and acetylcholine levels were also unchanged. Serum choline was doubled by ECMA. These studies suggest that both transport across the renal tubules and oxidation may be important in choline regulation, that high levels of choline may accumulate in the liver and kidney which are not available for acetylcholine synthesis but that longer term studies on the effects of Dimbunol might reveal useful ways of facilitating sustained elevation of serum choline in precursor therapy.     

硬膜外超前镇痛对患者围手术期应激反应及镇痛效果的影响

目的　观察硬膜外超前镇痛的临床效果及其对儿茶酚胺的影响。方法　 4 8例手术患者随机分为三组 ,硬膜外穿刺后经硬膜外导管注入曲马多 1mg/kg(Ⅰ组 ) ,氯胺酮 2 0mg加曲马多 1mg/kg(Ⅱ组 ) ,对照组于术毕注入曲马多 1mg/kg(Ⅲ组 )。术后均采用硬膜外自控镇痛 (PCEA)。观察术后视觉模拟 (VAS)评分和不良反应 ,并比较血浆去甲肾上腺素 (NE)、肾上腺素 (E)、多巴胺 (DA)变化。结果　Ⅰ组与Ⅲ组相比 ,观察指标差异无显著意义 ,Ⅱ组与Ⅰ、Ⅲ组相比 ,VAS评分降低。三组患者儿茶酚胺含量术后第 1天均高于术前 (P <0 0 1) ,术后第 3天下降 ,Ⅱ组下降最明显 ,接近术前 ;Ⅰ组和Ⅲ组 ,仍明显高于术前 (P <0 0 5 )。结论　联合应用氯胺酮和曲马多行超前镇痛效果较好 ,且能降低疼痛所致的应激反应     

Cresylbenzodioxaphosphorin oxide pretreatment alters soman-induced toxicity and inhibition of tissue cholinesterase activity of the rat

The toxicity of soman was investigated in the rat with and without pretreatment with cresylbenzodioxaphosphorin oxide (CBDP). Without pretreatment, the 24-h LD50 for soman was 118.2 micrograms/kg s.c., and soman inhibited carboxylesterase (CaE) activity in plasma (ED50 of 55 micrograms/kg) and cholinesterase (ChE) activity in brain regions (ED50 values of 65-105 micrograms/kg) in a dose-related manner. With pretreatment, the 24-h LD50 for soman was reduced by approximately 6-fold and 8-fold (by 1.0 mg/kg and 16.0 mg/kg of CBDP, respectively), and the ED50 values for soman-induced inhibition of ChE activity in brain regions were reduced by approximately 10-fold (by 1.0 mg/kg of CBDP). The dose-dependent severity of soman intoxication varied widely in rats treated with soman alone but not in CBDP-pretreated rats, and the ED50 for the occurrence of signs of soman intoxication was reduced approximately 7-fold following CBDP (1.0 mg/kg) pretreatment. These data support the hypothesis that CBDP pretreatment effectively blocks tissue CaE sites which serve to detoxify soman, thus potentiating both the soman-induced inhibition of ChE in the CNS and the lethality of soman.     

Endotracheal aerosolization of atropine sulfate protects against soman-induced acute respiratory toxicity in guinea pigs

The efficacy of endotracheal aerosolization of atropine sulfate for protection against soman (GD)-induced respiratory toxicity was investigated using microinstillation technique in guinea pigs. GD (841?mg/m³, 1.3 LCt₅₀ or 1121?mg/m³, 1.7 LCt₅₀) was aerosolized endotracheally to anesthetized male guinea pigs that were treated with atropine sulfate (5.0?mg/kg) 30 s postexposure by endotracheal microinstillation. Animals exposed to 841?mg/m³ and 1121?mg/m³GD resulted in 31 and 13% while treatment with atropine sulfate resulted in 100 and 50% survival, respectively. Cholinergic symptoms and increased body weight loss were reduced in atropine-treated animals compared to GD controls. Diminished pulse rate and blood O₂ saturation in GD-exposed animals returned to normal levels after atropine treatment. Increased cell death, total cell count and protein in the bronchoalveolar fluid (BALF) in GD-exposed animals returned to normal levels following atropine treatment. GD exposure increased glutathione and superoxide dismutase levels in BALF and that were reduced in animals treated with atropine. Respiratory parameters measured by whole-body barometric plethysmography revealed that treatment with atropine sulfate resulted in normalization of respiratory frequency, tidal volume, time of expiration, time of inspiration, end expiratory pause, pseudo lung resistance (Penh) and pause at 4 and 24?h post 841?mg/m³ GD exposure. Lung histopathology showed that atropine treatment reduced bronchial epithelial subepithelial inflammation and multifocal alveolar septal edema. These results suggest that endotracheal aerosolization of atropine sulfate protects against respiratory toxicity and lung injury induced by microinstillation inhalation exposure to lethal doses of GD.     

Endotracheal aerosolization of atropine sulfate protects against soman-induced acute respiratory toxicity in guinea pigs

The efficacy of endotracheal aerosolization of atropine sulfate for protection against soman (GD)-induced respiratory toxicity was investigated using microinstillation technique in guinea pigs. GD (841?mg/m(3), 1.3 LCt(50) or 1121?mg/m(3), 1.7 LCt(50)) was aerosolized endotracheally to anesthetized male guinea pigs that were treated with atropine sulfate (5.0?mg/kg) 30 s postexposure by endotracheal microinstillation. Animals exposed to 841?mg/m(3) and 1121?mg/m(3)GD resulted in 31 and 13% while treatment with atropine sulfate resulted in 100 and 50% survival, respectively. Cholinergic symptoms and increased body weight loss were reduced in atropine-treated animals compared to GD controls. Diminished pulse rate and blood O(2) saturation in GD-exposed animals returned to normal levels after atropine treatment. Increased cell death, total cell count and protein in the bronchoalveolar fluid (BALF) in GD-exposed animals returned to normal levels following atropine treatment. GD exposure increased glutathione and superoxide dismutase levels in BALF and that were reduced in animals treated with atropine. Respiratory parameters measured by whole-body barometric plethysmography revealed that treatment with atropine sulfate resulted in normalization of respiratory frequency, tidal volume, time of expiration, time of inspiration, end expiratory pause, pseudo lung resistance (Penh) and pause at 4 and 24?h post 841?mg/m(3) GD exposure. Lung histopathology showed that atropine treatment reduced bronchial epithelial subepithelial inflammation and multifocal alveolar septal edema. These results suggest that endotracheal aerosolization of atropine sulfate protects against respiratory toxicity and lung injury induced by microinstillation inhalation exposure to lethal doses of GD.     

微量泵硬膜外阻滞麻醉用于分娩镇痛的效果观察

目的：探讨微量泵硬膜外阻滞麻醉在分娩中的镇痛效果及对产程、母婴状况的影响。方法：采用微量泵硬膜外阻滞麻醉用于分娩镇痛186例作为镇痛组，将未采用任何镇痛药物186例作为对照组，比较两组的产痛程度、产程时间、分娩方式、产后出血、胎儿窘迫、新生儿窒息及新生儿神经适应能力评分等。结果：两组产痛、产程时间，差异有非常显著意义（P＜0．01）；胎儿窘迫、新生儿窒息及产生出血率，出生后新生儿神经适应能力评分（NACS）差异无显著意义（P＞0．05）。结论：微量泵硬膜外阻滞麻醉用于分娩镇痛能使疼痛阻滞完善，产程短，降低剖宫产及阴道难产率，对母婴均无不良影响，是一种理想的分娩方法。     

The effects of phorbol esters on choline phospholipid hydrolysis in heart and brain

The efflux of choline was determined in rat striatal slices, incubated chicken atria and perfused chicken hearts. 4 beta-Phorbol-12 beta,13 alpha-dibutyrate (PDB) and 4 beta-phorbol-12 beta-myristate, 13 alpha-acetate (PMA) were used to stimulate protein kinase C. The other phorbol esters, 4 beta-phorbol-13 alpha-acetate (PAc) and 4 alpha-phorbol-12 beta,13 alpha-didecanoate (4 alpha PDD), known to be inactive, were tested to evaluate the specificity of the responses. PDB markedly enhanced the efflux of choline in all of the three preparations. The PDB-evoked efflux of choline in incubated chicken atria was equal to the net production of choline and, therefore, was not caused by translocation of intracellular free choline. After inhibition of the cholinesterase activity, PDB linearly increased the efflux of choline in rat striatal slices, but failed to alter the spontaneous efflux of acetylcholine. Thus acetylcholine did not serve as the source of the PDB-evoked efflux of choline. PMA was as effective as PDB, whereas PAc and 4 alpha PDD failed to alter the choline efflux in the perfused heart. Both infusion of a Ca2(+)-free EGTA-containing Tyrode solution and mepacrine reduced the spontaneous efflux of choline by about 40% and blocked the PDB-evoked efflux of choline. In contrast, a Ca2(+)-free solution without EGTA failed to alter the spontaneous and the PDB-evoked choline efflux. It is concluded that phorbol esters stimulate the hydrolysis of choline-containing phospholipids in heart and brain via activation of protein kinase C.     

The effects of receptor selective opioid peptides on morphine-induced analgesia

Utilizing the mouse tail-flick assay, four opioid peptides, which have been reported to be selective for either μ- or δ-opioid receptors, were examined for their analgesic potency and for their ability to modify morphine-induced analgesia. [D-Ala²,D-Leu⁵]enkephalin and [D-Ser²,Thr⁶]leucine-enkephalin, putative δ-receptor selective peptides, produced a potent analgesic response and at subanalgesic doses potentiated morphine-induced analgesia. Morphiceptin and [D-Ala²,Pro⁵]enkephalinamide, putative μ-receptor selective peptides, were similarly found to produce analgesia. However, in contrast to the δ-receptor selective peptides, three μ-receptor selective peptides were unable to alter the potency of morphine. Thus, it would appear that the potentiation of morphine analgesia is a unique property of δ-receptor selective peptides.     

腰-硬联合自控镇痛分娩对宫缩的影响

目的探讨腰-硬联合自控镇痛分娩对宫缩的影响,有助于更好指导镇痛分娩处理。方法回顾性分析我院2007年4月至2008年4月采用腰-硬联合自控镇痛法分娩患者312例临床资料,并随机选择同期非镇痛分娩患者69例作对照分析。结果 312例分娩镇痛总有效率100%,发生宫缩乏力252例,发生率80.8%,使用缩宫素252例,宫缩素使用率80.8%,对照组发生宫缩乏力15例,发生率21.7%,使用缩宫素15例,宫缩素使用率21.7%,两组比较（P〈0.01）,差异有统计学意义;镇痛组例,宫缩乏力发生在第一产程活跃期223例,占88.5%,发生在第二产程29例,占11.5%,对照组宫缩乏力发生在第一产程活跃期6例,占40%,发生在第二产程9例,占60%,两组比较P〈0.01,差异有统计学意义。结论腰-硬联合自控镇痛分娩有效镇痛率达100%,但宫缩乏力发生率高,近九成宫缩乏力发生在第一产程活跃期,镇痛分娩过程中应密切监测宫缩情况,发现宫缩乏力时尽早应用缩宫素。     

The effects of trinitrotoluene toxicity on zinc and copper metabolism

Wistar rats were exposed to trinitrotoluene (TNT, 200 mg/kg/d x 6 d/wk) for 6 weeks, and a 2-week recovery period was continued after treatment. After initiation of TNT exposure, zinc and copper concentrations in rat testes, liver and serum, and serum caeruloplasmin activity were assayed every 2 weeks. Testicular size and zinc concentrations were decreased throughout the exposure and recovery periods. After 6 weeks of TNT exposure, rat testicular copper and serum zinc concentrations were significantly decreased and increased, respectively. The activities of caeruloplasmin were decreased after 4 and 6 weeks of exposure. Liver zinc and copper concentrations and serum copper concentrations had not changed significantly in rats throughout the exposure and recovery periods. Copper concentration in hair samples from TNT-exposed workers was lower than that in control workers, but zinc content was significantly increased compared with that in control workers.     

The effects of naloxone on opiate and placebo analgesia in healthy volunteers

Two double blind cross-over studies were performed using a submaximal effort tourniquet test (SETT) in healthy volunteers to investigate the role of endogenous opioids in placebo analgesia. In the first study IV naloxone significantly inhibited analgesia, miosis and sedation produced by the opioid dipipanone 10 mg in 12 subjects. In the second naloxone, which did not produce hyperalgesia, failed to inhibit significant placebo analgesia in 12 subjects. The results do not support the involvement of endogenous opioids in ischemic limb pain or placebo analgesia under these conditions.     

Acetylcholine and choline effects on erythrocyte nitrite and nitrate levels

Acetylcholine has been detected in human blood. Acetylcholine receptors and acetylcholinesterase are present in erythrocyte membranes. We tested the acetylcholine and choline effects on nitric oxide metabolites (NOx), namely nitrites and nitrates, and observed if they are dependent on interactions with muscarinic receptors and acetylcholinesterase. Human erythrocyte suspensions were incubated with acetylcholine and choline in the absence or presence of 10 microM atropine or 10 microM velnacrine maleate. The nitrite and nitrate concentrations were determined by the Griess method. Acetylcholine or choline increased NOx control concentrations (P <0.001). The nitrite concentrations decreased in the presence of atropine or velnacrine maleate (P <0.03). The nitrate concentrations only decreased when velnacrine maleate was incubated with acetylcholine or choline (10 microM, P <0.03). These results demonstrated that acetylcholine and choline modulate nitric oxide metabolites on erythrocytes and this effect is mediated by interactions with erythrocyte membrane muscarinic receptors and membrane enzyme acetylcholinesterase. A hypothesis for the signal transduction mechanism has been discussed for acetylcholinesterase and muscarinic receptor (M1) participation.     

鼻炎胶囊的抗炎止痛及急性毒性实验研究

目的检测鼻炎胶囊的有效性和急性毒性反应,为临床提供现代药理学及安全用药的科学依据。方法①药效学实验:4组实验动物,每组40只,随机分成大剂量鼻炎胶囊组、小剂量鼻炎胶囊组、阳性对照组(鼻炎康或阿司匹林)和空白对照组,每组各10只。分别灌胃给药,观察该药对小鼠二甲苯性耳壳炎症、冰醋酸致痛作用及冰醋酸致腹腔毛细血管通透性增高和大鼠棉球肉芽肿的影响。②急性毒性实验:20只小鼠灌胃给予最大浓度和最大剂量鼻炎胶囊溶液,用药24 h和1周后观察动物的一切行为活动及各主要脏器的外观形态。结果与空白对照组相比,大、小剂量鼻炎胶囊组对小鼠二甲苯性耳壳炎症、冰醋酸致痛作用及其腹腔注射后导致毛细血管通透性增高和大鼠棉球肉芽肿均有抑制作用(P<0.05),大剂量鼻炎胶囊组作用更强。急性毒性实验显示小鼠未见任何异常,无死亡,主要脏器外观形态无异常。结论该药可减轻小鼠二甲苯性耳壳炎症及降低冰醋酸腹腔注射后毛细血管的通透性和抑制大鼠棉球肉芽肿,并有止痛作用。急性毒性实验表明该药无毒性,安全性好。     

胆碱对乌头碱和哇巴因所诱发的心律失常的保护作用

目的探讨胆碱对乌头碱和哇巴因所诱发的心律失常的保护作用。方法大鼠和豚鼠分别注射乌头碱或哇巴因制备心律失常模型,观察预先给予低剂量(5 mg.kg-1)和高剂量(20 mg.kg-1)的胆碱对心律失常的保护作用。结果给予胆碱可明显对抗乌头碱或哇巴因所诱发的心律失常,表现为明显延迟心律失常的出现,推迟动物死亡时间等。高剂量胆碱对心律失常的保护作用优于低剂量。结论胆碱对心律失常具有保护作用,高剂量的作用优于低剂量。     

The effects of naloxone on body rotation-induced analgesia and anorexia in male mice

The effects of body rotation in a horizontal plane and the opiate antagonist, naloxone, on the nociceptive responses and the feeding behavior of male mice were examined. In the first experiment the mice were rotated (70 rpm, schedule of 15 sec on; 5 sec off) for 60 minutes or exposed to sham rotation for the same duration. Midway through the rotation or sham procedure the mice were either injected with naloxone (1 mg/kg) or isotonic saline. At the end of the 60-minute treatment period the animals were placed on a warm surface (47.5 degrees C) and their latency to show a foot-licking response was measured. The rotation procedure produced a significant (p less than 0.01) increase in response latency in the saline-injected mice and the naloxone injections blocked this analgesic effect. This finding provides evidence for opioid involvement in the rotation-induced analgesia. In Experiment 2 mice on a food restriction schedule were rotated (70 rpm, 15 sec on; 5 sec off) or sham exposed for 60 minutes. Midway through this treatment period the mice were either injected with naloxone (1 mg/kg) or isotonic saline. Following the treatment period the mice were given access to food for 2 hours. The rotation procedure produced a significant (p less than 0.01) reduction in feeding (anorexia) in the first 30 minutes of food access for the saline-injected mice. Injections of naloxone significantly (p less than 0.05) enhanced the rotation-induced anorexia. These experiments demonstrate that rotation-induced analgesia in mice is blocked by the opiate antagonist, naloxone, whereas rotation-induced anorexia is not.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combination anticonvulsant treatment of soman-induced seizures

These studies investigated the effectiveness of combination treatment with a benzodiazepine and an anticholinergic drug against soman-induced seizures. The anticholinergic drugs considered were biperiden, scopolamine, trihexaphenidyl, and procyclidine; the benzodiazepines were diazepam and midazolam. Male guinea pigs were implanted surgically with cortical screw electrodes. Electrocorticograms were displayed continually and recorded on a computerized electroencephalographic system. Pyridostigmine (0.026 mg x kg(-1), i.m.) was injected as a pretreatment to inhibit red blood cell acetylcholinesterase by 30-40%. Thirty minutes after pyridostigmine, 2 x LD50 (56 microg x kg(-1)) of soman was injected s.c., followed 1 min later by i.m. treatment with atropine (2 mg x kg(-1)) + 2-PAM (25 mg x kg(-1)). Electrographic seizures occurred in all animals. Anticonvulsant treatment combinations were administered i.m. at 5 or 40 min after seizure onset. Treatment consisted of diazepam or midazolam plus one of the above-mentioned anticholinergic drugs. All doses of the treatment compounds exhibited little or no antiseizure efficacy when given individually. The combination of a benzodiazepine and an anticholinergic drug was effective in terminating soman-induced seizure, whether given 5 or 40 min after seizure onset. The results suggest a strong synergistic effect of combining benzodiazepines with centrally active anticholinergic drugs and support the concept of using an adjunct to supplement diazepam for the treatment of nerve-agent-induced seizures.