Spectrophotometric investigation of complex formation of an oxime PAM-4Cl with palladium(II) and its analytical application

The colour reaction of 4-hydroxyiminomethyl-1-methylpyridinium chloride (PAM-4Cl) and palladium(II) chloride has been investigated. The optimum reaction conditions, spectral characteristics, conditional stability constant and composition of the yellow water-soluble complex have been established. A new spectrophotometric method is proposed for the microdetermination of PAM-4Cl.     

Pharmacokinetics of the acetylcholinesterase oxime reactivator, HI-6, in rhesus monkeys (Macaca mulatta): effect of atropine, diazepam, and methoxyflurane anesthesia

The pharmacokinetics of the bispyridinium oxime HI-6 (CAS reg. no. 34433-31-3; 1-(((4-aminocarbonyl)pyridinio)methoxy)methyl)-2-[hydroxy i mino)methyl)- pyridinium dichloride) was investigated in rhesus monkeys (Macaca mulatta). The effects of methoxyflurane anesthesia, administration of atropine with and without diazepam were determined on the serum half-life (t1/2), clearance rate (CL), and the volume of distribution (Vd) following intramuscular (IM) administration of HI-6 (30 mg kg-1). The control t1/2, CL and Vd of HI-offere 27 min, 8.6 ml min-1 kg-1 and 0.34 l kg-1, respectively. These parameters were unaffected by the co-administration of either atropine (0.5 mg kg-1, IM) or atropine and diazepam (0.5 mg kg-1, IM + 0.2 mg kg-1 IV, respectively). Methoxyflurane anesthesia resulted in a significant increase in the HI-6 t1/2 to 61 min concomitant with a decrease in the CL to 4.1 ml min-1 kg-1 with no change in the Vd. The increase in the t1/2 of HI-6 in methoxyflurane anesthetized monkeys is probably the result of a decrease in the clearance rate and, thus, excretion of HI-6 by the kidneys.     

Reactivating potency of obidoxime, pralidoxime, HI 6 and HLö 7 in human erythrocyte acetylcholinesterase inhibited by highly toxic organophosphorus compounds

The treatment of poisoning by highly toxic organophosphorus compounds (nerve agents) is unsatisfactory. Until now, the efficacy of new potential antidotes has primarily been evaluated in animals. However, the extrapolation of these results to humans is hampered by species differences. Since oximes are believed to act primarily through reactivation of inhibited acetylcholinesterase (AChE) and erythrocyte AChE is regarded to be a good marker for the synaptic enzyme, the reactivating potency can be investigated with human erythro‐cyte AChE in vitro. The present study was undertaken to evaluate the ability of various oximes at concentrations therapeutically relevant in humans to reactivate human erythrocyte AChE inhibited by different nerve agents. Isolated human erythrocyte AChE was inhibited with soman, sarin, cyclosarin, tabun or VX for 30?min and reactivated in the absence of inhibitory activity over 5–60?min by obidoxime, pralidoxime, HI 6 or HLö 7 (10 and 30?μM). The AChE activity was determined photometrically. The reactivation of human AChE by oximes was dependent on the organophosphate used. After soman, sarin, cyclosarin, or VX the reactivating potency decreased in the order HLö 7 > HI 6 > obidoxime > pralidoxime. Obidoxime and pralidoxime were weak reactivators of cyclosarin-inhibited AChE. Only obidoxime and HLö 7 reactivated tabun-inhibited AChE partially (20%), while pralidoxime and HI 6 were almost ineffective (5%). Therefore, HLö 7 may serve as a broad-spectrum reactivator in nerve agent poisoning at doses therapeutically relevant in humans.     

Evaluation of the cyto/genotoxicity profile of oxime K048 using human peripheral blood lymphocytes: An introductory study

This study investigates the effects of oxime K048 (730, 200, and 7.3 nM) on the viability and chromosome stability of human peripheral blood lymphocytes (PBLs) after a 30 min exposure in vitro. Cytotoxicity was tested by a viability assay with ethidium bromide and acridine orange. For the evaluation of the genotoxic potential, we used comet assays, cytokinesis-blocked micronucleus (CBMN) assay, and chromosome aberration (CA) analysis. We found acceptable cytotoxicity for K048 (9.7 ± 2.1% non-viable PBL at highest concentration vs. 7.3 ± 2.5% in control; apoptosis dominated over necrosis). Overall primary DNA damage was low and not significantly different from controls. The hOGG1-comet assay showed a slight increase in the level of oxidative DNA damage. In oxime treated PBLs, we found 13–19 MN compared to 15 MN in control cultures. The frequencies and types of CA in oxime-treated PBLs did not significantly differ from controls. K048 showed acceptable biocompatibility at the level of cell viability and chromatin/chromosome integrity. Since no increase in secondary genome damage was detected, the primary DNA lesions may have resulted from treatment-induced cell stress, subsequently becoming repaired and not fixed as chromosome aberrations. The toxicity profile of K048 should be further studied and compared with other clinically relevant oximes.     

复能剂持续性静脉维持对急性有机磷中毒伴呼吸衰竭患者疗效的影响

目的观察肟类复能剂持续性静脉给药和短时间重复静脉给药对急性有机磷中毒(AOPP)伴呼吸衰竭患者的疗效。方法采用前瞻性研究方法,将39例患者随机分成2组,均应用呼吸机辅助呼吸,静脉给予负荷量复能剂后,对照组19例短时间重复静脉给药;治疗组20例8 mg/(kg.h)微泵维持。2组其余治疗相同。结果治疗组机械通气时间、气管切开率、ICU住院时间均明显低于对照组(P<0.05);治疗3,5,7 d后治疗组的胆碱酯酶活性、3 d内脱机率明显高于对照组(P<0.05)。结论肟类复能剂持续性静脉维持可促进重度AOPP患者呼吸衰竭的缓解,减少机械通气时间及ICU住院时间,降低气管切开率,加速血胆碱酯酶活性的恢复。     

On a successfully treated acute oral paraoxone (E 600) poisoning

Summary A case of acute oral suicidal poisoning with paraoxone (E 600) and its treatment are described. The use of cholinesterase-reactivating substances and reanimation procedures achieved full success, even without a high dosage of atropine, in the treatment of that very serious poisoning. The problems concerned with the use of oximes in the therapy of organophosphate poisoning are discussed.     

芳香醛肟氧基乙酸的合成

目的：合成芳香醛肟的衍生物。方法：用芳香醛肟与氯乙酸反应得目标物。结果：合成5个芳香醛肟氧基乙酸化合物。结论：目标化合物的结构经IR、1HNMR、MS确证。     

美西律衍生物的合成及其抗惊厥活性

以美西律为先导化合物,合成了5个美西律的氮酰化衍生物Ⅲa-e和3个肟醚类化合物Ⅳa-c。氮酰化物用酰氯法合成,环状的酰亚胺衍生物以相应的二元酸酐为酰化剂,经单酰胺中间体,在适当的催化剂存在下脱水环合。肟醚类化合物采用酮肟钠盐与相应的氯苄反应制备。所合成的化合物经小鼠抗电惊厥试验,N-(1-甲基-2-(2,6-二甲基苯氧基)乙基)丁酰亚胺有一定抗惊厥活性,其它化合物无活性。     

急性有机磷农药中毒中间综合征17例分析

目的：探讨急性有机磷农药中毒中间综合征（IMS）的临床特点及临床处理对策。方法：对17例急性有机磷农药中毒中间综合征患者的临床资料进行分析。结果：IMS出现在中毒后1～5d,经积极救治17例中完全治愈13例,好转1例,死亡3例。结论：中间综合征以对症支持治疗为主。急性期应用阿托品的同时,及早、足量、重复应用肟类复能剂以及适时应用机械通气可有效防治中间综合征。