可逆性胆碱酯酶抑制剂的研究:2-氧化-1,3,2-二氧磷杂环己烷类化合物的合成

本文报道2-氧化-1,3,2-二氧磷杂环己烷类衍生物的合成,希望寻找效果较好的可逆性胆碱酯酶抑制剂。初步药理实验证明,所合成的大部分化合物具有一定的抑制乙酰胆碱酯酶的作用,且毒性较低。通过对中间体Ⅱ进行质谱分析,发现该类化合物中大部分存在M-57碎片离子峰,利用高分辨质谱和亚稳离子测定,确定了该碎片离子的生成过程。     

Role of Th1 and Th2 lymphocytes and cytokines produced by these cells in suppression of immune reactions during subacute poisoning with anticholinesterase toxicants

Experiments on Wistar rats showed that subacute poisoning with anticholinesterase toxicants zarin and agent VX (daily subcutaneous injections in 1/7 LD₅₀ for 6 days) led to suppression of cellular and humoral immune reactions and to a decrease in blood concentrations of cytokines (IL-2, IL-4, IFN-γ) with a reduction of the IFN-γ/IL-4 and IL-2/IL-4 ratios, which attests to more pronounced decrease in Th1 lymphocyte function in comparison with Th2 cells. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 7, pp. 62–64, July, 2007     

Changes in the sensitivity to cholinomimetic drugs of smooth and cardiac muscle in the rat induced by subacute administration of di-isopropyl phosphorofluoridate

The effect of subacute administration to rats of di-isopropyl phosphorofluoridate (DFP) on the sensitivity of the cardiovascular system to carbachol and on the sensitivity of various isolated tissues to acetylcholine, methacholine and carbachol was investigated. Cholinesterase inhibition produced by DFP in the isolated tissues was also determined.In the cardiovascular experiments both the magnitude of responses and the slope of the dose-response curves for hypotension and bradycardia produced by carbachol in the anaesthetized rat were reduced in the DFP-treated group.In experiments with isolated tissuesfrom DFP-treated animals it was found that sensitivity to methacholine and acetylcholine increased in the bladder to a greater extent that in the atria or ileum. The sensitivity to carbachol decreased to a similar extent in all 3 tissues. Acetylcholinesterase and butyrylcholinesterase levels in the bladder were inhibited to a greater extent than in the other 2 tissues.The results show that the degree of enzyme inhibition produced by DFP in the tissues after subacute administration for 10 days does not correlate with the decrease in the sensitivity of the tissues to carbachol. It is suggested that the association between accumulation of transmitter and enzyme inhibition is a more important factor than the degree of enzyme inhibition itself in the development of subsensitivity to carbachol.The release of cholinergic transmitter from the electrically stimulated isolated rat bladder may also be impaired following subacute administration of DFP.     

Effect of ambient temperature on thermoregulation in rats following preoptic/anterior hypothalamic injection of physostigmine

This experiment was designed to study the effect of ambient temperature (Ta) on the thermoregulatory response after the injection of the acetylcholinesterase blocking agent, physostigmine, into the preoptic/anterior hypothalamic area (POAH) of the rat. Three doses of physostigmine (3.0, 30.0 and 60.0 micrograms) were injected in a volume of 1.0 microliter in the preoptic/anterior hypothalamic area of unrestrained rats at three different ambient temperatures (15, 25 and 35 degrees C). Brain temperature (Tbr) and gross changes in behavior were monitored continuously throughout the duration of each experiment. Physostigmine induced hypothermia at ambient temperatures of 15 and 25 degrees C but not at 35 degrees C. Immediately prior to and during the hypothermic response the animals displayed behavioral reflexes such as fur licking and a sprawled posture which presumably enhanced heat loss. Generally, soon after the peak of the hypothermic response (approximately 30 min), the rats displayed heat-conserving behavior (huddled position, piloerection of the fur). These data indicate that the activity of cholinergic synapses within the preoptic/anterior hypothalamic area increases with decreasing ambient temperature. The behavioral observations suggest some role for the cholinergic system in the activation of heat-dissipating responses in the rat.     

Anticholinesterase activity of 7‐methoxyflavones isolated from Kaempferia parviflora

The rhizome of Kaempferia parviflora or kra‐chai‐dum (in Thai) is used traditionally as a folk medicine. The preliminary cholinesterase inhibitory screening of this plant extract exhibited significant acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. Thirteen known methoxyflavones (1–13) were isolated and their structures were completely elucidated based on NMR analysis and compared with literature reports. Minor compounds 12–13 were reported for the first time from this species. The cholinesterase inhibitory test results showed that the highest potential inhibitors toward AChE and BChE were 5,7,4′‐trimethoxyflavone (6) and 5,7‐dimethoxyflavone (7), respectively, with the percentage inhibitory activity varying over 43–85%. The structure‐activity relationship study led to the conclusion that compounds bearing 5,7‐dimethoxy groups and a free substituent at C‐3 had a significant inhibitory effect at a concentration of 0.1 mg/mL, but those bearing a 5‐hydroxyl group reduced the inhibitory potency. On the other hand, flavones bearing a 3′‐ or 5′‐methoxy group did not influence the inhibitory effect. Interestingly, 5,7‐dimethoxyflavone (7) exhibited strong selectivity for BChE over AChE which may be of great interest to modify as a treatment agent for Alzheimer's disease. Copyright © 2009 John Wiley & Sons, Ltd.     

Clinical presentation and laboratory findings of organic phosphorus poisoning

This study was conducted to evaluate the demographic, causative, and biologic characteristics of patients with organophosphate (OP) poisoning who were admitted to tertiary teaching and research hospitals at 2 different universities. All patients admitted to the emergency departments of Cukurova University Hospital in Adana, Turkey, between 2001 and 2003 and the Hospital of Mustafa Kemal University in Hatay, Turkey, between 2004 and 2006 were included. The study group consisted of subjects with a mean age of 28.5±14.1 y (range, 14–80 y), and the maximum number of cases in the second decade of life; the female-to-male ratio was 2.2:1. In all, 27 of 43 females and 16 of 20 males were married. Most subjects (n=55) had graduated from primary school; 3 were illiterate and 5 were highly educated. A total of 36 (57.1%) subjects belonged to lower socioeconomic groups. Fifty-three patients intended to commit suicide, and 10 cases were accidental. Mean arrival time of subjects to the hospital after poisoning was 9.9±16.1 h (range, 1–96 h); mean Glasgow Coma Scale score was 10.2±2.9 (range, 3–15). A total of 19 subjects were intubated, and 4 died. A total of 59 patients recovered completely. The mortality rate (6.3%) depended on various factors such as OP compound consumed, amount ingested, time interval before hospitalization, and patients’ general health. Chances for recovery were greater when the patient was hospitalized at the earliest indication. In conclusion, OPs especially affected young single females, and most cases were due to attempted suicide. Because OP poisoning is an important cause of morbidity and mortality, therapy should be started immediately to avoid undesirable consequences.     

氢溴酸加兰他敏口服液添加抑菌剂筛选与抑菌效力研究

目的:探索氢溴酸加兰他敏口服液中抑菌剂的合理添加剂量。方法:根据药物成分的特性,选择若干适宜的抑菌剂,并对不同配比浓度抑菌剂的抑菌效果进行初步考察,筛选出适宜的供试品抑菌剂加入量。选择有代表性的挑战微生物加入供试品中进行挑战试验,测试微生物在不同时间段的存活情况。结果:0.02%的对羟基苯甲酸丙酯与0.02%的对羟基苯甲酸甲酯复合使用对5种挑战微生物的生长有良好的抑制作用,为最低有效剂量。结论:0.02%的对羟基苯甲酸丙酯与0.02%的对羟基苯甲酸甲酯复合使用可作为氢溴酸加兰他敏口服液的抑菌剂。     

针刺结合拟胆碱能药物治疗膀胱逼尿肌收缩力低下症

目的：观察固定穴位针刺结合拟胆碱能药物治疗膀胱逼尿肌收缩力低下症的临床疗效。方法：对17例经尿流动力学检查诊断为膀胱逼尿肌收缩力低下症的患者,针刺百会、三阴交、关元、膀胱俞、肾俞、中极,同时口服拟胆碱能药溴吡斯的明,3例合并膀胱出口梗阻患者加用坦索洛辛。结果：治疗3疗程后,16例临床症状有不同程度缓解,其中4例恢复自行排尿;1例仍需膀胱造瘘引流。结论：固定穴位针刺结合拟胆碱能药物治疗膀胱逼尿肌收缩力低下症安全有效,疗效差异可能与原发疾病、病程长短和疗程有关。     

Antioxidant and anticholinesterase constituents from the petroleum ether and chloroform extracts of Iris suaveolens

The aim of this study was to investigate the phytochemical, antioxidant and anticholinesterase activities of Iris suaveolens. After determining total phenolic and flavonoid contents of the petroleum ether, chloroform and methanol extracts prepared from the rhizomes, the antioxidant capacity of the extracts was established using β‐carotene–linoleic acid and CUPRAC methods. The chloroform extract which was rich in phenolic content exhibited the highest inhibition of lipid peroxidation in the β‐carotene–linoleic acid system, and the best cupric reducing antioxidant capacity among the tested extracts. The petroleum ether extract indicated moderate anticholinesterase activity while the chloroform extract revealed significant butyrylcholinesterase inhibitory activity (75.03 ± 1.29%). Spectroscopic methods were used for the structural elucidation of the compounds (1–13) isolated from the petroleum ether and chloroform extracts. Coniferaldehyde (6), having the highest antioxidant activity in the β‐carotene–linoleic acid assay at 25 and 50 µg/mL, demonstrated also the best effect in the CUPRAC method among the tested compounds (1–12). 3‐Hydroxyirisquinone (10) showed the best anticholinesterase activity among the tested compounds (1–4, 6–12), and coniferaldehyde exhibited almost the same butyrylcholinesterase inhibitory activity (82.60 ± 2.33%) as galantamine (86.26 ± 0.66%). Copyright © 2010 John Wiley & Sons, Ltd.     

Cholinesterase inhibitory activity and chemical constituents of Stenochlaena palustris fronds at two different stages of maturity

Stenochlaena palustris fronds are popular as a vegetable in Southeast Asia. The objectives of this study were to evaluate the anticholinesterase properties and phytochemical profiles of the young and mature fronds of this plant. Both types of fronds were found to have selective inhibitory effect against butyrylcholinesterase compared with acetylcholinesterase. However, different sets of compounds were responsible for their activity. In young fronds, an antibutyrylcholinesterase effect was observed in the hexane extract, which was comprised of a variety of aliphatic hydrocarbons, fatty acids, and phytosterols. In the mature fronds, inhibitory activity was observed in the methanol extract, which contained a series of kaempferol glycosides. Our results provided novel information concerning the ability of S. palustris to inhibit cholinesterase and its phytochemical profile. Further research to investigate the potential use of this plant against Alzheimer’s disease is warranted, however, young and mature fronds should be distinguished due to their phytochemical differences.