鸡甲胺磷中毒性神经肌病电生理测定及药物干预研究
摘要
有机磷酸酯农药不仅能抑制胆碱酯酶，引起典型的胆碱能危象为主的急性中毒表现，还能使重症患者在急性期恢复后发生迟发神经病变，表现为肢体麻木乏力甚至瘫痪，病程长，重症者不能完全恢复，严重影响患者的生活和工作。
甲胺磷属高毒类有机磷农药，不同途径包括消化道，呼吸道和皮肤接触均可造成急性中毒，但以消化道中毒所致迟发性神经病的机率最大。不同的有机磷农药引起的0PIDN有种属特异性，以人类和鸡最为敏感，而啮齿动物则不敏感。鉴于消化道染毒毒物剂量易于控制，鸡对甲胺磷的敏感性高，我们本次实验选用莱亨母鸡进行甲胺磷染毒制成迟发性神经病的动物模型。
以往许多文献报告0PIDN选用大剂量B族维生素、ATP、地巴唑、硝酸一叶秋碱治疗以及一些中药制剂，但疗效不确切。目前普遍认为糖皮质激素可以加速0PIDN的恢复，但副作用大，禁忌症较多，因此寻找一种安全有效的治疗药物迫在眉睫。依美思为核苷酸类药物，主要有效成份为三磷酸胞苷(CTP)，在机体内参与磷脂类及核酸的合成和代谢。具有营养神经，支持神经细胞存活，延缓死亡，提高神经细胞抗损伤能力，增强神经细胞活性，促进神经突起生长的作用。本实验利用行为学及电生理检测方法来研究甲胺磷所致的周围神经系统损害，并观察CTP的防治作用，这在国内尚属首例。
本实验选用莱亨母鸡(鸡龄1年左右，体重1.5±O.5kg)105只，
其中5只为正常鸡，不染毒，也不给药。余100只均分为4组。室温
21～23℃，单笼饲养，甲胺磷用植物油溶解，浓度为5mg／ml,按2m1／kg体积通过套管直接灌入已断食24小时的鸡素囊中，染毒的
鸡用阿托品保持度过急性期，染毒前20分钟8mg／kg肌注，染毒后3、6、10小时4mg／kg肌注。A组为盐水组，染毒后每天肌注生理盐水(1ml／kg)，连续一周。B组为依美思小剂量组(浓度1.5 mg／ml)，染毒后每天肌注1ml／kg，连续一周。C组为依美思大剂量组(浓度3mg／m1)，染毒后每天肌注1m1／kg，连续一周。D组为激素组，染毒后每天肌注地塞米松1mg／kg，连续一周。分别于实验前后称量体重并观察临床表现。并于染毒后1、2、3、4、8周随机取各实验组2～6只进行标本取样，游离坐骨神经，于P0werlab生物记录仪上行电生理检测(包括波幅，时值，远端潜伏期，运动神经传导速度的测定)。
本实验急性期鸡经甲胺磷染毒后5—10分钟即表现萎靡、流涎、瞳孔缩小、喜卧，从第2天开始有动物死亡，共死亡1 5只，其中12只死亡时间为染毒后2—8天，另两只分别死亡于染毒后12天，15天和40天，急性期死亡率占总死亡率的80％，各组均有死亡，经四格表统计处理，各组间死亡率差异无显著性，说明依美思及地塞米松不降低急性期有机磷中毒表现及死亡率，此期死因为中间综合征。之后经过1周左右的潜伏期，出现迟发性神经病的症状，动物的表现开始呈全身无力状态，喜卧，后出现步态不稳，逐渐发展为站立困难，此期肌力下降表现为1级及2级，无完全瘫痪者。各实验组发病率见表，组间比较无统计学意义，说明依美思及地塞米松不降低有机磷中毒迟发性神经病的发病。
神经电生理检测结果表明，染毒后1周，波幅有明显降低，而运动神经传导速度及远端潜伏期无明显改变，提示周围神经早期以轴索损害为主。其后2，3周波幅逐渐升高，至第4周波幅已恢复正常。染毒后2成为周出现运动神经传导速度减慢及远端潜伏期延长，提示出现脱髓鞘改变。至第8周运动神经传导速度及远端潜伏
期方恢复正常。依美思治疗组及激素组与盐水组比较，各电生理指标变化均无组间差异，提示本病有自愈倾向。曾有学者认为小剂量激素治疗本病可缩短病程，本实验并不支持此学说。
实验前后称量莱亨母鸡体重，盐水组及依美思大剂量组，依美思小剂量组体重均有明显变化，即体重有增加，而应用地塞米松治疗后，体重无明显改变，提示地塞米松治疗效果欠佳，可能因其副作用而影响鸡的正常生长。
综上，我们得出以下结论：通过给莱亨母鸡经消化道甲胺磷染毒，成功的制作了迟发性神经病动物模型；甲胺磷致迟发性神经病早期以轴索损害为主(波幅降低)，继之出现脱髓鞘改变(远端潜伏期延长及运动神经传导速度减慢)；地塞米松治疗效果不明显且副作用大，不宜在临床上广泛使用；依美思可作为地塞米松的替代治疗使用，但早黟应用并不能防止迟发性周围神经病的发生；周围神经电生理改变早于神经肌肉病理改变，可以作为临床判定周围神经损害的早期诊断依据。
Organophosphorus pesticide can not only restrain cholinesterase, arosing acute poisoning representation giving priority to typical gallbladder alkali crisis, but also can cause serious sufferer developed into delayed nerve pathological changes after resume from urgent period, representing body anaesthesia, tired even paralysis, the course of diseases prolonged, serious sufferer can't resume entirely, severely infect the life and work of the sufferer.
Methamidophos is high toxic organophosphorus pesticide, different approach including alimentary canal, respiratory canal and cutis contact all can cause acute toxicosis, but the ratio of alimentary canal toxicosis caused delayed neuropathy is the highest.Different organophosphorus pesticide induced OPIDN have category specialty, human and hens have the most sensitivity, while rodent have no sensitivity.whereas poison dosage can be controlled easily through alimentary canal, hens have higher sensitivity to methamidophos, we select leghorn hens carrying through methamidophos then crank out delayed peripheral neuropathy animal model in our experiment.
Many literature reported that big dosage vitamine B family ,ATP(adenosine triphosphate),bendazol,securinine and some Chinese traditional medicine preparations can cure OPIDN ,however, the curative effect is not reliable.lt is urgent to find one safe and effective medcine to cure OPIDN,though it is believed that the glucocorticoid can quicken up the recovery of OPIDN,it has many side-effects and tabus. CTP is nucleotide ramification medicine,which participate in synthesis and metabolism of lecithoid and nucleic acid.lt can nurture nerve , sustain the nerve cell exist, postpone death, advance the ability of nerve cell to resist trauma , buildup the activity of nerve cell, advance the nerve axis grow .In this experiment,we carry out action study and electricity physiology check to research methamidophos induced peripheral nerve systeminjury.and
observe the prevention and cure effect of CTP, this is still the first case interiorly.
Inthisexperiment,wechoose105leghornhens(aboutone year-old , weigh1,5±0.5kg), among those hens ,5 are normal .given no poison and no medicine cure.The last 100 average into 4 groups.Room temperature is 21-23 with a 12-hr light/12-hr dark cycle , single cage breed, methamidophos is dissolved in plant oil, the concentration is 5mg/ml, and administered as a single dose in a volume of 2 ml/kg by oral cannula directly into the crop of hens fasted for 24 hr.The toxic hens survive the urgent period by administering atropin,muscle injecting 8mg/kg before administering poison 20 minutes, muscle injecting 4mg/kg after poisoning 3、6、10 hours. Group A is brine group, muscle injecting brine every day after poisoing (1 ml/kg), continueone week.Group B is small dosage CTP group (concentration 1.5 mg/ml), muscle injecting every day by 1 ml/kg after poisoing, continue one week.Group C is big dosage CTP group, (concentration 3 mg/ml), muscle injecting every day by 1 ml/kg after poisoing, continue one week.Group D is dexamethasone group, muscle injecting every day by 1 ml/kg after poisoing, continue one week.Quantify the avoirdupois before and after the testing ,and observe the clinic manifestation,After 1、2、 3、 4、 8weeks, randomly sampling 2-6 in each group , dissociating hucklebone nerve, carrying out electricity physiological test by the Powerlab biology record instrument (including amplitude , duration, terminal latent period, motor nerve conduct velocity).
In this experiment, the hens behave sag , salivate,pupil reduce,be fond of lying after methamidophos poisoning 5~10 minutes in urgent period, in the second day ,the hens begin to die, together death is 15, thereinto, 12 hens die in post 2~8 days after poisoning , the other
there died at post12 ,15and 40 days after poisoning respectly,occupy 80% in overall mortality . Each group all have death,through four metre
Stat, Disposal , mortality between each group have no marked difference , this tell us that CTP and dexamethasone c
甲胺磷属高毒类有机磷农药，不同途径包括消化道，呼吸道和皮肤接触均可造成急性中毒，但以消化道中毒所致迟发性神经病的机率最大。不同的有机磷农药引起的0PIDN有种属特异性，以人类和鸡最为敏感，而啮齿动物则不敏感。鉴于消化道染毒毒物剂量易于控制，鸡对甲胺磷的敏感性高，我们本次实验选用莱亨母鸡进行甲胺磷染毒制成迟发性神经病的动物模型。
以往许多文献报告0PIDN选用大剂量B族维生素、ATP、地巴唑、硝酸一叶秋碱治疗以及一些中药制剂，但疗效不确切。目前普遍认为糖皮质激素可以加速0PIDN的恢复，但副作用大，禁忌症较多，因此寻找一种安全有效的治疗药物迫在眉睫。依美思为核苷酸类药物，主要有效成份为三磷酸胞苷(CTP)，在机体内参与磷脂类及核酸的合成和代谢。具有营养神经，支持神经细胞存活，延缓死亡，提高神经细胞抗损伤能力，增强神经细胞活性，促进神经突起生长的作用。本实验利用行为学及电生理检测方法来研究甲胺磷所致的周围神经系统损害，并观察CTP的防治作用，这在国内尚属首例。
本实验选用莱亨母鸡(鸡龄1年左右，体重1.5±O.5kg)105只，
其中5只为正常鸡，不染毒，也不给药。余100只均分为4组。室温
21～23℃，单笼饲养，甲胺磷用植物油溶解，浓度为5mg／ml,按2m1／kg体积通过套管直接灌入已断食24小时的鸡素囊中，染毒的
鸡用阿托品保持度过急性期，染毒前20分钟8mg／kg肌注，染毒后3、6、10小时4mg／kg肌注。A组为盐水组，染毒后每天肌注生理盐水(1ml／kg)，连续一周。B组为依美思小剂量组(浓度1.5 mg／ml)，染毒后每天肌注1ml／kg，连续一周。C组为依美思大剂量组(浓度3mg／m1)，染毒后每天肌注1m1／kg，连续一周。D组为激素组，染毒后每天肌注地塞米松1mg／kg，连续一周。分别于实验前后称量体重并观察临床表现。并于染毒后1、2、3、4、8周随机取各实验组2～6只进行标本取样，游离坐骨神经，于P0werlab生物记录仪上行电生理检测(包括波幅，时值，远端潜伏期，运动神经传导速度的测定)。
本实验急性期鸡经甲胺磷染毒后5—10分钟即表现萎靡、流涎、瞳孔缩小、喜卧，从第2天开始有动物死亡，共死亡1 5只，其中12只死亡时间为染毒后2—8天，另两只分别死亡于染毒后12天，15天和40天，急性期死亡率占总死亡率的80％，各组均有死亡，经四格表统计处理，各组间死亡率差异无显著性，说明依美思及地塞米松不降低急性期有机磷中毒表现及死亡率，此期死因为中间综合征。之后经过1周左右的潜伏期，出现迟发性神经病的症状，动物的表现开始呈全身无力状态，喜卧，后出现步态不稳，逐渐发展为站立困难，此期肌力下降表现为1级及2级，无完全瘫痪者。各实验组发病率见表，组间比较无统计学意义，说明依美思及地塞米松不降低有机磷中毒迟发性神经病的发病。
神经电生理检测结果表明，染毒后1周，波幅有明显降低，而运动神经传导速度及远端潜伏期无明显改变，提示周围神经早期以轴索损害为主。其后2，3周波幅逐渐升高，至第4周波幅已恢复正常。染毒后2成为周出现运动神经传导速度减慢及远端潜伏期延长，提示出现脱髓鞘改变。至第8周运动神经传导速度及远端潜伏
期方恢复正常。依美思治疗组及激素组与盐水组比较，各电生理指标变化均无组间差异，提示本病有自愈倾向。曾有学者认为小剂量激素治疗本病可缩短病程，本实验并不支持此学说。
实验前后称量莱亨母鸡体重，盐水组及依美思大剂量组，依美思小剂量组体重均有明显变化，即体重有增加，而应用地塞米松治疗后，体重无明显改变，提示地塞米松治疗效果欠佳，可能因其副作用而影响鸡的正常生长。
综上，我们得出以下结论：通过给莱亨母鸡经消化道甲胺磷染毒，成功的制作了迟发性神经病动物模型；甲胺磷致迟发性神经病早期以轴索损害为主(波幅降低)，继之出现脱髓鞘改变(远端潜伏期延长及运动神经传导速度减慢)；地塞米松治疗效果不明显且副作用大，不宜在临床上广泛使用；依美思可作为地塞米松的替代治疗使用，但早黟应用并不能防止迟发性周围神经病的发生；周围神经电生理改变早于神经肌肉病理改变，可以作为临床判定周围神经损害的早期诊断依据。
Organophosphorus pesticide can not only restrain cholinesterase, arosing acute poisoning representation giving priority to typical gallbladder alkali crisis, but also can cause serious sufferer developed into delayed nerve pathological changes after resume from urgent period, representing body anaesthesia, tired even paralysis, the course of diseases prolonged, serious sufferer can't resume entirely, severely infect the life and work of the sufferer.
Methamidophos is high toxic organophosphorus pesticide, different approach including alimentary canal, respiratory canal and cutis contact all can cause acute toxicosis, but the ratio of alimentary canal toxicosis caused delayed neuropathy is the highest.Different organophosphorus pesticide induced OPIDN have category specialty, human and hens have the most sensitivity, while rodent have no sensitivity.whereas poison dosage can be controlled easily through alimentary canal, hens have higher sensitivity to methamidophos, we select leghorn hens carrying through methamidophos then crank out delayed peripheral neuropathy animal model in our experiment.
Many literature reported that big dosage vitamine B family ,ATP(adenosine triphosphate),bendazol,securinine and some Chinese traditional medicine preparations can cure OPIDN ,however, the curative effect is not reliable.lt is urgent to find one safe and effective medcine to cure OPIDN,though it is believed that the glucocorticoid can quicken up the recovery of OPIDN,it has many side-effects and tabus. CTP is nucleotide ramification medicine,which participate in synthesis and metabolism of lecithoid and nucleic acid.lt can nurture nerve , sustain the nerve cell exist, postpone death, advance the ability of nerve cell to resist trauma , buildup the activity of nerve cell, advance the nerve axis grow .In this experiment,we carry out action study and electricity physiology check to research methamidophos induced peripheral nerve systeminjury.and
observe the prevention and cure effect of CTP, this is still the first case interiorly.
Inthisexperiment,wechoose105leghornhens(aboutone year-old , weigh1,5±0.5kg), among those hens ,5 are normal .given no poison and no medicine cure.The last 100 average into 4 groups.Room temperature is 21-23 with a 12-hr light/12-hr dark cycle , single cage breed, methamidophos is dissolved in plant oil, the concentration is 5mg/ml, and administered as a single dose in a volume of 2 ml/kg by oral cannula directly into the crop of hens fasted for 24 hr.The toxic hens survive the urgent period by administering atropin,muscle injecting 8mg/kg before administering poison 20 minutes, muscle injecting 4mg/kg after poisoning 3、6、10 hours. Group A is brine group, muscle injecting brine every day after poisoing (1 ml/kg), continueone week.Group B is small dosage CTP group (concentration 1.5 mg/ml), muscle injecting every day by 1 ml/kg after poisoing, continue one week.Group C is big dosage CTP group, (concentration 3 mg/ml), muscle injecting every day by 1 ml/kg after poisoing, continue one week.Group D is dexamethasone group, muscle injecting every day by 1 ml/kg after poisoing, continue one week.Quantify the avoirdupois before and after the testing ,and observe the clinic manifestation,After 1、2、 3、 4、 8weeks, randomly sampling 2-6 in each group , dissociating hucklebone nerve, carrying out electricity physiological test by the Powerlab biology record instrument (including amplitude , duration, terminal latent period, motor nerve conduct velocity).
In this experiment, the hens behave sag , salivate,pupil reduce,be fond of lying after methamidophos poisoning 5~10 minutes in urgent period, in the second day ,the hens begin to die, together death is 15, thereinto, 12 hens die in post 2~8 days after poisoning , the other
there died at post12 ,15and 40 days after poisoning respectly,occupy 80% in overall mortality . Each group all have death,through four metre
Stat, Disposal , mortality between each group have no marked difference , this tell us that CTP and dexamethasone c
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19..Johnson MK .The target for nitiation of delayed neurotoxicity by Organophosphorus esters；Biochemical studies and toxicological applications[J].Rev Biochem Toxical ，1982，4：141.
20.Johnson MK.symposium introduction:retrospect and propects for neuropathy target esterase (NTE) and the delayed polyneuropathy(OPIDN) induced by some organophosphorus esterase[J].Chem Biol interract,1987:339-346.
21.Dudek BR，Richardson RJ. Evidence for the existence of neurotoxic esterase in neural and lymphatic tissue of the adult hen[J]. Biochem Pharmacol，1982，31：1117.
22.Glynn P. Neural development and neurodegeneration: two faces of neuropathy target esterase[J].Prog Neurobiol,2000,61(1):61-74.
23.Katoh K.A review of studies of the delayed neurotoxicity induced by organophosphorus esters[J].Sangyo Eiseigaku Zasshi 1995,37:309.
24.邵蓓，郑荣远.甲胺磷中毒引起格林---巴利综合征1例[J].临床神经病学杂志，1995，8：85.
25.林晓东.有机磷农药中毒后迟发性周围神经病20例临床分析[J].中风与神经疾病杂志，1993，10（2）：114.
26.Baker T,et al.Methyprednisolone treatment of an organoposphorus-induced neuropathy.Toxicol Appl Pharmacol 1985,79:318
27.Enrich M, Jortner BS ,Gross WB. Types of adrenocorticoids and their effect on organophosphorus-induced delayed neuropathy in chickens[J]. Toxicol Appl Pharmacol, 1988,92(2):214-223.
28.虞炳庆，刘保群，芮晓东等.糖皮质激素治疗有机磷农药中毒后迟发神经病的疗效观察.临床神经病学杂志，1995，11(1)：46
29.刘晓玲，刘凤民.中西医结合治疗有机磷中毒迟发性周围神经病变.中国民间疗法，2000，8（2）：32
30.张聚府，张志远，王月芬.当归四逆汤治疗有机磷杀虫药中毒后迟发性周围神经病变25例.新中医，2002，34（3）：56
31.路克文，卢智.清磷治痿方治疗有机磷中毒后周围神经损害的临床观察.河北中医，2002，24（12）：908
32.汤晓芙.临床肌电图学.北京医科大学中国协和医科大学联合出版社，1995，1：21
33.陈国田，曹起龙.简明神经电生理诊断学.科学技术文献出版社，1998，1：298
34.Lotti MD,et al.Organophosphate polyneuropathy:Pathogenesis and prevention.Neurol 1984,34:659
35.Fiol LD,et al.Immunological aspects of Tri-o-tolyl phosphate induced delayed neurophy in chickens.Toxical Appl Pharmacol 1980,56:259