盐酸戊乙奎醚对抗敌敌畏的毒性作用

 目的：研究盐酸戊乙奎醚（penequinine hydrochloride，PCHE）对敌敌畏（DDVP）诱发的呼吸循环抑制和脑电图（EEG）变化的影响。方法：同时测定麻醉大鼠的血压、心率、呼吸频率和呼吸通气量；记录清醒大鼠的EEG。结果：给麻醉大鼠iv DDVP 5mg·kg^－1，可使呼吸频率，呼吸通气量，血压及心率很快抑制。当iv不能通过血脑屏障的胆碱受体阻断剂甲基阿托品后，DDVP的呼吸循环抑制作用改善不明显；而应用PCHE1，2mg·kg^－1及阿托品2，4mg·kg^－1时能明显对抗DDVP引起的呼吸循环抑制。清醒大鼠DDVP中毒后EEG出现去同步化改变，少数出现癫痫波，PCHE可完全对抗DDVP诱发的EEG改变，阿托品仅部分对抗。结论：PCHE具有较强的中枢及外周抗DDVP中毒作用。     

不同剂型活性炭对有机磷杀虫剂的吸附性能比较体外实验

目的通过比较三种剂型活性炭对两种常见有机磷杀虫剂（敌敌畏和甲胺磷）在不同条件下的吸附作用,为临床使用活性炭治疗经口有机磷农药中毒寻找实验室依据。方法量取50%甲胺磷原油或68%敌敌畏原油后稀释100倍制备低浓度药剂或稀释10倍制备高浓度药剂,用0.1mmol/L盐酸溶液调节所配制溶液的pH值。分别取10ml具塞试管12支,分为粉状活性炭组、活性炭混悬液组、片剂活性炭组、空白对照组4组,每组试管3支。向粉状活性炭组试管中加入粉状活性炭0.3g,再分别向其他各组试管中加入活性炭含量相同的不同剂型活性炭。然后再向所有试管中加入配制好的低/高浓度敌敌畏或甲胺磷溶液5ml,震荡摇匀2min,放入37℃恒温水浴中孵育。分别在1h（低、高浓度组）、4h（低浓度组）时间点从每支试管中取0.5ml上清液,用气相色谱法检测其甲胺磷含量。结果不同剂型活性炭对低浓度敌敌畏和甲胺磷的吸附能力结果表明,无论是中性环境还是酸性环境下,在1及4h时间点对2种杀虫剂均有很好的吸附能力（P〈0.01）,且三种类型的活性炭间吸附能力无统计学意义（P〉0.05）。活性炭对于高浓度的敌敌畏（6.8%）均有很好的吸附能力（P〈0.01）,而且粉状炭的吸附能力最优（P〈0.01）。但对于高浓度的甲胺磷（5%）三类活性炭均不能有效的吸附（P〉0.05）。结论在模拟的胃肠道环境下,活性炭能有效的吸附低浓度的敌敌畏和甲胺磷;对于高浓度的敌敌畏,三类活性炭也显示出良好的吸附能力,以粉状炭的吸附能力最优;但对于高浓度的甲胺磷三类活性炭均不能有效的吸附。     

Methamidophos,dichlorvos, O‐methoate and diazinon pesticides used in Turkey make a covalent bond with butyrylcholinesterase detected by mass spectrometry

Organophosphorus pesticides used most commonly in Turkey include methamidophos, dichlorvos, O‐methoate and diazinon. These toxic chemicals or their metabolites make a covalent bond with the active site serine of butyrylcholinesterase. Our goal was to identify the adducts that result from the reaction of human butyrylcholinesterase with these pesticides. Highly purified human butyrylcholinesterase was treated with a 20‐fold molar excess of pesticide. The protein was denatured by boiling and digested with trypsin. MS and MSMS spectra of HPLC‐purified peptides were acquired on a MALDI‐TOF‐TOF 4800 mass spectrometer. It was found that methamidophos added a mass of +93, consistent with addition of methoxy aminophosphate. A minor amount of adduct with an added mass of +109 was also found. Dichlorvos and O‐methoate both made dimethoxyphosphate (+108) and monomethoxyphosphate adducts (+94). Diazinon gave a novel adduct with an added mass of +152 consistent with diethoxythiophosphate. Inhibition of enzyme activity in the presence of diazinon developed slowly (15 h), concomitant with isomerization of diazinon via a thiono‐thiolo rearrangement. The isomer of diazinon yielded diethoxyphosphate and monoethoxyphosphate adducts with added masses of +136 and +108. MSMS spectra confirmed that each of the pesticides studied made a covalent bond with serine 198 of butyrylcholinesterase. These results can be used to identify the class of pesticides to which a patient was exposed.     

4-Hydroxy TEMPO Attenuates Dichlorvos Induced Microglial Activation and Apoptosis

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雄激素受体在敌敌畏诱导小鼠尿道下裂中的表达

目的 探讨尿道下裂仔鼠阴茎皮肤和睾丸组织中雄激素受体(androgen receptor,AR)的表达情况及其发病机制.方法选取10只正常对照组仔鼠(A组),10只敌敌畏造模组非尿道下裂仔鼠(B组),10只敌敌畏造模组先天性尿道下裂仔鼠(C组),通过免疫组化法检测各组小鼠阴茎皮肤和睾丸组织AR的表达. 结果 尿道下裂仔鼠阴茎皮肤组织中AR含量明显低于空白对照组和造模组非尿道下裂组(P<0.05),而空白对照组仔鼠和造模组非尿道下裂仔鼠间AR含量无明显统计学差异(P>0.05).3组之间睾丸组织中AR含量总体上无明显统计学差异(P>0.05). 结论 有机磷农药敌敌畏诱导小鼠尿道下裂的发生,可能是由于敌敌畏导致小鼠阴茎皮肤组织AR的表达下降,从而导致雄激素和其受体的结合下降所致.     

Lysophosphatidylcholine hydrolases of human erythrocytes, lymphocytes, and brain: sensitive targets of conserved specificity for organophosphorus delayed neurotoxicants

Brain neuropathy target esterase (NTE), associated with organophosphorus (OP)-induced delayed neuropathy, has the same OP inhibitor sensitivity and specificity profiles assayed in the classical way (paraoxon-resistant, mipafox-sensitive hydrolysis of phenyl valerate) or with lysophosphatidylcholine (LysoPC) as the substrate. Extending our earlier observation with mice, we now examine human erythrocyte, lymphocyte, and brain LysoPC hydrolases as possible sensitive targets for OP delayed neurotoxicants and insecticides. Inhibitor profiling of human erythrocytes and lymphocytes gave the surprising result of essentially the same pattern as with brain. Human erythrocyte LysoPC hydrolases are highly sensitive to OP delayed neurotoxicants, with in vitro IC50 values of 0.13-85 nM for longer alkyl analogs, and poorly sensitive to the current OP insecticides. In agricultural workers, erythrocyte LysoPC hydrolyzing activities are similar for newborn children and their mothers and do not vary with paraoxonase status but have high intersample variation that limits their use as a biomarker. Mouse erythrocyte LysoPC hydrolase activity is also of low sensitivity in vitro and in vivo to the OP insecticides whereas the delayed neurotoxicant ethyl n-octylphosphonyl fluoride inhibits activity in vivo at 1-3 mg/kg. Overall, inhibition of blood LysoPC hydrolases is as good as inhibition of brain NTE as a predictor of OP inducers of delayed neuropathy. NTE and lysophospholipases (LysoPLAs) both hydrolyze LysoPC, yet they are in distinct enzyme families with no sequence homology and very different catalytic sites. The relative contributions of NTE and LysoPLAs to LysoPC hydrolysis and clearance from erythrocytes, lymphocytes, and brain remain to be defined.     

Measurement of pesticides in hair samples from pemphigus foliaceus and pemphigus vulgaris patients in Southeastern Brazil

BackgroundPesticides, mainly organophosphates (OP), have been related to increased risk of pemphigus vulgaris (PV) and pemphigus foliaceus (PF), nevertheless, their measurement has not been determined in pemphigus patients.ObjectiveTo evaluate pesticide exposure and pesticide measurement, comparing PV, PF and control groups in Southeastern Brazil.MethodsInformation about urban or rural residency and exposure to pesticides at the onset of pemphigus was assessed by questionnaire interview; hair samples from the scalp of PV, PF, and controls were tested for OP and organochlorines (OC) by gas-phase chromatography coupled to mass spectrometry.ResultsThe minority of PV (2 [7.1%] of 28) and PF (7 [18%] of 39), but none of the 48 controls, informed living in rural areas at the onset of pemphigus (p = 0.2853). PV (33.3%), PF (38.5%), and controls (20%) informed exposure to pesticides (p = 0.186). Twenty-one (14.8%) of 142 individuals tested positive for OP and/or OC: PV (2 [6.3%] of 32) and PF (11 [25.6%] of 43) had similar pesticides contamination as controls (8 [11.9%] of 67) (p = 0.4928; p = 0.0753, respectively), but PF presented higher contamination than PV (p = 0.034). PV did not present any positivity for OP. Three (7%) PF tested positive for both OP and OC. Some PF tested positive for three or four OP, mainly diazinon and dichlorvos.Study limitationLack of data for some controls.ConclusionAlthough the frequency of PV and PF patients exposed to pesticides was similar, pesticides were more frequently detected in hair samples from PF compared to PV. The cause-effect relationship still needs to be determined.     

Evaluation of respiratory dysfunction in a pig model of severe acute dichlorvos poisoning

Background  Respiratory failure is the main cause of death in acute organophosphorus pesticide poisoning. In this study, a pulse-induced contour cardiac output monitor was used to evaluate the respiratory status in a pig model of acute dichlorvos poisoning.

Methods  Twenty female pigs were randomly allocated to dichlorvos (n=7), atropine (n=7), and control (n=6) groups. In the dichlorvos group, pigs were administered 80% emulsifiable dichlorvos (100 mg/kg) via a gastric tube. In the atropine group, pigs were similarly administered dichlorvos, and 0.5 hours later, atropine was injected to attain and maintain atropinization. The control group was administered saline solution. Arterial blood gas was measured at 0, 0.5, 1, 2, 4, and 6 hours post-injection. The extravascular lung water index and pulmonary vascular permeability index were recorded by the pulse-induced contour cardiac output monitor. At termination of the study, the animals were euthanized, the lung wet-to-dry weight ratio was determined, and histopathology was observed.

Results  In the dichlorvos group, the extravascular lung water index and pulmonary vascular permeability index were substantially increased from 0.5 hours and were particularly high within 1 hour. In the atropine group, these indices increased initially, but decreased from the 1-hour mark. The control group exhibited no obvious changes. In both the dichlorvos and atropine groups, the extravascular lung water index was negatively correlated with partial pressure of oxygen/fraction of inspiration oxygen (PO₂/FiO₂) and positively correlated with the pulmonary vascular permeability index. Compared with the control group, the lung wet-to-dry weight ratio markedly increased and the histopathological findings obviously changed in the dichlorvos group, but only mildly increased and changed, respectively, in the atropine group.

Conclusion  The extravascular lung water index is an appropriate and valuable parameter for assessment of respiratory function in acute dichlorvos poisoning.

     

Protective effects of penehyclidine hydrochloride on acute lung injury caused by severe dichlorvos poisoning in swine

Background Organophosphate poisoning is an important health problem in developing countries which causes death mainly by inducing acute lung injury. In this study, we examined the effects of penehyclidine hydrochloride （PHC）, a selective M-receptor inhibitor, on dichlorvos-induced acute lung injury in swine. Methods Twenty-two female swines were randomly divided into control （n=5）, dichlorvos （n=6）, atropine （n=6）, and PHC （n=5） groups. Hemodynamic data, extravascular lung water index （EVLWI）, and pulmonary vascular permeability index （PVPI） were monitored; blood gas analysis and acetylcholinesterase （AchE） levels were measured. PaO2/FiO2, cardiac index （CI）, and pulmonary vascular resistance indices （PVRI） were calculated. At termination of the study, pulmonary tissue was collected for ATPase activity determination and wet to dry weight ratio （W/D） testing 6 hours post-poisoning. TUNEL assay, and Bax, Bcl-2, and caspase-3 expression were applied to pulmonary tissue, and histopathology was observed. Results After poisoning, PHC markedly decreased PVRI, increased CI more effectively than atropine. Anticholinergic treatment reduced W/D, apoptosis index （AI）, and mitigated injury to the structure of lung; however, PHC reduced AI and caspase-3 expression and improved Bcl-2/Bax more effectively than atropine. Atropine and PHC improved ATPase activities; a significant difference between groups was observed in Ca2＋-ATPase activity, but not Na＋-K＋-ATPase activity. Conclusions The PHC group showed mild impairment in pathology, less apoptotic cells, and little impact on cardiac function compared with the atropine group in dichlorvos-induced acute lung injury.     

庆余肾气丸,复方丹参片中有机磷农药多残留分析方法的研究

采用气相色谱法测定庆余肾气丸、复方丹参片中敌敌畏、甲胺磷、乐果、敌百虫残留量，样品经浸渍超声提取，液液萃取、柱层析净化后直接进样分析。方法检测限可达４×１０（－２）～８×１０（－２）μｇ／ｇ，方法回收率稳定在８２．００％～９３．２３％，变异系数为１．７７～７．７８％．农残测定结果显示，庆余肾气丸、复方丹参片中有机磷农药残留均低于世界各国的限量标准。