| Objective:Germany's Bernhard Langer for the first time synthesized organophosphorus compounds and it has been used in agriculture since 1932, the organophosphorus pesticide has become a class of effective insecticides that was used the most widely around the world, as many as hundreds of varieties of species.Because it is high toxicity and used widely, it is easy for storage and protection inadequate or caused to the poisoning by drinking wrongly, commit suicide, et al. Organophosphorus pesticide poisoning is one of common poisoning in rural areas of China and is also the most common pesticide poisoning. In recent years, the total number of pesticide poisoning has dropped, the number of cases of mixed pesticide poisoning has increased year by year. It is reported that the majority of complex cases of pesticide poisoning are the mixture of organophosphorus and pyrethroids pesticide poisoning in this year in our country, the number of cases of the mixture of organophosphorus and pyrethroids pesticide from 1991 to 1995 is four times than the number of cases that from 1985 to 1990. At the same time, since pyrethroids pesticide has been widely used to the prevention crops from pests injury in the early 80s, the drug resistance.has been increasingly widespread, the effect of prevention gradually decreased. To resolve the coexistence of a variety of diseases and the need to delay the drug resistance, such pesticides are used in the form of mixture, particularly with the organophosphorus pesticides which is registered in a large proportion in China. Pyrethroid pesticides have a low toxicity on humans, skin absorption for a long time, or through oral can cause poisoning, it can cause muscle spasms by influencing the transmission of nerve axons.At present, atropine and oxime cholinesterase agents are the effective drugs for the treatment of organophosphorus pesticide poisoning, but there's no effective drugs for the treatment of pyrethroid pesticide poisoning. For the treatment of the mixture of organophosphorus and pyrethroids pesticide poisoning, we can use the anti-cholinergic drugs (atropine) and cholinesterase agents (pralidoxime chloride) to rescue organophosphorus pesticide poisoning, and then give symptomatic and supportive therapy according to the condition of patients, keep the balance of water, electrolyte and acid-base, control tic and prevent pulmonary edema, cerebral edema and respiratory, circulatory failure. In short, the mixed pesticide poisoning is a new topic that we confront at present, find out the incidence and risk factors of mixed pesticide poisoning and explore biomarkers of mixed pesticide, and further solve the diagnosis and appropriate treatment programs of the mixed pesticide poisoning. In this study we prepared the model of rats of mixed pesticide poisoning with organophosphorus and pyrethroid pesticide, to observe the poisoning performance, the trends of serum cholinesterase and CRP,and the performance of nervous system injury in electron microscope of experimental animals, to explore the effect of the treatment for the rats of the mixture of organophosphorus and pyrethroids pesticide poisoning with different doses of atropine and pralidoxime chloride, to provide a theoretical basis for the clinical aspect.Methods:Selected 70 healthy adult SD rats that were randomly divided into 7 groups:the blank control group(groupA),10 rats, the non-treatment group (groupB),10 rats, large doses of pralidoxime chloride and moderate doses of atropine(groupC),10 rats, small doses of pralidoxime chloride and moderate doses of atropine(groupD),10 rats, large doses of atropine and moderate doses of pralidoxime chloride(groupE),10 rats, moderate doses of atropine and moderate doses of pralidoxime chloride(groupF),10 rats, small doses of atropine and moderate doses of pralidoxime chloride(groupG),10 rats. The rats of groupB, C, D, E, F, G were given 20% Cypermethrin·phoxim in the dose of 20mg/Kg (0.1ml/100g) by gavage for the poisoning, rats of group A was given the same dose of normal saline. After poisoning, the rats which were given treatment were given different doses of pralidoxime chloride and atropine by intramuscular:The 1st day:rats of groupC were given the first dose of pralidoxime chloride by 6mg,3mg q1h×3,3mg q2h×3,3mg q3h; and the first dose of atropine by 1.5mg, 1mg q2h×2,0.5mg q3h×2,0.5 mg q4h; rats of groupD were given the first dose of pralidoxime chloride by 3mg,1.5mg q2h×3; and the same dose of atropine with groupC; rats of groupE were given the first dose of atropine by 3mg,2mg q2h×2,1.5mg q3h×2,1 mg q4h; and the first dose of pralidoxime chloride by 3mg,1.5mg q2h×3,1.5mg q3h; rats of groupF were given the same dose of atropine with groupC; and the same dose of pralidoxime chloride with groupE; rats of groupG were given the first dose of atropine by 0.5mg,0.5mg q2h×2,0.25 mg q3h×2,0.25 mg q4h; and the same dose of pralidoxime chloride with groupE. The 2nd day:rats of groupC were given pralidoxime chloride by 3mg, q4h; and atropine by 0.5mg q4h; rats of groupD were given pralidoxime chloride by 1.5mg q6h; and the same dose of atropine with group C; rats of groupE were given atropine by 1mg, q4h; and pralidoxime chloride by 1.5mg, q4h×2,1.5 mg q6h; rats of groupF were given the same dose of atropine with groupC; and the same dose of pralidoxime chloride with groupE; rats of groupG were given atropine by 0.25mg q4h; and the same dose of pralidoxime chloride with groupE. The 3rd day:rats of groupC were given pralidoxime chloride by 3mg q6h; and atropine by 0.25mg q6h; rats of groupD were given pralidoxime chloride by 0.5mg q6h; and the same dose of atropine witn group C; rats of groupE were given atropine by 0.5mg q6h; and pralidoxime chloride by 1.5mg q6h; rats of groupF were given rhe same dose of atropine with groupC; and the same dose of pralidoxime chloride with groupE; rats of groupG were given atropine by 0.1mg q6h; and the same dose of pralidoxime chloride with groupE. The 4th and 5th day:rats of groupC were given pralidoxime chloride by 3mg q12h; and atropine by 0.25mg q12h; rats of groupD were given pralidoxime chloride by 0.5mg q12h; and the same dose of atropine with groupC;rats of groupE were given atropine by 0.5mg q12h; and pralidoxime chloride by 1.5mg q12h; rats of groupF were given the same dose of atropine with C; and the same dose of pralidoxime chloride with groupE; rats of groupG were given atropine by 0.1mg q12h; and the same dose of pralidoxime chloride with groupE. The 6th day and 7th day:rats of groupC were given pralidoxime chloride by 3mg qd; and atropine by 0.25mg qd; rats of groupD were given pralidoxime chloride by 0.5mg qd; and the same dose of atropine with groupC; rats of groupE were given atropine by 0.5mg qd; and pralidoxime chloride by 1.5mg qd; rats of groupF were given the same dose of atropine with groupC; and the same dose of pralidoxime chloride with groupE; rats of groupG were given atropine by 0.1mg qd; and the same dose of pralidoxime chloride with groupE. Rats in each group were cut off the tails with scissor to retain the blood for the determination of serum cholinesterase in the 12th hour, the 1st day, the 4th day, and the 7th day after poisoning; rats in each group were cut off the tails with scissor to retain the blood for the determination of serum CRP in the 1st day, the 3rd day, and the 7th day after poisoning; rats of each group were killed in the 1st week after poisoning, all of them were given 4% chloral hydrate(1ml/100g) for the anesthesia, to open the skulls for the craniotomy,retain the cortex and hippocampus of rats, and fixed with 4% glutaraldehyde, to observe the morphological structure of nerve cells under the electron microscope and to understand the condition of injury of the central nervous system(CNS).Results:1 Poisoning performance of rats:the rats of the non-treatment groupB appeared symptoms of tears, Salivation, muscle fibrillation, convulsions, muscle weakness, and limbs tremor et al, about 5mins～10mins after poisoning by gavage, and the symptoms were the most obvious in the 1st-3rd days; and the symptoms of the rats that were given the treatment witn different doses of pralidoxime chloride and atropine appeared more minor than the symptoms of the rats of groupB, the symptoms of the rats of groupC appeared no obvious symptoms of tears, salivation, muscle fibrillation, convulsions, muscle weakness, and limbs tremor et al, after treatment; the rats of groupE, F, G appeared more minor symptoms of tears, salivation, muscle fibrillation and muscle weakness of the hind legs et al, after treatment; the rats of groupD appeared minor symptoms of tears, salivation, muscle fibrillation and muscle weakness of the hind legs et al, after treatment. Overall, the poisoning performance of the rats of the groupD was more obvious than other rats after treatment, and the rats of groupE, F, G appeared no obvious difference, be classified as the second, and the rats of groupC was the most minor one(D>E=F= G>C).2 Determination of serum cholinesterase:After 12 hours of poisoning: comparison of each groups:H=65.222, P<0.05, there was a statistical significance, so it was thinked of as the difference between groups; among the comparisons of per two independent samples, the comparison between groupE and groupG,P=0.448>0.05, there was no statistical significance, so it was thinked that there was no difference between these two groups; among the comparisons of per two independent samples of other groups, P<0.05, there was a statistical significance, so it was thinked of as the difference between groups; after 12 hours of poisoning, the overall trend of changes of serum cholinesterase of rats appeared in sequence:A>C>F>E=G>D>B. After 1 day of poisoning:comparison of each groups:P<0.05, and there was a statistical significance, so it was thinked of as the difference between groups; among the comparisons of per two independent samples of other groups, P<0.05, there was a statistical significance, so it was thinked of as the difference between groups; after 1 day of poisoning, the overall trend of changes of serum cholinesterase of rats appeared in sequence; A>C>F>E>G>D>B. After 4 days of poisoning:comparison of each groups:H=65.369, P<0.05, there was a statistical significance, so it was thinked of as the difference between groups; among the comparisons of per two independent samples, the comparison between groupE and groupG,P=0.130>0.05, there was no statistical significance, so it was thinked that there was no difference between these two groups; among the comparisons of per two independent samples of other groups, P<0.05, there was a statistical significance, so it was thinked of as the difference between groups; after 4 days of poisoning, the overall trend of changes of serum cholinesterase of rats appeared in sequence: A>C>F>E=G>D>B. After 7 days of poisoning:comparison of each groups: H=62.509, P<0.05, there was a statistical significance, so it was thinked of as the difference between groups; among the comparisons of per two independent samples, the comparison between groupA and groupC, P=0.292>0.05, there was no statistical significance, so it was thinked that there was no difference between these two groups; the comparison between groupE and groupG, P=0.878>0.05, there was no statistical significance, so it was thinked that there was no difference between these two groups; the comparison among groupE, groupF and groupG, P=0.086>0.05, there was no statistical significance, so it was thinked that there was no difference among these three groups; among the comparisons of per two independent samples of other groups, P<0.05, there was a statistical significance, so it was thinked of as the difference between groups; after 7 days of poisoning, the overall trend of changes of serum cholinesterase of rats appeared in sequence: A=C>E=F=G>D>B.3 Determination of serum CRP:After 1 day of poisoning:comparison of each groups:H=63.295, P<0.05, and there was a statistical significance, so it was thinked of as the difference between groups; among the comparisons of per two independent samples, the comparison between groupE and groupF, P=0.327>0.05, there was no statistical significance, so it was thinked that there was no difference between these two groups; the comparison between groupE and groupG, P=0.175>0.05, there was no statistical significance, so it was thinked that there was no difference between these two groups; the comparison among groupE, groupF and groupG, P=0.055>0.05, there was no statistical significance, so it was thinked that there was no difference among these three groups; among the comparisons of per two independent samples of other groups, P<0.05, there was a statistical significance, so it was thinked of as the difference between groups; after 1 day of poisoning, the overall trend of changes of serum CRP of rats appeared in sequence:B>D>E=F=G>C>A. After 3 days of poisoning:comparison of each groups:H=63.401, P<0.05, there was a statistical significance, so it was thinked of as the difference between groups; among the comparisons of per two independent samples, the comparison between groupE and groupF, P=0.323>0.05, there was no statistical significance, so it was thinked that there was no difference between these two groups; the comparison between groupE and groupG, P=0.171>0.05, there was no statistical significance, so it was thinked that there was no difference between these two groups; the comparison among groupE, groupF and groupG, P=0.053>0.05, there was no statistical significance, so it was thinked that there was no difference among these three groups; among the comparisons of per two independent samples of other groups, P<0.05, there was a statistical significance, so it was thinked of as the difference between groups; after 3 days of poisoning, the overall trend of changes of serum CRP of rats appeared in sequence:B>D>E=F=G>C>A. After 7 days of poisoning: comparison of each groups,P<0.05, there was a statistical significance, so it was thinked of as the difference between groups; among the comparisons of per two independent samples, the comparison between groupA and groupC, P=0.174>0.05, there was no statistical significance, so it was thinked that there was no difference between these two groups; the comparison between groupE and groupG, P=0.761>0.05, there was no statistical significance, so it was thinked that there was no difference between these two groups; among the comparisons of per two independent samples of other groups, P<0.05, there was a statistical significance, so it was thinked of as the difference between groups; after 7 days of poisoning, the overall trend of changes of serum CRP of rats appeared in sequence:B>D>E=G>F>C=A.4 The observation results of cortex.and hippocampus of SD rats by electron mircoscopy about the blank control group, the group given treatment and the non-treatment group:the observation results of the blank control group (groupA):the morphological structure of nerve cells, glial cells, myelin lamellar, nerve microtubules inside of axonal, vascular basement membrane, perivascular were normal. The observation results of the non-treatment group(groupB):nerve cells and glial cells appeared edema severely, cell membrane was incomplete, there were severely edema vacuoles in cytoplasm, topical perinuclear gap expanded, topical bilayer dissolved to disappear, partial cell membrane merged to disappear. It appeared the phenomenon of stratification between myelin lamellar, nerve microtubules inside of axonal were in severe disorder, it appeared many vacuoles in vascular basement membrane, perivascular gap became broadened, there was a few mitochondria and swelling floated endoplasmic reticulum. The group given treatment(groupC, D, E, F, G):the observation results of cortex and hippocampus of rats by electron microscopy after poisoning but given different doses of pralidoxime chloride and atropine for treatment appeared different degrees of poisoning performance, compared with groupB, rats of groupC that given large dose pralidoxime chloride, the observation results were that nerve cells and glial cells appeared edema mildly, cell membrane was basically complete, it appeared no obvious phenomenon of stratification between myelin lamellar, nerve microtubules inside of axonal were in order, vascular basement membrane was basically complete, perivascular gap was basically normal; rats of groupE, F, G were given moderate dose of pralidoxime chloride, the obeservation results were that nerve cells and glial cells appeared relatively obvious edema, partial cell membrane were complete, it appeared no phenomenon of stratification between myelin lamellar, nerve microtubules inside of axonal were in relatively disorder, it appeared a few vacuoles in vascular basement membrane, perivascular gap was basically normal; rats of groupD were given small dose of pralidoxime chloride, the obeservation results were that nerve cells and glial cells appeared obvious edema, cell membrane was incomplete, it appeared the phenomenon of stratification between myelin lamellar, nerve microtubules inside of axonal were in relatively disorder, it appeared vacuoles in vascular basement membrane, perivascular gap became broadened. Overall, the injury degrees of cortex and hippocampus of the rats of the blank control group, the non-treatment group and the group that given different doses of pralidoxime chloride and atropine for treatment appeared in sequence:B>D>E=F=G>C>A. Conclusions:1 The performance of the mixture of organophosphorus and pyrethroids pesticide poisoning took the performance of organophosphorus pesticide poisoning as the mainly, and the partial was overlapped with the performance of pyrethroid pesticide poisoning, the symptoms of the central nervous system caused by pyrethroid pesticide poisoning was not obvious.2 To take cholinesterase agent as mainly application, and moderate doses of atropine as auxiliary application for the treatment of the mixture of organophosphorus and pyrethroids pesticide poisoning, and the main manifestation was the speedy resurrection of the serum cholinesterase, the rapid decline of the serum CRP and the relief of injury of the central nervous system in morphology after poisoning.3 Different doses of atropine had no effect on the resurrection of the serum cholinesterase, and the injury of the central nervous system caused by the mixture of organophosphorus and pyrethroids pesticide poisoning, but had an effect on the reduction of the serum CRP and the relief of the symptoms after poisoning.
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