Specific antidote for treating paraquat acute poisoning
阅读说明：本技术 一种治疗百草枯急性中毒特异性解毒药物 (Specific antidote for treating paraquat acute poisoning ) 是由 武春媛 吴东明 刘笑然 钱进 李勤奋 于 2019-09-25 设计创作，主要内容包括：本发明一种治疗百草枯急性中毒特异性解毒药物。该药的主要成分是氢醌类化合物或其药学上可接受的盐,优选为9,10-蒽氢醌-2,6-二磺酸或9,10-蒽氢醌-2,6-二磺酸盐(简称AHQDS)。应用方法是：针对百草枯中毒剂量,配比不同剂量解毒药物,通过灌胃方式予以治疗。该药剂能够使大鼠血液、尿液、肺部组织中的百草枯浓度迅速降低,明显减轻大鼠百草枯的毒性反应,对百草枯所引起的肺损伤产生保护作用,极大提高了百草枯急性中毒大鼠的存活率,为临床治疗百草枯中毒提供新的药物。(The invention relates to a specific detoxification medicine for treating paraquat acute poisoning. The main component of the medicine is hydroquinone compound or its pharmaceutically acceptable salt, preferably 9, 10-anthrahydroquinone-2, 6-disulfonic acid or 9, 10-anthrahydroquinone-2, 6-disulfonate (AHQDS). The application method comprises the following steps: aiming at the paraquat poisoning dose, the medicament is prepared into antidotes with different doses and is treated by a gastric lavage way. The medicament can rapidly reduce the concentration of paraquat in blood, urine and lung tissues of rats, obviously relieve the toxic reaction of paraquat in the rats, has a protective effect on lung injury caused by paraquat, greatly improves the survival rate of the rats suffering from acute paraquat poisoning, and provides a new medicament for clinically treating paraquat poisoning.)
1. Application of hydroquinone compounds and pharmaceutically acceptable salts, esters, acids and prodrugs thereof in preparing medicaments for treating paraquat poisoning.
2. The use of claim 1, wherein the hydroquinone-based compound has the following structure from formula (I) to formula (VI):
wherein R is1～R8Each independently selected from hydrogen, halogen, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Haloalkyl, cyano, ORa、COORa、NRaRb、SO2RaNitro group, C6-C12Aryl, 5-10 membered heteroaryl; wherein R isaAnd RbEach independently represents hydrogen or C1-C6An alkyl group.
3. Use according to claim 1 or 2, wherein the hydroquinone-like compound has the following structure:
wherein R is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Haloalkyl, cyano, ORa、COORa、NRaRb、SO2RaNitro group, C6-C12Aryl, 5-10 membered heteroaryl, wherein said halogen is selected from fluorine, chlorine, bromine or iodine, RaAnd RbEach independently represents hydrogen or C1-C6Alkyl radical, R1-R8Having the meaning as defined in claim 2.
4. Use according to claim 1 or 2, wherein the hydroquinone-like compound has the following structure:
wherein R has the meaning as defined in claim 31-R8Having the meaning as defined in claim 2.
5. Use according to claim 1 or 2, wherein the hydroquinone-like compound has the following structure:
wherein R has the meaning as defined in claim 31-R6Having the meaning as defined in claim 2.
6. Use according to claim 1 or 2, wherein the hydroquinone-like compound has the following structure:
wherein R has the meaning as defined in claim 31-R6Having the meaning as defined in claim 2.
7. Use according to claim 1 or 2, wherein the hydroquinone-like compound has the following structure:
wherein R has the meaning as defined in claim 31-R4Having the meaning as defined in claim 2.
8. Use according to claim 1 or 2, wherein the hydroquinone-like compound has the following structure:
wherein R has the meaning as defined in claim 31-R4Having the meaning as defined in claim 2.
9. Use according to claim 1, wherein the hydroquinone-like compound is selected from the following compounds:
(1) compound containing 9, 10-anthrahydroquinone basic structure
(2)1, 4-anthrahydroquinones
(3) Compound containing 1, 4-naphthahydroquinone basic structure
(4) Containing 1, 2-naphthohydroquinone basic structure (5) Compound containing p-phenol basic structure
10. The use according to any one of claims 1 to 9, wherein the hydroquinone-based compound or the pharmaceutically acceptable salt thereof is selected from any one of sodium, potassium, magnesium, calcium, aluminium salts thereof or any combination thereof.
11. A medicine for treating paraquat acute poisoning is characterized in that: the active ingredient of the medicament for treating paraquat acute poisoning is the hydroquinone compound as claimed in any one of claims 1 to 10, and pharmaceutically acceptable salts, esters, acids and prodrugs thereof, and a pharmaceutically acceptable carrier or diluent, wherein the salts are selected from any one of sodium salt, potassium salt, magnesium salt, calcium salt and aluminum salt or any combination thereof.
12. The medicament for treating acute toxicity of paraquat as claimed in claim 11, wherein said medicament is selected from the group consisting of aqueous solutions of hydroquinone compounds and pharmaceutically acceptable salts, esters, acids and prodrugs thereof.
13. The medicament according to claim 11 or 12, wherein the hydroquinone-based compound or the pharmaceutically acceptable salt thereof is selected from the group consisting of 9, 10-anthrahydroquinone-2, 6-disulfonic acid or 9, 10-anthrahydroquinone-2, 6-disulfonate, 9, 10-anthrahydroquinone-1, 5-disulfonic acid or 9, 10-anthrahydroquinone-1, 5-disulfonate, 9, 10-anthrahydroquinone-1-sulfonate, 9, 10-anthrahydroquinone-2-carboxylic acid, preferably 9, 10-anthrahydroquinone-2, 6-disulfonic acid sodium, 9, 10-anthrahydroquinone-1, 5-disulfonic acid sodium, 9, 10-anthrahydroquinone-1-, 9, 10-anthrahydroquinone-2-sulfonic acid sodium salt.
14. A construction method of an animal model for verifying a medicament for treating paraquat acute poisoning is characterized by comprising the following steps of:
the method comprises the following steps: selecting a healthy SD rat, and constructing a paraquat poisoning animal model by using a one-time gavage method;
step two: directly infusing an aqueous solution of a hydroquinone compound of any one of claims 1 to 10 and pharmaceutically acceptable salts, esters, acids and prodrugs thereof into the stomach of a rat 1 time per day for 7 days;
step three: observing and recording the toxic symptom change, the weight change, the behavioral characteristics, the survival condition of the rat in 30 days and the tissue morphology of the rat;
step four: detecting an index;
the detection indexes in the step four are as follows: 1) detecting the concentration of paraquat and the concentration of an antidote in blood plasma, urine and lung tissues, and analyzing the metabolic process of paraquat and the antidote in a rat body; 2) detecting the indexes of liver and kidney functions; 3) detecting the arterial blood gas condition of the rat by a blood gas analyzer; 4) observing the lung cell structure; 5) detecting the contents of superoxide dismutase SOD and malonaldehyde MDA at the lung tissue cell level.
15. The method according to claim 14, wherein the hydroquinone-based compound or the pharmaceutically acceptable salt thereof is selected from the group consisting of 9, 10-anthrahydroquinone-2, 6-disulfonic acid or 9, 10-anthrahydroquinone-2, 6-disulfonate, 9, 10-anthrahydroquinone-1, 5-disulfonic acid or 9, 10-anthrahydroquinone-1, 5-disulfonate, 9, 10-anthrahydroquinone-1-sulfonate, 9, 10-anthrahydroquinone-2-carboxylic acid, preferably 9, 10-anthrahydroquinone-2, 6-disulfonic acid sodium, 9, 10-anthrahydroquinone-1, 5-disulfonic acid sodium, 9, 10-anthrahydroquinone-1-sulfonic acid sodium, 9, 10-anthrahydroquinone-2-sulfonic acid sodium salt.
Technical Field
The invention belongs to the technical field of medicine, and particularly relates to a specific detoxification medicine for treating paraquat acute poisoning.
Background
Paraquat, as a quick non-selective quaternary ammonium salt herbicide, is widely applied to agricultural cultivation due to strong weeding effect and low price, makes great contribution to grain yield increase, production cost reduction and no-tillage technology development all over the world, and brings immeasurable economic benefits. Just because the application is wide, a large number of cases of poisoning are caused by self-taking or wrong taking, and the life health and safety of people in China are seriously threatened, so that the production of the paraquat water aqua is stopped in China from 7-1 month in 2014, the sale and use of the paraquat water aqua in China are stopped from 7-1 month in 2016, the production and sale of the paraquat emulsion are still allowed, and the export market is not limited. Every year in China, there are still ten thousand patients with paraquat poisoning, wherein the age is 0-40 years old, and the fatality rate is high, which seriously affects social labor force and causes great social loss. It is also anticipated that the number of patients with paraquat poisoning may not be reduced in the future.
Paraquat poisoning seriously threatens the life safety and the physical health of patients. The lung is used as a main target organ of paraquat poisoning, the damage is most prominent, chest distress, short breath, hypoxemia and progressive dyspnea are mainly manifested, acute pulmonary edema is mainly manifested in a poisoned patient within 1 week, pulmonary fibrosis can be changed and gradually worsened after 1 week, and obvious fibrosis is formed after 2-3 weeks to reach a peak. Toxic patients are mostly dead of Acute Respiratory Distress Syndrome (ARDS) caused by lung injury, and even if they survive, pulmonary fibrosis caused by lung injury seriously affects the quality of life of the patients.
At present, no good treatment method for paraquat poisoning exists, and the success rate of clinical rescue is lower than 40%. The treatment means are as follows:
1) the conventional treatment method comprises the following steps: emetic and gastric lavage, and performing total gastrointestinal lavage treatment (white, namely, Schmidt, and black, namely, activated carbon) by adopting a white and black scheme; blood perfusion can be carried out as early as possible; reasonable oxygen therapy and mechanical ventilation; the medicine treatment uses propranolol to competitively combine paraquat receptor, glucocorticoid anti-inflammatory, cyclophosphamide immunosuppressant, vitamin C/reductive glutathione/acetylcysteine anti-oxygen free radical, low molecular heparin anticoagulation, pirfenidone anti-fibrosis, liver and kidney protection, massive fluid replacement and diuresis, promotion of poison elimination, correction of water electrolyte balance and the like for symptomatic treatment.
2) The novel treatment method comprises the following steps: lung transplantation, bone marrow mesenchymal stem cell transplantation, methylprednisolone combined technology and the like.
However, the above conventional treatment methods only alleviate the disease to some extent, and do not completely control the progress of the disease and eventually cure it. Advanced technologies such as lung transplantation and stem cell transplantation are not mature enough. For example, in lung transplantation therapy, fibrosis is reoccurred in some cases; the bone marrow mesenchymal stem cell transplantation is combined with methylprednisolone to treat paraquat poisoning, and serious complications such as lung infection, drug-induced liver and kidney damage and the like can be caused.
The difficulty and significance for solving the technical problems are as follows: how to reduce the concentration of paraquat in blood early after poisoning, how to completely remove residual paraquat in intestinal tract and how to reduce subsequent continuous damage to lung tissues by advancing a treatment time window. If an antidote specifically combined with paraquat is found, the level of paraquat in plasma can be rapidly reduced, residual paraquat in intestinal tracts can be thoroughly removed, liver, kidney, lung and organ functions can be prevented from being damaged recently, and the continuous damage of long-term paraquat to tissue and organ functions can be reduced, so that the development of a novel antidote is a key point.
The inventor invents a paraquat rapid detoxification liquid in application number CN201610341330.6 (named as paraquat rapid detoxification liquid and method), wherein the preparation is a mixture of anthraquinone, Fe (III) humus reducing bacteria, a culture medium thereof, an electron donor and a pH buffer which are subjected to anaerobic culture in a dark environment until sufficient anthraquinone is reduced into hydroquinone. However, on one hand, the requirements of the safety, the effectiveness and the quality controllability of the medicament cannot be met due to the complex and unstable components in the preparation, and on the other hand, the inventor finds that after anthraquinone is reduced by utilizing sodium azide in the solution to generate hydroquinone, paraquat solution is injected into the solution, the reaction phenomenon is observed, no solid is generated, and the concentration of paraquat and AHQDS is not reduced after 24h and 48h detection, which shows that only hydroquinone is not enough to detoxify paraquat. However, in the invention of "CN 201610341330.6", the inventors did not consider the inhibitory effect of excess sodium azide on the reaction of hydroquinone with paraquat.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a medicament for treating paraquat acute poisoning and an animal model construction method thereof. The invention surprisingly discovers that by taking the hydroquinone compound or the water solution of the pharmaceutically acceptable salt thereof as the detoxification drug, on one hand, the safety, the effectiveness and the quality controllability of the drug can be improved, on the other hand, the treatment effect of the detoxification drug AHQDS on rats with paraquat poisoning can be remarkable, and the survival rate reaches 100 percent; meanwhile, the concentration of paraquat in blood, urine and lung tissues of rats can be obviously reduced; the damage of paraquat to the liver and kidney functions of rats can be obviously reduced; the lung function of a paraquat poisoning rat can be obviously improved, and alveolus inflammation is prevented; can increase the oxidation resistance of organism.
In order to solve the technical problem, the invention provides the following technical scheme:
application of hydroquinone compounds and pharmaceutically acceptable salts, esters, acids and prodrugs thereof in preparing medicaments for treating paraquat poisoning.
In the technical scheme of the invention, the hydroquinone compound has the following structures from (I) to (VI):
wherein R is1～R8Each independently selected from hydrogen, halogen, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Haloalkyl, cyano, ORa、COORa、NRaRb、SO2RaNitro group, C6-C12Aryl, 5-10 membered heteroaryl, wherein said halogen is selected from fluorine, chlorine, bromine or iodine; wherein R isaAnd RbEach independently represents hydrogen or C1-C6An alkyl group.
In the technical scheme of the invention, the hydroquinone compound has the following structure:
wherein R is1-R8Having the above definitions.
In the technical scheme of the invention, the hydroquinone compound has the following structure:
wherein R is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Haloalkyl, cyano, ORa、COORa、NRaRb、SO2RaNitro group, C6-C12Aryl, 5-10 membered heteroaryl, wherein said halogen is selected from fluorine, chlorine, bromine or iodine; wherein R isaAnd RbEach independently represents hydrogen or C1-C6Alkyl radical, R1-R8Having the above definitions.
In the technical scheme of the invention, the hydroquinone compound has the following structure:
wherein R is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Haloalkyl, cyano, ORa、COORa、NRaRb、SO2RaNitro group, C6-C12Aryl, 5-10 membered heteroaryl; wherein R isaAnd RbEach independently represents hydrogen or C1-C6Alkyl radical, R1-R6Having the above definitions.
In the technical scheme of the invention, the hydroquinone compound has the following structure:
wherein R is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Haloalkyl, cyano, ORa、COORa、NRaRb、SO2RaNitro group, C6-C12Aryl, 5-10 membered heteroaryl; wherein R isaAnd RbEach independently represents hydrogen or C1-C6Alkyl radical, R1-R6Having the above definitions.
In the technical scheme of the invention, the hydroquinone compound has the following structure:
wherein R is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Haloalkyl, cyano, ORa、COORa、NRaRb、SO2RaNitro group, C6-C12Aryl, 5-10 membered heteroaryl; wherein R isaAnd RbEach independently represents hydrogen or C1-C6Alkyl radical, R1-R4Having the above definitions.
In the technical scheme of the invention, the hydroquinone compound has the following structure:
wherein R is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Haloalkyl, cyano, ORa、COORa、NRaRb、SO2RaNitro group, C6-C12Aryl, 5-10 membered heteroaryl; wherein R isaAnd RbEach independently represents hydrogen or C1-C6Alkyl radical, R1-R4Having the above definitions.
In the technical scheme of the invention, the hydroquinone compound is selected from the following compounds:
(1) compound containing 9, 10-anthrahydroquinone basic structure
(2)1, 4-anthrahydroquinones
(3) Compound containing 1, 4-naphthahydroquinone basic structure
(4) Containing 1, 2-naphthohydroquinone basic structure (5) Compound containing p-phenol basic structure
In the technical scheme of the invention, the hydroquinone compound is preferably selected from 9, 10-anthrahydroquinone-2, 6-disulfonic acid sodium, 9, 10-anthrahydroquinone-1, 5-disulfonic acid sodium, 9, 10-anthrahydroquinone-1-sulfonic acid sodium, 9, 10-anthrahydroquinone-2-sulfonic acid sodium or 9, 10-anthrahydroquinone-2-carboxylic acid.
In the technical scheme of the invention, the hydroquinone compound or the pharmaceutically acceptable salt thereof is selected from any one of sodium salt, potassium salt, magnesium salt, calcium salt and aluminum salt thereof or any combination thereof.
In addition, the invention also provides a medicine for treating paraquat acute poisoning, which is characterized by comprising the following components in part by weight: the active ingredients of the medicament for treating paraquat acute poisoning are the hydroquinone compound, the pharmaceutically acceptable salt, ester, acid and prodrug thereof, and the pharmaceutically acceptable carrier or diluent.
In the technical scheme of the invention, the drug is selected from an aqueous solution of a hydroquinone compound and a pharmaceutically acceptable salt, ester, acid and prodrug thereof, and the aqueous solution of the hydroquinone compound and the pharmaceutically acceptable salt, ester, acid and prodrug thereof.
In the technical scheme of the invention, the water solution of the hydroquinone compound and the pharmaceutically acceptable salts, esters, acids and prodrugs thereof is 30-200 mmol/L, preferably 30-160 mmol/L, and more preferably 30-120 mmol/L or 30-60 mmol/L.
In addition, the invention also provides application of the hydroquinone compound and the water solution of pharmaceutically acceptable salts, esters, acids and prodrugs thereof in preparing medicaments for treating paraquat poisoning.
In the technical scheme of the invention, the aqueous solution of the hydroquinone compound and the pharmaceutically acceptable salts, esters, acids and prodrugs thereof is selected from 9, 10-anthrahydroquinone-2, 6-sodium disulfonate, 9, 10-anthrahydroquinone-1, 5-sodium disulfonate, 9, 10-anthrahydroquinone-1-sodium sulfonate, 9, 10-anthrahydroquinone-2-sodium sulfonate or 9, 10-anthrahydroquinone-2-carboxylic acid.
In addition, the construction method of the animal model for verifying the medicament for treating the paraquat acute poisoning is characterized by comprising the following steps of:
the method comprises the following steps: selecting a healthy SD rat, and constructing a paraquat poisoning animal model by using a one-time gavage method;
step two: directly infusing the hydroquinone compound and the water solution of pharmaceutically acceptable salt, ester, acid and prodrug thereof into the stomach of a rat, and infusing for 1 time every day for 7 days;
step three: observing and recording the toxic symptom change, the weight change, the behavioral characteristics, the survival condition of the rat in 30 days and the tissue morphology of the rat;
step four: detecting an index;
the detection indexes in the step four are as follows: 1) detecting the concentration of paraquat and the concentration of an antidote in blood plasma, urine and lung tissues, and analyzing the metabolic process of paraquat and the antidote in a rat body; 2) detecting the indexes of liver and kidney functions; 3) detecting the arterial blood gas condition of the rat by a blood gas analyzer; 4) observing the lung cell structure; 5) detecting the contents of superoxide dismutase SOD and malonaldehyde MDA at the lung tissue cell level.
In addition, the invention also provides a method for treating paraquat acute poisoning, which is characterized by administering the hydroquinone compound or the pharmaceutically acceptable salt thereof to a subject in need thereof.
Preferably, the mode of administration of the present invention comprises: oral administration, intravenous injection, intramuscular injection, intraperitoneal injection, intragastric administration and subcutaneous injection.
Preferably, the treatment method of the present invention comprises infusing 1 time per day for 7 days to an individual with an acute toxicant of paraquat.
The invention has the advantages and positive effects that: the detoxification drug disclosed by the invention can rapidly react with paraquat remained in gastrointestinal tracts locally, so that the concentration of paraquat in blood, urine and lung tissues is reduced, the levels of antioxidant substances such as cell SOD (superoxide dismutase) and the like are improved to resist oxidative stress, the generation of MDA (multidrug synthase) in cells is reduced, the toxic reaction of rat paraquat is obviously relieved, and the protective effect is generated on lung injury caused by paraquat. The antidote is given to rats with 200-400 mg/kg paraquat poisoning dose for 2-6h, the survival rate in 30 days reaches 100% (the paraquat acute poisoning dose is 150mg/kg body weight rats), the survival rate in 30 days of the non-detoxified group is 0, and the survival rate in 30 days of the rats in the white and black conventional treatment group is 0-42.9%.
The problem is solved by searching for new drugs, and an antidote drug of a paraquat acute poisoning rat with similar curative effect is not found.
Drawings
FIG. 1 is a graph of survival of groups of rats under different intervention conditions as provided in example 1 of the present invention.
FIG. 2 is a graph showing the variation of the concentration of paraquat in the plasma of rats in various groups at different time points, which is provided in example 1 of the present invention.
FIG. 3 is a graph showing the variation of the concentration of the antidote AHQDS in plasma of rats in various groups at different time points, provided in example 1 of the present invention.
FIG. 4 is a graph showing the change in the concentration of paraquat in lung tissue of various groups of rats at different time points, which is provided in example 1 of the present invention.
FIG. 5 is a graph showing the variation of the concentration of paraquat in the urine of rats in each group at different time points, which is provided in example 1 of the present invention.
FIG. 6 shows the partial blood pressure (PaO) of rats in different groups at different time points according to example 1 of the present invention2) And (5) a variation graph.
FIG. 7 is a graph of partial blood carbon dioxide (PaCO) for various groups of rats at different time points, as provided in example 1 of the present invention2) And (5) a variation graph.
FIG. 8 is a photograph (magnification × 400) of HE staining of lung cells at 3 days in rat lung tissue provided in example 1 of the present invention.
FIG. 9 is a photograph (magnification × 400) of HE staining of lung cells at 7 days in rat lung tissue provided in example 1 of the present invention.
FIG. 10 is a photograph (magnification × 400) of HE staining of lung cells at 15 days in rat lung tissue provided in example 1 of the present invention.
FIG. 11 is a photograph (magnification × 400) of HE staining of lung cells at 30 days in rat lung tissue provided in example 1 of the present invention.
FIG. 12 is a graph showing the levels of superoxide dismutase (SOD) in lung tissue of rats in each group, which is provided in example 1 of the present invention.
FIG. 13 is a graph of the levels of Malondialdehyde (MDA) in lung tissue of rats in various groups as provided in example 1 of the invention.
Fig. 14 is a flowchart of an application method of the drug for treating rats acutely poisoned by paraquat according to the embodiment of the invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The invention uses 9, 10-anthrahydroquinone-2, 6-disulfonic acid or 9, 10-anthrahydroquinone-2, 6-disulfonate (AHQDS for short) to treat rats with paraquat acute poisoning, and has excellent treatment effect.
The application method comprises the following steps: the detoxification drug is infused into the stomach of the SD rat with the poisoning through a gastric perfusion method, wherein the gastric perfusion is performed for 1 time within 6 hours after the poisoning, and the perfusion is performed for 1 time every day within the following 6 days. The method specifically comprises the following steps:
the method comprises the following steps: animal grouping, selecting healthy SD rats, constructing an animal model by using a one-time intragastric administration method, wherein the intragastric administration concentration is 200-400 mg of paraquat per kilogram of weight of the rats.
Step two: directly infusing the detoxification drug into the stomach of a rat, infusing for 1 time every day within 6 hours of poisoning, and subsequently infusing for 1 time every day for 7 days, wherein the concentration of the detoxification solution is 30-60 mmol/L, and the dosage is 5-10 mL.
Step three: the survival conditions of rats in paraquat poisoning group and rats in detoxification group were observed and recorded for 30 days.
Step four: the following criteria were examined.
1) Detecting the concentration of paraquat and the concentration of an antidote AHQDS in plasma by a liquid chromatography-mass spectrometry combined technology by using a method of taking blood from the inner canthus of an orbit;
2) collecting daily urine of each group of animals, and detecting the concentration of urine paraquat and the concentration of an antidote AHQDS by a liquid chromatography-mass spectrometry combined technology;
3) detecting the concentration of paraquat and an antidote AHQDS in lung tissues; 4) blood is taken from abdominal aorta under chloral hydrate anesthesia, part of the blood is used for detecting the functions of liver and kidney through a full-automatic biochemical detector, and part of the blood is used for detecting the blood and gas condition of rat artery through a blood and gas analyzer;
5) observing the lung cell structure of the rat by HE staining;
6) the content of superoxide dismutase (SOD) and Malondialdehyde (MDA) in lung tissue is detected by a colorimetric method.
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