CN110585180A - Specific antidote for treating paraquat acute poisoning - Google Patents
Specific antidote for treating paraquat acute poisoning Download PDFInfo
- Publication number
- CN110585180A CN110585180A CN201910908879.2A CN201910908879A CN110585180A CN 110585180 A CN110585180 A CN 110585180A CN 201910908879 A CN201910908879 A CN 201910908879A CN 110585180 A CN110585180 A CN 110585180A
- Authority
- CN
- China
- Prior art keywords
- paraquat
- anthrahydroquinone
- group
- hydroquinone
- rats
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- FIKAKWIAUPDISJ-UHFFFAOYSA-L paraquat dichloride Chemical compound [Cl-].[Cl-].C1=C[N+](C)=CC=C1C1=CC=[N+](C)C=C1 FIKAKWIAUPDISJ-UHFFFAOYSA-L 0.000 title claims abstract description 96
- 231100000570 acute poisoning Toxicity 0.000 title claims abstract description 16
- 229940124547 specific antidotes Drugs 0.000 title description 2
- 239000003814 drug Substances 0.000 claims abstract description 60
- -1 hydroquinone compound Chemical class 0.000 claims abstract description 46
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N 1,4-Benzenediol Natural products OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims abstract description 38
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Classifications
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- A—HUMAN NECESSITIES
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- A61D—VETERINARY INSTRUMENTS, IMPLEMENTS, TOOLS, OR METHODS
- A61D7/00—Devices or methods for introducing solid, liquid, or gaseous remedies or other materials into or onto the bodies of animals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
- A61K31/055—Phenols the aromatic ring being substituted by halogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
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.
Description
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.
Example 1:
(1) trial design 8 treatments: 152 male SD rats (body weight 300 + -g) were randomly divided into 8 groups of 19 rats each.
Group A: blank control group;
group B: negative control group, only using detoxification drug to lavage stomach;
group C: performing intragastric administration only with paraquat for the group without toxic materials and detoxification;
group D: in the antidote treatment group, after the rats are irrigated with paraquat for 2 hours, the rats are irrigated with the antidote for treatment;
QD group: in the antidote treatment group, after the rats are gazed with paraquat for 2 hours, the rats are treated with the gavage antidote for 7 days continuously;
BID group: in the antidote treatment group, after the rats are gazed with paraquat for 2 hours, the rats are gazed with the antidote for gavage treatment, and the rats are gavage for 2 times every day for the following 6 days;
TID group: in the antidote treatment group, after the rats are gazed with paraquat for 2 hours, the rats are gazed with the antidote for gavage treatment, and the rats are gavage for 3 times every day for the following 6 days;
group E: in the conventional treatment group, after 2 hours, the rats are gavaged with paraquat, and then are treated with gavage of 'white + black' (referring to a clinical conventional treatment scheme).
The gavage concentration of paraquat is 300mg/kg body weight; the concentration of the detoxification drugs is 40mmol/L, and specifically, the detoxification drugs used in the embodiment of the invention are selected from 9, 10-anthrahydroquinone-2, 6-disulfonic Acid (AHQDS), and the dosage is 6 mL; white and black (500mg/kg body weight of activated carbon +500mg/kg body weight of Cimpana +5mL of mannitol suspension liquid medicine), and 6mL of intragastric administration. The successful gastric lavage is counted by the conditions that vomit does not occur, the animal stomachs and nasal cavities do not overflow, convulsion and death do not occur immediately, and the like.
(2) Observation and detection index
Behaviourology and survival rate: selecting 7 mice from each group by a completely random method, wherein 56 rats in 8 groups are used for observing the behavioral change and survival condition of each group of rats within 30 days, the group of dead rats and the death date are recorded, the death mark is 1, and the death mark is 0 when no death occurs; the remaining 96 rats were involved in the following assays.
② C, D, E groups respectively selecting 5 rats at different time points (0.5h, 1h, 2h, 4h, 8h, 12h, 24h and 48h) randomly to take blood through the orbital inner canthus vein, detecting the paraquat concentration in the plasma by liquid chromatography-mass spectrometry, and analyzing the metabolic conditions of paraquat residue and detoxication medicine in the blood.
Collecting the daily urine of C, D animals, detecting the concentration of PQ and antidote in the urine by liquid chromatography-mass spectrometry technology, and knowing the metabolic process of paraquat and antidote in rat body.
Fourthly, 3 rats are killed each time by a method of anesthesia of chloral hydrate by intraperitoneal injection on the 3 rd day, the 7 th day, the 15 th day and the 30 th day respectively, abdominal aorta is separated, blood is collected by a blood gas needle and a blood collection tube with separation gel respectively, and then the blood gas is sent to a Hainan province medicine safety evaluation center for blood gas analysis and liver and kidney function examination; detecting the concentrations of paraquat and an antidote in lung tissue; ligating the trachea of the right lung, performing alveolar lavage of the left lung, collecting alveolar lavage fluid for subsequent cell counting and cytokine detection; fixing the lower lobes of the right lung with 4% paraformaldehyde, and performing hematoxylin-eosin staining (HE staining) subsequently; detecting the content of superoxide dismutase (SOD) and Malondialdehyde (MDA) in lung tissue.
(3) Test results
(ii) survival curves of rats between different treatments
As shown in fig. 1, the survival rates of the a, B, D, QD, BID, TID groups were all 100% in 30 days, and the survival rates of the C, E groups were 0 and 42.9%, respectively. C. The survival rate of the group E is statistically different from that of other groups, wherein P is 0.000 < 0.05, P is 0.023, and the groups A, B, D, QD, BID and TID have no difference. The rats in the poisoned non-detoxified group (group C) all die, half of the rats in the white and black treatment group (group E) die in 7 days, and the rats in the detoxified drug AHQDS treatment group (group D, QD, BID and TID) all survive, so that the cure rate of the detoxified drug to the rats with paraquat acute poisoning of 300mg/kg reaches 100% within 2 hours, and the effect is obviously better than that of the conventional white and black treatment scheme.
② blood, urine and lung tissue paraquat and detoxication medicine AHQDS concentration
As shown in figure 2, within 2h of infection, the concentration of paraquat in the plasma of C, D, E group was linearly increased, the concentration of paraquat in the C group was slowly decreased after reaching the peak value in 4h, the concentration of paraquat in the blood of D group was rapidly decreased immediately after using antidote in 2h, the concentration of paraquat in the E group was also rapidly decreased immediately after using "white plus black" in 2h, the concentration of paraquat in D, E group was significantly lower than that in the C group after 2h, the difference was statistical (P <0.001), the difference between D group and E group was significantly lower than that in the E group between 2h and 24h, the difference was statistical (P <0.001), and there was no significant difference between D group and E group after 24 h.
Figure 3 shows that after gavage of the antidote, the concentration of AHQDS in the blood of the rats in group D was significantly lower than that of the control in group B (24h), and the difference was statistically significant (P <0.001) because AHQDS was consumed by chemical reaction with paraquat.
Fig. 4 shows that the paraquat concentration in the lung tissue of C, D, E rats was highest on day 3, and after 7 days in groups D and E, to below 10 μ g/L, the paraquat concentration in both the detoxified group (group D) and the "white + black" treated group (group E) was significantly lower than that in the detoxified and non-detoxified group (group C), the difference was statistically significant (P <0.001), and the difference was significantly lower in group D than that in group E (P <0.001), and the difference was not significant between the two groups on days 15 and 30. The AHQDS concentration in each group was below the lowest detection limit in the lung.
Fig. 5 shows that after exposure, the urine concentration of paraquat in rats in the poisoned non-detoxified group (group C) reached a peak at 1 day, then gradually decreased, reached approximately 0 at day 3, and the urine concentration of paraquat in rats in the detoxified drug-treated group (group D) at day 0.5, reached a peak (significantly lower than the peak in group C), and then rapidly decreased, and reached approximately 0 at day 1. The AHQDS levels in the urine were below the lowest detection limit for each group.
The above results show that: treatment with the antidote AHQDS rapidly reduced the concentration of paraquat in the blood, lung tissue and urine of rats.
③ Effect of different treatments on the liver and kidney function of rats
As shown in Table 1, the level of glutamic-pyruvic transaminase (ALT) as a liver function index of C, E in two groups of rats is remarkably higher than a normal value (< 50U/L) after poisoning, reaches the highest level on the 7 th day, the level of the E group is remarkably lower than that of the C group, and the difference has statistical significance (P < 0.001); ALT levels of the rats in other groups tend to be normal in the first 15 days, the difference has statistical significance, and P is less than 0.001; A. no obvious difference exists among B, D, QD, BID and TID groups in each time period.
C. Liver function aspartate Aminotransferase (AST) levels in group E were significantly higher than normal (108.67 + -15.14U/L) after poisoning, and reached the highest on day 7, group E was significantly lower than group C, with the difference statistically significant (P < 0.001); the AST levels of the remaining groups were significantly lower than both C, E groups on the first 15 days, with AST levels in group B significantly higher than in groups a, D, QD, BID, TID on days 3 and 7, but AST levels returned to normal after 15 days, and AST levels in group D higher than in the other normal groups on day 3, but with no statistical significance. A. There is no obvious difference in each time period between QD, BID and TID groups.
TABLE 1 alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) changes (x + -s, n-3)
Note: "-" represents negative, "+" represents positive; the number of repetitions n is 3
As shown in table 2, the UREA nitrogen (UREA) levels of C, E rats in both groups were significantly higher than normal after intoxication, highest on day 7, with no significant difference between groups; the UREA levels were normal for the remaining groups and were not significantly different at each time period.
C. Creatinine (CREA) levels in group E were significantly higher than normal after intoxication, highest on day 7, with no significant difference between groups; the CREA levels of the other groups were significantly lower than those of the C, E two groups in the first 15 days, the differences were statistically significant, P < 0.001; group E CREA levels were lower than group C, but not statistically significant. The remaining groups were not significantly different at each time period.
Table 2 UREA nitrogen (UREA) vs Creatinine (CREA) changes (x ± s, n ═ 3)
Note: "-" represents negative, "+" represents positive; the number of repetitions n is 3
The above results show that: when the detoxification drug AHQDS is used for treating rats with paraquat poisoning, AST, ALT, CREA and UREA can be obviously reduced to normal level, and the damage of paraquat to the liver and kidney functions of the rats is reduced; the treatment effect of the 'white plus black' group on the liver and kidney function damage of rats is not obvious; different administration modes of the detoxification drugs have no obvious difference on the treatment effect.
Influence of different treatments on blood and qi of rat
As shown in FIG. 6, C, E partial pressure of arterial blood oxygen (PaO) of rats in two groups at each time period2) Are all significantly lower than the normal group (group A), and the B, D, QD, BID, TID groups have no significant difference with the group A (P)<0.001), no significant difference among groups; although group E showed an increased trend compared to group C, the differences were not statistically significant.
FIG. 7 shows the partial blood carbon dioxide pressure (PaCO) at day 3 in C, E for two groups of rats at each time period2) Are all significantly lower than normal (group a); 7 days old, PaCO group C2The value is significantly lower than that of the group A, and the group E and the group A do notA difference; however, after 15 days, PaCO group E2The value gradually rises, significantly higher than group A (P)<0.001); B. no significant difference was observed between D, QD, BID, TID and A groups (P)<0.001) and no difference between groups.
The above results show that: the lung function of a rat suffering from paraquat poisoning can be remarkably improved by treating the AHQDS serving as the detoxification drug; the treatment of 'white plus black' has no protective effect on the lung function of rats suffering from paraquat poisoning; different administration modes of the detoxification drugs have no obvious difference on the treatment effect.
Influence of different treatments on the cell structure of rat lung
FIGS. 8-11 show that B, D two groups are similar to the normal group A rat lung cells, with no collapse of alveolar wall, no thickening of alveolar space, no exudation in alveolar space, no telangiectasia, congestion, etc.; C. the lung tissues of the rats in the group E have pulmonary alveoli inflammation expression at 3 days and 7 days, pulmonary alveoli structure destruction, pulmonary alveoli intracavity edema, capillary blood vessel congestion and inflammatory cell infiltration.
The above results show that: the antidote AHQDS can protect the normal structure of lung tissues and can reduce and prevent alveolus inflammation; clinical routine "blacking out" treatment does not serve to reduce and prevent alveolar inflammation.
Analysis of the levels of cytokines in the Lung tissue of rats treated differently
Higher values of SOD indicate higher oxidation resistance. As shown in fig. 12, on day 3, the SOD levels of the C, D, QD, BID, TID, E groups were all significantly lower than the A, B two groups (P <0.001), wherein the SOD levels of the C, E two groups were the lowest, and there was no significant difference between the D, QD, BID, TID groups; within 7-30 days, the SOD levels of the four groups of D, QD, BID and TID gradually recover, and the SOD level approaches to the normal group at the 30 th day.
Higher MDA values indicate more severe oxidative damage. Figure 13 shows that on day 3, C, E both groups had significantly higher MDA levels than normal group a and exhibited a gradual trend of increase; B. d, QD, BID, TID groups were not significantly different from the normal group.
The above results show that: the antidote AHQDS can be used for treating rats with paraquat poisoning, so that lipid peroxidation level of organisms is reduced, and oxidation resistance of the organisms is improved.
(4) Conclusion
The curative effect of the antidote AHQDS treatment group on paraquat poisoning rats (paraquat 300mg/kg, 2h intragastric antidote) is remarkable, the survival rate reaches 100%, and the survival rates of the antidote group and the white and black treatment groups are respectively 0 and 42.9%; can significantly reduce the concentration of paraquat in blood, urine and lung tissues of rats, for example, the peak concentration of paraquat in the blood of the detoxification drug is 445.8 mug/L, while the peak concentration of paraquat in the blood of the detoxification drug is 5157 mug/L, and the peak concentration of paraquat in the non-detoxification drug is 973.7 mug/L in the white and black treatment group; can obviously reduce the damage of paraquat to the liver and kidney functions of rats; the lung function of a paraquat poisoning rat can be obviously improved, and alveolus inflammation is prevented; can increase the oxidation resistance of organism.
Example 2:
(1) the test method comprises the following steps: 9 male SD rats (body weight 300 + -g) were randomly divided into 3 groups of 3.
Group A: performing intragastric administration only with paraquat for the group without toxic materials and detoxification;
group B: in the antidote treatment group, after the rats are irrigated with paraquat for 6 hours, the rats are irrigated with the antidote for treatment;
group C: in the conventional treatment group, after the rats are subjected to gavage by paraquat for 6 hours, the rats are subjected to gavage 'white + black' (refer to a clinical conventional treatment scheme) for treatment.
The gavage concentration of paraquat is 200mg/kg body weight; the concentration of the detoxification medicine is 40mmol/L, and the dosage is 6 mL; white and black (5mL of active carbon, Simmada and mannitol suspension liquid medicine), the intragastric concentration is 500mg/kg of body weight, and the intragastric concentration is 6 mL. The successful gastric lavage is counted by the conditions that vomit does not occur, the animal stomachs and nasal cavities do not overflow, convulsion and death do not occur immediately, and the like. Observing behavior characteristics, and counting the survival rate of the rats.
(2) Test results
As shown in Table 3 (survival conditions of rats in each group), the rats in the non-detoxified group died within 3 days, the rats in the white and black treated groups died within 5 days, and before the death of the rats, the rats had extremely poor spirit, decreased respiratory frequency, increased wheezing, and respiratory distress symptoms such as nodding-head respiration, deep respiration, mouth-opening respiration, accompanied by symptoms such as limb spasm, convulsion, and increased muscle tension, and finally the respiratory movement of the rats disappeared.
All rats survived in the detoxification drug treatment group. The rats in this group recovered normal behavior at 12h after gavage, as follows: the rat has active actions, activities such as face washing, alarming, playing and the like, good mental state, complete restoration of normal hair, uniform and tidy breathing rhythm, normal water intake, food intake, urination, defecation and other basic physiological behaviors; after 30 days, the rat has active behavior, good mental state, normal hair, uniform and tidy breathing rhythm and increased weight compared with the rat when being perfused.
TABLE 3 statistical table of rat survival
Example 3:
(1) the test method comprises the following steps: 9 male SD rats (body weight 300 + -g) were randomly divided into 3 groups of 3.
Group A: performing intragastric administration only with paraquat for the group without toxic materials and detoxification;
group B: in the antidote treatment group, after the rats are irrigated with paraquat for 2 hours, the rats are irrigated with the antidote for treatment;
group C: in the conventional treatment group, after 2 hours, the rats are gavaged with paraquat, and then are treated with gavage of 'white + black' (referring to a clinical conventional treatment scheme).
The gavage concentration of paraquat is 400mg/kg body weight; the concentration of the detoxification medicine is 40mmol/L, and the dosage is 6 mL; white and black (5mL of active carbon, Simmada and mannitol suspension liquid medicine), the intragastric concentration is 500mg/kg of body weight, and the intragastric concentration is 6 mL. The successful gastric lavage is counted by the conditions that vomit does not occur, the animal stomachs and nasal cavities do not overflow, convulsion and death do not occur immediately, and the like. Observing behavior characteristics, and counting the survival rate of the rats.
(2) Test results
As shown in Table 4 (survival of rats in each group), the rats in the non-detoxified group died within 2 days, the rats in the white + black treated group died within 3 days, and the pre-dead state of the rats was the same as that of the rats in example 2.
All rats survived in the detoxification drug treatment group. When the rats of the group recovered to normal behavior after gastric lavage for 16 hours, the mental state was good, the hair recovered to be flat, the respiratory rhythm was uniform and regular, and the basic physiological behaviors such as normal water intake, food intake, urination and defecation were observed; after 30 days, the rat has active behavior, good mental state, normal hair, uniform and tidy breathing rhythm and increased weight compared with the rat when being perfused.
TABLE 4 statistical table of rat survival
After the AHQDS is used for intervening rats suffering from paraquat poisoning, the survival rate of the rats reaches 100%, the concentration of paraquat in blood, urine and lung tissues is rapidly reduced, and the liver and kidney functions and the antioxidant function damaged by paraquat are recovered. Hope can provide new medicine for clinical treatment of paraquat poisoning.
The above description is only exemplary of the present invention and should not be taken as limiting the invention, and any modifications, equivalents, improvements, etc. that are made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (15)
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.
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| CN110478341A (en) * | 2019-09-25 | 2019-11-22 | 海南医学院第一附属医院 | A method for the treatment of canine paraquat acute poisoning |
| WO2021057721A1 (en) * | 2019-09-25 | 2021-04-01 | 中国热带农业科学院环境与植物保护研究所 | Specific antidotal drug for treating paraquat acute poisoning |
| CN115364221A (en) * | 2022-07-11 | 2022-11-22 | 海南医学院第一附属医院 | Application of up-regulation expression promoter of Apelin/APJ pathway in medicine for treating renal injury caused by paraquat poisoning |
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| CN115364221A (en) * | 2022-07-11 | 2022-11-22 | 海南医学院第一附属医院 | Application of up-regulation expression promoter of Apelin/APJ pathway in medicine for treating renal injury caused by paraquat poisoning |
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