CN111228259A - Medicinal uses of 5-hydroxy-1-methyl hydantoin - Google Patents

Abstract

The invention belongs to the technical field of biological medicines, relates to a new medical application of 5-hydroxy-1-methylhydantoin, and particularly relates to a medical application of 5-hydroxy-1-methylhydantoin in preventing lung injury caused by paraquat. The invention provides application of 5-hydroxy-1-methylhydantoin in preparing a medicament for treating lung injury caused by paraquat, which can be prepared into a medicament by taking the single 5-hydroxy-1-methylhydantoin as a raw material, and can also be prepared into a compound preparation by matching the 5-hydroxy-1-methylhydantoin with other medicaments. According to the invention, the research finds that the 5-hydroxy-1-methylhydantoin has a protection mechanism on paraquat-induced lung injury. The 5-hydroxy-1-methylhydantoin is a small molecule compound which can easily reach lung tissues through a diffusion mechanism to exert curative effects, including elimination of hydroxyl free radicals, antioxidation and anti-inflammatory mechanisms. The invention further explores the biological activity of the 5-hydroxy-1-methylhydantoin, and provides theoretical basis and experimental basis for preventing and treating lung injury diseases caused by paraquat.

Description

Medicinal uses of 5-hydroxy-1-methyl hydantoin

technical field

The invention belongs to the technical field of biomedicine, relates to a new medical use of 5-hydroxy-1-methyl hydantoin, and particularly relates to a medical use of 5-hydroxy-1-methyl hydantoin to protect the lung damage caused by paraquat.

Background technique

Paraquat was first synthesized in the nineteenth century as a chemical indicator (redox indicator) and in agriculture in 1962 as a herbicide. It works on millions of growths and over a hundred crops and is still widely used in more than 120 countries around the world. As an important class of non-selective contact herbicides, paraquat has the following characteristics: a) It is non-selective, that is, it can kill most annual grass and broadleaf weeds, as well as established perennial weeds The parietal leaves of weeds; b) the onset of action is very fast; c) the effect is not affected by rain a few minutes after application; d) its biological activity is passivated after contact with the soil. Based on the above characteristics, paraquat has brought many benefits to farmers, the environment and society. Nonetheless, paraquat has also been blamed for serious acute and chronic health problems such as dermatitis, kidney failure, respiratory failure, rapid heart rate, second-degree burns, skin cancer, and Parkinson's disease. In addition, paraquat is commonly used as a suicide agent in many countries, especially developing countries. Therefore, the use of paraquat has attracted the attention of many organizations around the world, including the World Health Organization (WHO), the United States Environmental Protection Agency (US EPA), and the European Chemicals Agency (ECB). In 2002, some NGOs from Asia, America and Europe launched the "Stop Paraquat" campaign (Paraquat and Suicide, PAN Germany). Even so, due to the widespread use of paraquat and its widespread availability, low toxic doses (the Relatively cheap, there are still a large number of cases of accidental poisoning and suicide caused by paraquat. In 1966, British medical scientist Bullivant first described 2 cases of death caused by accidental paraquat poisoning. Subsequently, cases of paraquat poisoning have been reported around the world. About tens of thousands of deaths have been reported in the United States, Canada, Europe, Japan, Singapore, Hong Kong and other regions. Every year around the world, paraquat ingestion leads to suicide in the thousands, although the actual number is unknown due to incomplete reporting and statistics in developing countries. Paraquat causes such a high mortality rate (the total mortality rate is 25% to 75%, and it is as high as 95% for those who take 20% of the original solution, and there are few reports of survival for those who take more than 15ml or more) because so far there is no evidence of paraquat poisoning. Specific antidote and effective treatment measures (A.L.Jones, R.Elton, R.Flanagan, QJM-Int.J.Med. 1999, 92: 573-578; Zheng Guixin, China Industrial Medicine 2004, 17(2): 104-106 ).

Paraquat (PQ) is a widely used high-efficiency herbicide with strong toxicity to humans. Due to its small lethal dose of poisoning, no specific antidote, and extremely poor effect of conventional symptomatic treatment, the mortality rate remains high. The characteristic changes of paraquat poisoning are lung injury, which is manifested as damage to alveolar epithelial cells in the early stage, hemorrhage and edema in the alveoli, and intra-alveolar and interstitial fibrosis in the late stage. At present, the mechanism of PQ poisoning is still unclear and there is no effective antidote in clinical practice, resulting in the mortality rate of acute PQ poisoning as high as 50% to 80%. At present, the treatment of paraquat poisoning is still in the exploratory stage, and it is difficult to obtain satisfactory therapeutic effects, and the fatality rate is still high. The treatment of acute PQ poisoning mainly focuses on reducing absorption, promoting excretion, and inhibiting inflammatory response. Many domestic and foreign researches include hemoperfusion combined with hemodialysis, gene therapy and antibody therapy. The therapeutic drugs that have been used in clinic include anti-free radical and antioxidant drugs, hormones and immunosuppressive drugs. At present, scholars at home and abroad focus on the application of exogenous drugs for the treatment of PQ poisoning, while ignoring the development and utilization of endogenous substances in the body.

Hydantoin compounds refer to five-membered nitrogen heterocyclic compounds containing various substituents, also known as hydantoin compounds. Due to the existence of various functional groups in its structure and its large reactivity, various substituted hydantoin and its derivatives have been widely used in the fields of medicine, pesticide, chemical industry and textile. Among them, the pharmacological effects of hydantoin compounds are mainly manifested in antibacterial, anti-inflammatory, anti-epileptic, hypoglycemic, sodium channel blocker, and inhibiting the production of uremic toxins. 5-Hydroxy-1-methyl hydantoin is an important derivative of hydantoin compounds. The structure is shown in Figure 1. Studies have shown that 5-hydroxy-1-methyl hydantoin is suitable for refractory vascular inflammation. , hypoalbuminemia, renal failure, and used to eliminate free radicals and reactive oxygen species, have a significant inhibitory effect on citric acid-induced guinea pig cough, and 5-hydroxy-1-methyl hydantoin on paraquat poisoning The resulting renal injury has pharmacological activities such as protective effect. But so far, there is no relevant report that 5-hydroxy-1-methyl hydantoin can be used to prepare a drug for treating lung injury caused by paraquat.

SUMMARY OF THE INVENTION

The target organ of paraquat poisoning is the lungs, and there is currently no specific antidote for the treatment of paraquat. In view of the problems of the prior art, the purpose of the present invention is to provide the medical use of 5-hydroxy-1-methyl hydantoin for protecting the lung damage caused by paraquat. The present invention finds that 5-hydroxy-1-methyl hydantoin has a protective mechanism for paraquat-induced lung injury through research. 5-Hydroxy-1-methyl hydantoin is an endogenous substance, one of the metabolites of creatinine. 5-Hydroxy-1-methyl hydantoin is a small molecule compound that easily reaches lung tissue through diffusion mechanisms, and exerts therapeutic effects, including elimination of hydroxyl radicals, antioxidant and anti-inflammatory mechanisms.

In order to achieve the above objects, the present invention provides the following technical solutions.

Use of 5-hydroxy-1-methyl hydantoin in preparing a medicine for treating lung injury caused by paraquat.

Further, the purposes of 5-hydroxy-1-methyl hydantoin in the preparation of a medicine for treating lung injury caused by paraquat can be prepared into a medicament with a separate 5-hydroxy-1-methyl hydantoin raw material, or 5-Hydroxy-1-methyl hydantoin is combined with other drugs to make compound preparations.

Compared with the prior art, the present invention has the following beneficial effects.

(1) 5-Hydroxy-1-methyl hydantoin is a small molecule compound, which can easily reach lung tissue through diffusion mechanism and exert curative effects, including elimination of hydroxyl free radicals, antioxidant and anti-inflammatory mechanisms.

(2) The present invention further studies the biological activity of 5-hydroxy-1-methyl hydantoin by exploring the application of gold 5-hydroxy-1-methyl hydantoin in the preparation of medicines for treating lung injury caused by paraquat The exploration of paraquat provides theoretical basis and experimental basis for the prevention and treatment of lung injury disease caused by paraquat.

Description of drawings

Figure 1 shows the structural formula of 5-hydroxy-1-methyl hydantoin and partial metabolites of creatinine (5-hydroxy-1-methyl hydantoin is a degradation product of creatinine in vivo).

Figure 2 is the pathological section image of the normal lung in the control group in the pathological section image stained by H&E. It can be seen that the alveolar structure is complete, the alveolar wall has no edema, and the lung parenchyma has no inflammatory cell infiltration.

Figure 3 is the pathological section image of the paraquat (25 mg/kg) poisoning group in the pathological section of H&E staining, showing a large number of inflammatory cell infiltration, obvious intra-alveolar hemorrhage, and obvious membrane formation.

Figure 4 is the pathological section of the H&E stained pathological section of the lung after treatment with 5-hydroxy-1-methyl hydantoin (100 mg/kg) for 5 consecutive days after paraquat poisoning. Cells exudate hemorrhage.

Figure 5 shows the expression of HO-1 protein in the lung tissue of mice in each group detected by Western Blot. Western blot is a Western blot test, HO-1 is heme oxygenase-1, and β-actin is β-actin.

Figure 6 is a differential metabolite volcano plot obtained in negative ion mode. Red represents up-regulation, green represents down-regulation, gray represents no change, and VIP represents the importance projection value of the substance in the contrasted OPLS-DA model in this group.

Figure 7. Differential metabolite volcano plot obtained in positive ion mode. Red represents up-regulation, green represents down-regulation, gray represents no change, and VIP represents the importance projection value of the substance in the contrasted OPLS-DA model in this group.

FIG. 8 is a principal component analysis (PCA) diagram, the upper diagram represents the principal component analysis diagram obtained in the negative ion mode, and the lower diagram represents the principal component analysis diagram obtained in the positive ion mode. The abscissa t[1] and ordinate t[2] in the figure represent the scores of the first and second principal components, respectively, the blue dots represent the samples of the PQ group, and the red dots represent the samples of the HMH group.

FIG. 9 is a partial least squares-discriminant analysis diagram (PLS-DA), the upper diagram represents the negative ion mode, and the lower diagram represents the positive ion mode. The abscissa is the score of the sample on the first principal component; the ordinate is the score of the sample on the second principal component.

Figure 10 shows the pharmacological mechanism of 5-hydroxy-1-methylhydantoin in the protection of paraquat-induced lung injury.

Detailed ways

The present invention is described in detail below with respect to specific embodiments. The raw materials and equipment used in the specific embodiments of the present invention are all known products, which are obtained by purchasing commercially available common known raw materials.

Example 5-Hydroxy-1-methyl hydantoin was used in an experimental study on the treatment of paraquat-induced lung injury.

5-30 Kunming mice (weight about 30 g) were purchased from Liaoning Changsheng Biotechnology Co., Ltd. Animals were acclimated and fed in the animal department for 1 week from the date of purchase. Thirty mice were randomly divided into normal saline group (control group), paraquat poisoning group (gavage 20 mg/kg, completed at one time), and 5-hydroxy-1-methyl hydantoin treatment group (making paraquat poisoning small group). The mouse model was then injected intraperitoneally with 5-hydroxy-1-methyl hydantoin (100 mg/kg), administered once every 8 hours for 5 consecutive days. The whole experiment continued for 5 consecutive days, during which the condition of the mice was observed. The mice were sacrificed for six days. The effects of HMH on the lung tissue of the PQ-toxic model were studied from the pathological sections of the lungs and the SOD activity, MDA content, heme oxygenase protein-1 (HO-1) and metabolites in the lung tissue of the mice. protective effect.

Protective mechanism of 5-hydroxy-1-methyl hydantoin against paraquat-induced lung injury.

Through observation, it was found that the mice in the NS group had normal appetite and breathing, good mental state and flexible movement. Most of the mice in the PQ group developed symptoms of poisoning within 2 hours after exposure, manifested as fatigue, irritability, decreased food and water intake to varying degrees, bloody secretions from the nose and mouth, fluffy hair, and slow movements that were easy to catch. Mice in HMH group developed poisoning symptoms 12 hours after administration, manifested as lethargy, sluggish movements, and no bloody secretions were seen in the mouth and nose. Through the H&E staining experiment, it was found that the damage to the lungs of the paraquat poisoning group was relatively alleviated after administration of 5-hydroxy-1-methyl hydantoin, as shown in Figure 2-4. Observe the pathological section images of H&E staining. Figure 2 is the pathological section image of the normal lung in the control group. It can be seen that the alveolar structure is complete, the alveolar wall has no edema, and the lung parenchyma has no inflammatory cell infiltration; Figure 3 is paraquat (20mg/kg) poisoning The lung pathological section images of the group showed a large number of inflammatory cell infiltration, obvious intra-alveolar hemorrhage, and obvious membrane formation; Figure 4 shows the treatment of 5-hydroxy-1-methyl hydantoin (100 mg/kg) for 5 consecutive days after paraquat poisoning The pathological section of the lung showed mild damage to the alveolar structure and a small amount of inflammatory cell exudation and hemorrhage. By measuring the SOD and MDA indexes of lung tissue, the results are shown in Table 1, it can be found that 5-hydroxy-1-methyl hydantoin has antioxidant effect.

Table 1 Content of MDA and activity of SOD among each group

The changes in the expression of HO-1 protein in the lung tissue of mice were further observed, and the changes in the expression of HO-1 protein at a low level in the lung tissue of the control group were shown in Table 1 and Figure 5. Compared with the control group, the expression level of HO-1 in the lung tissue of the exposure group was significantly increased, and the expression level of the HMH group was significantly higher than that of the PQ group.

Through the metabolomics study on the lung tissue extraction of mice in each group, it was found that the changes of metabolites were observed in the positive and negative ion mode of the mass spectrometer. The results are shown in Figure 6-7, and the red color represents the up-regulated metabolites compared to the PQ group. , green represents the down-regulated metabolites compared to the PQ group, and gray represents the metabolites that were not different between the PQ and HMH groups. The VIP value represents the importance projection value of the metabolite in the OPLS-DA model compared in this group.

In order to obtain meaningful statistical results, principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were performed. See Figure 8, the HMH and PQ groups are well separated at 95% confidence intervals, and Figure 9, the HMH and PQ groups are well separated.

The differential metabolites in HMH group and PQ group were analyzed, see Table 2. The differential metabolite metabolic pathways between the HMH group and the PQ group were mainly concentrated in the citric acid cycle (TCA cycle), alanine, aspartate and glutamate metabolism, taurine and hypotaurine metabolism, microbial metabolism, Regulation of lipolysis and purine pyrimidine metabolism in adipocytes.

Table 2 Differential metabolites between HMH group and PQ group

Claims (2)

1. Use of 5-hydroxy-1-methylhydantoin in preparing medicine for treating lung injury caused by paraquat is provided.
2. 2. The use of 5-hydroxy-1-methylhydantoin as claimed in claim 1 in the preparation of a medicament for the treatment of lung injury caused by paraquat, wherein the medicament is prepared from 5-hydroxy-1-methylhydantoin alone or 5-hydroxy-1-methylhydantoin in combination with other medicaments to form a compound preparation.

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