CN103989701B - Macrogol 4000 or polyethylene glycol 6000 application in preparation prevention or treatment cardiotoxicity of physaliatoxin medicine - Google Patents

Abstract

The invention relates to the field of medical technology, in particular to the application of polyethylene glycol 4000 or polyethylene glycol 6000 in the preparation of drugs for the prevention or treatment of jellyfish toxin cardiotoxicity, so as to solve the current lack of clinically applicable drugs for the prevention or treatment of jellyfish toxin Cardiotoxic drugs to reduce the increasing number of jellyfish stings to human life. The invention mainly provides the application of polyethylene glycol 4000 or polyethylene glycol 6000 in the preparation of drugs for preventing or treating jellyfish toxin cardiotoxicity. Polyethylene glycol 4000 or polyethylene glycol 6000 can effectively antagonize the calcium overload of cardiomyocytes induced by jellyfish toxin, thereby effectively antagonizing the cytotoxic effect induced by jellyfish toxin, reducing the death caused by jellyfish stings, and filling the gap that is not currently available in clinical practice. There is a gap in drugs used to prevent or treat jellyfish toxin cardiotoxicity.

Description

Application of polyethylene glycol 4000 or polyethylene glycol 6000 in the preparation of drugs for preventing or treating jellyfish toxin cardiotoxicity

technical field

The invention relates to the technical field of medicine, in particular to the application of polyethylene glycol 4000 or polyethylene glycol 6000 in the preparation of drugs for preventing or treating jellyfish toxin cardiotoxicity.

Background technique

Jellyfish are a class of low-level invertebrate zooplankton, belonging to the phylum Cnidaria (also known as the phylum Coelenterate), and the Gang Jellyfish. In recent years, due to various factors such as global warming, seawater eutrophication, and fish overfishing, the marine ecological environment has deteriorated severely, and jellyfish have proliferated abnormally and caused disasters in many sea areas around the world. In fact, jellyfish is also one of the most harmful marine animals to humans, and jellyfish stings are the most common marine life injuries (Dong, Z., et al., Jellyfish blooms in China: Dominant species, causes and consequences [J]. MarPollutBull, 2010.60 (7): 954-63; Al-Rubiay, K., etal., Skin and systemic manifestations of jellyfish stings in Iraqi fishermen[J].LibyanJMed, 2009.4(2):75-7.), about 150 million sea bathing enthusiasts and fishermen are troubled by jellyfish every year in the world, Florida, USA About 200,000 people in Australia are stung by jellyfish every year, and tens of thousands of people are stung by jellyfish every year in Australia, and fatal cases are not uncommon. my country has not yet seen complete epidemiological data on jellyfish stings, but since 1983, there have been more than 2,000 clinical cases (including 13 deaths) reported in the literature, and most of them were reported in the past ten years. growing trend year by year. Patients with jellyfish stings may experience local symptoms such as severe pain, inflammation and necrosis. In severe cases, muscle spasm, respiratory and circulatory depression and even death may occur (Burnett, J.W., Medical aspects of jellyfishenvenomation:pathogenesis, case reporting and therapy[J]. Hydrobiologia, 2001.451: 1- 9.).

Jellyfish stings are caused by the nematocysts on the tentacles that emit nematocysts and release toxins. Jellyfish toxins are a kind of peptide toxins with novel structure and strong toxicity. They have skin necrosis, cardiovascular, hemolysis, nerve, liver and kidney. 、心脏等多种生物活性(XiaoL.,etal.Theacutetoxicityandhematologicalcharacterizationoftheeffectsoftentacle-onlyextractfromthejellyfishCyaneacapillata[J].MarDrugs,2011,9:526-534；XiaoL.,etal.Invitroandinvivohaemolyticstudiesoftentacle-onlyextractfromjellyfishCyaneacapillata[J].ToxicolInVitro,2010,24:1203- 1207.). Among them, acute circulatory failure caused by cardiotoxicity of jellyfish toxin is recognized as the main cause of death from jellyfish stings.

Although it has been shown in the literature that the mechanism of action of jellyfish toxin cardiotoxicity may be related to myocardial cell calcium overload, non-specific cation channel blockers (LaCl ₃ ) can effectively inhibit cardiomyocyte calcium overload (Bailey, PM, et al., Afunctional comparison of the venom of three Australian jellyfish— Chironexfleckeri, Chiropsalmus sp., and Carybdeaxaymacana—oncytosolic Ca ²⁺ , haemolysis and Artemia sp.lethality[J].Toxicon,2005.45(2):233-242.), but because the trivalent cations in these blockers also have an impact on other ion currents, such as Blocking I _{CaI and I CaT and} I _Kr , and cannot be applied under physiological conditions, limits their clinical application. Therefore, so far, the mechanism of action of jellyfish toxin cardiotoxicity has not been elucidated, and there have been no reports of successful research on drugs for the prevention or treatment of jellyfish toxin cardiotoxicity.

Polyethylene glycol (English name: Polyethyleneglycol), chemical formula: HO(CH ₂ CH ₂ O)n, chemical structural formula as follows:

Polyethylene glycol is a kind of non-toxic, non-irritating inorganic hydrophilic polymer. At present, the degree of polymerization of polyethylene glycol on the market mainly includes 200, 300, 400, 600, 800, 1000, 1500, 2000, 3000 , 4000, 6000, 8000. Polyethylene glycol can be injected directly into the bloodstream and is safe to use. Its main function is to effectively repair the cell membrane damage caused by various factors, thereby preventing the ion disturbance inside and outside the cell and preventing cell death. In traumatic brain injury and spinal trauma disease models, polyethylene glycol has a significant therapeutic effect, showing good application prospects (Borgens, R.B., et al., Understandingsecondaryinjury[J].QRevBiol,2012.87(2):89-127. ).

But so far, there are no relevant reports about the use of polyethylene glycol in the prevention or treatment of jellyfish toxin cardiotoxicity.

Based on the analysis of the above literature, there is an urgent need for a drug that can be used clinically to prevent or treat the cardiotoxicity of jellyfish toxins, so as to reduce the harm to people's lives caused by the increasing number of jellyfish stings.

Contents of the invention

In order to solve the current clinical lack of effective drugs for preventing or treating jellyfish toxin cardiotoxicity, the present invention provides a new use of polyethylene glycol 4000 or polyethylene glycol 6000.

The invention provides the application of polyethylene glycol 4000 or polyethylene glycol 6000 in the preparation of drugs for preventing or treating jellyfish toxin cardiotoxicity.

Tests in the present invention show that polyethylene glycol 4000 or polyethylene glycol 6000 can effectively antagonize the increase of cardiomyocyte Ca ²⁺ in the external calcium influx pathway caused by jellyfish toxin. In the isolated heart experiment, polyethylene glycol 4000 or 6000 effectively inhibited the abnormal heart function caused by jellyfish toxin. In the mouse or rat poisoning model, intravenous injection of polyethylene glycol 4000 or 6000 can significantly improve the survival rate of animals, and at the same time improve the cardiac dysfunction caused by jellyfish toxin.

The application of the polyethylene glycol 4000 or polyethylene glycol 6000 of the present invention in the preparation of a medicine for preventing or treating jellyfish toxin cardiotoxicity, and the dosage form of the medicine is an injection. The dose is generally 100-150 mg/kg body weight/day, which can be changed according to the age and condition of the individual.

The present inventors found that the venomous extract (tentacleextract, TE) of Cyanea capillata (C.capillata) can lead to an abnormal increase of Ca ²⁺ content in the heart tissue of experimental animals and the concentration of calcium in the cytoplasm of cardiomyocytes ([Ca ²⁺ ] _i ) abnormally increased (that is, calcium overload), indicating that jellyfish toxin affects the normal physiological function of the heart by inducing myocardial cell calcium overload.

In addition, the present inventors used drug intervention to study the pathway of Ca ²⁺ increase in cardiomyocytes, and found that TE can activate both the external calcium influx pathway and the internal calcium release pathway.

In the internal calcium release pathway, the RyR inhibitor Ryanodine (20 μM) could significantly inhibit the TE-induced increase in cytoplasmic [Ca ²⁺ ] _i , but the PKA inhibitor H89 (10 μM) could not inhibit the TE-induced cytoplasmic [Ca ²⁺ ] _i increased, indicating that TE does not activate the internal calcium release pathway through the cAMP/PKA/RyR signaling pathway, but may be directly (toxin components enter the cytoplasm to directly activate the RyR pathway) or through other pathways (such as calcium-induced calcium release pathway etc.) Activation of RyR causes internal calcium release. However, because the RyR inhibitor Ryanodine has obvious paralyzing effects on both skeletal muscle and cardiac muscle tissue, it cannot be used in human and animal drug development research.

In the external calcium influx pathway, L-type calcium channel blockers (including verapamil, nifedipine, diltiazem) have no antagonistic effect; the non-specific cation channel blocker LaCl ₃ (100 μM) can partially antagonize the TE-induced [Ca ²⁺ ] _i increased; the membrane blocking agent polyethylene glycol (25mM) has a strong inhibitory effect on the increase of calcium induced by TE, but it is closely related to its molecular weight: polyethylene glycol 200-1000 is almost ineffective , polyethylene glycol 2000 is partially effective, polyethylene glycol 4000 or 6000 completely inhibits the increase in calcium caused by TE, and polyethylene glycol 8000 has a poor inhibitory effect on the increase in calcium caused by TE due to its poor solubility. Therefore, we believe that TE does not affect the existing L-type calcium channel on the myocardial cell membrane. The toxin component of TE contains pore-forming protein, which can quickly form pores on the cell membrane and cause extracellular Ca ²⁺ influx. Eventually lead to calcium overload in cardiomyocytes, polyethylene glycol 4000 or polyethylene glycol 6000 can effectively repair the pores formed on the cell membrane and antagonize the increase in [Ca ²⁺ ] _i caused by TE.

The polyethylene glycol 4000 described in the present invention is polyethylene glycol with a degree of polymerization of 4000.

The polyethylene glycol 6000 described in the present invention is polyethylene glycol with a degree of polymerization of 6000.

The application of polyethylene glycol 4000 or polyethylene glycol 6000 of the present invention in the preparation of drugs for preventing or treating jellyfish toxin cardiotoxicity, wherein the jellyfish is jellyfish jellyfish.

The application of polyethylene glycol 4000 or polyethylene glycol 6000 in the preparation of medicines for preventing or treating jellyfish toxin cardiotoxicity, wherein the medicine for preventing or treating jellyfish toxin cardiotoxicity is used to improve cardiac dysfunction caused by jellyfish toxin.

The application of polyethylene glycol 4000 or polyethylene glycol 6000 in the preparation of medicines for preventing or treating jellyfish toxin cardiotoxicity, wherein the medicine for preventing or treating jellyfish toxin cardiotoxicity is used to improve acute circulatory failure caused by jellyfish toxin.

The invention provides the application of polyethylene glycol 4000 or polyethylene glycol 6000 in the preparation of drugs for preventing or treating jellyfish toxin cardiotoxicity, polyethylene glycol 4000 or polyethylene glycol 6000 can effectively antagonize the cardiomyocyte calcium induced by jellyfish toxin The ion overload can effectively antagonize the cytotoxic effect induced by jellyfish toxin, reduce the death caused by jellyfish sting, and fill in the gap that there is no drug currently used to prevent or treat jellyfish toxin cardiotoxicity.

Description of drawings

Fig. 1 is H9c2 cell level, the change of calcium ion concentration of calcium overload induced by the blank control group jellyfish toxin, wherein, A is the calcium fluorescence image (40 times); B is the time change diagram of calcium ion concentration;

Figure 2 is H9c2 cell level, PEG200 (25mM) antagonizes the calcium overload calcium ion concentration induced by jellyfish toxin, wherein, A is a calcium fluorescence image (40 times); B is a time-varying diagram of calcium ion concentration;

Figure 3 is H9c2 cell level, PEG600 (25mM) antagonizes the calcium overload calcium ion concentration induced by jellyfish toxin, wherein, A is the calcium fluorescence image (40 times); B is the time change diagram of calcium ion concentration;

Figure 4 is H9c2 cell level, PEG1000 (25mM) antagonizes the calcium overload calcium ion concentration induced by jellyfish toxin, wherein, A is the calcium fluorescence image (40 times); B is the time change diagram of calcium ion concentration;

Figure 5 is H9c2 cell level, PEG2000 (25mM) antagonizes the calcium overload calcium ion concentration induced by jellyfish toxin, wherein, A is the calcium fluorescence image (40 times); B is the time change diagram of calcium ion concentration;

Figure 6 is H9c2 cell level, PEG4000 (25mM) antagonizes the calcium overload calcium ion concentration induced by jellyfish toxin, wherein, A is the calcium fluorescence image (40 times); B is the time change diagram of calcium ion concentration;

Figure 7 is H9c2 cell level, PEG6000 (25mM) antagonizes the calcium overload calcium ion concentration induced by jellyfish toxin, wherein, A is the calcium fluorescence image (40 times); B is the time change diagram of calcium ion concentration;

Figure 8 is the level of H9c2 cells, PEG4000/6000 (10mM) antagonizes the cytotoxic effect induced by jellyfish toxin;

Fig. 9 is the isolated heart level, PEG4000/6000 (25 μ M) antagonizes the cardiotoxic effect of jellyfish toxin;

Among them, A is the heart rate change;

B is the change of coronary flow;

C is the maximum change rate of left ventricular pressure rise;

D is the maximum change rate of left ventricular pressure drop;

E is the change of left ventricular development pressure;

F is the change of left ventricular end-diastolic pressure;

Figure 10 is the whole animal level, PEG4000/6000 (25mM) antagonizes the change of acute mortality in mice induced by jellyfish toxin;

Figure 11 is the whole animal level, PEG4000/6000 (25mM) antagonizes the abnormal cardiac function of rats induced by jellyfish toxin;

Among them, A is the heart rate change;

B is the mean arterial pressure change;

C is the maximum change rate of left ventricular pressure rise;

D is the maximum change rate of left ventricular pressure drop;

E is the change of left ventricular development pressure;

F is the change of left ventricular end-diastolic pressure.

detailed description

The implementation of the present invention will be described in detail below in conjunction with the embodiments of the present invention and the accompanying drawings. The following embodiments are implemented on the premise of the technical solution of the present invention, and detailed implementation methods and specific operating procedures are provided. However, the present invention The scope of protection is not limited to the following examples.

The jellyfish C. capillata used in the following examples was collected from the Sanmen Bay sea area of Zhejiang Province in August 2012. After being identified by Professor Hong Huixin of the School of Fisheries of Jimei University, it belongs to the phylum Cnidaria (also known as the phylum Coelenterate), and the phylum Cnidaria. Jellyfish class, Xia jellyfish genus.

The PEG200-6000 used in the following examples was purchased from Sangon Biotechnology Co., Ltd., and can also be purchased from Tianjin Tiancheng Pharmaceutical Co., Ltd., etc.

Embodiment 1. prepare jellyfish crude poisonous extract

The jellyfish C. capillata was collected from the waters of Sanmen Bay, Zhejiang Province in August 2012. Its tentacles were cut off quickly, and the tentacles were immediately frozen on dry ice. When preparing TE, weigh an appropriate amount of tentacles, add an equal volume of self-prepared 3.34% seawater (NaCl28g, _{MgCl2 ·} 6H2O5g, KCl0.8g, _CaCl21.033g , add water to 1L) and autodissolve at 4°C4 Every day, the magnetic stirrer stirred twice a day, 30min/time. Filter 3 times with a 100-mesh cell sieve, and centrifuge the filtrate 3 times at 10,000×g for 15 min each time. The above operations are all carried out in an ice bath. The supernatant collected after centrifugation was TE, and after detecting the TE protein concentration (Bradford method), it was aliquoted in 50ml centrifuge tubes, and the samples were frozen at -70°C. Dialyze with PBS solution at 4°C overnight before each use of TE.

Example 2. PEG4000/6000 antagonizes jellyfish toxin cardiotoxicity experiment at three levels of cardiomyocytes, isolated heart and whole animal

The PEG200-6000 used in the experiment was purchased from Sangon Biotech, in which PEG200 and PEG600 were colorless transparent liquids, PEG1000 was a white waxy solid, and PEG2000, 4000, and 6000 were white solids.

2.1 At the level of cardiomyocytes, PEG4000/6000 can significantly antagonize the cellular calcium overload induced by jellyfish toxin

Rat cardiomyocyte cell line (H9c2, number: 1307) was purchased from the Cell Bank of the Chinese Academy of Sciences. The complete culture medium is DMEM high-glucose medium containing 10% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin, and the culture conditions are 37° C., 5% CO ₂ , and 95% relative humidity. Observe under a microscope, when the cells grow to about 80%, the cells are digested with 0.25% trypsin (containing 0.02% EDTA), and the cells are passaged. Change the culture medium every 2-3 days.

The H9c2 cells were cultured in the confocal dish for more than 48 hours, and the experiment was started when the cell density reached 80% under the light microscope. Add Fluo-4/AM (purchased from Invitrogen, USA) 10 μmol/L application solution to the petri dish and incubate for 30-40 minutes in the dark, then use calcium-free Hepes solution (160.8mMNaCl, 3.15mMKCl, 0.7mMNa ₂ HPO ₄ .12H ₂ O , 33mM HEPES, pH7.65) washed 3 times to remove the unloaded free Fluo-4/AM background. The experiment was divided into: TE group, PEG200-6000 drug intervention group. Specifically, add calcium-containing Hepes solution (160.8mMNaCl, _3.15mMKCl , _{0.7mMNa2HPO4.12H2O} , _33mMHEPES , 0.075% _CaCl.2H2O , pH7.65) and calcium-containing Hepes solution to the culture dish (Containing PEG200-6000, 25mM) 200 μl each, placed in a 37°C incubator for incubation, and placed on the stage of a confocal microscope after 15 minutes for inspection. Setting parameters: ① The excitation wavelength is 488nm, the emission wavelength is 526nm, scan once every 10s, and continuously scan 50 sheets; ② Scanning method: xyt (time series scanning); ③ Scanning density: 512×512; ④ Objective lens multiple: 40 times. After setting the above parameters, adjust the focal plane to make the fluorescence image clearest, select the cells to record and collect images, add TE (20 μg/mL) after the fifth image is taken, and continuously observe the intracellular Ca ² after TE is added. ⁺ Dynamic changes in fluorescence. Calculate the increase percentage of [Ca ²⁺ ] _i fluorescence intensity (%)=(F _max -F ₀ )/F ₀ ×100%, where F _max is the peak [Ca ²⁺ ] _i fluorescence intensity of each group after adding TE, F ₀ is the resting intensity of [Ca ²⁺ ] _i fluorescence before adding TE.

The effects of PEG200-6000 on the increase of [Ca ²⁺ ] _i induced by TE were compared to determine whether PEG can protect the cell membrane and inhibit the calcium overload of cardiomyocytes. The results are shown in Figures 1-7. It was found that PEG200-1000 was almost ineffective on TE-induced calcium overload, PEG2000 was partially effective, and PEG4000/6000 could completely inhibit TE-induced calcium overload, suggesting that PEG4000/6000 could effectively inhibit the calcium overload induced by jellyfish toxin. Overloading has a significant antagonizing effect on cardiotoxicity.

2.2 At the cardiomyocyte level, PEG4000/6000 can significantly antagonize the cardiomyocyte toxicity of jellyfish toxin

The viability of H9c2 cells was measured by MTT method, and the experiment was divided into TE group and PEG4000/6000 drug intervention group (n=6 in each group). Among them, in the TE group, an equal volume of culture solution without TE was added to the control wells, and different concentrations of TE (2.5-100 μg/ml) were added to the toxin wells; in the PEG4000/6000 drug intervention group, PEG4000/6000 (10mM) for incubation without TE; drug intervention wells were given PEG4000/6000 (10mM) for incubation, and then TE (2.5-100μg/ml) of different concentrations was added after 15min. After the treatment, put the 96-well plate into the incubator and continue to incubate for 2 hours, then add 20 μl of MTT solution (5 mg/mL) to each well, shake gently, and continue to incubate for 4 hours, suck up the culture medium, add 200 μl of DMSO solution to each well, and keep at room temperature. Shake gently for 30 min, and after the purple crystals are completely dissolved, detect the absorbance (OD value) of each group at a wavelength of 490 nm with a microplate reader. Cell survival rate (%) in TE group=OD value of TE concentration group/OD value of control group×100%. Cell survival rate in PEG group (%)=OD value of PEG intervention group/OD value of PEG internal reference group×100%

The cell survival rate of the PEG4000/6000 group was compared with the corresponding cell survival rate of the TE group, so as to determine whether PEG4000/6000 has the effect of antagonizing the cytotoxic effect of jellyfish toxin at the cardiomyocyte level. The results are shown in Figure 8, showing that both PEG4000/6000 can significantly increase the survival rate of cardiomyocytes treated with jellyfish toxin, indicating that at the level of cardiomyocytes, PEG4000/6000 has an obvious effect of antagonizing cardiomyocyte toxicity.

2.3 At the isolated heart level, PEG4000/6000 can antagonize jellyfish toxin cardiotoxicity

24 male SD rats (purchased from the Experimental Animal Center of the Second Military Medical University of the Chinese People's Liberation Army), weighing 300±20g, were treated with 1.2g/kg of urethane containing heparin (400IU/kg) (purchased from Sinopharm Chemical Reagent Company) After intraperitoneal anesthesia, the heart was quickly opened and placed in Krebs-Henseleit (KH, mmol/L: NaCl118, KCl4.7, MgSO ₄ 1.2, NaHCO ₃ 25, KH ₂ PO ₄ 1.2, CaCl ₂ 2.5, glucose 11.0, pH7.35-7.45) in the solution for arrest. According to the classic Langendorff method, the aorta was fixed on a cannula on the cannula holder of the perfusion device, the three-way valve was opened, and the KH perfusate preheated at 37°C was connected to restart the heart. The perfusate was fully saturated with 95% _O2 and 5% _CO2 in advance, and the perfusion pressure was maintained at 60-80mmHg. After the cardiac perfusion was stable, the left atrial appendage was incised, a balloon was inserted into the left ventricle through the incision, and a biosignal analysis system (MPA-2000, Alcott, Shanghai) was connected through the pressure sensor. Then slowly inject water into the balloon to maintain the pressure inside the balloon at 2-8mmHg.

Heart rate (HR), maximum rise rate of left ventricular pressure (dP/dtmax), maximum drop rate of left ventricular pressure (dP/dtmin), left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure ( Cardiac function indicators such as LVEDP) and coronary flow (CF).

24 SD rats were randomly divided into 4 groups: control group (normal saline+normal saline), TE poisoning group (normal saline+TE) and PEG4000/6000 drug intervention group (PEG4000/6000+TE), 6 rats in each group . Among them, PEG was administered through perfusion of KH solution (25 μM), and TE was administered through a side tube (0.18 mg). After administration, the changes of each heart function index in the isolated heart were observed. The results are shown in Figure 9, showing that HR, CF, dP/dt and LVDP of the PEG4000/6000 drug intervention group were significantly better than those of the TE group, indicating that PEG4000/6000 had a significant antagonistic effect on the jellyfish at the isolated heart level. Cardiotoxic effects of toxins.

2.4 At the whole animal level, PEG can antagonize the acute death of mice induced by jellyfish toxin

Kunming mice (purchased from the Experimental Animal Center of the Second Military Medical University of the Chinese People's Liberation Army) were randomly divided into normal control group (normal saline+normal saline), negative treatment group (TE+normal saline), PEG4000/6000 treatment group (TE+PEG4000 /6000), 10 in each group. Among them, the treatment group was given tail vein injection of TE (8.4mg/kg), and then immediately injected with normal saline or PEG; the normal control group was given two injections of equal volume of normal saline, and the death of mice within 48 hours was observed and recorded after administration. Condition. The results are shown in Figure 10, PEG4000/6000 significantly reduced the acute mortality induced by TE, compared with the TE group (all mice died within 2h), all mice survived 2h after PEG4000 injection, and the survival rate was 20% after 48h; PEG6000 The survival rate of mice was 80% 2 hours after injection, and 50% after 48 hours, indicating that PEG4000/6000 can significantly reduce the acute poisoning death induced by TE.

2.5 At the level of the whole animal, PEG can antagonize the abnormal cardiac function indexes of rats induced by jellyfish toxin

24 male SD rats (purchased from the Experimental Animal Center of the Second Military Medical University of the Chinese People's Liberation Army), weighing 200±20g, were randomly divided into normal control group (normal saline+normal saline), negative treatment group (TE+normal saline), PEG4000 /6000 treatment group (TE+PEG4000/6000) consisted of 4 groups, 6 rats in each group. After intraperitoneal anesthesia with 25% urethane (purchased from Sinopharm Chemical Reagent Company) 1.2g/kg, fixation, and intravenous catheterization. Among them, the left femoral artery cannula was connected to the baroreceptor, and the biological signal analysis system (MPA-2000, Alcott, Shanghai) monitored and recorded the change of mean arterial pressure (MAP). The right common carotid artery was cannulated into the left ventricle, and the following cardiac function indicators were monitored: HR, dP/dtmax, dP/dtmin, LVDP, and LVEDP. The right external jugular vein cannula was used for intravenous administration. The treatment group was given TE (2.4 mg/kg) first, and then normal saline or PEG4000/6000 were given 1 min later as the negative treatment group and PEG4000/6000 treatment group; normal control The group was given two injections of equal volume of normal saline.

The results are shown in Figure 11, showing that PEG4000/6000 significantly alleviated the decline in TE-induced cardiac function indicators (HR, MAP, dP/dtmax, dP/dtmin, LVDP), indicating that at the overall animal level, PEG4000/6000 can significantly antagonize jellyfish Cardiotoxicity of the toxin.

The above examples are preferred implementations of the present invention, but the implementation of the present invention is not limited by the above examples. Any other modifications made without departing from the spirit and principle of the present invention shall be considered within the protection scope of the present invention.

Claims (5)

1. The application of polyethylene glycol 4000 or polyethylene glycol 6000 in the preparation of drugs for preventing or treating jellyfish toxin cardiotoxicity. 2. the application of polyethylene glycol 4000 or polyethylene glycol 6000 as claimed in claim 1 in the preparation prevention or treatment jellyfish toxin cardiotoxicity medicine, it is characterized in that, described prevention or treatment jellyfish toxin cardiotoxicity medicine is injection . 3. The use of polyethylene glycol 4000 or polyethylene glycol 6000 as claimed in claim 1 in the preparation of drugs for the prevention or treatment of jellyfish toxin cardiotoxicity, wherein the jellyfish is jellyfish jellyfish. 4. the application of polyethylene glycol 4000 or polyethylene glycol 6000 as claimed in claim 1 in the preparation prevention or treatment jellyfish toxin cardiotoxicity medicine, it is characterized in that, described prevention or treatment jellyfish toxin cardiotoxicity medicine is used To improve cardiac dysfunction caused by jellyfish toxin. 5. the application of polyethylene glycol 4000 or polyethylene glycol 6000 as claimed in claim 1 in the preparation prevention or treatment of jellyfish toxin cardiotoxicity medicine, it is characterized in that, described prevention or treatment jellyfish toxin cardiotoxicity medicine is used To improve acute circulatory failure caused by jellyfish toxin.