CN112494498A - Application of tetracycline in preparation of medicine for preventing or relieving jellyfish sting - Google Patents
Application of tetracycline in preparation of medicine for preventing or relieving jellyfish sting Download PDFInfo
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Abstract
The invention relates to the technical field of medicines, and provides application of tetracycline or a derivative thereof in preparing a medicine for preventing or relieving systemic poisoning caused by jellyfish sting. Experiments prove that the simultaneous administration and the early administration of the mouse sting can obviously prolong the survival time of the mouse, obviously reduce the rise of the heart blood pressure of the mouse caused by irradiation, improve the hemolysis phenomenon in the systemic poisoning caused by jellyfish, and provide a new theoretical basis for preventing or relieving the systemic poisoning caused by the jellyfish sting by tetracycline or derivatives thereof. The tetracycline has mature anti-inflammatory and immunosuppressive effects, clear pharmacological action, small toxic and side effects and clinically approved medicine safety, so that the new indication of the tetracycline provided by the invention can quickly realize clinical transformation. Because tetracycline has great potential in the application of injury protection caused by systemic poisoning due to jellyfish sting, the invention also provides a new clinical medicine for preventing or relieving the injury caused by the systemic poisoning due to jellyfish sting.
Description
Technical Field
The invention belongs to the field of biological medicines, provides a new application of tetracycline, and particularly relates to an application of tetracycline or a derivative thereof in preparation of a medicine for preventing or relieving systemic poisoning caused by jellyfish stings.
Background
Jellyfish (Jelly fish) is one of the oldest and mysterious organisms in the world, and has existed on the earth about 6.5 million years ago, and is distributed in almost all sea areas. In quantity, the number of jellyfishes is increased explosively in recent decades, which not only causes the destruction of a marine ecosystem and causes catastrophic damage to marine fishery, but also causes the jellyfish sting events to increase continuously, thousands of people suffer injury every year, and the problem becomes very troublesome.
Since the 40 th century of the 20 th century, Pubmed began to pay attention to and gradually reported the cases, treatments and related studies of the poisoning mechanism of representative poisonous jellyfish bites such as grapevine warship jellyfish (pertuguese man-of-war), Irukandji jellyfish, wasp jellyfish (Chironex fleckeri), sandjelly jellyfish (Stomolophus mellearis) and Cyanea jellyfish (Cyanea capitata), and it was basically clarified that systemic poisoning caused by jellyfish bites can be divided into two categories, local skin symptoms and systemic poisoning. Topical skin conditions include severe pain, itching, rash, pigmentation, etc.; systemic poisoning symptoms are caused by severe inflammatory reactions after jellyfish stings, and if the jellyfish is soaked in the jellyfish toxin for a long time, the jellyfish toxin can possibly penetrate through the skin and enter the blood, so that the death is further caused by extensive damage to a plurality of internal organs in the body such as the heart, the liver, the kidney and the like.
At present, the mainstream view is that cardiovascular toxicity is the main cause of death of jellyfish Toxin (TE), and antitoxic serum and MgSO4、Ca2+Channel blockers and the like are effective therapeutic agents for jellyfish delayed toxicity systemic syndrome (DJES). However, the antagonistic effect of different jellyfishes has obvious difference, and even the intervention effect of the same experiment in different laboratories has completely opposite conditions, such as C4And verapamil, and the like.
Tetracycline (Tetracycline) is a broad-spectrum antibiotic that inhibits bacterial proteins, causing the bacteria to fail to grow and multiply normally, eventually leading to bacterial death. Tetracycline can treat infections caused by a plurality of different parts of a body, such as bronchitis, keratitis, otitis media, gastrointestinal tract infection, sphagitis, pneumonia, nasosinusitis, urinary tract infection, skin infection and the like, but the prevention and treatment effect of Tetracycline on systemic poisoning caused by jellyfish stings in the sand sea is not reported at present.
Disclosure of Invention
The invention aims to provide a new medical application of tetracycline or a derivative thereof.
The first aspect of the present invention provides the use of tetracycline or a derivative thereof for the manufacture of a medicament for preventing or alleviating jellyfish stings, which causes systemic poisoning after jellyfish stings, which is a medicament for reducing the hemolytic reaction after stings or reducing the degree of blood pressure drop after stings.
The experiments of mice verify that the hemolytic activity can be remarkably reduced by mixed injection of tetracycline and aequorin, and the condition of blood pressure reduction of the mice can be remarkably improved by pre-injection of tetracycline or mixed injection of tetracycline and aequorin, so that the acute poisoning symptom of the mice can be antagonized, and the survival rate of the mice can be improved.
Furthermore, the medicine for preventing or relieving systemic poisoning caused by jellyfish sting is a medicine for inhibiting the aequorin protein, and is essentially a medicine for neutralizing the aequorin protein. From the foregoing, it can be seen that the aequorin protein is a key link in the sting reaction, and that neutralization of the aequorin contributes to protection against multiple organ injury in systemic poisoning after jellyfish sting.
The tetracycline derivative in the present invention refers to a tetracycline compound capable of exerting a pharmacological action, such as doxycycline, dimethylaminocycline and the like.
In order to verify that the tetracycline can play a role in inhibiting the protective effect of the aequorin protein, the invention verifies the protective effect of the tetracycline on the systemic poisoning of jellyfish sting including multi-organ injury by a mouse survival experiment, a hemolysis experiment and blood pressure change detection.
ICR mice, 7-week-old male mice were selected for the experiment, and the tail of the mice was injected with tetracycline (3mg/kg) simultaneously or 30min in advance at the time of sting. The sting method of the mouse is that the tail vein is injected with jellyfish toxin, the dose is 5.70mg/kg, and the mouse is placed in a 1000ml lunch box containing 0.5cm of high seawater.
Experiments show that the survival time of the mouse can be obviously prolonged and the survival rate can be improved by simultaneously or in advance administering the mouse sting; obviously reducing the reduction of the blood pressure of the heart of the mouse caused by irradiation; simultaneous sting administration can improve hemolysis in systemic poisoning caused by jellyfish toxin sting.
The medicament for preventing or relieving systemic poisoning caused by jellyfish stings is tetracycline or a derivative thereof serving as the only active ingredient or a pharmaceutical composition containing tetracycline or a derivative thereof.
The medicine or the medicine composition can be prepared into any dosage form together with pharmaceutically commonly used auxiliary materials, for example, the medicine or the medicine composition can be prepared into decoction, powder, pills, vinum, pastille, colloid, tea, leaven, cake, lotion, stick, thread, strip, nail, moxibustion, paste, pellet, liposome, aerosol, injection, mixture, oral ampoules, tablets, capsules, dripping pills, emulsion, membranes or sponginum.
The medicine or the pharmaceutical composition is suitable for the situations that marine workers, naval fighters, seaside visitors and marine lifeguards suffer jellyfish sting, can be used for preventing or relieving jellyfish sting, and recommends that the medicine is taken in advance and is taken immediately when the jellyfish sting occurs, and the administration mode is not limited to oral administration, injection and the like.
Action and Effect of the invention
Experiments prove that the simultaneous administration and the early administration of the mouse sting can obviously prolong the survival time of the mouse, obviously reduce the rise of the heart blood pressure of the mouse caused by irradiation, improve the hemolysis phenomenon in the systemic poisoning caused by the jellyfish toxin, and provide a new theoretical basis for preventing or relieving the systemic poisoning caused by the jellyfish sting by tetracycline or derivatives thereof.
In addition, tetracycline has mature anti-inflammatory and immunosuppressive effects, is available in the tradenames of BAOMYCIN Capsule, Tetracycline hydrochloride Capsule and the like, has definite pharmacological action, small toxic and side effects and clinically approved medicine safety, so that the new indication of tetracycline provided by the invention can quickly realize clinical transformation. Because tetracycline has great potential in the application of injury protection caused by jellyfish sting, the invention also provides a new clinical medicine for preventing or relieving the injury caused by systemic poisoning of the whole body after jellyfish sting.
Drawings
FIG. 1 shows the effect of different tetracycline injection timings on the survival rate of mice after stinging. Wherein A is a survival analysis chart of a mouse injected with tetracycline in advance; b is a survival analysis chart of the mice injected with mixed tetracycline; c is the survival analysis of mice injected with tetracycline.
FIG. 2 is a graph showing the effect of different injection timings of tetracycline on the hemolytic activity of cells after stinging, wherein A is a microscopic result graph of hemolysis of cells with different injection sequences of tetracycline, B is a plot of hemolytic activity of cells with different injection sequences of tetracycline, and C is a plot of cell survival counts with different injection sequences of tetracycline.
FIG. 3 shows the effect of different tetracycline injection timings on blood pressure of post-stinging mice.
FIG. 4 is a graph of the effect of varying doses of mixed tetracycline injections on survival of mice. Wherein A is a survival curve chart of mixed injection of tetracycline with different doses; and B is a survival rate chart of mixed injection of different doses of tetracycline.
Detailed Description
The present invention will be described in detail below with reference to examples and the accompanying drawings. The following examples should not be construed as limiting the scope of the invention.
Example 1: survival analysis of acute mouse lethality by tetracycline at different injection times
First, experiment method
Male ICR mice were divided into several groups (n.gtoreq.6), six mice per group, and the tetracycline injection sequence was different for the different groups: the first injection was performed by pre-injection, in which Tetracycline (TCH) was administered to three mice at a dose of 50mg/kg in the tail vein, and PBS (0.01mol) was administered to three other mice as a control. After 30min, the six mice were injected with aequorin (TE) at a dose of 5.70mg/kg, respectively. Repeating one group by the above method, stopping if the repeatability is consistent, and repeating one group if the repeatability is not strong; the second injection mode is that equal volumes of TE and TCH are mixed, and then tail vein injection is carried out, wherein the injection sequence and grouping are consistent with the above; the third injection mode is TE injection in the tail vein, TCH injection is carried out 2-3min later, and the injection sequence and grouping are consistent with the above. The time to death of the mice was observed and recorded and median survival time and survival curves were calculated for the mice using GraphPad prism 7.00 software.
Second, experimental results
In the TCH pre-injection mode, as shown in FIG. 1A, after comparing the TCH pre-injection (50mg/kg) with the PBS pre-injection (0.01mol), the TCH pre-injection can improve the sting death of the jellyfish toxin to a small extent, and two mice even survive, but most of the mice die within 2h, which indicates that the prevention effect of TCH is not obvious.
As shown in fig. 1C, comparing the group of TCH (50mg/kg) and PBS (0.01mol) after TE injection, TCH was found to improve the lethality of TE only to a small extent and slightly delay the death time of mice, but mice died within 2h, indicating that TCH could not be used as antidote.
Interestingly, TE and TCH were mixed and injected into mice, as shown in figure 1B, with a significant improvement compared to TE and PBS mixed injection controls, with 100% survival. The TCH can instantly neutralize lethal component in the aequorin to achieve the treatment effect, and can be made into emulsion to be smeared on the skin to achieve the prevention effect.
Example 2: effect of different injection timings of tetracycline on post-sting cell hemolytic activity
The first experiment method comprises the following steps:
the negative control group was 100. mu.L of 0.45% erythrocyte suspension and 1% whole blood to which 100. mu.L of 0.01M PBS solution was added, and the positive control group was 100. mu.L of 0.45% erythrocyte suspension and 1% whole blood to which 100. mu.L of aequorin was added at a concentration of 30. mu.g/ml. In the experimental group, TCH concentration gradient was 50mg/mL, TE concentration was 0-300. mu.g/mL.
The experimental components are divided into three groups, wherein in the first group, 2 mul of TCH solution with the concentration of 50mg/mL is respectively added into 99 mul of 0.45 percent erythrocyte suspension and 1 percent whole blood to be mixed evenly, and then TE 99 mul with different dilution times is added; experiment second group 2. mu.l TCH solution 50mg/mL and TE solution 99. mu.l of different dilution times were mixed and added to 99. mu.l of red blood cell suspension or 1% whole blood; in the third group of experiments, 99. mu.L of TE solution with different concentration coefficients is added into 99. mu.L of erythrocyte suspension or 1% whole blood, then 50mg/mL of TCH is added, the total volume of each corresponding system is 200. mu.L, and the TE solution and the erythrocyte suspension or the 1% whole blood are mixed evenly.
The samples were incubated in a 37 ℃ water bath for 30min with gentle horizontal shaking. After the incubation period, the cells were centrifuged at 2000 Xg for 5min to remove unreacted erythrocytes and broken membranes of erythrocytes. After centrifugation, 150. mu.L of the supernatant was transferred to a 96-well microplate and photographed by microscopic observation and then measured for light absorption at 415nm (OD415) by a spectrophotometer.
Taking the absorbance value of the negative control and the absorbance value of the positive control as 0% hemolysis and 100% hemolysis respectively, calculating the hemolysis fraction of the experimental group: experimental hemolysis fraction (%) (OD experimental-OD negative control)/(OD positive control-OD negative control) × 100 and curves were fitted according to Hill equation using origin software.
Second, experimental results
The hemolytic activity detection experiment and the survival experiment have better consistency: under microscopic observation, the number of cells with fold rupture is extremely rare no matter after 0min or 30 min; in the positive control group, a large number of cells appeared in the wrinkled state at 0min, and after 30min, the cells observed in the microscope were significantly reduced, which also appeared in the pre-injection TCH and the post-injection TCH of the experimental group, while the mixed injection TCH significantly improved, and after 30min, a large number of intact erythrocytes were still observed, the number of which was consistent with that of the negative control group, and no significant hemolysis was observed at 0min (fig. 2A).
For the three different injection modes, TE concentration was diluted in a gradient (300. mu.g/ml-0. mu.g/ml), and it was found that mixed TCH injection can significantly reduce hemolytic activity, while pre-injection and post-injection have no obvious therapeutic effect, and the hemolytic condition is consistent with that of the positive control group (FIG. 2B).
Cell counting is carried out on the survival cells, and similarly, the number of the survival cells after 30min is consistent with that of the negative control group and is more than 80% after mixed injection of TCH, and the number of the survival cells after 30min of the positive control group is different from that of the survival cells after 30min of the negative control group and is not more than 20%. Pre-injection also did not improve hemolysis and the number of cells surviving was 0 (fig. 2C). Example 3: effect of different tetracycline injection timings on post-sting mouse blood pressure
The first experiment method comprises the following steps:
ICR mice (20 + -2 g) were randomly divided into 4 groups, which were a pre-injection TCH group of 50mg/kg, a mixed injection TCH of 50mg/kg, a post-injection TCH of 50mg/kg and a single injection TE of 5.74mg/kg, respectively.
After anesthesia by intraperitoneal injection of 20% urethane (1.5mg/kg), the mice were fixed, and then were surgically clipped to the neck with an elbow to make a slightly right incision, the right jugular vein was isolated, cannulated with an intravenous catheter filled with physiological saline and fixed for injection administration, and administered at a fixed volume of 0.2ml/10g body weight. Cutting the left groin with an elbow surgical scissors, separating the left femoral artery, inserting and fixing the arterial catheter filled with 0.3% heparin normal saline from the centripetal end, connecting a pressure sensor, continuously monitoring the changes of Mean Arterial Pressure (MAP) and Heart Rate (HR) by adopting an MPA-2000 biological signal analysis system, observing for 30min, and recording. Half-lethal dose of TE (LD50) was calculated using GraphPad Prism 7.0 software and mice survival curves were plotted.
Second, experimental results
According to FIG. 3, TE has a significant dose-dependent effect on both the electrocardiogram and blood pressure of the mice, and the blood pressure of the mice shows an irreversible sharp drop after a single injection of 5.72mg/kg of aequorin, which drops by 90% after 30 min. The blood pressure of the three groups injected with TCH has improvement effect to a certain extent, wherein the improvement effect of the pre-injection group and the mixed injection group is most obvious, the blood pressure is kept stable in the first 10min and is reduced by 20% after 30 min; the blood pressure of mice injected with TCH keeps stable in the first 10min and is maintained at the initial 50% after 30min, which shows that TCH is very likely to improve the survival rate of mice by improving the cardiovascular of mice to antagonize the acute toxic symptoms of mice.
Example 4: survival analysis of mice by mixed injections of tetracycline at different doses
The first experiment method comprises the following steps:
ICR mice were divided into several groups (n.gtoreq.6), the first injection was performed by injecting TCH (50mg/kg, 30mg/kg,15mg/kg,5mg/kg,3mg/kg,0.5mg/kg) into the tail vein of 3 mice, then injecting PBS (0.01mol) into 3 mice as a control, and after 30min, injecting TE (5.70mg/kg) into the 6 mice, respectively. And repeating one group by the method, stopping if the repeatability is consistent, and repeating one group if the repeatability is not strong. The time to death of the mice was observed and recorded and median survival time and survival curves were calculated for the mice using GraphPad prism 7.00 software.
Second, experimental results
By analysis, we found that there was a significant improvement in the survival rate of mice when the TCH dose was above 5mg/kg, the survival rate was above 70% and 100% when the dose was 50mg/kg (fig. 4A). By analyzing the death curve, the IC50 value of the half effective dose of TCH was 9.2mg/kg (FIG. 4B).
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are given by way of illustration of the principles of the present invention, and that various changes and modifications may be made without departing from the spirit and scope of the invention as defined by the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (6)
1. Application of tetracycline or its derivative in preparing medicine for preventing or relieving systemic poisoning caused by jellyfish sting is provided.
2. Use of tetracycline or a derivative thereof according to claim 1 in the manufacture of a medicament for the prevention or alleviation of systemic poisoning caused by jellyfish stings, characterized in that:
wherein the medicament for preventing or relieving systemic poisoning caused by jellyfish stings is a medicament for reducing hemolytic reaction after the stings or reducing the degree of blood pressure reduction after the stings.
3. The use of a tetracycline or derivative thereof in the manufacture of a medicament for the prevention or alleviation of systemic poisoning after jellyfish stings, as claimed in claim 2, wherein:
wherein the medicament for preventing or relieving systemic poisoning caused by jellyfish sting is a medicament for inhibiting jellyfish toxin protein.
4. Use of tetracycline or its derivatives according to claim 3 in the manufacture of a medicament for the prevention or alleviation of systemic poisoning caused by jellyfish stings, characterized in that:
wherein the drug inhibiting the aequorin protein is a drug neutralizing the aequorin protein.
5. Use of a tetracycline or derivative thereof according to any one of claims 1-4 in the manufacture of a medicament for the prevention or alleviation of systemic poisoning caused by jellyfish stings, wherein:
wherein the agent for preventing or alleviating systemic poisoning caused by jellyfish stings is tetracycline or a derivative thereof as the only active ingredient or a pharmaceutical composition containing tetracycline or a derivative thereof.
6. Use of tetracycline or a derivative thereof according to claim 1 in the manufacture of a medicament for the prevention or alleviation of systemic poisoning caused by jellyfish stings, characterized in that:
wherein the medicine for preventing or relieving jellyfish sting is decoction, powder, pill, medicated wine, lozenge, colloid, tea, yeast, cake, lotion, stick, thread, stick, nail, moxibustion, ointment, pellet, liposome, aerosol, injection, mixture, oral ampoule, tablet, capsule, drop pill, emulsion, membrane or sponge.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102917702A (en) * | 2009-09-23 | 2013-02-06 | 夏威夷大学 | Zinc-containing compositions for the treatment of diseases, illnesses and syndromes associated with exposure to pore forming toxins |
| CN107249578A (en) * | 2014-11-21 | 2017-10-13 | 奥菲瑞克斯股份有限公司 | Venom is stung into treatment method and relevant pharmaceutical composition, system and kit |
| CN111803701A (en) * | 2020-06-15 | 2020-10-23 | 中国人民解放军海军特色医学中心 | Preparation method of antibacterial drug-loaded cyclo-gamma-polyglutamic acid modified hydrogel |
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2020
- 2020-12-11 CN CN202011456713.0A patent/CN112494498A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102917702A (en) * | 2009-09-23 | 2013-02-06 | 夏威夷大学 | Zinc-containing compositions for the treatment of diseases, illnesses and syndromes associated with exposure to pore forming toxins |
| CN107249578A (en) * | 2014-11-21 | 2017-10-13 | 奥菲瑞克斯股份有限公司 | Venom is stung into treatment method and relevant pharmaceutical composition, system and kit |
| CN111803701A (en) * | 2020-06-15 | 2020-10-23 | 中国人民解放军海军特色医学中心 | Preparation method of antibacterial drug-loaded cyclo-gamma-polyglutamic acid modified hydrogel |
Non-Patent Citations (2)
| Title |
|---|
| KANG C. ET AL: "Protective Effect of Tetracycline against Dermal Toxicity Induced by Jellyfish Venom", 《PLOS ONE》 * |
| LI R. ET AL: "Combined Proteome and Toxicology Approach Reveals the Lethality of Venom Toxins from Jellyfish Cyanea nozakii", 《J. PROTEOME RES.》 * |
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