CN108309964B - Application of metformin in preparation of products for preventing and treating noise hearing loss - Google Patents
Application of metformin in preparation of products for preventing and treating noise hearing loss Download PDFInfo
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- CN108309964B CN108309964B CN201810301498.3A CN201810301498A CN108309964B CN 108309964 B CN108309964 B CN 108309964B CN 201810301498 A CN201810301498 A CN 201810301498A CN 108309964 B CN108309964 B CN 108309964B
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- A—HUMAN NECESSITIES
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Abstract
The invention relates to application of metformin in preventing and treating noise-induced hearing loss, and pharmacological experiments on the prevention and treatment effects of metformin on the hearing loss of noise-exposed rats show that metformin can obviously prevent and treat hearing loss caused by noise exposure, and has the effect of preventing and treating the noise-induced hearing loss.
Description
Technical Field
The invention relates to a new application of metformin, in particular to an application of metformin in preparing a product for preventing and treating noise-induced hearing loss.
Background
With the development of modern industrial and weaponry, the harmfulness of noise is increasing and in many respects, noise exposure can cause structural and functional impairment of the auditory and non-auditory systems or organs, as well as pathological damage, the most prominent of which is sensorineural hearing damage, which is manifested primarily as hearing loss. However, the noise is difficult to be reduced to a harmless level by the current technical level and economic conditions, so that the enhancement of the noise medical protection of industrial or military operation environments is of great significance.
The most major target organ of noise damage is the auditory organ, and the loss of noisy hearing is mainly manifested by decreased hearing sensitivity, increased hearing threshold, decreased speech reception and signal discrimination ability, which is a process from physiological shift to pathological one, and pathological damage must reach a certain noise intensity and/or contact time. The harm of noise to the auditory system is related to factors such as the intensity, frequency, exposure time and individual sensitivity of the noise, and within a certain range, a dose effect relationship exists between noise exposure and hearing loss. Noise can cause damage to most cells of the cochlea, the most significant of which is damage to cochlear hair cells. The mechanism by which noise causes hearing damage is by damaging the inner ear sensory hair cells through mechanical or metabolic effects. Research proves that noise exposure can obviously inhibit aerobic energy metabolism of cochlear hair cells, and further consumes a large amount of glycogen for anaerobic glycolysis, and abnormal metabolic processes of the energy can trigger hair cell damage; in addition, excitotoxicity-induced oxidative damage is also the major trigger mechanism for hair cell death due to acoustic exposure at the cellular level.
The low molecular dextran and adenosine triphosphate can promote aerobic metabolism and energy generation of cochlea, phenylisopropyl glycoside (PIA) can increase glutathione and SOD level in perilymph, enhance the antioxidant capacity of cochlea, effectively reduce noise hearing loss and hair cell loss, allopurinol, polyethylene glycol, mannitol, N-acetylcysteine, acetyl L-carnitine, salicylate and other antioxidants can clear or inhibit oxygen free radicals, and can also effectively prevent and treat noise damage, peroxidation inhibitors, and antioxidants such as ulinastatin, α -lipoic acid, ginkgo biloba polysaccharide and the like are also proved to be effective.
Metformin is suitable for type 2 diabetic patients who are not well controlled with diet and exercise alone. The mechanism of metformin for lowering blood glucose is: 1 increase the sensitivity of the surrounding tissues to insulin, increasing insulin-mediated glucose utilization. 2 increasing glucose utilization by non-insulin dependent tissues, such as brain, blood cells, renal medulla, intestinal tract, skin, etc. 3 inhibiting hepatic gluconeogenesis and reducing hepatic glucose output. 4 inhibit glucose uptake by intestinal wall cells. Different from the action of insulin, metformin has no function of promoting fat synthesis, has no obvious effect of reducing blood sugar of normal people, and generally does not cause hypoglycemia when being applied alone to type 2 diabetes. In the prior art, the effect of metformin on preventing and treating noise-induced hearing loss is not reported at present.
Disclosure of Invention
The invention aims to provide the application of metformin in preparing products for preventing and treating noise-induced hearing loss aiming at the defects in the prior art, and the metformin can play good effects of resisting oxidation and excitotoxicity, improving aerobic metabolism and energy generation of inner ears and the like, further effectively improving the hair cell state caused by noise exposure and preventing or relieving the hearing loss.
In order to achieve the purpose, the invention adopts the technical scheme that:
application of metformin in preparing products for preventing and treating noise-induced hearing loss is provided.
Further, the noisy hearing loss is auditory sensorineural hearing impairment mainly manifested as hearing loss due to noise exposure exceeding a limit.
Further, the use of metformin for the preparation of a hearing loss control product which is predominantly manifested by temporary and/or permanent hearing threshold shifts due to noise exposure.
Further, metformin is used as the only active ingredient.
Further, the product comprises one or more of medicines, reagents, foods and health care products.
Further, the metformin may be used alone or in the form of a pharmaceutical composition comprising a therapeutically effective amount of metformin, a pharmaceutically acceptable salt thereof or a prodrug thereof, and a pharmaceutically carrier.
Further, the pharmaceutical carrier includes excipients, such as one or more of starch or water; one or more of a lubricant, such as glycerin or magnesium stearate, and the like; disintegrants, such as microcrystalline cellulose and the like; fillers, such as one or more of starch or lactose; a binder such as one or more of pregelatinized starch, dextrin, cellulose derivatives, alginate, gelatin, or polyvinylpyrrolidone, etc.; osmotic pressure regulators, such as one or more of glucose, sucrose, sorbitol, or mannitol; diluents such as water and the like; disintegrating agents, such as one or more of agar, calcium carbonate or sodium bicarbonate; absorption accelerators such as quaternary ammonium compounds and the like; surfactants such as cetyl alcohol and the like; an adsorption carrier, such as one or more of kaolin, bentonite, etc.; lubricants, such as one or more of talc, calcium stearate, magnesium stearate, or polyethylene glycol; in addition, other adjuvants such as one or more of flavoring agent or sweetener can also be added into the pharmaceutical composition.
Further, the metformin may be administered in the form of one of its pharmaceutically acceptable salts, and specifically the pharmaceutically acceptable salts thereof include: hydrochloride, acetate, benzoate, citrate, fumarate, pamoate, chlorophenoxyacetate, glycolate, aspartate, methanesulfonate, maleate, p-chlorophenoxyisobutyrate, formate, lactate, succinate, sulfate, tartrate, cyclohexanecarboxylate, trimethoxybenzoate, p-toluenesulfonate, adamantanecarboxylate, glutamate, pyrrole one carboxylate, naphthalenesulfonate, 1-phosphogluconate, nitrate, sulfite, dithionate or; a phosphate salt. Among the preferred salt forms are hydrochloride, fumarate, pamoate or chlorophenoxyacetate.
The invention has the advantages that:
the invention screens and proves the new activity and the new application of the metformin by carrying out experimental research on a plurality of compounds. Pharmacological experiments on the prevention and treatment effects of the metformin on the hearing loss of noise-exposed rats show that the metformin can obviously prevent and therapeutically protect the hearing loss caused by noise exposure, and the metformin has the effect of preventing and treating the noise-induced hearing loss, so that the metformin can be used as a medicine for preventing and treating the noise-induced hearing loss. The invention not only provides a new therapeutic application of the metformin, but also provides a new medicament for preventing and treating noise hearing loss.
Drawings
Figure 1 is the dose-effect relationship of metformin to control noisy hearing loss. Metformin has a remarkable prevention effect on temporary hearing threshold shift and permanent hearing threshold shift after a long time caused by noise exposure, and metformin has a clear dose-effect relationship in preventing and treating noise hearing loss.
Detailed Description
The invention will be further illustrated with reference to specific embodiments. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention. Furthermore, it should be understood that various changes and modifications can be made by those skilled in the art after reading the disclosure of the present invention, and equivalents fall within the scope of the appended claims.
The term "acceptable" as used herein means that a prescribed component or active ingredient does not unduly adversely affect the health of the general therapeutic target.
The term "preventing" as used herein includes preventing, alleviating, inhibiting or ameliorating the symptoms or conditions of a disease; inhibiting the generation of complications; inhibiting the development of a disease or condition, such as controlling the development of a disease or condition; alleviating the disease or symptoms; regression of the disease or symptoms; alleviating a complication caused by the disease or symptom, or preventing or treating a symptom caused by the disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, can ameliorate a disease, symptom, or condition, particularly severity, delay onset, slow progression, or reduce duration of a condition. Whether fixed or temporary, sustained or intermittent, may be due to or associated with administration.
The term "pharmaceutically acceptable" as used herein refers to a substance, such as a carrier or diluent, which does not diminish the biological activity or properties of the compound and which is relatively non-toxic, e.g., a substance that is administered to an individual without causing unwanted biological effects or interacting in a deleterious manner with any of the components it contains. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, or the like, and combinations thereof. In many cases, it will be desirable to include isotonic agents, for example, one or more of sugars, polyalcohols such as mannitol, sorbitol, sodium chloride and the like in the composition. The pharmaceutically acceptable carrier may also contain minor amounts of auxiliary substances such as one or more of wetting or emulsifying agents, preservatives or buffers, and the like.
In particular aspects of use, the metformin of the present invention may be used alone or in combination with a number of other chemicals. Whether or not these chemical substances have biological activity or function for treating diseases, including auxiliary functions such as synergistic amplification, antagonism or alleviation of side effects of metformin, etc., these chemical substances include one or more of pharmaceutically acceptable carriers, foods, natural products, chemically synthesized drugs or human drugs, etc.; preferably comprises one or more of pharmaceutically acceptable carriers or food, etc.; further preferably a pharmaceutically acceptable carrier.
The metformin used in the following examples is a white powder with a content of > 99% and a grade of medical grade, and the following inventive procedure only summarizes the experimental contents of significance in the present invention.
Example 1 prevention and treatment of noise-induced hearing loss with metformin
(ii) animal grouping and handling
Healthy adult Sprague Dawley rats, body mass 230-. Animals were observed 3 days before the experiment and randomized into 4 groups, of which: experimental control group, total of 5 Sprague Dawley rats (10 ear); the experimental control group was subjected to intragastric gavage with deionized water. Metformin was administered to the low dose group of 5 Sprague Dawley rats (10 ears) at a dose of 75 mg/kg/day. Metformin mid-dose group, 5 Sprague Dawley rats (10 ears) were given metformin at 150 mg/kg/day. Metformin was administered to the metformin high-dose group in a total of 7 Sprague Dawley rats (14 ears) at a dose of 300 mg/kg/day. Dissolving metformin in deionized water to obtain 500mg/100ml suspension, and performing intragastric administration. Dosing was performed 3 days before exposure through the end of the experiment on day 7 after exposure.
(II) noise exposure of experimental animals
All rats tested were placed in wire cages, placed on the floor of an acoustic reverberation chamber, and a speaker suspended above. White noise is emitted by a signal generating system (B & K3560C, Denmark) and is connected to a loudspeaker through a power amplifier. The noise exposure sound intensity is (130.0 +/-1) dB SPL and the continuous exposure is 4h, and the monitoring and the control are carried out by a B & K2209 type precision sound level meter (B & K company, Denmark).
(III) threshold detection
Before and after the noise exposure, respectively measuring a basic value and the hearing threshold change condition after the noise exposure in 0 day, 3 days, 7 days and 14 days, wherein the measuring method comprises the following steps: 3 needle electrodes were inserted subcutaneously into guinea pigs. The recording electrode is inserted in the middle of the skull top, the reference electrode is arranged at the position of the mastoid process of the same side of the skull, and the ground electrode is inserted under the skin of the mastoid process of the opposite side of the skull and then is arranged in an electric shielding iron box. A Smart-EP Manual Version 3.97 test System (IHS, USA) was applied. The stimulation signal is short sound 100ms, the stimulation frequency is 11.1/s, the filter bandwidth is 100-3000Hz, the superposition is carried out for 512 times, the observation time interval is 12.8ms, and a TDH-49P earphone is adopted for sound supply during measurement.
(IV) statistical treatment
Data are expressed as mean ± standard deviation, and results were statistically analyzed using the SPSS 19 software package, with differences of P <0.05 being statistically significant.
(V) results of the experiment
TABLE 1 prevention and treatment of noise-induced hearing loss by metformin
In table 1, group 0 is an experimental control group, group 1 is a metformin low dose group, group 2 is a metformin medium dose group, and group 3 is a metformin high dose group; in comparison with the group 0,*P<0.05，**P<0.01。
as shown in table 1: immediately after the noise exposure, the hearing thresholds of all groups have no significant difference, which indicates that the hearing threshold displacements of all groups caused by the noise exposure are basically the same, namely the hearing loss degrees are basically the same; on days 3, 7 and 14 after noise exposure, the hearing threshold value of each group is remarkably lower than that of a control group by applying different doses of metformin, and the metformin has remarkable prevention and treatment effects on temporary hearing threshold displacement and permanent hearing threshold displacement caused by the noise exposure. In addition, as shown in fig. 1: metformin has a clear dose-effect relationship in preventing and treating noise-induced hearing loss.
(IV) conclusion of the experiment
Metformin can prevent and treat sensorineural hearing loss mainly manifested by hearing loss due to noise exposure exceeding the limit, and has the effect of preventing and treating noise-induced hearing loss.
EXAMPLE 2 preparation of metformin tablet
The preparation process comprises the following steps: hydroxypropyl methylcellulose is dissolved in a proper amount of water to prepare a solution with the concentration of 8 percent, and lactose is dissolved in the hydroxypropyl methylcellulose solution to be used as a binder solution. Metformin is ground and sieved through a 100 mesh sieve and mixed with microcrystalline cellulose using a binder plasmid. And adding magnesium stearate into the prepared granules, uniformly mixing, and tabletting by using a tabletting machine to obtain the metformin tablet.
EXAMPLE 3 preparation of metformin capsules
The preparation process comprises the following steps: (1) premixing metformin, microcrystalline cellulose and 2% hydroxypropyl methylcellulose, and performing wet granulation; (2) drying and straightening granules obtained by wet granulation to obtain dry granules; (3) mixing the dried granules and magnesium stearate to obtain total mixed granules; (3) and (4) filling the total mixed particles into capsules to obtain the metformin capsule preparation.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and additions can be made without departing from the method of the present invention, and these modifications and additions should also be regarded as the protection scope of the present invention.
Claims (5)
1. Use of metformin as the sole active ingredient in the manufacture of a product for the treatment of noisy hearing loss.
2. Use according to claim 1, wherein the noisy hearing loss is sensorineural hearing impairment with a predominant expression of hearing loss due to noise exposure exceeding a limit.
3. Use according to claim 1, wherein metformin is used in the preparation of a product for the treatment of hearing loss predominantly manifested by temporary and/or permanent threshold shifts due to noise exposure.
4. The use according to any one of claims 1 to 3, wherein the product comprises one or more of a drug, an agent.
5. The use according to any one of claims 1 to 3, wherein metformin is used alone.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP2561866A1 (en) * | 2011-08-26 | 2013-02-27 | Heinrich-Heine-Universität Düsseldorf | Morphinan-derivatives for treating diabetes and related disorders |
| CN104546815A (en) * | 2014-12-27 | 2015-04-29 | 中国人民解放军第四军医大学 | Application of sodium butyrate for preventing noise-induced hearing loss |
| CN104664407A (en) * | 2015-03-26 | 2015-06-03 | 中国人民解放军军事医学科学院卫生学环境医学研究院 | Nutritional agent with noise induced hearing loss resistance |
| CN105535009A (en) * | 2016-01-27 | 2016-05-04 | 邦泰生物工程(深圳)有限公司 | Drug or health care product for preventing and treating hearing loss |
| CN107847489A (en) * | 2015-05-18 | 2018-03-27 | 森索睿翁公司 | For treating department's fine jade class Calcineurin inhibitors of hearing loss |
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| WO2003045977A2 (en) * | 2001-11-26 | 2003-06-05 | Trustees Of Tufts College | Peptidomimetic Inhibitors of Post-Proline Cleaving Enzymes |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2561866A1 (en) * | 2011-08-26 | 2013-02-27 | Heinrich-Heine-Universität Düsseldorf | Morphinan-derivatives for treating diabetes and related disorders |
| CN104546815A (en) * | 2014-12-27 | 2015-04-29 | 中国人民解放军第四军医大学 | Application of sodium butyrate for preventing noise-induced hearing loss |
| CN104664407A (en) * | 2015-03-26 | 2015-06-03 | 中国人民解放军军事医学科学院卫生学环境医学研究院 | Nutritional agent with noise induced hearing loss resistance |
| CN107847489A (en) * | 2015-05-18 | 2018-03-27 | 森索睿翁公司 | For treating department's fine jade class Calcineurin inhibitors of hearing loss |
| CN105535009A (en) * | 2016-01-27 | 2016-05-04 | 邦泰生物工程(深圳)有限公司 | Drug or health care product for preventing and treating hearing loss |
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