CN111568908A - Medicine for preventing and treating motion sickness and Meniere disease and medical application of spironolactone - Google Patents

Abstract

The invention relates to the technical field of medical treatment, in particular to a medicament for preventing and treating motion sickness and meniere disease and medical application of spironolactone, wherein the medicament comprises spironolactone with effective dose for preventing and treating motion sickness, the medicament is in a dose unit form, and the dose of the spironolactone is 20-60mg when adults inject the spironolactone once. Through the mode, the invention can play an effective reference role in preventing and treating the motion sickness and the Meniere disease, and further possibly play an effective medicine role.

Description

Medicine for preventing and treating motion sickness and Meniere disease and medical application of spironolactone

Technical Field

The invention relates to the technical field of medical treatment, in particular to a medicine for preventing and treating motion sickness and Meniere's disease and medical application of spironolactone.

Background

People-carrying space flight realization breakthrough in China in 2003, rapid development of transportation, ocean development, particularly military navigation business, and continuous increase of operation opportunities and operation population in special environments in recent years; meanwhile, with the improvement of living standard, the travel times of people are greatly increased. The factors cause the number of the sick people to be increased obviously, bring pain and inconvenience to people going out, and also bring influence to the health, the operation safety and the navigation military operation of the operating personnel in special environment.

When people take vehicles such as vehicles, ships and airplanes or do operations such as aerospace and navigation, many people can suffer from motion sickness mainly manifested by pale complexion, cold sweat, salivation, indifference, abdominal discomfort, dizziness, nausea, vomiting and the like due to abnormal vestibular stimulation or/and abnormal visual stimulation, and the motion sickness is also called as carsickness, seasickness, air sickness, simulator diseases, aerospace motion diseases and the like. Literature data shows that almost all passengers can sea sickness when sailing under severe sea conditions; during the aerospace operation, the occurrence rate of motion sickness can still reach 60% -80% despite the simulated training on the ground. Although the motion sickness is gradually relieved after the user leaves the motion environment, the motion sickness obviously influences normal travel of the user and operation in special environments such as aviation, spaceflight, navigation and the like. At present, the detailed pathogenesis of the motion sickness is still not quite clear, and the prevention and treatment aspect still lacks of drugs with high efficiency and no side effect. The existing anti-motion sickness drugs comprise antihistamine, anticholinergic drug, sympathomimetic drug, calcium antagonist, gastric motility drug, traditional Chinese medicine such as red sage root, tall gastrodia tuber, ginger or compound preparation and the like. At present, the most commonly used medicine for preventing and treating motion sickness is antihistaminic medicine dimenhydrinate (dimenhydrinate), and the single medicine with the best effect is anticholinergic medicine scopolamine, but the effective action parts of the medicines are not clear, the side effects are large, particularly the side effects of central inhibition, blurred vision, memory impairment and the like influence the operation of people under various special environmental conditions such as navigation, aerospace and the like. Therefore, there is a need to further study the pathogenesis of motion sickness, search for more suitable targets, and develop new anti-motion sickness drugs with good effect, strong specificity, and no obvious side effect, especially no central inhibition side effect.

Meniere's disease is a sudden onset of rotational vertigo accompanied by symptoms such as tinnitus, deafness, fullness in the head or ear, and the like, and severe vertigo may be accompanied by symptoms such as nausea, vomiting, cold sweating, and the like. The disease is common and frequently encountered in otolaryngology, frequently encountered in single ear, better in young and strong years, and has no obvious difference in incidence rate between men and women. The basic pathology is changed into membranous labyrinth hydrops, and the exact cause is unknown. The meniere's disease is related to immune reaction, vegetative nerve functional disturbance or infection, which interfere capillary vessel function of inner ear, block capillary vessel and vein reflux, block inner lymph vessel, absorb disorder of inner lymph fluid, cause membranal labyrinth hydrops and cause inner ear balance dysfunction. Meniere's disease is usually acute and repeated, and is a difficult treatment in the ear, nose and throat department. For the treatment of meniere's disease, the etiology has not been completely clarified so far, so at present, clinically, the pathophysiology process is mainly based on symptomatic treatment, and therapeutic measures such as anti-dizziness, sedation, blood vessel dilation, dehydration and supporting therapy are adopted, or destructive surgery or non-surgical treatment is adopted, and when conservative treatment is ineffective, surgical treatment is considered, such as endolymphatic sac decompression or shunt surgery, vestibular nerve amputation, labyrinthine damage or excision and the like. These methods either affect the therapeutic effect or bring serious side effects such as unnecessary or even impaired hearing and balance function. Therefore, the Meniere's disease has not been treated by a method of specifically applying drugs such as spironolactone to eliminate membranous labyrinth hydrops.

Many studies found that plasma Arginine Vasopressin (AVP) levels were significantly elevated in motion sickness, which is very similar to plasma Arginine vasopressin changes in meniere's disease. Rowe (1979) et al demonstrate that plasma arginine vasopressin levels are associated with nausea. Intravenous or intracerebroventricular injection of arginine vasopressin can induce nausea, vomiting, and other motor symptoms in humans and animals (Ikegaya, 2002). Kim et al (1997) found that increased plasma arginine vasopressin levels induced nausea by visual stimuli and that large injections of arginine vasopressin also induced nausea in subjects.

Recent studies show that the plasma arginine vasopressin level of patients with Meniere disease is increased abnormally, and arginine vasopressin phosphorylates the S256 site of the inner ear AQP2 through an AVP-V2R-cAMP-PKA signal path, so that translocation and membrane growth are increased; meanwhile, the PKA is also used for promoting CREB phosphorylation, so that the expression level of AQP2 of the inner ear is increased, the lymph fluid in the inner ear is excessively formed, the reabsorption of water by the epithelium of the endolymphatic sac is reduced, the membranous labyrinth hydrops is caused, and finally symptoms such as dizziness, nausea and vomiting are induced (Takeda, 1995, 2009, 2010; Maekawa, 2010). Inhibition of AQP2 expression using arginine vasopressin antagonists or lithium agents reduces endolymphatic edema (Takeda, 2003; Fukushima, 2005).

Motion sickness is very similar to symptoms in meniere patients, and blood arginine vasopressin levels are elevated. Our studies in recent two years show that the polymorphism difference of arginine vasopressin gene may affect the susceptibility of rat motion disease, and the high-susceptibility rat rotationally stimulates the high expression of paraventricular arginine vasopressin (Xu, 2015); the plasma arginine vasopressin level of beagle dogs and rats can be increased by the rotary stimulation, and the arginine vasopressin increase response of animals to the induction stimulation of motion sickness can be inhibited while the vestibular function exercise and the motion sickness inhibition of the anti-motion sickness drugs are carried out (Shenhuaxiang, 2012; JiangRui, 2012). Meanwhile, by using the rat conditioned taste aversion model, we found that the phosphorylation level and the total expression of AQP2 in the inner ear of the lymphatic sac are increased while rat motion disease is induced by rotational stimulation or arginine vasopressin, and the expression of cAMP, pPKA and pCREB is increased, so that the motion disease induced by rotational stimulation or arginine vasopressin and the changes of cAMP and AQP2 can be blocked by using a V2 receptor antagonist mozavaptan. Therefore, the role of arginine vasopressin in motion sickness is probably the same as that in meniere's disease, and is also related to excessive stimulation of vestibular system caused by formation of inner ear V2 receptor, AQP2 and endolymphatic excess, namely, the main pathophysiological process of motion sickness is probably similar to that of meniere's disease, and if measures or medicines are taken to inhibit the endolymphatic excess formation in inner ear, the occurrence of motion sickness is probably inhibited, and the meniere's disease is alleviated.

Aldosterone (Aldosterone, alder.) is an important hormone involved in water-salt balance and maintaining homeostasis in the body, namely Mineralocorticoid (Mineralocorticoid). Research shows that the phenomenon of membrane labyrinth hydrops of cochlea of guinea pigs is caused by injecting aldosterone into abdominal cavity, and the suggestion that aldosterone probably promotes lymphangiogenesis in inner ear and/or reduces endolymph reabsorption, thereby having the effect of increasing endolymph volume. In addition, it is also found that the membrane labyrinthine hydrops phenomenon induced by intraperitoneal aldosterone injection in the cochlea of guinea pig causes the increase of the expression of the epithelial sodium channel (alpha-ENaC) protein in the cochlear tissue and the decrease of the expression of aquaporin 1(AQP 1). Meanwhile, the expression level of AQP1 protein has a negative correlation with motion sickness sensitivity. These studies suggest that the mineralocorticoid hormone aldosterone may affect the aqueous salt balance of the inner ear through the action of target proteins in the inner ear and thus be involved in the development of motion sickness.

Therefore, in the prevention and treatment of both motion sickness and meniere's disease, Spironolactone (Spi), an antagonist of aldosterone, has been used to inhibit the production of lymph fluid in the inner ear and to alleviate the effects of vestibular stimulation. As a low-effect diuretic, the compound is low in side effect and is the first choice for antagonizing actions of mineralocorticoids (aldosterone). Therefore, a Mineralocorticoid Receptor (MR) signaling pathway can be used as a target, and a new anti-motion sickness drug is developed from the spi of MR antagonism.

Disclosure of Invention

The invention mainly aims to provide a medicament for preventing and treating motion sickness and Meniere's disease and medical application of spironolactone, which can play an effective reference role in preventing and treating motion sickness and Meniere's disease and further possibly play an effective medicament role.

In order to achieve the above purpose, the invention adopts a technical scheme that: a medicament for the prevention and treatment of motion sickness, the medicament comprising spironolactone in an amount effective in the prevention and treatment of motion sickness.

Further, the medicament is in dosage unit form.

Further, the dose of said spironolactone is 20-60mg upon a single injection of said spironolactone into an adult.

In order to achieve the purpose of the invention, the invention adopts another technical scheme that: a medicament for the prevention and treatment of Meniere's disease, said medicament comprising spironolactone in an amount effective for the prevention and treatment of Meniere's disease.

Further, the medicament is in dosage unit form.

Further, the dose of said spironolactone is 20-60mg upon a single injection of said spironolactone into an adult.

In order to achieve the purpose of the invention, the invention adopts another technical scheme that: an application of spironolactone in preparing medicine for preventing and treating motion sickness is disclosed.

In order to achieve the purpose of the invention, the invention adopts another technical scheme that: an application of spironolactone in preparing medicine for preventing and treating Meniere disease is disclosed.

Compared with the prior art, the invention has the following beneficial effects:

1) the medicament for preventing and treating motion sickness and meniere disease and the medical application of spironolactone, which are disclosed by the invention, have the advantages that spironolactone is applied to antagonize the effects of rotary stimulation and increased arginine vasopressin and mineralocorticoid aldosterone on inner ears, the vestibule stimulation sensitivity is reduced, the occurrence of motion sickness is inhibited, the smooth operation of people in pleasant and comfortable travel and special environments can be ensured, and the medicament has very important practical significance for promoting the development of the industries such as national transportation and ocean development, aerospace, military navigation and the like;

2) the spironolactone is used for antagonizing the generation of lymph fluid in inner ears in a targeted manner on the pathophysiological mechanism of the Meniere disease, namely the formation mechanism of the membranous labyrinth hydrops, so that the spironolactone is beneficial to inhibiting the progress of the disease course and relieving the membranous labyrinth hydrops, thereby achieving the purpose of treatment, relieving the state of illness as soon as possible and relieving the pain of patients.

Drawings

Figure 1 is a graph showing the effect of rotational stimulation on the amount of sodium saccharin solution (n-20) in rats according to the examples of the invention.

Fig. 2 is a graph showing the results of the change in the amount of sodium saccharin solution (n-6) in rats after intraperitoneal injection of Ald. (36 μ g/kg) in the present example.

FIG. 3 is a graph showing the results of the change in the drinking amount of the sodium saccharin solution from rats after intraperitoneal injection of Spi (30mg/kg) in the example of the present invention.

Detailed Description

The technical solutions of the present invention will be described in further detail below with reference to several preferred embodiments and accompanying drawings, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. It is to be noted that the following examples are intended to facilitate the understanding of the present invention, and do not set forth any limitation thereto. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention. The test methods in the following examples, which are not specified under specific conditions, are generally carried out under conventional conditions.

The spironolactone is used for antagonizing the effects of rotational stimulation and increased arginine vasopressin and mineralocorticoid aldosterone on the inner ear, reducing the stimulation sensitivity of the vestibule and inhibiting the occurrence of motion sickness, can ensure that people travel pleasantly and comfortably and work smoothly under special environment, and has very important practical significance for promoting the development of the industries such as transportation and ocean development, aerospace, military navigation and the like in China.

Spironolactone, an artificially synthesized steroid, a low-potency diuretic, structurally similar to aldosterone, is a competitive inhibitor of aldosterone. The medicine only acts on the distal convoluted tubule and the collecting duct, and has no effect on other parts of the renal tubule, so the diuretic effect is weaker. In addition, the medicine also has effects on aldosterone target organs except renal tubules.

The application provides a medicament for preventing and treating motion sickness and Meniere disease, which comprises spironolactone with effective dose for preventing and treating motion sickness and Meniere disease.

In one embodiment, the agents for the prevention and treatment of motion sickness, meniere's disease, provided herein are in dosage unit form. The dosage of the spironolactone contained in the medicaments in different dosage forms can be the same or different, and the dosage of the spironolactone contained in the medicaments in the same dosage form can be the same or different; for example, in the case of a drug in the form of a liquid, the spironolactone may be contained in an amount of 20mg or 40 mg.

In one application scenario, the effective amount of spironolactone in a drug for the treatment of a disease can be readily determined and prescribed by the skilled physician, depending on the species of the patient (e.g., human, dog, chimpanzee, etc.), sex, weight, age, medical condition, route of administration, severity of the condition being treated, and the like. In addition, the effective dose administered will vary with the mode of administration, the treatment desired, and the disease condition indicated. The total daily dose may be administered in a single dose or in divided doses. For example, in the case of a single intravenous injection of a medicament for the prevention or treatment of motion sickness in an adult, the dose of spironolactone in the medicament is 20 to 60mg, for example, 20mg, 40mg, 60mg, etc.

The dosage ranges listed in the above examples are exemplary only, and the dosage may be adjusted according to pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Accordingly, this application encompasses dose escalation in patients as determined by one of skill in the art. Determining suitable dosages and schedules for administering spironolactones is well known in the relevant art and, once the teachings disclosed herein are provided, should be understood to be covered by those skilled in the art.

The medicaments of the present application may be prepared, packaged or sold in bulk form, in single unit dosage form, or in multiple single unit dosage forms. As used herein, a "unit dose" is an individual amount of a drug comprising a predetermined amount of spironolactone. The amount of spironolactone is typically equal to the dose of spironolactone to be administered to the subject, or a convenient fraction of such a dose, such as, for example, one-half or one-third of such a dose.

The application also provides application of the spironolactone in preparation of a medicine for preventing and treating motion sickness/Meniere's disease.

Specific data are used for explaining that spironolactone provides effective reference in preventing and treating motion sickness and Meniere disease.

Referring to fig. 1 to 3, the present application demonstrates the anti-motion and anti-meniere effects of spironolactone of the present invention through the following three experimental steps. In the related technical research, the adopted experimental animals are Sprague-Dawley (SD) rats with the weight of 200-220g and female animals, the experimental animals are bred adaptively for 3 days, and then the experiments of two halo models of rotating stimulation, aldosterone stimulation induced motion disease and Meniere disease are carried out, and conditioned taste aversion is taken as a model; then, an antihalation experiment of spironolactone was performed, and conditioned taste aversion induced by rotational stimulation was used as a model.

Spironolactone (Spironolactone, Spi.) used in the following experiments was purchased from Sigma-Aldrich, west codex, usa, Aldosterone (aldsterone, Ald.) used in the experiments was purchased from kaman, Cayman, usa, sodium Saccharin (saccharorin sodium) was produced by tianjin north food limited, and SD rats were provided by the laboratory animals center of southern university.

First, rotational stimulation induces conditioned taste aversion in rats

The rotational stimulation induced conditioned taste aversion (dizziness) in SD rats, and the 0.15% saccharin sodium solution was allowed to drink freely from the rats, and the drinking amount was measured every 24 h. The assessment was made by measuring the reduction in the intake of 0.15% Saccharin Sodium Solution (SSS) by rats.

The rotary stimulation device was developed with reference to the reported methods of Crampton and Lucot (1985). The rats were freely and unrestrained placed in a rotary stimulation device with an embedded upper and lower layer of partition plates (each partition plate was divided into 6 parts on average, and 1 rat was placed in each part). The device slowly rotates clockwise at a constant speed around a vertical shaft, simultaneously rotates at a variable speed around a horizontal shaft, is accelerated at an angular acceleration of 16 degrees/s 2, and is decelerated at an angular acceleration of-48 degrees/s 2 immediately after the angular velocity reaches a maximum value of 120 degrees/s until the device stops, 10s is a period, and then the period is repeated anticlockwise, and the stimulation is repeated for 120 min. Continuously monitoring the drinking amount of each SD rat to the 0.15% saccharin sodium solution two days before and two days after the rotary stimulation, recording corresponding experimental data, and calculating the intake change of the saccharin sodium solution, wherein the indexes are as follows: the change percentage of the drinking amount of the saccharin sodium solution is (average drinking amount of the saccharin sodium solution 2 days after rotation-2 balance average drinking amounts before rotation)/2 balance average drinking amounts before rotation. Then, statistical analysis is carried out, independent sample t test (Student's test) is adopted for comparison between two groups, one-factor analysis of variance (Oneway ANOVA) is adopted for comparison between multiple groups, and two-two comparison is carried out by an LSD method, and when p is less than 0.05, the difference is considered to have significance, namely the statistical significance is achieved.

The results in fig. 1 show that the consumption of saccharin sodium solution after rotation was significantly reduced (p <0.05) compared to the Control (Control) in the rotation-stimulated group (Rot.) SD rats compared to the consumption of saccharin sodium solution before rotation, indicating that the rotation stimulation caused the SD rats to produce the conditioned taste aversion behavior of the aversion to drinking saccharin sodium solution, i.e., the motor disease, meniere disease (dizziness) expression.

Second, aldosterone induces conditioned taste aversion in rats

After the drinking amount of the 0.15% saccharin sodium solution in the rat is detected for two days, namely the 3 rd day, the aldosterone is given through the intraperitoneal injection, and the dosage is 36 mu g/kg.

The SD rats were further tested for changes in the amount of 0.15% Saccharin Sodium Solution (SSS) consumed following intraperitoneal injection of aldosterone (Ald.36 μ g/kg) following the same experimental procedure as the rotational stimulation induced conditioned taste aversion in rats, except that the rotational stimulation was replaced by intraperitoneal injection of aldosterone.

The results in fig. 2 show that the consumption of saccharin sodium solution is significantly reduced (p <0.05) after injecting Ald intraperitoneally into SD rats in the aldosterone group (Ald.) compared with the Control group (Control), indicating that injecting Ald intraperitoneally (36 ug/kg) can cause the SD rats to produce conditioned taste aversion behavior of the saccharin sodium solution, similar to the behavior of rat motion disease and meniere disease (dizziness) induced by rotation stimulation, indicating that mineralocorticoid aldosterone can promote the occurrence of motion disease or meniere disease.

Third, spironolactone inhibition of rotational stimulus-induced conditioned taste aversion behaviors in rats

The administration of spironolactone (30mg/kg) was intraperitoneally administered 1h before the SD rats were subjected to 2h of rotational stimulation, and the change in the drinking amount of 0.15% saccharin sodium solution by rats two days after the rotational stimulation was examined, as compared with that before the rotational stimulation.

The results in fig. 3 show that the consumption of saccharin sodium solution was significantly reduced (p <0.05) in the SD rats in the rotational stimulation group (Rot.) compared to the Control group (Control), while the consumption of saccharin sodium solution in the spironolactone group (Spi. + Rot.) was suppressed (p <0.05) compared to the rotational stimulation group (Rot.). The consumption of the sodium saccharin solution of rats in the single spironolactone treatment group (Spi.) was not significantly changed. The results show that the aldosterone antagonist spironolactone (Spi) can inhibit the expression of conditioned taste aversion behaviors caused by rotation stimulation, namely the motion disease and the Meniere disease (vertigo), and the spironolactone can be used as a medicament for preventing and treating the motion disease and the Meniere disease.

In summary, the present invention shows that the rotational stimulation can effectively stimulate Sprague-Dawley rats to produce the manifestations of motion sickness and Meniere's disease (areola), and the intraperitoneal injection of aldosterone can produce the manifestations of motion sickness and Meniere's disease (areola) with conditioned taste aversion as an index, i.e. aldosterone can promote the occurrence of motion sickness and Meniere's disease (areola). Conditioned taste aversion in rats is an important index for determining the occurrence of motion sickness and meniere's disease (dizziness). As an aldosterone antagonist, spironolactone intraperitoneal injection can relieve conditioned taste aversion caused by rotational stimulation, namely antagonism of motion sickness and Meniere's disease (areola). At the same time, spironolactone can antagonize changes in target protein expression downstream of the inner ear Ald./MR/SGK1/Nedd4-2 signaling pathway, which are mostly caused by aldosterone. Therefore, the application speculates that the spironolactone can regulate the water and ion balance of the inner ear and inhibit the formation of endolymph through inhibiting the pathway of the activity of the Ald./MR/SGK1/Nedd4-2 signal channel of the inner ear, thereby playing a role in resisting motion sickness (areola). Meanwhile, as the pathogenesis of the meniere disease is directly related to the action of the lymph hydrops in the inner ear and the aldosterone on the inner ear, the application result also supports that the spironolactone can play a role in treating the meniere disease.

The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes, which are made by the present specification, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.

Claims (8)

1. A medicament for preventing and treating motion sickness, which is characterized by comprising spironolactone with an effective dose for preventing and treating motion sickness.

2. A medicament for the prevention and treatment of motion sickness according to claim 1, wherein said medicament is in dosage unit form.

3. The agent for the prophylaxis and treatment of motion sickness according to claim 1, wherein the dose of said spironolactone is 20-60mg per single injection of said spironolactone into an adult.

4. A medicament for preventing and treating Meniere's disease, wherein said medicament comprises spironolactone in an amount effective for preventing and treating Meniere's disease.

5. The drug for preventing and treating Meniere's disease as claimed in claim 4, wherein said drug is in dosage unit form.

6. The drug for preventing and treating Meniere's disease according to claim 4, wherein the dose of said spironolactone is 20-60mg per single injection of said spironolactone into an adult.

7. An application of spironolactone in preparing medicine for preventing and treating motion sickness is disclosed.

8. An application of spironolactone in preparing medicine for preventing and treating Meniere disease is disclosed.

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