MXPA00004450A - Application of vasopressin antagonists for treating disturbances or illnesses of the inner ear - Google Patents

Abstract

The invention relates to the application of at least one vasopressin receptor antagonist or mixture of such antagonists in order to treat disturbances or illnesses of the inner ear. These disturbances/illnesses can be connected to at least one of the following symptoms:vertigo, impairment of hearing or tinnitus. The symptoms can especially relate to those of so-called Ménièr's disease. According to the invention, especially vasopressin V2 receptor antagonists can be applied, whereby the antagonists can be peptidic or non-peptidic substances.

Description

USE OF VASOPRESSIN ANTAGONISTS DESCRIPTION The invention relates to the use of at least one vasopressin receptor antagonist or mixtures thereof. As is known, vasopressin (VP) is a peptide hormone from the posterior lobe of the pituitary gland. As a result of its action a n t i di u r e t i c a is also recognized as a n t i di ur e t an n an d i t i di u t i t i n a t i di (ADH). The form of the hormone that occurs in humans and in many mammals is a cyclic peptide of nine amino acids with a disulfide bridge, in which arginine is in the eighth position. This form is also known correspondingly to vasopressin arginine (AVP). As established, the influence of vasopressin on the diuresis of water in the kidneys, the action at which it produces, is particularly and physiologically important. The vasopressin makes the collecting tubules in the kidney permeable to water and in this way allows the re-absorption of water in the kidneys and consequently the concentration of urine. The epithelial tissues of the collecting ducts react to the presence of vasopressin. The hormone supplfrom the blood side of the epithelial cells, binds to the specific receptors and by means of the intracellular cAMP (cyclic second messenger ade n or s i n-3 ', 5 -mono f or s f a t o) stimulates the increase of water permeability. The fundamental mechanism can be devised in such a way that the aqueous molecules formed in the channels are formed in the so-called principal cells. In the case of the main cells of the collecting ducts of the kidney, this gl i c op r o t t i n is still the only acuporma-2 detected there. It is stored micially in small vesicles inside the cell and in the presence of vasopressin in the receptor is incorporated into the apical cell membrane. As a result, water is allowed to enter the regulated cell according to lme n t e. Vasopressin receptors that carry a c MP -dependent regulation in the canal water in the epithelial cells of collecting ducts in the kidney are known as receptors.

V2 • Thus, in the epithelial cells of the collecting tubules of the kidney, vasopressin has a r e-r e s r e r e r e r e r action of water. This can be inhibited with vasopressin receptor antagonists. Correspondingly, the antagonists oppose the action in the kidney of vasopressin and consequently increases the. urine flow while simultaneously diluting the urine. Antagonists of the vasopressin receptors are already known in addition to the anticancer action of vasopressin. These can be peptidic or non-peptidic substances. In addition to the peptide substances, reference is made to the publications of M. Manning and .H. Sa yer in J. Lab. Clin. Med. 114, 617-632 (1989) and F. A. Laszlo et al. in Pharmacol. Rev., 43, 73-108 (1991). Descriptions of non-peptidic substances appear in Y. Yamamura et al. in Br. J. Pharmacol. 105, 787-791 (1992) and C. Serradeil-Le Gal et al. in J. Clin. Invest. , 98 (12) 2729-2738 (1996). All of these substances are investigated and used in conjunction with the action at n t i di u t i t of vasopressin. Hitherto, the discoveries and investigations concerning disturbances and diseases of the inner ear can not be brought into agreement with the discoveries described in the foregoing, which concern the action a n t i d i u r i t of vasopressin and the inhibition of this action by antagonists. This also applies particularly to the so-called hydropsies in the inner ear, in which there is an excess of endolymph fluid in the endoliphatic area of the inner ear. These drops can be linked to an overproduction or effusion or a discharging disorder of the endolymph, particularly in the so-called sac at the end of the first stage (Saccus e nd 1 i n f a t i c u s). Although the existence of vasopressin in the inner ear has been detected, the use of vasopressin antagonists can not be considered as a result of existing discoveries regarding the action of vasopressin in water. In the case of an increase in the volume of fluid in the inner ear, which can trigger symptoms of disease, it would be desirable to know the action of vasopressin. This action would be inhibited by the use of the antagonist. Surprisingly it has now been found that in the inner ear, particularly in the epithelial cells, which include the endolymph, water permeability can be restored and improved with the use of vasopressin receptor antagonists. As a result of this unexpected antagonistic action of the antagonist compared to its action on the kidney, it becomes possible to use such substances or their mixtures for the treatment of disturbances or diseases of the inner ear. Thus, the problem of the invention of making available the active ingredients for the treatment of disturbances or diseases in the inner ear, is solved with the use according to claim 1. Preferred developments are given in the dependent claims 2 to 16 The content of all these rei indications is established by reference to the content part of the description. According to the invention, at least one vasopressin receptor antagonist or generated mixtures can be used for the treatment of disorders or diseases of the inner ear. This in particular also covers the use of producing a corresponding medicament or a corresponding pharmaceutical composition and the antagonist can optionally be used in the form of its pharmaceutically acceptable salts and optionally mixed with a pharmaceutically acceptable diluent or carrier. The receptor antagonists which are used according to the invention are preferably those which interact with one of the aforementioned V2 receptors. According to the present state of knowledge, these V2 receptors are those that are fundamentally linked to the action a n t i di u r e t of the vasopressin. The disturbance or disease of the inner ear that is to be treated with the use according to the invention is preferably associated with one of the symptoms of vertigo (vestibular disorders), defective hearing, auriu tinnitus or a sensation of pressure in the ear. The symptoms of vertigo, 5 defective hearing or tinnitus are particularly emphasized. In the use according to the invention one of these symptoms may occur alone, but there may also be a random combination of two or three symptoms or also the presence 0 of the total of three or four symptoms are typical in the case of disturbances of the ear internal. The defective hearing symptom can in particular be presented as a profoundly defective sound hearing, preferably as a profound defective sound of fluctuating sound.

^^ - - ^^^^ Erturbations or diseases of the inner ear treatable through the use according to the invention can, according to the present state of knowledge, frequently and preferably be linked with the so-called dropsy, particularly dropsy in do 1 inf. What is known as dropsy is an accumulation of fluid or fluid gathering in the body, particularly in the cavities present in that regard. In the case of the hydropsies in 11 a f a 11 c a s mentioned above is an excess of fluid of the so-called endolymph. This excess of fluid can be attributed to an overproduction or disturbance by discharge of the endolymph, particularly in the so-called bag 1 i n f a t i c o. Droplet endo 11 n f a t i c a s lead to an increase in pressure and an increase in volume in the space in which the endolymph is located. As this is associated with a modified deviation of the sensory hairs, which are responsible for vestibular and hearing sensation, such symptoms, particularly dizziness, defective hearing and tinnitus, can be explained by dropsy of 11 n f a 11 c a.

Among the treatable diseases or disturbances, a particular reference is made to Meniere's disease, which is associated with the symptoms of vertigo, defective hearing, and tmnitus aurium. There may be numerous influences that act as triggers for Meniere's disease such as, for example, tension, infections, tumors, disturbances, immuno-logical or neurological conditions, etc. In the present case, Meniere's disease should be understood as a collective term for disturbances in which the corresponding symptoms may present with different intensities, such as, for example, vestibular Meniere's disease. Another possible application is Lermoyez's disease. Preferably, the p e r t u r b c i one s / in f e rm e of the inner ear, which manifest themselves in defective deep sound hearing, can be treated. The corresponding deep-sounding defective auditions frequently also occur following inflammatory diseases, such as insidious inflammation of the middle ear or syphilis, in the case of toxic influences or as a delayed dropsy syndrome, or also as a consequence of venostasis or vascular disturbances of the inner ear. All erturbation of the inner ear in addition to those indicated hereinabove, which may also be linked to disturbances by effusion of the endolymph in the endolymphatic sac, are possibly suitable for the use of the present invention. . According to the invention it is possible use known or novel vasopressin receptor antagonists, particularly vasopressin receptor antagonists V2 - These substances, such as vasopressin, can be peptide compounds, which in the same way that the vasopresma interact with the receptor. Such peptide compounds are for example described in the aforementioned publication of M. Manning and. H. Sa yer. These can in particular be easily accessible linear peptides Comparatively and in particular it is possible to use the peptide propiol? LD-Tir (Et) -Phe-Val-As n -bu-P ro-g-rg -NH2 • The components of the reproduced peptide sequence have the standard meaning in biochemistry and Abu is the A-L-aminobutyric acid. A selection of linear peptide compounds, which are in principle usable as vasopressin receptor antagonists, include cyclohexamine, the compound in particular "emphasis", appears in the publication of M. Manning et al in Int. J. Peptide Protein Res., 32, 445-467 (1988) The compound reproduced in the above with its peptide sequence is marketed by BACHEM Fe in chemi ka 1 ien AG, Bubendorf, S itzerland, under product No. H-9400. It is also fundamentally possible to use non-peptide receptor antagonists for vasopressin and these are preferably non-peptide organic substances, which are preferably produced again synthetically. In the case of the organic substances known hitherto these can be derived from benzazepine, such as for example those described in EP-Al-514667. Particular reference is made to the substance 5 -imime 111 ammo-1-. { 4 - (2-methylbenzoylamine) -benzoyl} -2, 3, 4, 5-tetrahydro-lH-benzacepma, described under the name OPC-31260 in the publication of Y. Yamamura et al. in Br. J. Pharmacol, 105, 787-791 (1992). The content of this publication is made by reference in part to the content of the present description. Other possible nonpeptide organic substances are those derived from mdol, as they are fundamentally known from WO 93/15051, WO 95/18105 and EP-A 1-645375. As the derivative Ns u 1 fon 11-2-oxoi ndo 1, a particular reference is made to 1 - [4 - (N-tert.-bu ti 1 carbomyl) -2-methoxybenzene sulfonyl] -5-ethoxy-3-spiro- [4- (2-morpholmoethoxy) -cyclohexane] -indol-2-one fumarate described under the name SR 121463A in J. Clin. Invest. 98 (12), 2729-2738 (1996). According to the invention, it is preferable for the receptor antagonist to be orally and / or intrazymly adm in te r ab 1 e. One possibility of oral administration, as in the case of non-peptide receptor antagonists compared to antagonists, the peptide receptor for vasopressin, is particularly favorable, because this greatly facilitates the possibilities of administration to a patient. The use according to the invasion of the receptor antagonists of the vasopresma, can fundamentally take place in randomized forms and the selected form of administration can be adapted to the age, sex or other characteristic of the patient, the severity of the disturbances / illness. da of s and other parameters. When oral administration is used it is for example possible to produce tablets, pills, solutions, suspensions, emulsions, granules or capsules. Pharmaceutical carriers with excipients, diluents or additives may be present with salts. For intravenous administration, the antagonists can be provided alone or together with auxiliary fluids with entionals, such as, for example, glucose, amino acid solutions, etc. Optionally, a preparation for intramuscular, subcutaneous, or intramuscular administration is also possible. It is also conceivable to administer in the form of a suppository. The dose can fundamentally be freely selected as a function of the clinical picture and the condition of the patient. Conventionally, amounts of 0.1 to 50 mg / kg of body weight and per day are used. Per dosage unit, the vasopressin receptor antagonist is conventionally contained in an amount of about 10 to 1,000 mg per unit. In a corresponding formulation or medicament provided for administration, the receptor antagonist for vasopressin is preferably contained in an amount of 1 to 75% by weight. Within this range, values between 5 and 50% by weight, particularly 5 and 25% by weight, are preferred. The use of a formulation prepared according to the invention or a corresponding medicament essentially takes place in the flesh, with preference being given to the aforementioned oral route. In certain circumstances a local application in the direction of the inner ear is possible, if for example as a result of an operation an access is made in the inner ear. Thus, the application of drainage following the exposure of the infarct endo-sac is possible and then, for example, with the help of a pump via a corresponding catheter, the receptor antagonist of vasopresma can be passed directly to the site of the action of a corresponding erturbation. or n / femme d of the inner ear. The invention also covers a process for the treatment of disturbances or diseases of the inner ear and which are characterized in that at least one vasopressin receptor antagonist or originating mixtures are administered in an amount ? ^ ljiá? g »j suitable for the body of the animal or the person treated. Together with the individual characteristics of such a process, reference is made specifically to the text up to the moment of this description, in which in particular the p r e r t u r b a c t ion / e n f e rmable d treatable and the usable receptor antagonists are defined. The invention finally covers a pharmaceutical composition or a medicament for the treatment of disturbances or diseases of the inner ear, which contain at least one vasopressin receptor antagonist or mixtures originated. Together with the individual characteristics of such a composition or medicament, reference is again made to the corresponding description of the text so far. The described features and the additional features of the invention can be gathered from the following description of preferred inclusions together with the s and r and the drawings and drawings. The individual characteristics can imply eme n t a rs either individually or in the form of sub-combinations. In the drawings shown: Figure 1. The position of the Reissner membrane in the cochlea in the adult guinea pig without addition of vasopressor b with the chronic addition of vasopressin c with the acute addition of vasopressin d with the acute addition of vasopressin (in enlarged detail) Figure 2. Expression of a V2 receptor and b acuaporin-2 in the epithelium of the endo-1 sac in the inner ear of the rat Figure 3. Di ographie of the sac in 11 nf a ti c human c in the epithelium with 1251 - as op resi na d control test in the presence of unlabelled vasopressin Figure 4. Organotypic culture of the sac inlet 1 of the rat to complete radiogram b infrared light microscopy c radiogram SEM d SEM radiogram (higher magnification) i Figure 5. Result of the membrane in the culture according to Fig. 4. to endosomes FIT (^ | xtrano-labeled in the absence of vasopressin b endosomes FI TC - dextromatous in the presence of vasopressin c radiogram SEM in the case ad radiogram SEM in the case be endosomes FITC - of xtr ano -ma r ca do s in the presence of foscolm f endosomes Fl TC - of tr ano -ma rca s s in the presence of choleratoxin g endosomes FITC - de xtrano -ma rcados in the presence of vasopressin and receptor antagonist V2 H-9400.

Experiment 1 Guinea pigs with a standard Preyer reflex and weighing between 300 and 500g were used for the inigation. For the intrelation of the acute action of Pitressm® vasopressin (a r a n i n a - a r s s a n a p p e r) of Sankyo, Japan was injected i n t r a p e r 11 o n e a lmen t e (0.2 units / g). For the histology, the guinea pigs were killed two hours after the injection. For the chronic experiments, 0.5 units / g of vasopressin was administered subcutaneously for 60 days once a day. To investigate the acute action, 20 animals were used and 10 animals were investigated for chronic action. For comparative purposes, in the case of the 10 control animals, 0.2 ml of a physiological solution of common salt was injected into the tank. The cochlea of all the test animals was embedded in celloidin and the modiolar half sections were stained with h ema t ox 11 i n a / e or s i n a (HE). As a result of the deviation of the Reissner membrane, the presence of an endolymphatic hydrops was determined. The results of experiment 1 are shown in Figure 1. The figure shows that the Reissner membrane indicated in the manner exemplified by an arrow is not deviated in the control animals (n = 10) and correspondingly there is no endolymphatic hydrops. According to Figure Ib in the case of a test animal with chronic administration of vasopressin (n = 10) it is possible to detect a strong endolymphatic dropsy as a result of the pronounced displacement of the Reissner membrane. In the cochlear spiral, which corresponds to the one marked with the arrow in Figure 1, Reissner's membrane is still in contact with the healthy septum between spiral turns 3 and 4. Four out of ten of the test animals chronically treated with vasopresma had severe hydrops according to Figure Ib and three others had light to moderate hydrops. The Figure shows a slight to moderate dropsy endophylaxis in a test animal after an individual injection of vasopressin, ie acute treatment. At n = 20 of these twenty test animals had light to moderate hydrops. Figure Id shows the same case as Figure 1, but with a larger increase Opposed to Figure Ib no contact with healthy septum is detected but there are clear prominences of Reissner's membrane. Thus, Experiment 1 and Associated Figure 1 show that increased values of plasma vasopressin can give rise to hydropsies in the first place. ? * 'f * -Experiment 2 Experiments were carried out using the primers AQP2s, AQP2as, V2s, and V2as in PCR (polymerase chain reaction). The primers had the following nucleotide sequences: AQP2s GAT CGC CGT GGC CTT TGG TCT AQP2as AGG GAG CGG GCT GGA TTC AT V2s AGT GCT GGG GGC CCT AAT ACG V2as CAA ATC GGG CCC AGC AAT CAÁ ACÁ The cDNAs of aquaporin-2 and the V2 receptor were amplified with the use of the primer pairs AQP2s / AQP2as and V2s / V2as. The PCRs were brought to a total volume of 50 μl containing 5 μl of tr an scr inverse rate, in each case 0.8 μM of primer, in each case 200 μM of dNTPs, an incubation buffer (containing 1.5 mM MgCl 2 from Pharmacia ) and 1.25 U of Taq polymerase (also from Pharmacia). After a denaturation step of 7.5 minutes at 94 ° C at the beginning there were 40 cycles that lasted 50 seconds at 94 ° C, 50 seconds at 55 ° C and 50 seconds at 72 ° C and a ten minute stage at 72 ° C until the end. The expected product lengths were 428 bp and 419 bp. The PCR products were developed in the usual manner and were detected by subcloning and spiking. As can be inferred from Figure 2, both the V2 receptor and the acuaporm-2 were strongly expressed in the epithelium of the infarcted sac 1, while in another epithelium of the inner ear, also in contact with the endolymph, such detection was unsuccessful. According to Figure 2a in the inner ear of the rat, the V2 receptor could be detected on postnatal day 4 (p4) and in the grown rat (ad). Very thin bands were obtained in the endolymphatic sac on postnatal day 1 (pl), stria vascularis (StV), vestibular organ (V) or Reissner's membrane (RM). According to Figure 2b, the expression of acuapopn-2 was more clearly detectable in the endo 11 bag nfa 11 co grown on postnatal day 4, but it was not possible to detect any expression in the stria vascularis, the vestibular organ or the membrane of Reissner Experiment 3 The human bag was taken from six autopsies and two patients who had undergone surgery with the authorization of relatives or patients. Frozen sections (20 μm) were sectioned in a cryostat at -16 ° C and applied to gelatin-coated platelets and stored overnight under vacuum at 4 ° C. Tissue sections were incubated overnight at 4 ° C with 125t-arginine na-va soresine in the absence (total binding) or presence of 10 μM of unlabelled arginine vasopresma (binding and necrosis) in 10 minutes. mM frozen buffer of tps-HCl (pH 7.4) containing 10 mg of MgCL2, 0.5 mg / ml bacitracin and 0.1% serum of bovine albumin. The different sections were covered with NTB-2 nuclear emulsion (Eastman Kodak) and prepared for light microscopic use. The covered plates were stored for 3 to 8 days in the dark at 4 ° C. after development and fixation the plates were stained with heme t ox 11 i na / e or n a. Figure 3 shows the states of experiment 3. It is possible to see the specific binding of the radioactive vasopressin in the sac a n d 1 i n f a 11 c or human. The dots in Figure 3c show the binding of the vasopresma in the epithelium of the endo 1 inf inflate, whereas according to Figure 3d the same treatment in the presence of unlabelled vasopressin excludes a nonspecific vasopressin binding in The bag.

Experiment 4 On the postnatal day 4 the rats were put to sleep using sodium t ob a r i t 1 (0.4 mg / g body weight) and then decapitated. The temporary bones were immediately removed and transferred to a cold buffered HEPES-buffered saline solution (4 ° C with salt solution (HHBSS) and adjusted with Hank.) The sac in complete infusion was separated from the temporal bone. it was opened in the corner of the distal part of the sac and inserted flat in a culture plate, which was covered with 20 μl 1 of Cell Tek of Becton Dickinson Labware, USA, with a dilution of 1: 5 and covered with 300 μl of culture medium. The culture medium consisted of the minimal essential medium with D-valine to suppress the growth of fibroblasts and which was supplemented with 10% of fetal calf serum (.FCS), 10 mM HEPES, 100 IU / l of penicillin and 2 M of glutamine. The cultures were kept in a 5% carbon dioxide atmosphere at 37 ° C For 5 days. The morphology of the culture was observed with infrared light microscopy. A detailed morphology of the surface of the epithelium was obtained, it was obtained by SEM (scanning electron microscopy). Tissue layers of tissues were fixed for 120 minutes in 1 g of 1 to 2.5%, 0.1 M of sodium cacodylate buffer, re-fixed for 60 minutes in 1% osmium tetroxide, washed , dried, gilded according to a standard process and investigated in a Hitachi 500-SEM. Figure 4 shows the results of the e xp e r r eme n t 4. Figure 4a provides a study of a sack 1 i n f a t i c o after 4 days in the crop, showing the proximal (PSP), intermediate parts (ISP) and distal (DSP) of the sac. The structural analysis of the culture of the epithelium of the pouch in n f a t i c o shown in Figure 4b and 4c shows a clear similarity with the native organ with cells of a typical configuration rich in mitochondria and ribosomes. Thus, the radiogram of the infrared light microscope shows the individual cells in the middle part and the two types of cells can differ on the basis of the configuration and morphology of the surface. Polygonal-shaped cells corresponding to ribosome-rich cells (RRC) have a flat surface, whereas round cells corresponding to mitochondrial-rich cells (MRC) have numerous microvilli projecting into the opening. This is also clearly visible from the SEM radiogram according to Figure 4c. The largest increase according to Figure 4d to d i c l o n t e n e clearly shows the clathrin-covered fovea of the membrane of the lummal cell in the RRC cells of the sac e n d 1 i n f a t i c o (see arrow).

Experiment 5 In a culture according to experiment 4 after 12 hours of culture in the endolmático sac in HHBSS (pH 7.3), which contains 1.0 mg / ml of fluorescein isothiocyanate (FITC) -dextran (from Sigma, Germany), the incubation took place for approximately 10 minutes at 37 ° C. The bag was then washed with HHBSS and fixed for 20 minutes in PBS with 4 to 4% strength. The contrast and fluorescence contrast images were recorded with * iwjsa í? sw * a microscope of ep if 1 uo res cen cia (Olympus AX-70, Germany) with a set of standard FITC filters (excitation: 485 ± 20 nm, emission:> 510 nm) and superimposed to return also visible to non-fluorescent cells and to discriminate cells rich in mitochondrions and rich in pbosomes. Subsequently, vasopresma, forscolma, choleratoxin (all from Sigma, Germany) or the receptor antagonist of V2 H-9400 (BACHEM, Switzerland) together with the dextran FITC were added to the solution, in the amounts described hereinafter. Figure 5 shows the results of experiment 5. Thus, Figure 5a shows the endocytosis represented by two dextran-labeled endosomes FITC and observed in the culture of the bag in C 11 nfa 11 co in RRC and MRC in the absence of additional substances, that is, in a control experiment (n = 120). By adding 1 nM of vasopressin (n = 84) the change of the membrane in RRC is inhibited, ie there are no marked endosomes visible in RRC. The marked endosomes are still observed in MRC. This means that in the endo 1 i n f a t i c o vasopressin (as opposed to the situation in the epithelium of the collecting ducts of the kidney) inhibits FITC dextran absorption in ribosome-rich cells (RRC). Thus, in the example according to Figure 5b 10.5 ± 2.1 of 118.5 ± 2.8 cells revealed FITC dextran absorption (n = 20) compared to an untreated specimen according to the example of Figure 5a in which 90.5 ± 2.5 of 116.5 ± 2.4 cells revealed FITC dextran uptake (an = 20). The inhibitory effect of vasopresma on membrane change is also demonstrated by the disappearance of the clathrin-covered foveae from the surface of the epic cells of the ribosome-rich cells according to the SEM radiograms of Figures 5c and 5d. A) Yes, under controlled conditions the RRC revealed numerous covered foveas (see arrow in Figure 5c), which showed a higher increase in Figure 4d. The bar traversed in Figure 5d represents a length of 1 um. Following a treatment with 1 mM of vasopressin according to Figure 5d, there are almost no visible pits, which reveals the i n t e r n e 1 i z a c ion of the probable cloned aquaporin-2 clathrin. As in the case of the vasopresma, according to Figure 5e and 5 f almost no endosomes were detected when 50 μM of forscolin (n = 48) or 0.1 nM of choleratoxin (n = 36) was used. As surprising as the result of the experiment shown in Figure 5b is the result of the test according to Figure 5g, in which a simultaneous application of 10 nM vasopressin and 10 nM of the receptor antagonist V2 H-9400 canceled the effect of vasopressin according to Figure 5b. FITC dextran-filled endosomes are still present (a number of tests n = 30). The described FITC dextran tests make use of the known fact that the behavior of the membrane can be represented with dextran FITC and can be correlated with transport through the membrane. A high membrane change revealed by the FITC dextran makes it possible to conclude that there is a high transport of water. Since the epithelium of the pouch is almost exclusively comprised of RRC and MRC cells, the test provided according to experiment 5 is valid for the complete pouch and the supply duct. The results are also in accordance with the fact that vasopressin is active in the RRC cells and consequently the effect of the vasopressin or the vasopressin antagonist can be detected here. MRC cells are not active with vasopressin and correspondingly do not reveal effect according to experiment 5. Due to the fact that the H-9400 peptide antagonist used is a comparatively selective V2 receptor antagonist, the results of the test constitute a strong demonstration that the vasopressin receptor in the endopharmonary sac of the inner ear is of the V2 type. However, surprisingly, vasopressin in the inner ear clearly has an inverse action to that of the epithelial cells of the kidney collecting duct. This explains the surprising result that the receptor antagonist of vasopressin increases the change in the membrane and consequently the water transport in opposition to the known actions in the kidney and consequently a water mixing action is obtained through the use of the antagonist. This methodical discovery makes possible the use according to the invention of the receptor antagonist of the vasopresma for the treatment of diseases or disturbances of the inner ear, particularly those related to dropsy, such as hydropsies in 11 n f a 11 c a s. An opposite action associated with a decrease in volume on the luminal side, unlike the action in the kidney, in the inner ear in the case of overpressure or excessive volume leads to a decrease in volume and pressure. These are suitable for improving or eliminating the symptoms, that is to say in particular the vertigo, deterioration of the hearing and tmnitus. The use according to the invention can also have a prophylactic effect with such disturbances of the inner ear.

Claims (20)

1. Use of at least one vasopressin receptor antagonist or mixtures of such antagonists for the treatment of disorders or diseases of the inner ear.

2. Use according to claim 1, characterized in that the receptor antagonist is a V2 receptor antagonist of vasopressin.

3. Use according to claim 1 or 2, characterized in that the disturbance or disease of the inner ear is associated with at least one of the symptoms of dizziness, defective hearing or tinnitus.

4. Use according to claim 3, characterized in that the defective hearing is a profound deterioration of the hearing of the sound.

5. Use according to one of the preceding claims, characterized in that the disturbance or disease of the inner ear is linked with a dropsy, particularly an endolymphatic dropsy.

6. Use according to one of the preceding claims, characterized in that the disturbance or disease of the inner ear is Meniere's disease.

7. Use according to one of the preceding claims, characterized in that the receptor antagonist is a peptide compound.

8. Use according to claim 7, characterized in that the peptide compound is a linear peptide, particularly propionyl-D-Tir (Et) -Phe-Val-Asn-Abu-Por-Arg-Arg-NH2.

9. Use according to one of claims 1 to 6, characterized in that the receptor antagonist is a non-peptide, preferably a non-peptide organic substance.

10. Use according to claim 9, characterized in that the organic substance is a derivative of benzazepine.

11. Use according to claim 10, characterized in that the benzazepine derivative is 5-dime t i 1 amino-1 -. { 4- (2-methoxy-benzoylamino) -benzoyl} -2, 3, 4, 5-tetrahydro-lH-benzazepine.

12. Use according to claim 9, characterized in that the organic substance is a derivative of indole.

13. Use according to claim 12, characterized in that the indole derivative is fumarate of 1 - [4 - (N-ter. - bu 111 carb amo i 1) - 2-ethoxybenzene sulfonyl] -5-ethoxy-3 -spiro- [4- (2-morpholinoethoxy) -cyclohexane] -? ndol-2-one.

14. Use according to one of the preceding claims, characterized in that the receptor antagonist can be administered orally and / or intravenously, particularly orally.

15. Use according to one of the preceding claims, characterized in that the receptor antagonist is used in an amount of 0.1 to 50 mg / kg of body weight and per day.

16. Use according to one of the preceding claims, characterized in that the receptor antagonist is contained in a formulation or medicament proposed for administration in an amount of 1 to 75% by weight, preferably 5 to 50% by weight, preferably 5% by weight. to 25% by weight.

17. Process for the treatment of disturbances or diseases of the inner ear, characterized in that at least one vasopressin receptor antagonist or a mixture of such antagonists is administered in a suitable, compatible amount.

18. Process according to claim 17, characterized by at least one of the features of claims 2 to 16.

19. A pharmaceutical composition or medicament for the treatment of disturbances or diseases of the inner ear, characterized in that they contain at least one vasopressor receptor antagonist or mixtures of such antagonists.

20. Composition or medicament according to claim 19, characterized by at least one of the features of the rei indications 7 to 16.