RU2376041C1 - Method for otoprotection in case of noise effect at human body - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: present invention is related to the field of medicine and may be used in otorhinolaryngology. Method includes breathing of oxygen-nitrogen-argon gas mixture by person at normal pressure. Gas mixture of the following composition is used: 16.01 - 16.50% of oxygen, 59.00 - 59.98% of nitrogen and 24.01 - 24.99% of argon.

EFFECT: method makes it possible to obtain explicit therapeutical effect and prevent ototoxic processes in cochlea caused by noise.

1 tbl, 4 dwg

Description

The present invention relates to medicine and will find application in otorhinolaryngological practice, for example, for the treatment of patients with sensorineural hearing loss.

The inventors have found that breathing an oxygen-nitrogen-argon gas mixture at normal pressure provides the snail's protective effect against the negative effects of noise. The revealed protective effect of argon during experimental hypoxia and during exposure to noise in humans opens up the prospect of a new therapeutic strategy for noise damage to the organ of hearing, ototoxic processes in the cochlea and, possibly, a new direction in the treatment of sensorineural hearing loss and ear noise.

Currently, studies in this area relate to the determination of indications for various types of human exposure, prediction of results, providing for clinical and audiological examination (RU 2168932 C1 A61B 5/02 Pub. 20.06.2001). At the same time, the positive effect of the complex effect in the treatment of sensorineural hearing loss of the active substance in combination with the action of gas respiratory mixtures, for example, 40-45% air-oxygen mixture (RU 2232014 C1 A61K 31/02 Pub. 2004.07.10) was established.

In recent years, researchers have shown increased interest in studying the biological effects of inert gases, which include: xenon (Xe), argon (Ar), krypton (Kr), helium (He), neon (Ne) and radon (Ra). Some of these gases (Xe) exhibit an anesthetic effect under normal atmospheric pressure in a mixture with oxygen, in others (Ar and Kr) this effect is observed only in a hyperbaric environment, while others (He, Ne and Ra) are completely devoid of this effect. The most important result of recent studies is the confirmed neuroprotective effect of Xe in neuronal damage caused by hypoxia [1, 2, 3]. The mechanism of this effect is not fully understood, but the leading role in this process belongs to the regulation of calcium homeostasis, which prevents its accumulation in the cell by inhibition of N-methyl-D-aspartate (NMDA) receptors, which are involved in cell death due to hypoxia and ischemia [ 4, 3].

The biological protective effect of Ar on the cell has hardly been studied, although this gas is less expensive and has no anesthetic effect under normal pressure [5]. Using the organotypic culture of Wistar rats, a study was conducted of the effect of Ar during hypoxia and drug-induced (gentamicin, cisplatin) damage to the external hair cells (IHC) and internal hair cells (IHC) of the Corti's organ [5, 6, 7]. The survival of hair cell cultures (VK) of the Corti's organ of the newborn rat in absolute argon (95% Ar - 5% CO ₂ ) hypoxia was significantly higher than in nitrogen (95% N ₂ - 5% CO ₂ ) hypoxic medium [6, 7] .

Abraini et al., [40] found that Ar can have a direct effect on gamma-aminobutyric acid (GABA) receptors by potentiating the subtype “GABA-A” neurotransmission [41].

Under conditions of a hypoxic state, breathing with a gas mixture consisting of: ≥25% Ar and 4-5% oxygen (O ₂ ) at normal pressure increased the survival of rats compared to animals that were in similar conditions, but without the content of gas in the gas environment [ 8].

In previous studies with human participation in the SSC RF - IBMP RAS, it was found that a long (7 days) stay in a normoxic (O ₂ -N ₂ -Ar) environment is safe. Indicators of the cardiovascular and respiratory systems, biochemical parameters of blood and urine, as well as the results of tests for mental and physical performance were within the age physiological norm [9, 10].

The objective of the invention is to obtain a protective heat-protective effect in humans with exposure to noise.

The technical result is to obtain a pronounced therapeutic effect of argon when exposed to noise on the human body, as well as the possibility of preventing the destruction of cells of the human auditory system. In addition, since the claimed method has no analogues, the implementation of the claimed purpose is also a technical result.

The task and technical result are achieved by the method of heat protection under the influence of noise on the human body, including the human breathing of an oxygen-nitrogen-argon gas mixture at normal pressure, using a gas mixture of the following composition: 16 ± 0.5% oxygen, 60 ± 1% nitrogen and 24 ± 1% argon.

The method is as follows.

The study involved 10 healthy male volunteers aged 18–25 years. The studies were conducted on the basis of the approved program and the permission of the Commission on Biomedical Ethics at the SSC RF IMBP RAS dated November 25, 2005 in full compliance with the requirements of the Russian National Committee on Bioethics. All subjects signed informed consent to participate in these studies.

All volunteers underwent a medical examination, according to the results of which they were found to be healthy and allowed to participate in the research. Volunteers did not have any indications of ear diseases in the past, otomicroscopic examination revealed no changes in the eardrum. According to tonal audiometry and tympanometric examination (tympanogram type “A”), the pathology of the auditory system was excluded.

The subjects were informed that in the 7 days preceding the start of the experiment, they should eliminate the noise load (listening to loud music, using a player, etc.).

Consider three examples, conventionally called "Background", "Noise" (comparative) and an example of the implementation of the claimed method "Noise + Argon".

The test report included 3 series of studies: I - background studies of the functional state of the auditory system ("Background"); II - study of the auditory system before and after a 1-hour exposure to noise with an intensity of 85dB ("Noise"); III - a study of the auditory system before and after a 1-hour exposure to noise with an intensity of 85 dB and breathing of the examined oxygen-nitrogen-argon mixture: [used a gas mixture of the following composition: 16 ± 0.5% oxygen, 60 ± 1% nitrogen and 24 ± 1% argon], at normal pressure ("Noise + Argon"). During the II and III experimental series, the well-being of the subjects was monitored by means of a survey, heart rate measurement (according to RR - ECG interval and registration of blood pressure according to Korotkov).

The volume of studies of the functional state of the auditory system included: tonal threshold audiometry; study of delayed evoked otoacoustic emission (Transient evoked otoacoustic emission - TEOAE) and otoacoustic emission at the frequency of the distortion product (Distortion product otoacoustic emission - DPOAE); registration of acoustic brainstem evoked potentials - (Brain evoked response audiometry - "BERA"); extrathympal electrococholeography (Electrocochleography - "EcohG").

The studies were conducted in a sound-attenuation chamber of Tracor Inc., Austin Texas (model AR9S, USA). Noise was transmitted through TDH 39P Telephonics air telephones from the AC40 Interacoustics clinical audiometer (Denmark).

To register purely tonal hearing thresholds for air and bone conduction of sound, an AC40 audiometer of the same company and a standard audiometric procedure were used (less than 10dB of hearing loss in the octave range from 125 to 8000 Hz for each ear).

To evaluate TEOAE, the "EP25 - Interacoustics" system was used, equipped with the corresponding program for registering OAU. During registration of the TEOAE, the probe was positioned in the external auditory canal of the subject using a special individual sized ear obturator. We used standard TEOAE registration modes: stimulation - non-linear; intensity of "click" - stimuli 75dB / SPL; the number of incentives - 1000; signal to noise ratio; screening algorithm - 3 dB; the minimum number of frequency bands is 5.

To register DPOAE, the portable OtoRead ™ OAE system from Interacoustics (Denmark) was used. Frequency bands: 1.5; 3.0; 4.0; 6.0 kHz.

Registration of BERA was carried out using the Interacoustics EP25 system, according to the standard procedure with a “vertex mastoid” lead. The program included: 2000 sound “clicks” with a frequency of 11.1 / sec and an intensity of 70 dB above the hearing threshold, presented in the frequency range of 150-3000 Hz. The evoked response was recorded ipsilaterally with an analysis time of 10 ms. A 40-dB masking noise was applied to the contralateral ear.

EcohG was also produced using the Inte25oustics EP25 system. The stimulus intensity was 100 dB / SPL (13.1 stim./s.). The number of stimuli is 1200 (alternating mode, the frequency band is up to 3000 Hz, the analysis window is 8 ms). We used tip-trode extratemporal porous electrodes coated with gold foil. After thoroughly treating the skin of the external auditory canal with alcohol, an electrode lubricated with an electrically conductive gel was introduced into the auditory canal in a compressed form. Such manipulation provided a low impedance (less than 10K ohm) and a more efficient detection of early EcohG components. Using a special “alligator” clamp, a wire was attached to the foil connecting the electrode to the preamplifier.

The oxygen-nitrogen-argon gas mixture was breathed under normal pressure through a mask. The gas mixture was supplied from the cylinders through a special reducer with heating the mixture to a comfortable temperature.

The digital values of the studied indicators were subjected to statistical processing using the program "Microsoft Excel".

The conducted three series are three examples of the implementation of the method.

As follows from the described specific implementation examples, all volunteers in the II and III experimental series subjectively transferred the effect well. An analysis of questionnaires showed that the general state of health of the subjects did not deteriorate during the period of exposure to noise and when breathing oxygen-nitrogen-argon mixture against a background of noise. Fluctuations in heart rate and blood pressure were within the age range.

An assessment of the dynamics of tonal hearing thresholds showed that after a 1-hour exposure to noise, there was an increase in tonal hearing thresholds over almost the entire range of studied frequencies, ranging from 1 to 4.5 dB (for the right ear) and from 1 to 5.5 dB (for left ear). In the “Noise + Argon” series, a decrease in hearing thresholds was noted within (0.5-3.5 dB and 0.5-3 dB for the right and left ear, respectively). At individual frequencies, the improvement in hearing was significant.

Thus, from the examples it follows that under conditions of breathing an oxygen-nitrogen-argon gas mixture against a background of noise, volunteers showed a tendency to improve threshold hearing sensitivity compared to the Noise series.

According to the TEOAE registration data, it can be noted that already in the background a certain spread in the amplitude and frequency components of the delayed evoked otoacoustic emission was noted, which corresponds to the literature on the large individual variability of these indicators in healthy individuals [11]. However, individual responses of the subjects were relatively stable during repeated studies, which is consistent with published data [12, 13].

In the series "Noise" there was a clear tendency to decrease the amplitude of TEOAE in almost all octave bands of the studied frequencies (Figa). Moreover, in the frequency range [0.5-1.5 kHz and 1.5-2.5 kHz], the decrease in amplitude was significant. In the series “Noise + Argon”, there is a moderate tendency to increase the amplitude of TEOAE, except for the frequency range of 4.5-5.5 kHz. However, these changes were unreliable.

Assessing the changes in TEOAE in terms of “reproduction” (Fig. 1B), it can be noted that with the initial values of 79% and 74% (for the right and left ear, respectively), a distinct decrease in this indicator to 68% and 67 was recorded in the Noise series % On the contrary, in the “Noise + Argon” series, this indicator significantly increased and almost corresponded to the background values.

According to the study of the absolute level of DPOAE and the signal-to-noise ratio in the DPOAE test, a distinct tendency to decrease in these indicators in the Noise series (Figure 2) with a subsequent tendency to increase them in the Noise + Argon series (except frequency 6 kHz).

The study of evoked acoustic potentials of the brain stem (BERA) revealed a tendency to decrease the amplitude of the I peak in the Noise series (Figure 3) and a significant increase in this indicator in the Noise + Argon series to values close to the original ones. As for the latent periods (LP) of peaks I and V (table 1), an increase in these indicators was recorded in the “Noise” series, followed by a significant (P <0.05 and P <0.001, respectively) decrease in the LP in the “Noise + Argon” series ".

Table 1 Latent periods of peaks I, V peaks BERA Experimental series Background Noise Noise + Argon Test ear Right Left Right Left Right Left LP I peak 1.73 ± 0.1 1.75 ± 0.1 1.75 ± 0.1 1.81 ± 0.3 1.64 ± 0.18 * 1.62 ± 0.17 * LP V peak 5.47 ± 1.23 5.48 ± 1.3 5.57 ± 1.15 5.59 ± 1.12 5.43 ± 1.16 ** 5.41 ± 1.15 ** Legend:
LP - latent period (ms).
BERA - acoustic brain-triggered brain potentials.
* P <0.05
** P <0.001

The results of electrocholeography (Figure 4) showed that the ratio of the "sum / action" potential of the cochlea in the Noise series increased (more than 2-fold) with the subsequent significant (P <0.05) decrease in this indicator in the Noise + Argon series ".

Thus, the general orientation of the response of the auditory system of volunteers under the influence of noise during breathing with a gas mixture containing argon allows us to formulate the opinion that breathing with an oxygen-nitrogen-argon mixture [16 ± 0.5% oxygen, 60 ± 1% nitrogen and 24 ± 1% argon] is able to provide a heating effect when exposed to noise.

The prior art describes the phenomenon of “individual sensitivity of the human auditory system to the effects of noise” [14, 15, 16, 17]. The individual character of the auditory response of the volunteers was observed with almost all the methods used to assess hearing - both subjective (tonal audiometry) and objective (TEOAE, DPOAE, BERA and EcohG). DPOAE, BERA, and EcohG were the most effective tests in identifying the adverse effect of noise on the inner ear of volunteers, as well as the heating effect of the oxygen – nitrogen – argon gas mixture, which is in good agreement with published data [18, 19].

It is known that exposure to noise can lead to changes in most cochlear cell systems and can be a cause of hearing loss caused by exposure to noise (noise induced hearing loss) - [NIHL] - [20]. The degree of hearing loss depends on the intensity and duration of exposure to noise. Hearing loss due to exposure to noise can be manifested in two types of reactions: temporary (short-term) shift of thresholds of hearing (temporary threshold shift) - [TTS] and constant (continuous) shift of thresholds of hearing (permanent threshold shift) - [PTS].

The physiological basis for a temporary shift in hearing thresholds after exposure to noise (TTS) may be reversible changes in the cochlear VC [20]. They are associated primarily with lesions of synaptic transmission, as well as with a decrease in the ability of stereocilia to provide mechanoelectric transduction due to the loss of permeability of transduction channel proteins in the stereocilia cell membrane [21, 22]. The shift of the stereocilia of NEC from the point of its contact with the tectorial membrane can lead to loss of auditory sensitivity [23].

The basis of the constant shift in hearing thresholds (PTS) is lesions leading to apoptosis and death of the cochlea VK [24, 25].

The leading pathogenetic link in noise exposure, along with a purely mechanical effect, is a violation of microcirculation in the cochlea with the occurrence of local hypoxia, since there is a direct correlation between the noise damage to the organ of hearing and the partial pressure of oxygen in the perilymph. In this case, hypoxia occurs both due to vascular and metabolic disorders [26, 27, 28, 29, 6, 7]. Changes in cochlear blood flow can cause a shift in hearing thresholds and lead to damage to the vital structures of the cochlea [30].

Under conditions of oxidative stress resulting from exposure to noise, ionic cell homeostasis is impaired [31, 20], resulting in calcium intoxication of the cochlea VK due to the active “input” of extracellular calcium (Ca ²⁺ ). On the one hand, this is due to the activation of volatile ionic calcium channels and N-methyl-D-aspartate receptors (NMDA). On the other hand, the blockade of energy-dependent transport of proteins that regulate calcium metabolism, especially the concentration of Ca-ATPase, which is a key enzyme in maintaining low Ca ²⁺ concentration [32, 33, 28, 29]. Ultimately, this process leads to prolonged depolarization of VK with their transition to apoptosis.

Another no less important effect of oxidative stress when exposed to noise is the activation of free peroxide radicals with the formation of reactive oxygen species (ROS), which adversely affect the intracellular molecular pathways in the VC of the cochlea [34]. ROS in hypoxia accelerate catabolic processes leading to aloptosis and death of VK [35].

The synapses of the “VVK - auditory nerve” are very sensitive to the excess of glutamate released upon exposure to noise [36]. NMDA and glutamate receptors are involved in the transmission of nerve signals from VVC to spiral ganglion neurons [37, 29, 38]. An excessive increase in extracellular Ca ²⁺ leads to cell damage through activation of proteases, lipases, and endonucleases. The direct toxic effect of glutamate on snail VC is described by Duan et al., [39]. Excess or incomplete metabolism of glutamate and its analogues when exposed to noise can cause toxic damage to the VC in connection with “ionotropic overstimulation of the receptor” [37, 36].

Thus, Ar can exhibit a heat-resisting effect for all types of the cochlear VC lesion models described today, associated with hypoxia, oxidative stress, activation of peroxide radicals, toxic effect of glutamate, etc. [34, 35, 6, 7, 32].

The inventors have proved the possibility of a heat-protective effect of argon with exposure to noise in humans. Breathing an oxygen-nitrogen-argon gas mixture at normal pressure did not cause any side effects in humans. The revealed protective effect of argon during experimental hypoxia and during exposure to noise in humans opens up the prospect of a new therapeutic strategy for noise damage to the organ of hearing, ototoxic processes in the cochlea and, possibly, a new direction in the treatment of sensorineural hearing loss and ear noise.

LITERATURE

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Claims (1)

The method of heat protection when exposed to noise on the human body, including human breathing an oxygen-nitrogen-argon gas mixture at normal pressure, using a gas mixture of the following composition: 16.01-16.50% oxygen, 59.00-59.981% nitrogen and 24, 01-24.99% argon.

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