Cough treatment device

Abstract

The cough treatment device is characterized in that the cough treatment device is provided with a light source for emitting light rays and a light ray irradiation probe for irradiating the light rays, and the light rays emitted by the light source are irradiated from the light ray irradiation probe to the vagus nerve of the neck of a patient and the vicinity of the vagus nerve in a percutaneous manner; the purpose of the present invention is to provide a safe and effective therapeutic method, which has few side effects, instead of a drug therapy that causes systemic symptoms, by directly suppressing hyperfunction of vagus nerves in the vicinity of the respiratory tract, which is a cause of cough.

Description

Technical Field

[0001] This invention relates to a cough treatment device that treats cough by irradiating the vagus nerve with light. Background Technology

[0002] Coughing is a biological defense mechanism used to expel secretions or foreign objects trapped in the respiratory tract. Based on duration, coughs are classified as acute (less than 3 weeks), prolonged (more than 3 weeks but less than 8 weeks), and chronic (more than 8 weeks). The most common cause of acute cough is the viral common cold, but most patients recover with treatment targeting the underlying cause. Prolonged or chronic coughs are further divided into dry cough (without sputum) and wet cough (with sputum). Most coughs are dry, and the cough itself becomes the focus of treatment. It should be noted that wet coughs are caused by excessive mucus secretion from the respiratory tract.

[0003] A cough lasting more than 8 weeks is called a chronic cough, with a prevalence estimated at 2-4% in Japan (approximately 2.5-5 million people). Chronic cough is diagnosed and treated according to guidelines, and most cases respond well to treatment based on the underlying disease, such as cough-asthma, allergic cough, gastroesophageal reflux disease, post-infectious cough, or sinus-bronchial syndrome. However, there are refractory cases that do not respond to treatment even when the underlying disease is addressed.

[0004] It is estimated that approximately 20% (about 200,000 to 400,000 people) of patients with chronic cough in Japan are refractory to treatment. Furthermore, in recent years, the concept of CHS (cough hypersensitivity syndrome) has been proposed to describe a common pathology of treatment-resistant cough unrelated to the presence or absence of underlying medical conditions, and refractory chronic cough is receiving increasing attention.

[0005] As a treatment for cough, centrally acting antitussives containing codeine or dihydrocodeine are sometimes used. Recently, a selective P2X3 receptor antagonist (gefapisen citrate) was approved in Japan as a treatment for refractory chronic cough. However, in the treatment of cough using this medication, side effects such as constipation, nausea, vomiting, dizziness, and taste disturbances have been reported (Non-Patent Literature 1), and the development of new drugs with reduced side effects is underway (Patent Literature 1).

[0006] LLLT (Low Level Laser Therapy), as a type of phototherapy, has been studied for its application in various diseases such as overactive bladder, irritable bowel syndrome, chronic pain, and facial neuralgia as a physical therapy method with anti-inflammatory effects or inhibition of nerve hyperactivity (Patent Document 2).

[0007] Existing technical documents Patent documents Patent Document 1: Japanese Patent No. 6725188, Patent document 2: WO2022 / 019293.

[0008] Non-patent literature Non-patent literature 1: Lyfnua tablets 45mg instruction manual (MSD / Xinglin). Summary of the Invention

[0009] The problem that the invention aims to solve While chronic cough is not a life-threatening illness, it can significantly reduce both public and private well-being, leading to a decline in patients' quality of life (QOL). As mentioned above, although medications exist, they have side effects, and current treatments and preventative measures are not entirely effective. Therefore, there is a desire for new treatments or preventative methods for chronic cough.

[0010] Selective P2X3 receptor antagonists, developed as a treatment for refractory or unexplained chronic cough, are substances that inhibit the binding of extracellular ATP to adenosine triphosphate (ATP) receptors expressed on C fibers of the vagus nerve in the respiratory tract, thus suppressing cough associated with respiratory inflammation. P2X3 receptors are specifically expressed on C fibers, which act as afferent nerves (sensory nerves), and are densely distributed in viscera, skin, joints, etc. Therefore, when taken orally, this treatment inhibits P2X3 receptors throughout the body, outside the respiratory tract, contributing to side effects.

[0011] The present invention provides a cough treatment device that achieves a safe and effective treatment method with fewer side effects by directly inhibiting the overactivity of the vagus nerve near the respiratory tract, which is the cause of cough, in order to replace drug therapy that causes systemic symptoms.

[0012] Methods for solving problems The present invention provides a phototherapy device, as shown below, for suppressing cough by irradiating the vagus nerve with light such as low-power laser.

[0013] (1) A cough treatment device, characterized in that it has a light source for emitting light and a light irradiation probe for irradiating the light, wherein the light emitted by the light source is irradiated percutaneously from the light irradiation probe to the vagus nerve and its vicinity in the patient's neck.

[0014] (2) The cough treatment device according to (1) above is characterized in that the light irradiation probe is a device for irradiating the lower ganglion, upper ganglion, pharyngeal branch or superior laryngeal nerve in the cervical vagus nerve.

[0015] (3) The cough treatment device according to (1) above, characterized in that the light irradiation probe is a device for irradiating the area behind the angle of the mandible or below the mastoid process of the patient's neck.

[0016] (4) The cough treatment device according to (1) above, characterized in that the average power of the light irradiated from the light irradiation probe is 200mW~8W, and the average power density obtained by dividing the average power of the light irradiated from the light irradiation probe by the irradiation area is 250mW / cm². 2 Above ~10,000mW / cm 2 The energy of the light irradiated from the light irradiation probe is 60J~4,800J per treatment, and the energy density, obtained by dividing the energy of the light irradiation probe by the irradiated area, is 75J / cm² per treatment. 2 ~6,000 J / cm 2 The wavelength of the light emitted from the light irradiation probe is 700nm~900nm.

[0017] The effects of the invention The cough treatment device of the present invention, by percutaneously irradiating a low-power laser near the vagus nerve in the neck, exhibits the effect of reducing the frequency of coughing, similar to dihydrocodeine as a centrally acting antitussive. As a novel treatment method without the side effects of drug therapy such as constipation, vomiting, or taste disturbance, it can be used clinically. Attached Figure Description

[0018] [ Figure 1 [A schematic diagram of an embodiment of the light therapy device of the present invention.]

[0019] [ Figure 2 [A schematic diagram of an embodiment of the light therapy device of the present invention.]

[0020] [ Figure 3 [Graph showing the effect of cough treatment] Detailed Implementation

[0021] The vagus nerve, one of the cranial nerves, originates from the medulla oblongata and is widely distributed in the external auditory canal, auricle, pharynx, larynx, trachea, bronchi, lungs, heart, and esophagus (all organs within the thoracic cavity), and stomach, intestines, liver, pancreas, spleen, and kidneys (all organs within the abdominal cavity). Similarly, the glossopharyngeal nerve, also a cranial nerve, provides sensation from the pharynx and the posterior third of the tongue to the ear. These cranial nerves are broadly divided into efferent fibers, which transmit information from the brain to peripheral organs and control movement, and afferent fibers, which transmit sensory information from peripheral organs to the brain. Information perceived in various organs is transmitted to the brain via the afferent vagus nerve and then acts through the efferent fibers to participate in various physical activities, such as swallowing, coughing, and vomiting.

[0022] The vagus nerve, which extends from the medulla oblongata, emerges outside the cranial cavity and runs longitudinally along the carotid artery on both sides of the neck. Along the way, it branches to the pharynx or lungs. Near the auricle, at the lower ganglion, where the neuronal cell bodies are gathered, it merges with the pharyngeal branch or superior laryngeal nerve, which branches to the pharynx and larynx.

[0023] Cough receptors are located between or beneath the epithelial cells of the respiratory tract. When a foreign object or inflammation is applied to these receptors, the vagus nerve is excited, and the signal is transmitted to the cough center in the medulla oblongata, triggering a cough reflex. As a result, the diaphragm or thoracic tissues move rapidly, causing a cough, which expels the foreign object or secretions to the outside.

[0024] Chronic cough, which persists for a long time after recovery from a cold or viral infection, has various pathological conditions, but its cause is mostly related to the hyperactivity of the peripheral nervous system involved in inducing cough, namely, the respiratory tract reactivity. In particular, in pathological conditions of hypersensitivity to cough receptors, activation of the C fibers that make up the unmyelinated, delicate, and slow-conduction sensory nerves manifests as an overactive cough reflex.

[0025] The phototherapy device of the present invention treats cough patients by irradiating prescribed light upstream of the afferent nerve where cough receptors are located, thereby inhibiting the activation and hyperactivity of the vagus nerve and suppressing the cough reflex.

[0026] [Light therapy device] Embodiments of the light irradiation device 1 of the present invention will be described with reference to the accompanying drawings. Figure 1 As shown, the light irradiation device 1 of this embodiment is a medical device for treating or preventing cough by percutaneously irradiating the vagus nerve and its vicinity along the patient's neck with light. The light irradiation device includes a light irradiation probe 2 for irradiating light, a light source 3, a probe cable 4 connecting the light source and the light irradiation probe, and a main body 5 with a built-in light source.

[0027] The patient places the light-emitting probe 2 on the skin directly above the lower ganglion of the vagus nerve in the neck, and uses light to treat or prevent the condition. Figure 1This indicates that light is guided through probe cable 4, and the main body has a power supply (not shown). It should be noted that, as... Figure 2 As shown, a portable device can also be used by incorporating a built-in light source and power supply 6 into the light irradiation probe 2, allowing for treatment or prevention even when traveling. In this disease, many patients can lead normal lives without hospitalization, just like healthy individuals; therefore, a portable treatment or prevention device is convenient and can be used when necessary.

[0028] To improve the safety of light irradiation, a structure is preferred in which the tip of the light irradiation probe contacts the skin, and the diffused and reflected light on the skin does not leak to the outside. More preferably, a structure is provided that uses sensors and a control computing unit at and near the tip of the light irradiation probe to detect contact with the skin, thereby allowing irradiation only when the light irradiation probe is in correct contact with the skin at the irradiation site.

[0029] As a side effect of light, burns can occur due to an increase in skin temperature. To avoid burns, the increase in skin temperature can be mitigated by intermittently irradiating the skin with pulsed light while maintaining the energy and energy density of the light source. In this case, the repetition frequency is preferably 0.5 to 10 Hz. Furthermore, a structure that uses a fan or compressor as an air source to deliver air to the skin via a flow path, thereby reducing temperature through forced convection, is preferred.

[0030] [The area illuminated by the light] The light irradiation site in this invention is the vagus nerve and its vicinity in the patient's neck, characterized by percutaneous light irradiation of this area. Specifically, the light is percutaneously irradiated into the lower ganglion, superior ganglion, pharyngeal branch of the vagus nerve, superior laryngeal nerve, or glossopharyngeal nerve running nearby. The vicinity of the lower ganglion where the branches of the vagus nerve converge is an ideal irradiation site. However, since these nerves ascend in parallel before converging with the vagus nerve in the lower ganglion, it is sufficient to irradiate only the area near the lower ganglion. Preferably, the light is irradiated into the lower ganglion where the branches of the vagus nerve converge, or concentrated on the vagus nerve, laryngeal branch, superior laryngeal nerve, or glossopharyngeal nerve.

[0031] The specific location of the vagus nerve in the neck is the part of the vagus nerve that runs longitudinally through the lateral neck region, near the top of the head. From the perspective of the body surface, it is located behind the angle of the mandible or below the mastoid process, or in the area between the two.

[0032] [Illuminating light] In order to demonstrate a therapeutic effect on cough, the light irradiation device of the present invention preferably has any one or more of the following light conditions: That is, conditions where the average power is 200mW or more, and the average power density, obtained by dividing the average power by the irradiated area, is 75mW / cm². 2 The energy of the light dose is above 130J per treatment, and the energy density obtained by dividing the energy of the light dose by the area irradiated by the light is 45J / cm² per treatment or prevention. 2 The wavelengths mentioned above are 700-900 nm. Among these conditions, average power, average power density, energy, and energy density are specified by converting the light conditions from experiments using cough model animals into clinically hypothetical conditions based on light transmittance obtained through simulation. Furthermore, the irradiated light can be a single irradiation based on continuous irradiation, or intermittent irradiation with repeated irradiation / stopping.

[0033] In the treatment or prevention of cough, the light irradiation device of the present invention can be set to a preferred light condition for irradiation, and the light irradiation device can also be equipped with a light source that irradiates the specified preferred light condition.

[0034] As light that satisfies the irradiation conditions of the present invention, such as average power, average power density, energy, energy density, and wavelength, laser light excited by semiconductor elements or the like can be used. Alternatively, LED light that satisfies the conditions of the present invention can also be used. As reported in Photochemical & Photobiological Sciences 2018;17(8):1003-1017, LED light, like laser light, is widely used as light for treatment or prevention.

[0035] [Range of average power] As shown in the Journal of Clinical Laser Medicine & Surgery, 1991;9(4):267-75, the relationship between light intensity and effect can be explained by the Arndt-Schuwltz rule. The Arndt-Schuwltz rule states that if the light intensity exceeds a threshold, it promotes biological activity; if it is further increased, it inhibits biological activity. In this invention, the conditions representing light intensity are peak power, average power, average power density, energy, and energy density. Therefore, if a condition is greater than the lower limit of the effect confirmed in each condition, it is considered that the same inhibitory effect on neurotransmission exists.

[0036] Using the light scattering simulation based on Monte Carlo Modeling of Light Transport in Multi-layered Tissues (hereinafter referred to as MCML) as described in WO2022 / 019293 (Patent Document 2), the transmittance of light was verified in the embodiments as follows, thereby attempting to convert non-clinical experimental conditions into clinically equivalent conditions. The peak power, average power, average power density, energy, and a condition 0.3 times the energy density, which are related to light intensity in guinea pigs, became the lower limits for human-equivalent conditions for each parameter. Therefore, the average power in this invention is 0.2 W (200 mW) or more, preferably 0.2 W (200 mW) to 8 W, and more preferably 0.2 W (200 mW) to 0.8 W (800 mW).

[0037] [Range of average power density] In this invention, the average power density, which is the average power per unit area, is 250 mW / cm². 2 The above, more preferably 250~10,000 mW / cm 2 More preferably, it is 250~1,000 mW / cm 2 .

[0038] [Range of energy] In this invention, the energy representing the amount of light is 60J or more per treatment, preferably 60J to 4,800J, more preferably 60J to 2,400J, and even more preferably 240J to 2,400J.

[0039] [Range of energy density] In this invention, the energy density representing the amount of light is 75 J / cm² per treatment. 2 The above is preferably 75 J / cm. 2 ~6,000 J / cm 2 More preferably 75 J / cm 2 ~3,000 J / cm 2 More preferably 300 J / cm 2 ~3,000 J / cm 2 .

[0040] [Wavelength range] The wavelength 808 nm used in the effectiveness test of the embodiment is within the 700 nm to 900 nm range of the near-infrared region. As shown in the Journal of Physics D: Applied Physics, 2005, 38, 2543-2555, since the transmittance to organisms is equivalent in the near-infrared region, there is equivalent effectiveness in the 700 nm to 900 nm range. In addition, the absorption spectrum of cytochrome C oxidase, which has been reported to be involved in the mechanism of phototherapy, as shown in the Journal of Biological Chemistry, 2005; 280(6):4761-4771, has been reported to be equivalent in the 780 nm to 850 nm range. Therefore, the wavelength in the present invention is preferably 700 nm to 900 nm, more preferably 780 nm to 850 nm, and even more preferably 788 nm to 828 nm.

[0041] [Irradiation method] As a treatment or prevention method, a frequency of twice a day to once a week is preferred. Additionally, depending on the individual's condition, it can be used during or before an attack of the disease. The preferred treatment duration is approximately 3 to 60 minutes. However, prolonged continuous laser irradiation may cause burns to the skin. When irradiating at high power, intermittent irradiation can be performed, for example, with repeated irradiation for 1 minute followed by a 10-second pause or irradiation for 30 seconds followed by a 5-second pause. In this case, the surface area of ​​the irradiated area is approximately 0.5 cm². 2 ~approximately 6cm 2 The preferred size is 0.6cm. 2 ~3cm 2 The shape can be round, oval, rectangular, etc. Example

[0042] [Example 1] Studying the transmissibility of light through simulation The effectiveness of phototherapy depends on the amount of light in the target tissue. On the other hand, due to repeated scattering and absorption of light as it reaches a living organism, the amount of light decreases exponentially with distance from the skin surface (Lambert-Beer Law). Therefore, effectiveness in deep tissues requires consideration of light transmission. Thus, it is effective to calculate optimal output conditions by comparing the distance to the nerve in non-clinically used animals with that distance in humans. For example, the distance between the vagus nerve in the neck of a guinea pig, used as a cough model, and the skin surface is approximately 15 mm. In contrast, when the location of the vagus nerve in the human neck is imaged using ultrasound echo, it exists in a depth range of approximately 10 mm to 15 mm. Therefore, since the vagus nerve in guinea pigs may be located at a deeper depth than the vagus nerve in humans, it is believed that clinically equivalent irradiation conditions could be smaller than experimental conditions used in non-clinical trials. It should be noted that although there are differences in skin structure between humans and rodents, since the composition is identical, it can be said that light transmittance depends on the distance from the skin surface to the target tissue, rather than differences in animal species.

[0043] Next, the inventors used the light scattering simulation based on Monte Carlo modeling of light transmission in multilayer tissues using the Monte Carlo method (hereinafter referred to as MCML) as described in WO2022 / 019293 (Patent Document 2) (Computer Methods and Programs in Biomedicine, Vol. 47, No. 2, July 1995, pp. 131-146) to verify the amount of light transmitted, thereby attempting to convert the experimental conditions of non-clinical trials into conditions equivalent to clinical trials. The conditions and results of MCML are described. A three-layer structure of skin, fat, and muscle was fabricated, and the optical properties of each were set as follows. Wherein, the values ​​are the values ​​of skin, fat, and muscle, respectively (Phys. Med. Biol. 44(1999)2689-2702).

[0044] Refractive index n: 1.4 for all. absorption coefficient μ a: 0.15cm -1 0.02cm -1 0.3cm -1 , Scattering coefficient μ s: 100cm -1 80cm -1 33cm -1 , The isotropic scattering parameter g is 0.85 for all values. Thickness: 0.1cm, 0.4cm, 2.0cm.

[0045] It should be noted that the layer below the muscle layer with a refractive index of 1.4 is assumed to extend infinitely. The light illumination conditions are set as follows: the beam profile representing the spatial intensity distribution is Gaussian, the illumination radius is set to 0.9 cm, and the energy is set to 600 J. The number of photons is set to 10 million, and calculations are performed in units of 0.05 cm in both the depth and radius directions.

[0046] The results are explained. The average power density at a depth equivalent to 15 mm of the guinea pig vagus nerve was 6.1 mW / cm². 2 The average power density at a depth of 10 mm in the human vagus nerve is equivalent to 20.3 mW / cm². 2 Therefore, in order to reproduce the average power density of the guinea pig vagus nerve depth in humans, optimal clinically equivalent irradiation conditions can be derived by multiplying the peak power, average power, energy, and energy density, which are conditions related to the amount of light in guinea pigs, by 0.3 times, where the 0.3 times is obtained by dividing the average power density of the guinea pig vagus nerve depth by the same average power density in humans.

[0047] [Example 2] Effectiveness evaluation test of light irradiation using a cough model To investigate the effectiveness of low-power laser therapy (LLLT) for cough, experiments were conducted using animal models of cough. A guinea pig citrate-induced cough model, which is widely used in non-clinical trials of cough and induces cough by activating the vagus nerve, was used as the cough model.

[0048] The experimental procedures are as follows.

[0049] [Model animal used] Using citric acid to stimulate A δ A guinea pig citrate-induced cough model was established using Slc:Harltley, 6-week-old male guinea pigs. Groups were set as follows: 1: healthy group; 2: laser sham irradiation group; 3: laser irradiation group; 4: positive subject group, with 8 rats in each group. It should be noted that the non-laser irradiation group did not emit laser light but only underwent the same experimental behavior as laser irradiation, while the positive subject group was given codeine dihydrophosphate as an antitussive.

[0050] Prior to the experiment, the location of the vagus nerve ganglion in the guinea pig's neck was confirmed by dissection. A ganglion was confirmed to exist on the medial side of the masseter muscle, where the vagus nerve intersects with the superior laryngeal nerve, which is responsible for coughing. This ganglion is located approximately 15 mm deep from the epidermis, confirming that this is the depth at which the laser can adequately reach the nerve.

[0051] [Laser irradiation conditions] Transdermal laser irradiation was performed on the area near the masseter muscle of a guinea pig under the following conditions: Wavelength: 808 nm, Average power: 0.75 W, Peak power: 7.5 W, Pulse oscillation frequency: 5 Hz, Duty cycle: 10%, Irradiated area: 0.8 cm². 2 Irradiation time: 5 minutes on each side.

[0052] [Evaluation Method] The effectiveness of cough treatment is assessed by visually counting the number of coughs and comparing the number of coughs after laser irradiation or administration of antitussive medication (Post).

[0053] [Experimental Techniques] (1) The animal was placed in a chamber for cough detection and citric acid was atomized using an ultrasonic nebulizer. The animal was inhaled for 10 minutes while the number of coughs was visually counted (Pre measurement).

[0054] (2) After the Pre measurement, the participants were divided into groups based on the number of cough reflexes.

[0055] (3) Thirty minutes before inhalation of citric acid (approximately 3 hours after Pre-measurement), the laser irradiation group underwent cervical vagus nerve laser irradiation, while the positive subjects were given codeine dihydrogen phosphate.

[0056] (4) The animal was placed back into the chamber used for cough detection, and citric acid was atomized using an ultrasonic nebulizer and inhaled by the animal for 10 minutes while the number of coughs was visually counted (Post measurement).

[0057] (5) The effectiveness of laser irradiation was evaluated based on the number of cough reflexes measured by Post. Dunnett's multiple comparison test was performed between the sham group and all groups, with a significance level set at 5%.

[0058] [result] The evaluation results of the effectiveness of LLLT in cough treatment are as follows: Figure 3 As shown in Table 1 below.

[0059] [Table 1] There was no significant difference between the laser sham irradiation group (sham group) and the healthy group (control group). Significant reductions in cough frequency were confirmed in the sham group and the positive subject group (dihydrocodeine group) and the sham group and the laser irradiation group (LLLT group).

[0060] Although the reduction in cough frequency was smaller in the LLLT group compared to the dihydrocodeine group, this may be due to the influence of evaluation time and irradiation site deviation. It can be confirmed that low-power laser irradiation of the cervical vagus nerve significantly reduces cough frequency in a manner comparable to dihydrocodeine as a centrally acting antitussive.

[0061] Practicality in industry As a novel treatment for cough, the cough-suppressing effect of phototherapy can be confirmed, providing a new physical therapy approach.

[0062] Symbol Explanation 1. Light irradiation device, 2. Illuminate the probe with light. 3. Light source 4. Probe cable, 5 main components 6. Light source and power supply.

Claims

1. A cough treatment device, characterized in that, It has a light source that emits light and a light irradiation probe that irradiates the light, and the light emitted by the light source is irradiated percutaneously from the light irradiation probe to the vagus nerve and its vicinity in the patient's neck.

2. The cough treatment device according to claim 1, characterized in that, The light irradiation probe is a device that irradiates light onto the lower ganglion, upper ganglion, pharyngeal branch, or superior laryngeal nerve of the vagus nerve in the neck.

3. The cough treatment device according to claim 1, characterized in that, The light irradiation probe is a device that irradiates light into the area behind the angle of the mandible or below the mastoid process on the patient's neck.

4. The cough treatment device according to claim 1, characterized in that, The average power of the light irradiated by the light irradiation probe is 200mW~8W, and the average power density obtained by dividing the average power of the light irradiated by the light irradiation probe by the irradiated area is 250mW / cm². 2 Above ~10,000mW / cm 2 The energy of the light irradiated from the light irradiation probe is 60J~4,800J per treatment, and the energy density, obtained by dividing the energy of the light irradiation probe by the irradiated area, is 75J / cm² per treatment. 2 ~6,000 J / cm 2 The wavelength of the light emitted from the light irradiation probe is 700nm~900nm.

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