JP7719601B2 - ciliary movement activator for the upper respiratory tract mucosa - Google Patents

Description

The present invention relates to an agent that activates ciliary movement in the upper respiratory tract mucosa.

Pathogens such as viruses and bacteria cause infectious diseases by entering the body. The emergence of new pathogens leads to new infectious diseases, and at a stage when effective treatments and vaccines have not yet been established, the best countermeasure is to defend against pathogens.

In particular, in defense against pathogens that cause pulmonary infections, the function of the mucous membranes and cilia that line the inner walls of the respiratory tract (lower respiratory tract) from the throat to the lungs is important, preventing pathogens inhaled through the mouth or nose from reaching the lungs. For this reason, research is being conducted into components that activate ciliary movement in the respiratory tract mucosa.

For example, Non-Patent Document 1 reports the effect of Hochuekkito on the ciliary movement of airway mucosal epithelial cells. Non-Patent Document 2 reports that the expectorant effect of Seifeito promotes the secretion of airway fluid in the bronchi, expelling viscous phlegm and contaminants such as tobacco and exhaust fumes, while also activating ciliary movement, expelling contaminants along with the phlegm.

Cilia are present not only in the airways (lower respiratory tract) from the throat to the lungs, but also in the nasal mucosa. Foreign substances that enter the nasal mucosa are transported by the function of the cilia and excreted into the throat. Non-Patent Document 3 reports that a decrease in nasal mucus ciliary clearance is a characteristic of the elderly, and Non-Patent Document 4 reports that nasal mucus ciliary transport function is reduced in smokers compared to non-smokers.

"Effect of Hochuekkito on ciliary movement of airway mucosal epithelial cells," Japan Society for Bronchology, 17(5):385-389, 1995 "Seihaito Navi: Research Results of Seihaito," [online], 2013, Kobayashi Pharmaceutical Co., Ltd., [Retrieved December 5, 2020], Internet <URL: https://www.seihaito.jp/mechanism/> Management of community-acquired pneumonia in older adults. Ther Adv Infect Dis.2014;2:3-16. "Method for measuring human nasal mucociliary function using Technetium 99m," Journal of the Japanese Rhinologic Society, Group 4, Basics IV, pp. 54-59, 1982

The upper respiratory tract mucosa (especially the nasal cavity) is constantly in contact with the outside world and can therefore be said to be the first line of defense against pathogens. Therefore, activating the cilia in the upper respiratory tract mucosa is even more important in defending against pathogens. Recently, an increasing number of people are using Chinese herbal medicines due to increased awareness of self-medication in managing their own health and preventing disease, but there are currently no Chinese herbal medicines known to activate ciliary movement in the upper respiratory tract mucosa.

The present invention therefore aims to provide a new herbal medicine that can activate ciliary movement in the upper respiratory tract mucosa.

After extensive research, the inventors unexpectedly discovered that a Chinese herbal extract containing six or more of the eight herbal medicines consisting of Pueraria root, Ephedra, Chinese Root, Ginger and/or Kankyo, Cinnamon Bark, Peony Root, Pinellia Root, and Licorice Root has the effect of activating ciliary movement in the upper respiratory tract mucosa. Based on this finding, the present invention was completed through further research.

That is, the present invention provides the following aspects.
Item 1. An agent for activating ciliary movement in the mucous membrane of the upper respiratory tract, comprising a Chinese herbal extract containing six or more of eight herbal medicines consisting of (i) Pueraria root, (ii) Ephedra, (iii) Chinese Root, (iv) Ginger and/or Kankyo, (v) Cinnamon bark, (vi) Peony root, (vii) Pinellia root, and (viii) Licorice.
Item 2. The ciliary movement activator for the upper respiratory tract mucosa according to Item 1, wherein the Chinese herbal medicine is Sho-seiryu-to and/or Kakkon-to.
Item 3. The ciliary movement activator for upper respiratory tract mucosa according to Item 1 or 2, which is used for physically frail people.
Item 4. The ciliary movement activator for upper respiratory tract mucosa according to Item 1 or 2, which is used for physically fit individuals.
Item 5. The ciliary movement activator for upper respiratory tract mucosa according to any one of Items 1 to 3, which is applied to a subject in a state without runny nose.

The present invention provides a new pharmaceutical product that can activate ciliary movement in the upper respiratory tract mucosa.

1 shows the saccharin time before and after administration of Sho-seiryu-to extract to a group of physically fit subjects. 1 shows the saccharin time before and after administration of Sho-seiryu-to extract to a group of subjects with a weak constitution. 1 shows the saccharin time before and after administration of Kakkonto extract to a group of subjects with a weak constitution.

The ciliary movement activator for upper respiratory tract mucosa of the present invention is characterized by containing a Chinese herbal extract containing six or more of eight specified herbal medicines. The ciliary movement activator for upper respiratory tract mucosa of the present invention is described in detail below.

The ciliary movement activator for the upper respiratory tract mucosa of the present invention contains as an active ingredient a herbal extract containing six or more of eight herbal medicines: (i) Pueraria lobata, (ii) Ephedra, (iii) Chinese cabbage, (iv) Ginger and/or Kankyo, (v) Cinnamon, (vi) Peony, (vii) Pinellia, and (viii) Licorice.

Kakkon (Pueraria lobata) is the root of Pueraria lobata Ohwi, a plant of the Leguminosae family, with the periderm removed, and is used as a herbal medicine (Japanese Pharmacopoeia) for purposes such as antipyretic, analgesic, and anti-inflammatory. Pueraria lobata powder is commercially available from Nippon Funa Pharmaceutical Co., Ltd., Tochimoto Tenkaido Co., Ltd., and other companies.

Ephedra herb is the aerial stem of Ephedra sinica Staf, Ephedra intermedia Schrenk et C. A. Meyer, or Ephedra equisetina Bunge, which belong to the Ephedraceae family. It is used as a herbal medicine (Japanese Pharmacopoeia) for purposes such as a bronchodilator, antirhinitis medication, and antipyretic, analgesic, and anti-inflammatory agent. Ephedra powder is commercially available from Nippon Powder Pharmaceuticals Co., Ltd., Tochimoto Tenkaido Co., Ltd., and other companies.

Zizyphus jujuba (Zizyphus jujuba Miller var. inermis Rehder) is the fruit of the jujube (Rhamnaceae) plant, and is used as a herbal medicine (Japanese Pharmacopoeia) for cold remedies, analgesics, antispasmodics, stomachic digestives, antidiarrheal and intestinal regulators, and psychotropic medicines. Powdered jujube is commercially available from Takasago Pharmaceutical Co., Ltd., Tochimoto Tenkaido Co., Ltd., and other companies.

Zingiber officinale (Roscoe) is the rhizome of the ginger plant (Zingiberaceae), sometimes with the pericarp removed. It is used as a crude drug (Japanese Pharmacopoeia) for purposes such as aromatic stomachicity. Powdered ginger is commercially available from Nippon Funa Yakuhin Co., Ltd., Takasago Pharmaceutical Co., Ltd., Tochimoto Tenkaido Co., Ltd., etc. Kankyo (dried ginger) is the blanched or steamed rhizome of the ginger plant (Zingiberaceae), Zingiber officinale (Roscoe), and is used as a crude drug (Japanese Pharmacopoeia) for fever relief and tonic purposes. Powdered kankyo is commercially available from Nippon Funa Yakuhin Co., Ltd., Takasago Pharmaceutical Co., Ltd., Tochimoto Tenkaido Co., Ltd., etc.

Cinnamon bark is the peeled bark from the thick trunk of Cinnamomum cassia Blum, a plant of the Lauraceae family, or other plants of the same genus, and is used as a herbal medicine (Japanese Pharmacopoeia) as an aromatic stomachic, etc. Cinnamon bark powder is commercially available from Nippon Funa Yakuhin Co., Ltd., Tochimoto Tenkaido Co., Ltd., etc.

Peony (Shakuyaku) is the root of Paeonia lactiflora Pallas or other related plants of the Paeoniaceae family, and is used as a herbal medicine (Japanese Pharmacopoeia) for purposes such as an analgesic and antispasmodic (gastrointestinal medicine), a women's medicine, a medicine for sensitivity to colds, and a cold remedy. Note that Shakuyaku is both the name of the herbal medicine (Japanese Pharmacopoeia) and the name of the plant. Peony powder is commercially available from Maruzen Pharmaceutical Co., Ltd., Mikuni Co., Ltd., Ichimaru Pharcos Co., Ltd., and others.

Pinellia ternata (Pinellia ternata Breitenbach), a plant of the Araceae family, is the tuber from which the cork layer has been removed. It is used as a herbal medicine (Japanese Pharmacopoeia) for purposes such as stomachic digestive medicine and antiemetic. Pinellia ternata powder is commercially available from Takasago Pharmaceutical Co., Ltd., Tochimoto Tenkaido Co., Ltd., and other companies.

Licorice (Glycyrrhiza uralensis Fischer) or Glycyrrhiza glabra Linne (Glycyrrhiza glabra) is the root and stolons of the Leguminosae (Fabaceae) plant, sometimes with the periderm removed (peeled licorice), and is used as a herbal medicine (Japanese Pharmacopoeia) for purposes such as treating stomach ulcers. Licorice powder is commercially available from Nippon Funa Yakuhin Co., Ltd., Takasago Pharmaceutical Co., Ltd., Tochimoto Tenkaido Co., Ltd., and others.

There are no particular limitations on herbal medicines containing six or more of the eight herbal medicines listed above, but specific examples include Shoseiryuto and Kakkonto.

Shou Qing Long Tang is based on the "Shanghan Lun" and "Jingui Yaolue" and is a mixed herbal medicine made from eight herbs: Pinellia Root, Ephedra, Peony Root, Ginger Root (Can also be used with Kankyo), Licorice, Cinnamon Bark, Chinese Root, and Gomizun.

In the present invention, there are no particular limitations on the mixing ratio of the herbs that make up Shoseiryuto, but examples include 3 to 6 parts by weight of Pinellia Root, 1.5 to 3 parts by weight of Ephedra Root, 1.5 to 3 parts by weight of Peony Root, 1.5 to 3 parts by weight of Zingiber officinale (can also be Zingiber officinale), 1.5 to 3 parts by weight of Licorice Root, 1.5 to 3 parts by weight of Cinnamon Bark, 1.5 to 3 parts by weight of Chinese Cabbage Stalk, and 1.5 to 3 parts by weight of Gomiso Seed.

A suitable example of a medicinal herb preparation to be used in the production of the Sho-seiryu-to extract used in the present invention is a mixture of 6.0 parts by weight of Pinellia Root, 3.0 parts by weight of Ephedra Root, 3.0 parts by weight of Peony Root, 3.0 parts by weight of Kankyo Root, 3.0 parts by weight of Glycyrrhiza Root, 3.0 parts by weight of Cinnamon Bark, 3.0 parts by weight of Saishin, and 3.0 parts by weight of Gomizunomi.

Kakkonto is a mixed herbal medicine based on the "Shanghan Lun" and is made up of seven herbs: Pueraria root, licorice, cinnamon bark, peony root, ephedra, ginger, and rhizome.

In the present invention, there are no particular limitations on the mixing ratio of the herbal medicines that make up Kakkonto, but examples include 4 to 8 parts by weight of Pueraria lobata, 3 to 4 parts by weight of Glycyrrhiza Root, 2 to 3 parts by weight of Cinnamon Bark, 2 to 3 parts by weight of Peony Root, 3 to 4 parts by weight of Ephedra Root, 1 to 2 parts by weight of Zingiber officinale, and 3 to 4 parts by weight of Taiso Root.

A suitable example of a medicinal herb preparation to be used in the production of Kakkonto extract for use in the present invention is a mixture of 8 parts by weight of Pueraria lobata, 2 parts by weight of Glycyrrhiza Root, 3 parts by weight of Cinnamon Bark, 3 parts by weight of Peony Root, 4 parts by weight of Ephedra Root, 1 part by weight of Ginger Root, and 4 parts by weight of Taiso Root.

In addition to the above herbal extracts, there is also an extract of a mixed herbal medicine consisting of 12 species: Pueraria root, Ephedra root, Chinese Root, Ginger, Cinnamon bark, Apricot kernel, Peony root, Pinellia root, Platycodon grandiflorum, Scutellaria root, Bupleurum root, and Licorice root. A suitable example of a herbal medicine blend used to produce this mixed herbal extract is a mixture of 16 parts by weight of Pueraria root, 14 parts by weight of Ephedra root, 10 parts by weight of Apricot kernel, 6 parts by weight of Ginger root, 6 parts by weight of Cinnamon bark, 6 parts by weight of Apricot kernel, 7 parts by weight of Peony root, Pinellia root, Platycodon grandiflorum, 7 parts by weight of Scutellaria root, 9 parts by weight of Bupleurum root, and 5 parts by weight of Licorice root.

The above-mentioned herbal extracts may be in the form of liquid extracts such as fluid extracts or soft extracts, or solid dried extract powders.

The liquid extract of the above-mentioned Kampo medicine can be obtained by extracting a mixture of herbs according to the above-mentioned Kampo medicine and concentrating the resulting extract as necessary. The extraction solvent used in the extraction process is not particularly limited, and examples include water or aqueous ethanol, preferably water. The dried extract powder of the above-mentioned Kampo medicine can be obtained by drying the liquid extract. The drying method is not particularly limited, and examples include spray drying, and a method in which a suitable adsorbent (e.g., silicic anhydride, starch, etc.) is added to a soft extract with an increased extract concentration to produce an adsorbed powder.

In the present invention, the extracts of the above-mentioned Kampo medicines may be extracts prepared by the above-mentioned methods, or commercially available products may be used. For example, soft extracts of shoseiryuto include "Shoseiryuto Extract" (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), dried extracts of shoseiryuto include "Shoseiryuto Dried Extract-A," "Shoseiryuto Extract (27D・ATS)" (all manufactured by Nippon Powder Pharmaceutical Co., Ltd.), and "Shoseiryuto Dried Extract-F" (Alps Pharmaceutical Co., Ltd.), etc.; dried extracts of kakkonto include "Kakkonto Extract (17D・W)," "Kakkonto Extract (25D・AT)," and "Kakkonto Extract (25D・AZ)" (all manufactured by Nippon Powder Pharmaceutical Co., Ltd.), and soft extracts of kakkonto include "Kakkonto Extract-A(T)" (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), etc., and are commercially available.

The above herbal medicines may be used alone or in combination with multiple types.

Among the above-mentioned herbal medicines, Shoseiryuto and Kakkonto are preferred, with Shoseiryuto being more preferred, from the viewpoint of further enhancing the effect of activating ciliary movement in the upper respiratory tract mucosa.

In the upper respiratory tract mucosa ciliary movement activator of the present invention, the content of the herbal extract is not particularly limited as long as the effects of the present invention are achieved, and may vary depending on the dosage form, etc. However, the content is typically 10 to 100% by weight, preferably 20 to 90% by weight, and more preferably 40 to 80% by weight, calculated as the amount of dried herbal extract powder. In the present invention, the amount of dried herbal extract powder refers to the amount of dried herbal extract powder itself when a dried herbal extract powder is used, and refers to the amount remaining after removing the solvent when a liquid herbal extract is used. Furthermore, if the dried herbal extract powder contains additives such as adsorbents added during production, the amount refers to the amount excluding these additives.

The ciliary movement activator for the upper respiratory tract mucosa of the present invention may consist solely of the above-mentioned herbal extract, or may contain additives or bases depending on the formulation. Such additives and bases are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include excipients, binders, disintegrants, lubricants, isotonicity agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, stabilizers, suspending agents, adhesives, coating agents, glossing agents, water, oils and fats, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymers, surfactants, metal soaps, lower alcohols, polyhydric alcohols, pH adjusters, buffers, antioxidants, UV protection agents, preservatives, corrigents, fragrances, powders, thickeners, pigments, and chelating agents. These additives may be used alone or in combination of two or more. The contents of these additives and bases are appropriately determined depending on the types of additives and bases used, the formulation of the ciliary movement activator for the upper respiratory tract mucosa, and the like.

In addition to the herbal extract, the upper respiratory tract mucosal ciliary movement activator of the present invention may contain other nutritional components or pharmacological components as needed. Such nutritional components and pharmacological components are not particularly limited as long as they are pharmaceutically acceptable, and examples include antacids, stomachics, digestive aids, intestinal regulators, antispasmodics, mucosal repair agents, anti-inflammatory agents, astringents, antiemetics, antitussives, expectorants, anti-inflammatory enzymes, sedatives, hypnotics, antihistamines, caffeine, cardiac diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, herbal extracts, vitamins, and menthols. These nutritional components and pharmacological components may be used alone or in combination of two or more. The content of these components is determined appropriately depending on the type of components used, etc.

Formulations The formulation of the agent for activating ciliary movement of the upper respiratory tract mucosa of the present invention is not particularly limited, as long as it can be administered orally. Examples of formulations include solid formulations such as powders, fine granules, granules, tablets, troches, chewable tablets, capsules (soft capsules, hard capsules), and pills; semi-solid formulations such as jellies; and liquid formulations such as solutions, suspensions, and syrups, with liquid formulations being preferred.

Production Method The method for producing the ciliary movement activator for upper respiratory tract mucosa of the present invention is to prepare a formulation using the above-mentioned herbal ingredients according to a conventional formulation method used in the pharmaceutical field.

The ciliary movement activator for upper respiratory tract mucosa of the present invention is used for the purpose of activating ciliary movement of upper respiratory tract mucosa, more specifically, activating cilia movement of nasal mucosa and/or pharyngeal mucosa. Activating ciliary movement of upper respiratory tract mucosa enhances the ability to expel foreign substances such as viruses, and therefore can be used for the purpose of preventing infectious diseases.

The ciliary movement activator for the upper respiratory tract mucosa of the present invention can be used for subjects belonging to various physical fitness classifications. In other words, the ciliary movement activator for the upper respiratory tract mucosa of the present invention can be used for subjects belonging to physical fitness classifications that are not suitable for the above-mentioned specified herbal extracts, including those who are physically weak, slightly weak, moderately fit, relatively fit, and well-fit. These physical fitness classifications are criteria used by those skilled in the art when determining the application of herbal medicines.

Among people who fall into the above physical fitness categories, those with weak physical fitness are preferred, from the perspective of further enhancing the effect of activating ciliary movement in the upper respiratory tract mucosa. More specific examples of those with weak physical fitness include those with weak stomachs, those who are sensitive to cold, and the elderly (specifically, those aged 65 or older).

As described above, the ciliary movement activator for the upper respiratory tract mucosa of the present invention can be used for the purpose of preventing infectious diseases, and therefore is preferably used in subjects who do not have a runny nose.

The ciliary movement activator for the upper respiratory tract mucosa of the present invention is particularly preferably used in subjects with reduced ciliary movement function in the upper respiratory tract mucosa. Examples of such subjects include smokers and the elderly (specifically, those aged 65 or older).

The ciliary movement activator for upper respiratory tract mucosa of the present invention is administered orally . The dose of the ciliary movement activator for upper respiratory tract mucosa of the present invention is appropriately determined depending on the age, constitution, severity of symptoms, etc. of the recipient. For example, for a human, the total amount (equivalent to the amount of raw herbs) of (i) Pueraria root, (ii) Ephedra root, (iii) Chinese cabbage, (iv) Ginger root and Chinese ginger, (v) Cinnamon bark, (vi) Peony root, (vii) Pinellia root, and (viii) Licorice used in the preparation of the herbal extract is about 5 to 40 g, preferably about 6.5 to 30 g, more preferably about 8 to 28 g, per day, 1 to 3 times a day, preferably 3 times a day.

The timing of administration of the ciliary movement activator for upper respiratory tract mucosa of the present invention is not particularly limited, and it may be administered before, after, or between meals, although it is preferable to administer it before meals (30 minutes before a meal) or between meals (2 hours after a meal). Furthermore, because the ciliary movement activator for upper respiratory tract mucosa of the present invention is fast-acting, it can also be administered before exposure to an environment where foreign matter may enter the nasal cavity, for example, before meeting others or before going out, more specifically, 3 to 5 hours before meeting others or going out. Furthermore, the administration period of the ciliary movement activator for upper respiratory tract mucosa of the present invention can be, for example, 1 to 5 days, preferably 1 to 3 days, and more preferably 1 to 2 days.

The present invention will be explained in more detail below using examples, but the present invention is not limited to these examples.

Test Example 1
(1) Preparation of ciliary movement activators for upper respiratory tract mucosa The following two types of ciliary movement activators for upper respiratory tract mucosa were prepared.
(1-1) Ciliary Motility Activator for Upper Respiratory Tract Mucosa Containing Sho-seiryu-to Extract A mixture of 6.0 g of Pinellia Root, 3.0 g of Ephedra Root, 3.0 g of Peony Root, 3.0 g of Kankyo, 3.0 g of Licorice Root, 3.0 g of Cinnamon Bark, 3.0 g of Saishin, and 3.0 g of Gomizunomi was used as raw herbal ingredients. The mixed herbal ingredients were placed in an extractor, purified water was added, and the mixture was extracted with stirring at 80-90°C for 2 hours, followed by filtration. The resulting filtrate was concentrated using a vacuum concentrator (temperature: 50-60°C), and additives were added to the concentrate to obtain a Sho-seiryu-to extract liquid (daily dose, 27 g in terms of the crude herbal ingredients) as a ciliary motility activator for upper respiratory tract mucosa.

(1-2) Ciliary Motility Activator for Upper Respiratory Tract Mucosa Containing Kakkonto Extract A mixture of 8.0 g of Pueraria root, 2.0 g of Licorice Root, 3.0 g of Cinnamon Bark, 3.0 g of Peony Root, 4.0 g of Ephedra Root, 1.0 g of Zingiber officinale, and 4.0 g of Rhizome Rhizome was used as raw herbal ingredients. The mixed herbal ingredients were placed in an extractor, purified water was added, and the mixture was extracted with stirring at 80-90°C for 2 hours, followed by filtration. The resulting filtrate was concentrated using a vacuum concentrator (temperature: 50-60°C), and additives were added to the concentrate to obtain a Kakkonto extract liquid (daily dose, 25 g in terms of the amount of raw herbal ingredients) as a ciliary motility activator for upper respiratory tract mucosa.

(2) Experimental Method (2-1) Subjects The subjects were adult men and women with well-fit and frail constitutions. Neither the well-fit nor the frail subjects belonged to the physical fitness classification for which shoseiryuto was prescribed, and the frail subjects did not belong to the physical fitness classification for which kakkonto was prescribed. The frail subjects all lacked physical strength, easily fatigued, had weak stomachs and intestines, and were prone to cold. Furthermore, unlike the subjects for whom shoseiryuto was prescribed, none of the subjects had a runny nose. The subjects were divided into three groups: a well-fit group (5 men and women) taking an upper respiratory tract mucosal ciliary motility activator containing shoseiryuto extract; a frail group (5 men and women) taking an upper respiratory tract mucosal ciliary motility activator containing shoseiryuto extract; and a frail group (5 men and women) taking an upper respiratory tract mucosal ciliary motility activator containing kakkonto extract.

(2-2) Administration Method Each subject was administered one-third of the daily dose of each ciliary motility activator for the upper respiratory mucosa before meals. Care was taken to prevent significant changes due to meals during the test period. A saccharin test was conducted before and 3 hours after administration. The subjects were allowed to acclimate for 15 minutes in a test room at a room temperature of 25°C and a humidity of 55%. After acclimatization, a saccharin pellet approximately 2 mm in diameter was attached to the area near the right inferior turbinate (7-10 mm from the anterior end of the inferior turbinate). The subjects were then swallowed every 30 seconds, and the time it took for the subject to sense sweetness (saccharin time) was measured, doubled from the time of attachment.

The results for the group of physically fit subjects who took shoseiryuto extract are shown in Figure 1, the results for the group of frail subjects who took shoseiryuto extract are shown in Figure 2, and the results for the group of frail subjects who took kakkonto extract are shown in Figure 3. As shown in Figures 1 to 3, in all groups, the ciliary movement of the upper respiratory tract mucosa was activated because the saccharin time was earlier. In particular, as shown by comparing Figures 1 and 2, the effect of activating ciliary movement of the upper respiratory tract mucosa was even greater in subjects with a frail constitution.

Claims (2)

Contains Xiaoqinglongtang extract and is an agent that activates ciliary movement in the upper respiratory tract mucosa, and is used for people with weak physical strength . The ciliary movement activator for the upper respiratory tract mucosa according to claim 1 , which is applied to a subject in a condition without runny nose.