Neutrophil / lymphocyte ratio lowering agents

Abstract

The purpose of the present invention is to provide a drug or a food composition for decreasing a neutrophil-to-lymphocyte ratio.　Provided is an agent for decreasing a neutrophil-to-lymphocyte ratio in blood, which contains a curcumin compound as an active ingredient.

Description

Technical Field

[0001] The present invention relates to a neutrophil / lymphocyte ratio reducing agent in blood.

Background Art

[0002] Leukocytes are immune cells involved in biological defense, and perform functions such as elimination of foreign substances such as bacteria and viruses invading from outside the body, elimination of tumor cells and cells that have completed their roles. There are five types of leukocytes: monocytes, lymphocytes, neutrophils, basophils, and eosinophils. Among these, lymphocytes are divided into natural killer cells, T cells, and B cells, and have a function of attacking small foreign substances such as viruses and tumor cells. On the other hand, neutrophils show migratory properties against inflammatory cytokines, bacteria, and fungi, gather at the site of inflammation, and perform phagocytosis, sterilization, and decomposition of foreign substances such as bacteria and fungi to defend the living body. Thus, neutrophils and lymphocytes have different roles, the number of lymphocytes does not change much, and the number of neutrophils increases in bacterial infections, inflammation, cancer, etc.

[0003] Recently, it has been reported that a high neutrophil / lymphocyte ratio is involved in the prognosis of various diseases involving chronic inflammation such as breast cancer, colorectal cancer (Non-Patent Document 1), diabetes, coronary artery disease, or bacterial / viral infections, particularly chronic inflammation such as COVID-19 (novel coronavirus infection). Also, in the Rotterdam Study (epidemiological survey) targeting the general population aged 45 and over, it has been shown that a high neutrophil lymphocyte ratio leads to a shorter lifespan.

[0004] In recent years, curcumin has been shown to have pharmacological effects such as tumor formation inhibitory action, antioxidant action, anti-inflammatory action, cholesterol lowering action, anti-allergic action (such as anti-IL-6 action), brain disease preventive action, heart disease preventive and therapeutic action, etc., and its use in pharmaceuticals, foods, cosmetics, etc. has been under consideration (Patent Document 1). Also, Mazumdar A. et al. have reported on the HIV inhibitory action of curcumin (Non-Patent Document 3).

Prior Art Documents

[0005] [Patent Document 1] Japanese Patent Publication No. 2013-95723 [Non-patent literature]

[0006] [Non-Patent Document 1] Journal of the Japan Society of Coloproctology 69:154-158, 2016 [Non-Patent Document 2] Life Science 254(2020)117788 [Non-Patent Document 3] Cur.Biochem.Pharmacol.1,995,49:1165-1170 [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] However, no drugs have yet been found that can lower the neutrophil / lymphocyte ratio. Therefore, the object of the present invention is to provide a drug or food composition that can reduce the neutrophil / lymphocyte ratio. [Means for solving the problem]

[0008] Therefore, the inventors administered components that had been confirmed to be highly safe to relatively older individuals in succession and measured changes in the neutrophil / lymphocyte ratio. They discovered that curcumins have a strong effect in lowering the neutrophil / lymphocyte ratio in the blood, thus completing the present invention.

[0009] In other words, the present invention provides the following inventions [1] to

[12] . [1] A blood neutrophil / lymphocyte ratio-lowering agent containing curcumin as the active ingredient. [2] The blood neutrophil / lymphocyte ratio lowering agent according to [1] above, wherein the curcumins are one or more selected from curcumin, curcumin derivatives, and conjugates thereof with water-soluble substances. [3] The blood neutrophil / lymphocyte ratio lowering agent according to [2] above, wherein the curcumin derivative is one or more selected from bisdemethoxycurcumin, demethoxycurcumin, and tetrahydrocurcumin. [4] The blood neutrophil / lymphocyte ratio lowering agent according to [2] above, wherein the water-soluble substance is one or more selected from glucuronic acid, sulfate, glutathione, and amino acids. [5] The blood neutrophil / lymphocyte ratio lowering agent according to [2] above, wherein the water-soluble substance is one or more selected from glucuronic acid and sulfuric acid. [6] The blood neutrophil / lymphocyte ratio-lowering agent according to [1] above, wherein the curcumin is curcumin monoglucuronide. [7] A food composition containing curcumin for reducing the neutrophil / lymphocyte ratio in the blood. [8] The composition according to [7] above, wherein the curcumins are one or more selected from curcumin, curcumin derivatives, and conjugates thereof with water-soluble substances. [9] The composition according to [8] above, wherein the curcumin derivative is one or more selected from bisdemethoxycurcumin, demethoxycurcumin, and tetrahydrocurcumin.

[10] The composition according to [8] above, wherein the water-soluble substance is one or more selected from glucuronic acid, sulfuric acid, glutathione, and amino acids.

[11] The composition according to [8] above, wherein the water-soluble substance is one or more selected from glucuronic acid and sulfuric acid.

[12] The composition according to [7] above, wherein the curcumins are curcumin monoglucuronide.

[13] Curcumins used to lower the neutrophil / lymphocyte ratio in the blood.

[14] The curcumins described in

[13] above, wherein the curcumins are one or more selected from curcumin, curcumin derivatives, and conjugates thereof with water-soluble substances.

[15] Use of curcumins for the production of neutrophil / lymphocyte ratio-lowering agents in the blood.

[16] The use according to

[15] above, wherein the curcumins are one or more selected from curcumin, curcumin derivatives, and conjugates thereof with water-soluble substances.

[17] A method for reducing the neutrophil / lymphocyte ratio in blood, characterized by administering an effective amount of curcumins.

[18] The method according to

[17] above, wherein the curcumins are one or more selected from curcumin, curcumin derivatives, and conjugates thereof with water-soluble substances. [Advantages of the Invention]

[0010] When curcumins are administered, the neutrophil / lymphocyte ratio in blood decreases. Therefore, the prognosis of diseases suffered by patients with a high neutrophil / lymphocyte ratio can be improved. Such diseases include allergic diseases such as bronchial asthma and atopic dermatitis, autoimmune diseases such as rheumatoid arthritis, arteriosclerosis, cardiovascular diseases, heart failure, kidney diseases, Alzheimer's disease, etc., as well as severe infectious diseases such as sepsis and pneumonia, rheumatic fever, malignant tumors, chronic myeloproliferative leukemia, polycythemia vera, essential thrombocythemia, myelofibrosis, and viral infections such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19 (SARS-CoV-2), etc., and the prognosis of these diseases can be improved. [Modes for Carrying Out the Invention]

[0011] The active ingredient of the agent for improving the neutrophil / lymphocyte ratio in blood and the food composition for improving the neutrophil / lymphocyte ratio in blood of the present invention is curcumins. Examples of the curcumins include one or more selected from curcumin, curcumin derivatives, and conjugates thereof with water-soluble substances.

[0012] Curcumin is the main component of curcuminoids contained in turmeric pigment and is a compound represented by the following structural formula (1).

[0013] [Chemical Formula]

[0014] Examples of curcumin derivatives include bisdemethoxycurcumin, demethoxycurcumin, and tetrahydrocurcumin. In the present invention, curcumin may be chemically synthesized curcumin or commercially available curcumin pigment. Examples of curcumin pigment include turmeric powder obtained by powdering the dried rhizome of turmeric (Curcuma longa LINNE) of the Zingiberaceae family, crude curcumin or oleoresin (turmeric oleoresin) obtained by extracting the turmeric powder with a suitable solvent (e.g., ethanol, oils and fats, propylene glycol, hexane, acetone, etc.), and purified curcumin. Curcumin contains both tautomers, the keto and enol forms.

[0015] In the conjugate of curcumin or a curcumin derivative of the present invention with a water-soluble substance, the water-soluble substance can be one or more selected from glucuronic acid, sulfate, glutathione, and amino acids. Examples of amino acids include those present in living organisms, such as essential amino acids. For example, a conjugate of curcumin with a water-soluble substance can maintain a high blood concentration of free curcumin. This allows for the full utilization of the pharmacological effects of curcumin. Furthermore, since the conjugate of curcumin with a water-soluble substance is a metabolite of curcumin in the body, it is highly safe and therefore preferable. The molar ratio of curcumin to the water-soluble substance is preferably curcumin:water-soluble substance = 1:1 to 1:3, more preferably 1:1 to 1:2, and even more preferably 1:1.

[0016] The conjugation form (binding form) of curcumin and the water-soluble substance is, for example, the form shown in formula (2).

[0017] [ka]

[0018] (In the formula, R 1 and R 2 At least one of them is a residue of the water-soluble substance, and the remainder is a hydrogen atom.

[0019] In equation (2) above, R 1 and R 2 One or both of these are preferably glucuronic acid residues or sulfate residues, and the remainder is preferably a hydrogen atom. In particular, R 1 R is a glucuronic acid residue 2 Curcumin monoglucuronide, in which the atom is a hydrogen atom, is more preferable. A conjugate of curcumin and a water-soluble substance can be produced by the method described in publication WO2018 / 003857.

[0020] As shown in the examples below, the curcumins have the effect of strongly lowering the neutrophil / lymphocyte ratio in the blood. Therefore, the neutrophil / lymphocyte ratio lowering agent and the food composition for lowering the neutrophil / lymphocyte ratio in the blood, which contain the curcumins, have the effect of improving the prognosis of diseases with a high neutrophil / lymphocyte ratio in the blood. Diseases for which the prognosis is likely to improve include allergic diseases such as asthma and atopic dermatitis, autoimmune diseases such as rheumatoid arthritis, arteriosclerosis, cardiovascular diseases, heart failure, kidney disease, Alzheimer's disease, as well as severe infections such as sepsis and pneumonia, rheumatic fever, malignant tumors, chronic myeloproliferative leukemia, polycythemia vera, essential thrombocythemia, myelofibrosis, and viral infections such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19 (SARS-CoV-2). Furthermore, curcumin derivatives are already widely used as functional foods, and their high level of safety has been confirmed.

[0021] The curcumin content in the agent and composition of the present invention cannot be determined in general terms, but for example, 1 to 100% by mass is preferred, 5 to 100% by mass is more preferred, and 10 to 100% by mass is even more preferred.

[0022] The administration route of the neutrophil / lymphocyte ratio-lowering agent in the blood of the present invention can be selected from systemic and local administration, as well as from oral and parenteral routes, depending on the disease, symptoms, etc. Depending on the method and route of administration, a suitable dosage form can be selected, such as oral administration in the form of tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration in the form of injections (e.g., intravenous injection, intramuscular injection, etc.), suppositories, transdermal preparations, nasal preparations, inhalations, etc.

[0023] The oral formulations according to the present invention may be solid formulations such as tablets, capsules, powders, or granules. Such formulations are manufactured by conventional methods by mixing one or more active substances with inert excipients, lubricants, disintegrants, or solubilizers. Excipients may include, for example, lactose, cellulose, mannitol, or glucose. The lubricant may be, for example, magnesium stearate. The disintegrant may be, for example, sodium carboxymethyl starch. The tablets or pills may be coated with a sugar coating or a gastric-soluble or enteric coating agent as needed.

[0024] Therapeutic agents for oral administration may be liquid formulations such as pharmacologically acceptable extracts, emulsions, solutions, suspensions, syrups, alcoholic preparations, or elixirs. Such formulations may contain commonly used inert solvents (e.g., purified water, ethanol, etc.) and may further contain solubilizers, wetting agents, suspending agents, sweeteners, flavoring agents, fragrances, buffering agents (e.g., sodium citrate, etc.), stabilizers, or preservatives.

[0025] Therapeutic agents for parenteral administration may include sterile aqueous or non-aqueous solutions, suspensions, or emulsions, as well as injectable preparations, ointments, lotions, sublingual preparations, oral patches, aerosols, or suppositories for intranasal administration. In the case of injectable preparations, they can be administered not only by normal intravenous or intra-arterial administration, but also by injection into the joint, subcutaneously, intradermally, or intramuscularly. Aqueous solvents for injectable preparations may be, for example, distilled water or physiological saline. Non-aqueous solvents for injectable preparations may be, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, or polysorbate 80 (pharmacopoeia name). Such preparations may further contain isotonic agents (e.g., sodium chloride, glucose, etc.), preservatives, wetting agents, emulsifiers, dispersants, stabilizers, pH adjusters (e.g., sodium citrate, sodium acetate, sodium phosphate, etc.), buffers, local anesthetics (e.g., procaine hydrochloride, lidocaine hydrochloride, etc.) or solubilizers. These formulations can be sterilized, for example, by filtration using a bacterial retention filter, incorporation of a bactericide, or irradiation. Alternatively, compositions obtained by dissolving or suspending a sterile solid composition in sterile water or an injectable solvent before use can also be used as these formulations. These formulations can be manufactured by known methods commonly used in the formulation process.

[0026] The food composition for reducing the neutrophil / lymphocyte ratio in the blood according to the present invention can take the form of tablets, pills, capsules, granules, powders, liquids (including drinks), etc. These forms can be manufactured in the same manner as the oral formulation described above.

[0027] The dosage of the blood neutrophil / lymphocyte ratio-reducing agent or food composition for reducing the blood neutrophil / lymphocyte ratio of the present invention is not particularly limited, but 10 mg to 10 g of curcumin per day is preferred for adults, and 30 mg to 10 g is more preferred. [Examples]

[0028] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0029] Example 1 Twenty men and women aged 60 and over were administered curcumin-containing capsules (each capsule containing 90 mg of curcumin) twice a day, in the morning and evening, for four weeks (daily dose of 180 mg). Venous blood was collected at the start and end of administration, and the neutrophil / lymphocyte ratio was measured. As a result, a non-parametric test (Wilcoxon signed-rank test) showed that the neutrophil / lymphocyte ratio at the start of administration was 1.7 (1.3, 2.1), while the neutrophil / lymphocyte ratio at the end of administration was 1.4 (1.2, 1.7). This represents a statistically significant decrease at a significance level of 0.02%.

Claims

1. A neutrophil / lymphocyte ratio-lowering agent in human blood, containing curcumin as the sole active ingredient, for oral administration of 30 mg to 10 g of curcumin per day to adults.

2. A food composition containing only curcumin as the active ingredient, intended for oral intake of 30 mg to 10 g of curcumin per day for adults, for the purpose of lowering the neutrophil / lymphocyte ratio in human blood.

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