Use of chemokine receptor 2 antagonist in preparation of treatment of anxiety disorders associated with diabetes

Abstract

A use of a CCR2 antagonist, in particular, relating to the use of one or a combination of the following compounds or a pharmaceutically acceptable salt thereof in the preparation of treatment of anxiety disorders associated with diabetes.

Description

Application of chemokine receptor 2 antagonist in the preparation of treatment for diabetes-related anxiety disorder Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to the application of chemokine receptor 2 antagonists in the preparation of drugs for treating diabetes-related anxiety disorders. Background Art

[0002] Diabetes is a major challenge to global health, and its complications have become a problem that cannot be ignored. Epidemiological studies have shown that anxiety is one of the most common complications of diabetes, threatening the quality of life of 110 million diabetic patients worldwide. Anxiety disorders associated with diabetes not only affect the patient's mental health, but may also increase the difficulty of controlling diabetes and the risk of other complications. In addition, anxiety-like behaviors have also been observed in diabetic mice (such as db / db mice). Although diabetic mice and diabetic patients have been found to increase the risk of anxiety, in clinical practice, it is difficult for most patients with diabetes-associated anxiety to obtain effective treatment. Drugs generally selected for the treatment of anxiety disorders include selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and benzodiazepines. However, these traditional anti-anxiety drugs carry the risk of weight change and the promotion of diabetic complications.

[0003] Therefore, there is a need to explore potential drugs without the risk of metabolic deterioration to treat diabetic anxiety.

[0004] Summary of the Invention

[0005] The object of the present invention is to provide a use of a CCR2 antagonist or a pharmaceutically acceptable salt thereof.

[0006] Specifically, the present invention provides the use of a CCR2 antagonist or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or alleviating or treating diabetes-related anxiety.

[0007] The first aspect of the present invention provides the use of a CCR2 antagonist or a pharmaceutically acceptable salt thereof for preparing a medicament or pharmaceutical composition for treating diabetes-related anxiety;

[0008] The CCR2 antagonists are selected from the following group:

[0009] or a combination thereof.

[0010] In another preferred embodiment, the CCR2 antagonist is selected from the following group:

[0011] or a combination thereof.

[0012] In another preferred embodiment, the treatment of anxiety disorder includes antianxiety.

[0013] In another preferred embodiment, the diabetes includes type 1 diabetes and / or type 2 diabetes.

[0014] In another preferred embodiment, the diabetes mellitus has one or more of the following characteristics:

[0015] (c1) fasting blood glucose greater than or equal to 7.0 mmol / L;

[0016] (c2) Blood glucose level is greater than or equal to 11.1 mmol / L two hours after a meal.

[0017] In another preferred embodiment, the pharmaceutical composition comprises:

[0018] (a) a first active ingredient, a CCR2 antagonist or a pharmaceutically acceptable salt thereof;

[0019] (b) a second active ingredient, an active ingredient for treating diabetes; and

[0020] (c) a pharmaceutically acceptable carrier.

[0021] In another preferred embodiment, the drug or pharmaceutical composition is an oral preparation or an injectable preparation.

[0022] In another preferred embodiment, the oral preparation is selected from the following group: capsules, tablets, powders, sprays, sustained-release preparations, oral liquids, pills, and nano preparations.

[0023] In a second aspect, the present invention provides a method for treating anxiety, comprising the steps of administering to a subject in need thereof an effective amount of a compound selected from the following group, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, thereby improving anxiety:

[0024] or a combination thereof.

[0025] In another preferred embodiment, the anxiety disorder is diabetes-related anxiety disorder.

[0026] In another preferred embodiment, the compound is selected from the following group:

[0027] or a combination thereof.

[0028] In another preferred embodiment, the pharmaceutical composition further contains a pharmaceutically acceptable carrier.

[0029] In another preferred embodiment, the drug or pharmaceutical composition is an oral preparation, an injection preparation, or a tablet.

[0030] In another preferred embodiment, the concentration of the compound of the present invention or a pharmaceutically acceptable salt thereof in the method is 0.5-20 μM, preferably 1-10 μM.

[0031] In another preferred embodiment, the subject has one or more of the following characteristics:

[0032] (c1) fasting blood glucose greater than or equal to 7.0 mmol / L;

[0033] (c2) Blood glucose level is greater than or equal to 11.1 mmol / L two hours after a meal.

[0034] In another preferred embodiment, the subject is a human or a non-human mammal (such as a mouse).

[0035] In another preferred embodiment, after administration of the compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, the blood glucose level of the subject remains substantially unchanged.

[0036] In another preferred embodiment, the administration of the compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, reduces the anxiety behavior of the subject.

[0037] In another preferred embodiment, the blood glucose level is a fasting blood glucose level.

[0038] In another preferred embodiment, the subject suffers from diabetes mellitus and anxiety disorder.

[0039] The third aspect of the present invention provides a medicine kit comprising:

[0040] (a) a first pharmaceutical composition comprising a first active ingredient for treating diabetes or a pharmaceutically acceptable carrier thereof;

[0041] (b) a second pharmaceutical composition, comprising a compound selected from the group consisting of:

[0042] or a combination thereof.

[0043] In another preferred embodiment, the medicine kit is used to treat diabetes-related anxiety.

[0044] In another preferred embodiment, the compound is selected from the following group:

[0045] or a combination thereof.

[0046] In another preferred embodiment, the medicine kit contains instructions.

[0047] In another preferred embodiment, the instructions state that the first pharmaceutical composition and the second pharmaceutical composition can be taken simultaneously or sequentially.

[0048] In another preferred embodiment, the first pharmaceutical composition comprises sulfonylurea drugs, biguanide antidiabetic drugs, α-glucosidase inhibitors, insulin sensitizers, glinide insulin secretagogues, insulin preparations, or a combination thereof.

[0049] In another preferred embodiment, the sulfonylurea drug is selected from the group consisting of tolbutamide, glibenclamide, gliclazide, glipizide, gliquidone, glimepiride, or a combination thereof.

[0050] In another preferred embodiment, the biguanide hypoglycemic drug is selected from the group consisting of phenformin, metformin, buformin, or a combination thereof.

[0051] In another preferred embodiment, the α-glucosidase inhibitor is selected from the group consisting of acarbose, voglibose, or a combination thereof.

[0052] In another preferred embodiment, the meglitinide insulin secretagogue is selected from the group consisting of repaglinide, nateglinide, or a combination thereof.

[0053] In another preferred embodiment, the insulin preparation is selected from the following group: animal insulin, human insulin, insulin analogs, or a combination thereof.

[0054] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] FIG1 shows the blood glucose levels of normal mice, diabetic model mice and diabetic model mice treated with the compound of the present invention.

[0056] Figure 2 shows the anxiety-like behavior of diabetic model mice after treatment with the compounds of the present invention using a light-dark box test. Figure 2A shows the number of times mice in different groups entered the light box, and Figure 2B shows the duration of time mice in different groups entered the light box.

[0057] Figure 3 shows the elevated plus maze test to evaluate the anxiety-like behavior of diabetic model mice after treatment with the compounds of the present invention. Figure 3A shows the movement distance of the open arms of mice in different groups, and Figure 3B shows the duration of the mice in different groups entering the open arms. DETAILED DESCRIPTION

[0058] After extensive and intensive research, the present inventors unexpectedly discovered, through extensive screening, for the first time, a class of compounds (CCR2 antagonists) that improve diabetic anxiety, or pharmaceutically acceptable salts, enantiomers, diastereomers, or racemates thereof. The present inventors discovered that the compounds of the present invention can significantly improve diabetic anxiety without increasing fasting blood glucose levels in diabetics. This is the basis for the completion of the present invention.

[0059] the term

[0060] In order to make the present invention easier to understand, certain technical and scientific terms are specifically defined below. Unless otherwise clearly defined in this article, all other technical and scientific terms used herein have the meanings generally understood by those of ordinary skill in the art to which the present invention belongs. Before describing the present invention, it should be understood that the present invention is not limited to the specific methods and experimental conditions described, because such methods and conditions can change. It should also be understood that the terms used herein are intended only to describe specific embodiments and are not intended to be restrictive, and the scope of the present invention will be limited only by the appended claims.

[0061] As used herein, the term “comprise” or variations thereof such as “include” or “comprising”, etc., is understood to include the elements or components stated but does not exclude other elements or components.

[0062] As used herein, the term "INCB3284" refers to a compound having the structure depicted by Formula (I),

[0063] As used herein, the term "BMS-813160" refers to a compound having the structure shown in formula (II),

[0064] As used herein, the term "MK-0812" refers to a compound having the structure shown in formula (III),

[0065] As used herein, the term "PF-04634817" refers to a compound having the structure shown in formula (IV),

[0066] As used herein, the term "Cenicriviroc" refers to a compound having the structure shown in Formula (V),

[0067] As used herein, "CCR2 antagonists of the present invention" include, but are not limited to, INCB3284, BMS-813160, MK-0812, PF-04634817, and Cenicriviroc.

[0068] anxiety disorders

[0069] Anxiety disorder, also known as anxiety neurosis, is the most common type of neurosis, and is characterized by the experience of anxious emotions.

[0070] Diabetes and anxiety disorder

[0071] Diabetes is a lifelong disease with no cure. Diabetics can only maintain normal circulation through oral medication or insulin injections.

[0072] Diabetes is also prone to developing complications, up to more than 100 types, making it the disease with the most known complications, such as diabetic anxiety, diabetic nephropathy, diabetic eye complications, diabetic cerebrovascular disease, diabetic neuropathy, etc.

[0073] Diabetes anxiety disorder refers to patients' worries and fears related to their long-term struggle with diabetes, including their blood sugar management, the threat of complications, potential loss of function, and concerns about receiving responsive care.

[0074] Active compounds and active ingredients of the present invention

[0075] The present invention provides an active ingredient that can effectively improve anxiety. The active ingredient is selected from the following group: a CCR2 antagonist, or a pharmaceutically acceptable salt thereof, or a combination thereof, or a crystal thereof, or a solvate thereof;

[0076] The CCR2 antagonists are selected from the following group: or a combination thereof.

[0077] As used herein, the terms "compound of the present invention", "active compound of the present invention", "active ingredient of the present invention", "medicament or pharmaceutical composition of the present invention", and "CCR2 antagonist of the present invention" are used interchangeably to refer to a CCR2 antagonist, or a pharmaceutically acceptable salt thereof, or a combination thereof, or a crystal thereof, or a solvate thereof;

[0078] The CCR2 antagonists are selected from the following group: or a combination thereof.

[0079] It should be understood that the active ingredients of the present invention include the active compounds of the present invention, or pharmaceutically acceptable salts, enantiomers, diastereomers or racemates thereof, or prodrugs thereof. It should be understood that the active ingredients of the present invention also include crystalline forms, amorphous compounds, and deuterated compounds of the active compounds of the present invention.

[0080] The "pharmaceutically acceptable salt" is a conventional non-toxic salt formed by the reaction of the pharmaceutical composition of the present invention with an inorganic acid or an organic acid. For example, conventional non-toxic salts can be prepared by reacting the active compound of the present invention with an inorganic acid or an organic acid, wherein the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid and phosphoric acid, and the organic acid includes citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid and isethionic acid, etc.; or the active compound of the present invention forms an ester with propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid or glutamic acid, and then forms a sodium salt, potassium salt, calcium salt, aluminum salt or ammonium salt with an inorganic base; or the active compound of the present invention forms an ester with lysine, arginine, or ornithine, and then forms a corresponding inorganic acid salt with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid, or a corresponding organic acid salt with formic acid, acetic acid, picric acid, methanesulfonic acid or ethanesulfonic acid.

[0081] Pharmaceutical compositions and applications

[0082] The present invention also provides the use of a CCR2 antagonist, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or an extract thereof, or a mixture of one or more of the medicinal materials thereof as an effective ingredient in the preparation of a drug for treating anxiety.

[0083] Experiments have shown that the pharmaceutical composition of the present invention can effectively improve the anxiety-like behavior of diabetic model mice.

[0084] The pharmaceutical composition provided by the present invention preferably contains a compound of the present invention in a weight ratio of 0.001-99wt%, preferably 0.01wt% to 90wt% or 0.05wt% to 50wt% of the total weight of the compound of the present invention, with the remainder being a pharmaceutically acceptable carrier, diluent or solution or saline solution.

[0085] When necessary, the drug of the present invention may further include a pharmaceutically acceptable carrier, which includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field.

[0086] The compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and can be present in suitable solid or liquid carriers or diluents and suitable sterile devices for injection or infusion.

[0087] The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit dosage of the formulation generally contains 0.05-1000 mg of the compound of the present invention, preferably 1 mg-500 mg of the compound of the present invention.

[0088] The compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, and can be administered via the oral, nasal, dermal, pulmonary, or gastrointestinal routes. Oral administration is most preferred. The most preferred daily dose is 0.01-10 mg / kg body weight, taken as a single dose, or 0.01-5 mg / kg body weight, taken in divided doses. Regardless of the route of administration, the optimal individual dose will depend on the specific treatment being used. Typically, a low dose is started and gradually increased until the most suitable dose is found.

[0089] The drugs or inhibitors of the present invention can be administered by various means, for example, by injection, spray, nasal drops, eye drops, permeation, absorption, physical or chemically mediated introduction into the body, such as intramuscularly, intradermally, subcutaneously, intravenously, or into mucosal tissues; or by being mixed with or encapsulated in other substances for introduction into the body. For ease of administration, the preferred pharmaceutical composition is a liquid composition, particularly an injectable formulation.

[0090] The main advantages of the present invention include:

[0091] (a) The compounds of the present invention can prevent the occurrence of anxiety-like behaviors without causing significant metabolic changes or increasing fasting blood glucose levels, thereby treating anxiety disorders associated with diabetes.

[0092] (b) The compound of the present invention can be prepared into a medicine for treating diabetes-related anxiety.

[0093] (c) The drug of the present invention has low toxicity and side effects and good drugability, which suggests that the compound of the present invention has a good medicinal prospect in treating anxiety associated with diabetes.

[0094] The present invention is further described below with reference to specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit its scope. Where specific experimental conditions and methods are not specified in the following examples, conventional conditions such as those described in DL Spector et al., Cell Experiment Guide, Science Press, 2001; Lv Hongsheng, Science Press, 1982, or the manufacturer's recommended conditions were generally followed.

[0095] C57 mice were purchased from Weitong Lihua Laboratory Animal Technology Co., Ltd.; the CCR2 inhibitor INCB3284 was purchased from MCE; and behavioral experimental equipment was purchased from Shanghai Xinruan Information Technology Co., Ltd. Unless otherwise stated, percentages and parts are by weight.

[0096] Example 1 Blood Glucose Levels in Normal Mice, Diabetic Model Mice, and Diabetic Model Mice Treated with INCB3284

[0097] 1.1 Method

[0098] Six-week-old C57 mice were first divided into two groups: a normal mouse group (11 mice) and a diabetic model mouse group (17 mice). The diabetic model mice were intraperitoneally injected with 60 mg / kg streptozotocin for five consecutive days, while the normal mice group received an equal dose of phosphate-buffered saline (the streptozotocin solvent) as a control. One week after the streptozotocin injection, the diabetic model mice were divided into two groups. One group received daily oral administration of 5 mg / kg INCB3284, while the other group received an equal dose of 0.5% sodium carboxymethylcellulose (the solvent for INCB3284) as a control. Simultaneously, the normal mice group also received an equal dose of 0.5% sodium carboxymethylcellulose. One week after INCB3284 administration, the three groups of mice were fasted for six hours, and their fasting blood glucose levels were measured.

[0099] The fasting blood glucose of the three groups of mice was measured by Blood glucose meter measurement.

[0100] 1.2 Results

[0101] The fasting blood glucose of diabetic mice increased by 1 times compared with that of normal mice. However, the fasting blood glucose of diabetic mice treated with INCB3284 was not significantly different from that of untreated diabetic mice (Figure 1).

[0102] The above results indicate that administration of INCB3284 does not further worsen fasting blood glucose in diabetic mice.

[0103] Example 2: Evaluation of anxiety-like behavior in diabetic model mice after INCB3284 treatment using a light-dark box test

[0104] 2.1 Methods

[0105] The light-dark box test is a widely used paradigm for measuring anxiety-related behaviors. Specifically, the apparatus consists of two boxes, one light and one dark, separated by a shuttle door. The walls of the dark box are painted black, with a removable black lid on top. Mice from different groups are placed in the covered dark box and allowed to freely enter the light box. The number of times a mouse enters the light box and the duration of these entries are counted. Each mouse is tested for 5 minutes.

[0106] 2.2 Results

[0107] The number of times diabetic model mice entered the light box was significantly reduced by about 2 times compared with the normal mouse group, which indicated an increase in anxiety-like behavior in diabetic model mice and suggested that the construction of the diabetes-related anxiety model was successful.

[0108] Compared with diabetic mice, the number of entries into the light box in diabetic model mice treated with INCB3284 increased significantly by about 1 times, indicating that anxiety-like behavior was significantly improved (Figure 2A).

[0109] The duration of light box entry in diabetic mice was significantly reduced by 2-fold compared to the normal mice group. Compared to diabetic mice, the duration of light box entry in diabetic mice treated with INCB3284 increased significantly by 1.5-fold, indicating a significant improvement in anxiety-like behavior (Figure 2B).

[0110] Example 3: Evaluation of anxiety-like behavior in diabetic model mice after INCB3284 treatment using the elevated plus maze test

[0111] 3.1 Methods

[0112] The elevated plus maze test is another widely used anxiety measurement method. The experimental apparatus is a cross-shaped maze consisting of two open arms and two closed arms. The entire apparatus is approximately 400 mm above the ground. Mice are placed at the center junction of the maze, facing the open arms. The test time for each mouse is 5 minutes. A camera placed above the maze records the distance the mouse moves in the open arms and the duration of time in the open arms, and the data are analyzed using SuperMaze software.

[0113] 3.2 Results

[0114] The distance traveled in the open arms of diabetic mice was significantly reduced by approximately 2.5-fold compared to the normal control group, indicating increased anxiety-like behaviors in diabetic mice and the successful establishment of a diabetes-related anxiety model. Compared to diabetic mice, mice treated with INCB3284 showed a significant 2-fold increase in distance traveled in the open arms, demonstrating significant improvement in anxiety-like behaviors (Figure 3A).

[0115] The duration of time spent in the open arms by diabetic mice was significantly reduced by approximately 2.5-fold compared to the control group. In diabetic mice treated with INCB3284, the duration of time spent in the open arms increased by 2-fold, indicating a significant improvement in anxiety-like behavior (Figure 3B).

[0116] Example 4 Effects of CCR2 Inhibitors on Diabetes-Complication Anxiety

[0117] 4.1 Methods

[0118] The materials and methods used in this example are the same as those in Examples 1-3, and the CCR2 antagonists used are BMS-813160, MK-0812, PF-04634817, or Cenicriviroc.

[0119] 4.2 Results

[0120] The results showed that MK-0812 and Cenicriviroc had excellent efficacy in treating diabetic anxiety, consistent with the therapeutic efficacy of INCB3284. PF-04634817 and BMS-813160 were less effective in treating diabetic anxiety.

[0121] Comparative Example

[0122] The materials and methods used in this example are the same as those in Example 1-3. The antianxiety drug used is mirtazapine (structural formula: ).

[0123] The results showed that the antianxiety drug exacerbated blood sugar and metabolic disorders in diabetic mice.

[0124] in conclusion:

[0125] The active compound of the present invention can significantly improve the anxiety-like behavior of diabetic model mice.

[0126] CCR2 can be used as a new target for the treatment of diabetic-comorbid anxiety.

[0127] discuss:

[0128] Diabetes is a lifelong, incurable disease that carries numerous complications. Diabetics can only maintain normal circulation through oral medication or insulin injections. Long-term use of diabetes medications can lead to drug resistance and safety issues. Long-term medication use can also put diabetic patients under significant psychological pressure, making them susceptible to diabetes-related anxiety, which can negatively impact their condition.

[0129] The above experiments show that the compounds of the present invention and their pharmaceutically acceptable salts can effectively improve anxiety behavior while maintaining blood sugar levels. The compounds of the present invention have low toxicity and side effects and good drugability, making them suitable for patients with diabetes and anxiety who require long-term medication.

[0130] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. Use of a CCR2 antagonist or a pharmaceutically acceptable salt thereof, characterized in that: Used for preparing a medicine or a pharmaceutical composition for treating diabetes-related anxiety; The CCR2 antagonists are selected from the following group: or a combination thereof.

2. The use according to claim 1, characterized in that The diabetes mellitus includes type 1 diabetes mellitus and / or type 2 diabetes mellitus.

3. The use according to claim 1, characterized in that The diabetes mellitus has one or more of the following characteristics: (c1) fasting blood glucose greater than or equal to 7.0mmol / L; (c2) Blood glucose level is greater than or equal to 11.1 mmol / L two hours after a meal.

4. The use according to claim 1, characterized in that The pharmaceutical composition also contains a pharmaceutically acceptable carrier.

5. The use according to claim 1, characterized in that The medicine or pharmaceutical composition is an oral preparation or an injection.

6. The use according to claim 5, characterized in that The oral preparation is selected from the following group: capsules, tablets, powders, sprays, sustained-release preparations, oral liquids, pills, and nano preparations.

7. A medicine box, characterized in that: include: (a) a first pharmaceutical composition, a first active ingredient for treating diabetes or a pharmaceutically acceptable carrier thereof; (b) a second pharmaceutical composition, a compound selected from the group consisting of: or a combination thereof.

8. The medicine box according to claim 7, characterized in that The first pharmaceutical composition and the second pharmaceutical composition may be taken simultaneously or sequentially.

9. The medicine box according to claim 7, characterized in that The first pharmaceutical composition comprises sulfonylurea drugs, biguanide hypoglycemic drugs, α-glucosidase inhibitors, insulin sensitizers, glinides, insulin secretagogues, insulin preparations, or a combination thereof.

10. The medicine box according to claim 7, characterized in that The medicine kit is used for preparing medicine for treating diabetes-related anxiety.

11. A method for treating anxiety, characterized in that: The method comprises the steps of administering an effective amount of a compound selected from the following group, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a subject in need thereof, thereby improving anxiety disorder: or a combination thereof.

12. The method according to claim 11, characterized in that The anxiety disorder is diabetes-complicated anxiety disorder.

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