KR101844816B1 - Composition For Improving Or Treating Anorexia Including Guanabenz And Method Using Thereof - Google Patents
Composition For Improving Or Treating Anorexia Including Guanabenz And Method Using Thereof Download PDFInfo
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- KR101844816B1 KR101844816B1 KR1020170025703A KR20170025703A KR101844816B1 KR 101844816 B1 KR101844816 B1 KR 101844816B1 KR 1020170025703 A KR1020170025703 A KR 1020170025703A KR 20170025703 A KR20170025703 A KR 20170025703A KR 101844816 B1 KR101844816 B1 KR 101844816B1
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- guanabenz
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- treating anorexia
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
Abstract
Description
본 발명은 구아나벤즈를 포함하는 식욕부진증의 개선 또는 치료용 조성물 및 이를 이용한 방법에 관련된다. The present invention relates to a composition for improving or treating anorexia nervosa comprising a guanabenz and a method using the same.
최근 식욕부진에 시달리는 고령인구, 암환자가 급속히 증가하면서 이들의 식욕을 높여주는 식욕증진제가 주목을 받고 있다. 식욕부진은 노화, 만성 또는 급성 질환, 신경성 무식욕증 등 다양한 원인에 기인할 수 있는 증상이다. In recent years, an aging population suffering from anorexia, and appetite boosters that increase their appetite with the rapid increase of cancer patients are attracting attention. Anorexia is a symptom that can be caused by various causes such as aging, chronic or acute disease, and anorexia nervosa.
노화는 종종 식욕 부진, 체중 유지 곤란, 특히 몸무게 감소로 특징지어지는 영양 및 대사 감퇴를 수반한다. 그러므로 많은 나이든 사람들이 식사 장애 또는 영양장애를 앓게 된다. Aging often involves anorexia, difficulty in maintaining weight, and nutrition and metabolic decline, especially characterized by weight loss. Therefore, many older people will suffer from eating disorders or malnutrition.
만성 질환 환자 및 급성 상태나 질병을 앓는 환자에게는 그 질병이나 상태 또는 이의 치료에 기인한 식욕 부진이 있을 수 있다. 예를 들어 암 화학요법을 받는 환자, AIDS 등에 기인한 면역타협(免疫妥協) 환자, 또는 기관 이식 등에 기인한 면역억제 환자 등이 공통적으로 식욕 감퇴를 경험한다. 또한, 수술후의 환자도 식욕 감퇴를 경험할 수 있다.Patients with chronic diseases and patients with acute conditions or diseases may have anorexia due to the disease or condition or treatment thereof. For example, patients receiving cancer chemotherapy, immunocompromised patients due to AIDS, or immunosuppressed patients due to organ transplantation experience common appetite loss. In addition, the postoperative patient may experience loss of appetite.
신경성 무식욕증 (또는 신경성 식욕결핍, 거식(拒食))은 척루(脊瘻, emaciation)에 대한 특징적 열망 및 비정상적인 식사 거동 등의 정신병성 증상뿐 아니라 표준 체중의 20 % 이상의 체중 감량 및 무월경(無月經) (여성의 경우) 등의 신체 증상을 보이는 질병이다.Neurogenic anorexia (or anorexia nervosa, anorexia nervosa) is associated with psychotic symptoms such as characteristic aspiration and abnormal eating behavior of the spinal column and emaciation, as well as weight loss and amenorrhea (In the case of women).
암환자 식욕부진 개선제의 예로서, 메게이스는 미국 BMS사에서 1971년 자궁내막암, 유방암 치료제로 개발했는데 임상 과정에서 식욕 개선과 체중 증가 효과가 입증되면서 암 환자의 식욕 개선 치료제로 사용되고 있다. 그러나 장기간 복용 시 부신 기능 저하, 혈전증, 지방 증가 등의 부작용이 나타날 수 있다. 특히 가임기 여성이나 임신 중인 여성의 경우 이를 복용하면 기형아 출산의 우려도 있다.As an example of a cancer patient anorexia suppressant, Megase was developed by BMS in the US in 1971 as a treatment for endometrial cancer and breast cancer, and has been used as an appetite remedy for cancer patients as it has been shown to improve appetite and gain weight in clinical practice. However, long-term adverse effects such as adrenal insufficiency, thrombosis, and fat increase may occur. Especially in the case of women who are pregnant or pregnant, there is a concern about birth defects if they are taken.
이와 같이 식욕부진증의 치료에 유용하다고 당업계에 공지되어 있는 화합물은 매우 적을 뿐만 아니라 많은 부작용이 초래되므로 식욕부진 개선을 위한 새로운 물질에 대한 연구가 필요하다.As described above, compounds known to be useful in the treatment of anorexia nervosa are very few, and many side effects are caused. Accordingly, researches on new substances for improving anorexia are needed.
본 발명은 식욕부진증의 개선 또는 치료용 조성물 및 식욕촉진제를 제공하고자 한다. 또한, 본 발명은 식욕부진증의 개선 또는 치료 방법을 제공하고자 한다.The present invention is intended to provide a composition for improving or treating anorexia and an appetite stimulating agent. The present invention also provides a method for improving or treating anorexia nervosa.
본 발명의 일 구현 예는 유효량의 구아나벤즈를 포함하는 식욕부진증의 개선 또는 치료용 조성물을 제공한다. One embodiment of the present invention provides a composition for improving or treating anorexia nervosa comprising an effective amount of guanabenz.
상기 조성물은 혈관내 주입될 수 있다. 또한, 상기 조성물의 주입은 시상하부의 신경세포의 활성을 증가시킬 수 있다. The composition may be injected intravascularly. In addition, the injection of the composition may increase the activity of hypothalamic neurons.
본 발명의 다른 구현 예는 유효량의 구아나벤즈를 포함하는 식욕촉진제를 제공한다. Another embodiment of the present invention provides an appetite stimulant comprising an effective amount of a guanabenz.
또한, 본 발명의 또 다른 구현 예는 유효량의 구아나벤즈를 포함하는 조성물을 인간을 제외한 개체에 투여하는 단계를 포함하는, 식욕부진증의 개선 또는 치료 방법을 제공한다. Yet another embodiment of the present invention provides a method of improving or treating anorexia, comprising administering to a subject other than human a composition comprising an effective amount of a guanabenz.
상기 구아나벤즈를 포함하는 조성물은 혈관내 주입될 수 있으며, 상기 구아나벤즈를 포함하는 조성물의 주입은 개체의 시상하부의 신경세포의 활성을 증가시킬 수 있다.The composition comprising the guanabenz may be injected intravascularly, and the injection of the composition containing the guanabenz may increase the activity of the hypothalamic neurons of the individual.
본 발명의 식욕부진증의 개선 또는 치료용 조성물은 구아나벤즈를 포함함으로써 식욕부진증을 효율적으로 개선하거나 치료할 수 있다.The composition for improving or treating anorexia of the present invention can efficiently improve or treat anorexia by including guanabenz.
도 1은 실시예 1 및 비교예 1의 식품 섭취량 및 체중 변화 측정 결과를 도시한다.
도 2는 비교예 1-3의 식품 섭취량 및 체중 변화 측정 결과를 도시한다.
도 3은 실시예 1 및 비교예 1의 시상하부 신경세포 활성의 측정 결과를 도시한다.Fig. 1 shows the results of measurement of food intake and weight change in Example 1 and Comparative Example 1. Fig.
2 shows the results of measurement of food intake and weight change of Comparative Example 1-3.
Fig. 3 shows the results of measurement of hypothalamic neuronal activity of Example 1 and Comparative Example 1. Fig.
종래의 식욕부진증 치료제는 장기간 복용 시 부신 기능 저하, 혈전증, 지방 증가 등의 부작용을 가지고 있다. 따라서 본 발명의 발명자는 좀 더 안전하고 효과적인 식욕부진증 치료제에 대하여 연구하던 중 종래 고혈압치료제로서 알려져 있던 구아나벤즈의 새로운 효능으로서 식욕촉진 효능이 있음을 확인하고 본 발명을 완성하였다.Conventional treatments for anorexia nervosa have side effects such as adrenal insufficiency, thrombosis, and fat increase when taken over a long period of time. Accordingly, the inventor of the present invention confirmed that the new potency of guanabenz, which has been known as a therapeutic agent for hypertension, has an appetite-promoting effect while studying a more safe and effective treatment for anorexia nervosa, and completed the present invention.
구아나벤즈는 다음의 화학식을 갖는 화합물로 알파 2-아드레날린성 수용체 작용제의 일종이다.Guanabenz is a compound having the following formula and is a class of alpha 2-adrenergic receptor agonists.
또한, 구아나벤즈는 고혈압치료제로서 일반적으로 알려져 있었다. 그러나, 구아나벤즈와 관련하여 식욕 조절 기능을 개시하고 있는 문헌은 없다. 이에, 본 발명에서는 일 구현 예로서 구아나벤즈를 포함하는 식욕부진증의 개선 또는 치료를 위한 조성물을 제공한다.In addition, guanabenz has been generally known as a therapeutic agent for hypertension. However, there is no document disclosing an appetite control function with regard to guanabenz. Accordingly, the present invention provides a composition for improving or treating anorexia nervosa comprising guanabenz as an embodiment.
상기 식욕부진증의 개선 또는 치료용 조성물은 약학 조성물 또는 식욕촉진제로서 제공될 수 있다.The composition for improving or treating anorexia can be provided as a pharmaceutical composition or an appetite stimulating agent.
상기 약학 조성물은 담체, 부형제, 붕해제, 감미제, 피복제, 팽창제, 윤활제, 활택제, 향미제, 항산화제, 완충액, 정균제, 희석제, 분산제, 계면활성제, 결합제 및 윤활제로 이루어진 군에서 선택되는 하나 이상의 보조제를 추가로 포함할 수 있다. 구체적으로 담체, 부형제 및 희석제는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 사용할 수 있다.The pharmaceutical composition may be selected from the group consisting of carriers, excipients, disintegrants, sweeteners, coating agents, swelling agents, lubricants, lubricants, flavors, antioxidants, buffers, bacteriostats, diluents, dispersants, surfactants, The above-mentioned adjuvant may be further included. Specific examples of carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
본 발명에 따른 약학 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.The pharmaceutical composition according to the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method .
제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제할 수 있다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, Lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of suppository bases include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like.
본 발명에 따른 식욕부진증 개선 또는 치료 조성물의 유효성분인 구아나벤즈의 사용량은 환자의 나이, 성별, 체중, 질환에 따라 달라질 수 있으나, 0.001 내지 100mg/kg으로, 바람직하게는 0.01 내지 10mg/kg을 일일 1회 내지 수회 투여할 수 있다. The amount of guanabenz which is an active ingredient of the composition for the treatment or amelioration of anorexia nervosa according to the present invention may vary depending on the age, sex, weight and disease of the patient, but is preferably 0.001 to 100 mg / kg, preferably 0.01 to 10 mg / kg May be administered once to several times per day.
또한, 본 발명에 따른 구아나벤즈를 포함하는 식욕부진증 개선 또는 치료 조성물의 투여량은 투여경로, 질병의 정도, 성별, 체중, 나이 등에 따라서 증감될 수 있다. 따라서, 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.In addition, the dose of the composition for improving or treating anorexia nervosa containing guanabenz according to the present invention may be increased or decreased depending on the route of administration, degree of disease, sex, weight, age, and the like. Thus, the dosage amounts are not intended to limit the scope of the invention in any manner.
상기 식욕부진증 개선 또는 치료 조성물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 기관지 내 흡입, 자궁 내 경막 또는 뇌혈관내(intracerebroventricular) 주사에 의해 투여될 수 있다. 본 발명의 식욕부진증 개선 또는 치료 조성물을 적정량 혈액 내 투여할 경우 경구투여에 비해 효과적으로 식욕이 개선이 이루어질 수 있다.The composition for the amelioration or treatment of anorexia nervosa may be administered to mammals such as rats, mice, livestock, humans, and the like in a variety of routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intratracheal, intrauterine or intracerebroventricular injections. When the composition for ameliorating or treating anorexia of the present invention is administered in an appropriate amount of blood, the appetite can be effectively improved as compared with oral administration.
또한, 식욕부진증은 암 또는 종양의 화학요법에 따른 식욕부진을 포함할 수 있으며, 따라서 본 발명의 조성물은 공지된 항암제와 병용될 수 있다. 공지된 항암제는 파클리탁셀(paclitaxel), 도세탁셀(docetaxel), 빈크리스틴(vincristine), 빈블라스틴(vinblastine), 빈노렐(vinorelbin), 다우노마이신(daunomycin), 독소루비신(doxorubicin), 토포테칸(topotecan), 이리노테칸(irinotecan), 악티노마이신(actinomycin) 및 에토포시드(etopocid)로 이루어진 군으로부터 선택되는 하나 이상일 수 있다. In addition, anorexia may include anorexia due to chemotherapy of cancer or tumor, and thus the composition of the present invention may be used in combination with known anti-cancer agents. Known anticancer agents include paclitaxel, docetaxel, vincristine, vinblastine, vinorelbin, daunomycin, doxorubicin, topotecan, , Irinotecan, actinomycin, and etopocid. The term " pharmaceutically acceptable carrier "
본 발명의 다른 구현 예는 유효량의 구아나벤즈를 포함하는 식욕촉진제를 제공한다. 이는 분말, 과립, 정제, 캡슐, 시럽 또는 음료의 형태로 제공될 수 있으며, 상기 식욕촉진제는 유효량의 구아나벤즈 이외에 다른 식품 또는 식품 첨가물과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적 예를 들어 예방, 건강 또는 치료적 처치에 따라 적합하게 결정될 수 있다.Another embodiment of the present invention provides an appetite stimulant comprising an effective amount of a guanabenz. It may be provided in the form of a powder, granules, tablets, capsules, syrups or beverages. The appetite stimulant may be used with other food or food additives in addition to an effective amount of guanabenz, and may be suitably used according to conventional methods. The amount of the active ingredient to be mixed can be suitably determined according to its use purpose, for example, prevention, health or therapeutic treatment.
상기 식욕촉진제에 함유된 구아나벤즈의 유효용량은 상기 약학 조성물의 유효용량에 준해서 사용할 수 있으나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로도 사용될 수 있음은 분명하다.The effective dose of guanabenz contained in the appetite stimulating agent may be used in accordance with the effective dose of the pharmaceutical composition, but may be less than the above range for health and hygiene purposes or for long-term intake for health control purposes. And it is clear that the active ingredient can be used in an amount exceeding the above range because there is no problem in terms of safety.
상기 식욕촉진제의 종류에는 특별한 제한이 없고, 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등을 들 수 있다.There is no particular limitation on the type of the appetite stimulating agent and examples thereof include meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, Drinks, alcoholic beverages and vitamin complexes.
본 발명의 또 다른 구현 예는 유효량의 구아나벤즈를 포함하는 조성물을 개체에 투여하는 단계를 포함하는, 식욕부진증의 개선 또는 치료 방법을 제공한다. 상기 구아나벤즈를 포함하는 조성물은 혈관내 주입될 수 있으며, 그 사용량 및 횟수 등은 앞에서 언급한 바와 동일하다. Another embodiment of the present invention provides a method of improving or treating anorexia, comprising administering to a subject a composition comprising an effective amount of a guanabenz. The composition containing the guanabenz may be injected intravascularly, and the amount and the number of times of use thereof are the same as those mentioned above.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.
준비예Preparation Example
1.1. 혈관 내 캐뉼라(cannulae)를 위한 정위수술법(Stereotaxic surgery)1.1. Stereotaxic surgery for cannulae
동물들은 트리브로모에탄올(tribromoethanol, 250 mg/kg, Sigma-Aldrich, ST. Louis, MO, USA)을 IP 주입하여 마취시키고, 뇌(정위)고정 장치(stereotaxic apparatus, Stoelting, Wood Dale, IL, USA)에 넣었다. 캐뉼라(26게이지)의 우측 뇌실 내로 주입하고(1.0mm 측면, 0.3mm 후방 그리고 2.4mm 복부(ventral)부터 정수리(bregam)까지), 치과용 시멘트로 두개골에 고정하였다. 동물들이 마취에서 회복한 후 따뜻한 온도를 유지시켜 주고, 개별 케이지에 놓았다. 수술 후 실험 전까지 약 7일간 회복기간을 주었다.Animals were anesthetized by IP injection of tribromoethanol (250 mg / kg, Sigma-Aldrich, St. Louis, Mo., USA) and injected into a stereotaxic apparatus (Stoelting, Wood Dale, IL, USA). Were injected into the right ventricle of the cannula (26 gauge) (1.0 mm lateral, 0.3 mm posterior and 2.4 mm ventral to bregam) and secured to the skull with dental cement. After the animals recovered from the anesthesia, they maintained a warm temperature and placed them in individual cages. After the operation, the patient was allowed to recover for about 7 days before the experiment.
1.2. 시험물질의 주입1.2. Injection of test material
구아나벤즈 100 ng/2.5 ㎕ 으로 멸균 생리 식염수에 용해시켜 실시예 1의 시험물질을 준비하고, 이를 캐뉼라를 통해 뇌 실내(icv, 100 ng/mice)에 주입하였다. The test material of Example 1 was prepared by dissolving 100 ng / 2.5 구 of guanabenz in sterile physiological saline and injected into the brain (icv, 100 ng / mice) through a cannula.
비교예 1로는 0.9% 식염수를 사용한다. 또한, 상기 구아나벤즈 대신 클로니딘(Clonidine) 및 덱스메데토미딘(Dexmedetomidine)을 각각 사용하여 비교예 2 및 3의 시험물질을 제조한 후 위와 동일한 방식으로 뇌 실내에 주입하였다.As Comparative Example 1, 0.9% saline solution was used. The test materials of Comparative Examples 2 and 3 were prepared using Clonidine and Dexmedetomidine instead of the guanabenz, respectively, and then injected into the brain room in the same manner as above.
시험예Test Example
2.1. 식품 섭취량 및 체중 변화 측정2.1. Measurement of food intake and weight change
실시예 1, 비교예 1-3의 시험물질 투여 후, 식품 섭취량과 체중의 변화를 매시간마다 직접 저울로 측정하였다. 실시예 1과 비교예 1을 비교한 결과를 도 1에 나타내며, 비교예 1 내지 3을 비교한 결과를 도 2에 나타낸다. 데이터는 mean ± SEM(CTL n=3, Clonidine n=3, Dexmeteromidine n=4)으로 대표된다.After the administration of the test materials of Example 1 and Comparative Example 1-3, changes in food intake and body weight were measured directly with an hourly scale. The results of comparison between Example 1 and Comparative Example 1 are shown in Fig. 1, and the results of comparison of Comparative Examples 1 to 3 are shown in Fig. Data are represented as mean ± SEM (CTL n = 3, Clonidine n = 3, Dexmeteromidine n = 4).
도 1을 참고하면, 식품 섭취량 및 체중이 구아나벤즈를 투여한 군에서 매우 증가된 것을 확인할 수 있다.Referring to FIG. 1, it can be seen that the food intake and body weight were greatly increased in the group administered with guanabenz.
도 2를 참고하면, 알파 2-아드레날린성 수용체 작용제의 일종인 클로니딘 및 덱스메데토미딘의 경우 0.9% 식염수를 사용한 비교예 1과 비교하여 식품 섭취량 및 체중의 변화에 있어 큰 차이가 없으며 오히려 섭취량 및 체중이 저하된 것을 확인할 수 있다. 따라서, 알파 2-아드레날린성 수용체 작용제가 모두 구아나벤즈와 같은 식욕촉진 효과를 나타내지 않음을 확인할 수 있다.2, there is no significant difference in the changes in food intake and body weight compared to Comparative Example 1 using 0.9% saline in the case of clonidine and dexmedetomidine, one of the alpha 2-adrenergic receptor agonists, It can be confirmed that the weight is decreased. Thus, it can be seen that both alpha 2 -adrenergic receptor agonists do not exhibit appetite stimulating effects like guanabenz.
2.2. 시상하부 신경세포 활성2.2. Hypothalamic neuron activity
면역조직화학법으로 c-fos를 측정한 결과를 도 3에 도시한다. 그 구체적인 과정은 다음과 같다.The results of measurement of c-fos by immunohistochemistry are shown in Fig. The concrete procedure is as follows.
마우스는 triboromoethanol을 이용하여 깊게 마취시킨 후(250 mg/kg, Sigma-Aldrich, ST. Louis, MO, USA), 경심관류로(transcardially) 인산 완충액(phosphate buffer, PB, 0.1M, pH 7.4)의 신선한 고정액4% 파라포름알데하이드(paraformaldehyde)를 관류시킨 후, 차가운 0.9% 식염수(saline)에 포함된 헤파린(heparin, 10 mg/L)을 관류시켰다.The mice were anesthetized with triboromoethanol (250 mg / kg, Sigma-Aldrich, St. Louis, Mo., USA) and transcardially transfected with phosphate buffer (PB, 0.1M, pH 7.4) Fresh perfusion solution 4% paraformaldehyde was perfused, and heparin (10 mg / L) contained in cold 0.9% saline was perfused.
뇌는 절개한 후 상기 고정액으로 하룻밤 동안 고정하였다. 그런 후 차가운 PB(0.1M)에 여러번 세척하고, 바이브라톰(vibratome, VT1000P; Leica Microsystems, Wetzlar, Germany)을 이용하여 시상하부의 ARC(arcuate hypothalamic nuclei)를 포함하여 절단하였다.The brain was incised and fixed with the fixative overnight. The cells were then washed several times in cold PB (0.1 M) and digested with the hypothalamic ARC (arcuate hypothalamic nuclei) using a vibratome (VT1000P; Leica Microsystems, Wetzlar, Germany).
50 μm 두께의 관상 뇌 섹션(coronal brain sections)은 PB로 여러번 세척하고 내인성 퍼옥시다아제(endogenous peroxidase)의 활성을 차단하기 위하여 1% 과산화수소(H2O2)를 포함한 PB에 넣고 암실에서 20분간 배양하였다.Coronal brain sections of 50 μm thickness were washed several times with PB and placed in PB containing 1% hydrogen peroxide (H 2 O 2 ) to block the activity of endogenous peroxidase and incubated for 20 min in the dark Respectively.
PB로 수차례 세척한 후, 0.2% 트립톤(Triton) X-100이 포함된 PB에 넣고 30분간 사전 배양하였다. PB로 워싱한 후, 섹션과 일차 항체(primary antibody)를 쉐이커에 넣고 15시간, 4℃에서 반응시켰다. PB로 워싱한 후, 섹션과 이차 항체(secondary antibody)를 쉐이커에 넣고 2시간 동안 실온에서 반응시켰다.PB, and then pre-incubated for 30 minutes in PB containing 0.2% Triton X-100. After washing with PB, sections and primary antibody were added to the shaker and allowed to react for 15 hours at 4 ° C. After washing with PB, the section and secondary antibody were added to the shaker and reacted at room temperature for 2 hours.
도 3에서 구아나벤즈를 주입한 경우 시상하부 궁상핵의 신경세포의 활성이 증가되는 것을 확인할 수 있다. 일반적으로 시상하부는 신체 에너지 항상성 조절에 중추적인 역할을 수행하며, 섭식 행동 및 에너지 소비 등을 조절하여 에너지 균형을 유지한다. 본 발명에서는 유효량의 구아나벤즈가 시상하부에 작용함으로써 식욕증가 및 체중증가에 영향을 미치는 것으로 예상된다.In FIG. 3, when the guanabenz was injected, the activity of neurons in the hypothalamic-arch nucleus was increased. In general, the hypothalamus plays a pivotal role in regulating body energy homeostasis and maintains energy balance by controlling eating behavior and energy consumption. In the present invention, it is expected that an effective amount of guanabenz will act on the hypothalamus thereby affecting the appetite increase and weight gain.
Claims (7)
상기 조성물은 혈관내 주입되는, 식욕부진증의 개선 또는 치료용 조성물.The method according to claim 1,
A composition for improving or treating anorexia, wherein said composition is injected intravascularly.
상기 조성물의 주입은 시상하부의 신경세포의 활성을 증가시키는, 식욕부진증의 개선 또는 치료용 조성물.3. The method of claim 2,
The composition for improving or treating anorexia, wherein the injection of the composition increases the activity of nerve cells in the hypothalamus.
상기 구아나벤즈를 포함하는 조성물은 혈관내 주입되는, 식욕부진증의 개선 또는 치료 방법.6. The method of claim 5,
Wherein the composition comprising the guanabenz is injected intravascularly.
상기 구아나벤즈를 포함하는 조성물의 주입은 개체의 시상하부의 신경세포의 활성을 증가시키는, 식욕부진증의 개선 또는 치료 방법.The method according to claim 6,
Wherein the injection of the composition comprising the guanabenz increases the activity of the hypothalamic neurons of the individual.
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