KR20040060226A - Acanthopanacis Cortex - Google Patents
Acanthopanacis Cortex Download PDFInfo
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- KR20040060226A KR20040060226A KR1020020086768A KR20020086768A KR20040060226A KR 20040060226 A KR20040060226 A KR 20040060226A KR 1020020086768 A KR1020020086768 A KR 1020020086768A KR 20020086768 A KR20020086768 A KR 20020086768A KR 20040060226 A KR20040060226 A KR 20040060226A
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- South Korea
- Prior art keywords
- pain
- analgesic
- test
- formalin
- analgesic effect
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
- A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
- A61K36/254—Acanthopanax or Eleutherococcus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/035—Animal model for multifactorial diseases
- A01K2267/0356—Animal model for processes and diseases of the central nervous system, e.g. stress, learning, schizophrenia, pain, epilepsy
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Orthopedic Medicine & Surgery (AREA)
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- Zoology (AREA)
- Mycology (AREA)
- Biomedical Technology (AREA)
- Toxicology (AREA)
- Urology & Nephrology (AREA)
- Alternative & Traditional Medicine (AREA)
- Medicines Containing Plant Substances (AREA)
- Endocrinology (AREA)
- Pathology (AREA)
- Biotechnology (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Microbiology (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Diabetes (AREA)
Abstract
Description
본 발명은 행동학적 지표인 신경병리성 통증(neuropathic pain) 모델과 포르말린 테스트(formalin test))를 이용한 동물모델을 이용한 통증에 대한 오가피의 진통효과 검증방법 및 이 진통효과 검증방법을 이용하여 진통효과가 검증된 오가피를 유효성분으로 하는 오가피 진통 제제에 대한 것이다.The present invention provides a method for verifying the analgesic effect of Ogapi on pain using an animal model using a neuropathic pain model and a formalin test, which are behavioral indicators, and an analgesic effect using the analgesic effect verification method. The present invention relates to a stagnation analgesic formulation using proven stamens as an active ingredient.
통증, 특히 만성 통증(chronic pain)은 인간에게 몹시 견디기 어려운 것으로, 만성 통증을 가진 환자는 그 아픔 때문에 정상적인 생활을 영위하는데 많은 어려움을 겪게 된다. 이러한 고통에서 벗어나기 위해 환자는 통증을 호소하며 도움을 청하게 되며, 통증을 제어하고자 하는 노력이 의학계에서 끊임없이 진행되어져 왔다. 한약은 오랜 기간동안 전통한의학에서 사용되어져 통증에 대한 우수한 치료효과를 보여 왔다. 최근 여러 가지 한약재가 통증 억제에 어떠한 영향을 미치며 어떠한 작용기전에 매개되는지를 연구할 필요성이 제기되어 왔다.Pain, especially chronic pain, is extremely difficult for humans, and patients with chronic pain have a lot of difficulty in living a normal life because of the pain. In order to escape this pain, patients complain of pain and seek help, and efforts to control pain have been continuously made in the medical community. Chinese medicine has been used in traditional Chinese medicine for a long time and has shown excellent treatment effect for pain. Recently, there has been a need to study how various herbal medicines affect pain inhibition and what mechanism of action is mediated.
기존에 한약물을 이용한 진통억제효과에 대한 보고를 살펴보면, 우슬약침액은 CFA(complete Freund's adjuvant) 관절염 유발 쥐에 작용하여 염증을 억제시키고, 염증상태를 나타내는 백혈구의 총수를 유의성있게 감소시키며, 혈청내 면역 글로불린(Globulin) 및 알부민(albumin)에 작용하여 조직학적으로 근육조직의 괴사를 억제시켜 관절염으로 인한 염증에 대하여 치유 효과를 나타내는 등의 효과가 검증된 바 있었다. 또한, 포공영은 초산법을 이용하여 Writhing syndrome의 빈도를 측정한 결과 포공영의 진통효과가 유의성 있었다. 또한, 초산법과 후지가압법에 의해 갈근을 주재로 한 갈근해기탕의 진통효과가 인정되었다.Previously, the report on the analgesic inhibitory effect using herbal medicines showed that E. coli acts on CFA (complete Freund's adjuvant) arthritis-induced rats to suppress inflammation, significantly reduce the total number of inflammatory cells, and serum It has been proved that the effects on the immunoglobulin (Globulin) and albumin (albumin) to suppress the necrosis of the muscle tissue to show a healing effect on the inflammation caused by arthritis. In addition, pogongyoung showed significant analgesic effect by measuring the frequency of Writhing syndrome using acetic acid method. In addition, the analgesic effect of Galgehaegigi-tang, which is mainly composed of acquaintance, was recognized by acetic acid method and Fuji pressure method.
한편, 이전 연구에서 가시오가피의 면역강화와 항염증효과(Li XY, 1991), 그리고 항독성효과와 항스트레스약(Deyama T등, 2001)으로 쓰임이 보고 되었다.Meanwhile, previous studies have reported the use of prickly scab for immune strengthening and anti-inflammatory effects (Li XY, 1991), as well as anti-toxic effects and antistress drugs (Deyama T, 2001).
본 발명은 상기와 같은 종래기술의 필요성과 문제점을 해결하기 위한 것으로, 오가피의 유효한 진통효과를 검증하기 위해 사용되어지는 행동학적 지표인 신경병리성 통증(neuropathic pain) 모델과 포르말린 테스트(formalin test)를 이용한 동물모델을 제공하는 것을 그 목적으로 한다.The present invention is to solve the necessity and problems of the prior art as described above, the neuropathic pain model and formalin test which is a behavioral indicator that is used to verify the effective analgesic effect of Ogapi The object of the present invention is to provide a used animal model.
또한, 본 발명의 목적은, 행동학적 지표인 신경병리성 통증(neuropathic pain) 모델과 포르말린 테스트(formalin test)를 이용한 동물모델을 이용하여 오가피의 유효한 진통효과를 검증하는 것이다.It is also an object of the present invention to verify the effective analgesic effect of Ogapi using animal models using neuropathic pain model and formalin test, which are behavioral indicators.
도1a 및 도1b는 본 발명에 따른 신경병리성 통증 모델의 통증부위 사진 및 개념도.Figures 1a and 1b is a photograph of the pain area and conceptual diagram of a neuropathological pain model according to the present invention.
도2는 본 발명에 따른 오가피의 기계적 이질통 억제에 미치는 효과 그래프.Figure 2 is a graph of the effect on the mechanical allodynia suppression of agap according to the present invention.
도3은 본 발명에 따른 오가피의 냉각 이질통 억제에 미치는 효과 그래프.Figure 3 is a graph of the effect on the inhibition of cooling allodynia of ogapi according to the present invention.
도4a는 본 발명에 사용되는 포르말린 테스트 장치의 사진.Figure 4a is a photograph of the formalin test apparatus used in the present invention.
도4b 및 도4c는 포르말린 테스트에 의한 동물의 행동 사진들.4B and 4C show behavioral photographs of animals by formalin test.
도5는 본 발명에 따른 오가피의 포르말린 테스트에 따른 오가피의 통증의 억제에 미치는 효과 그래프5 is a graph showing the effect on the suppression of the pain of the organ according to the formalin test of the organ according to the present invention
본 발명의 한약제인 오가피에 대하여 간단히 살펴보면 다음과 같다. 오가피(Acanthopanacis Cortex)는 숲속에서 자라는 낙엽관목으로 우리나라 전남북, 충남북, 경기지역, 강원도지역 특히 정선, 평창, 철원등지의 산지지역에 야생분포한다. 오가피나무의 새순은 담백하면서 영양가가 높을 뿐 아니라 피로회복과 강장의 효과 및 건위, 정장작용효과까지 있는 독특한 맛과 향을 지닌 우리 몸에 유익하고 좋은 스태미나식품으로 알려져 있다.Brief description of the herbal medicine Ogapi of the present invention is as follows. Ogapi (Acanthopanacis Cortex) is a deciduous shrub that grows in the forest and is wildly distributed in the mountainous areas of Jeonnam, Chungnam, Gyeonggi, and Gangwon-do, especially Jeongseon, Pyeongchang, and Cheorwon. Cucumber sprouts are known as beneficial and good stamina foods for our bodies with a unique taste and aroma that is not only light and nutritious, but also has the effects of fatigue, tonic, health, and suitability.
실시예1Example 1
1. 신경병리성 동통 모델1. Neuropathic Pain Model
가. 개요end. summary
신경병리성 통증 증후군(neuropathic pain syndrome)은, 관절염, 근육통, 만성통과 같이 만성 통증의 하나로서 말초 신경이나 조직이 손상을 받았을 때 발생하게 된다. 신경의 손상으로 인해 유발되는 신경병리성 동통(neuropathic pain)은 매우 고통스러울 뿐만 아니라, 아편제를 비롯한 통상적인 진통제를 사용하더라도 자주 재발된다(Tanelian and Cousins, 1989; Brose and Cousins, 1991).Neuropathic pain syndrome is one of chronic pain, such as arthritis, myalgia, and chronic pain, which occurs when peripheral nerves or tissues are damaged. Neuropathic pain caused by nerve damage is very painful and frequently recurs even with conventional analgesics, including opiates (Tanelian and Cousins, 1989; Brose and Cousins, 1991).
신경병리성 동통의 증후군은 과통증(hyperalgesia), 이질통(allodynia), 자발적 동통(spontaneous pain) 등이 있다. 정상의 경우에도 통증을 유발시킬 수 있는 정도의 자극에 대해 그 이상의 과도한 통증을 유발하는 것을 "과통증"이라 하고, 정상적으로는 통증을 유발시킬 수 없을 정도의 미약한 자극에 민감하게 반응하여 통증을 유발하는 경우를 "이질통"이라 하며, 아무런 자극이 없는 경우에도 통증이 나타나는 것을 "자발적 동통"이라고 한다.Neuropathic pain syndromes include hyperalgesia, allodynia, and spontaneous pain. Even in normal cases, causing excessive pain with respect to the stimulus that can cause pain is called "pain pain", and the pain is sensitively responded to the weak stimulus that cannot normally cause pain. Induced cases are referred to as "allodynia", and pain even when there is no stimulation is called "voluntary pain".
본 발명자들중 이배환 등은 좌골신경의 말초 쪽의 분지를 손상시키는 새로운 모델(Lee et al., 2000)을 개발하였다. 좌골신경에 말초 쪽에서 접근하면 3개의 분지가 있는데, 이들 신경 분지를 여러 가지 집단으로 나누어 선택적으로 손상시켜 신경병리성 동통이 발생되는 정도를 비교한 결과, 총비골신경(common peroneal nerve)은 남겨두고, 경골신경(tibial nerve)과 비복신경(sural nerve)을 손상시킨 집단에서 가장 격심한 동통 증상이 유발되었다(Lee et al., 2000). 이러한 좌골신경 분지의 손상으로 유발된 신경병리성 동통은 손상이 일어난 후 점차 증가하다가 손상 후 2주 정도에서 최고도에 달하였다. 그 후 점차 감소하는 추세를 보였으나 수술 후 약 28주에 이르기까지 지속되었다.Among the present inventors, Lee Bae-hwan et al. Developed a new model (Lee et al., 2000) that damages the peripheral branch of the sciatic nerve. When the sciatic nerve is approached from the peripheral side, there are three branches, and these nerve branches are divided into various groups to selectively damage and compare the degree of neuropathic pain, leaving the common peroneal nerve, The most severe pain symptoms were induced in the tibial and non-sural nerves (Lee et al., 2000). The neuropathic pain caused by the injury of the sciatic nerve branch increased gradually after the injury and reached its peak at about 2 weeks after the injury. Afterwards, the trend gradually decreased, but continued until 28 weeks after surgery.
본 실시예는, 실험동물의 경골신경과 비복신경의 결찰 및 절단을 통해 신경병리성 동통증후군을 유발할 수 있는 동물모델을 만든 다음, 폰프레이 헤어(von-Frey hair)에 의한 기계적 이질통 검사와 아세톤(acetone)에 의한 냉각 이질통 검사를 실시하여 오가피의 처치가 이러한 검사에서 유효한 효과가 나타나는지를 측정하였다.In this embodiment, an animal model that can induce neuropathic pain syndrome through ligation and cleavage of the tibial and gastrocnemius nerves of an experimental animal is made, and then a mechanical allodynia test and acetone using von-Frey hair Cold allodynia testing with acetone was performed to determine whether the treatment of agarpies had an effective effect on these tests.
나. 실험내용I. Experiment Content
(1) 신경병리성 동통 모델 제작(1) Model of neuropathic pain
실험동물로는 체중 150-200 gm내외의 흰쥐를 사용한다.Rats weighing 150-200 gm are used as experimental animals.
먼저 할로세인(halothane)으로 쥐를 마취시킨 후 뒷다리 피부의 털을 깎고 포비돈 아이오다인 (povidone iodine) 용액과 이소프로필 알콜(isopropyl alcohol)로 소독한다. 피부를 절개한 후 실체 줌 현미경을 사용하여 좌골신경을 찾아 좌골신경에서 경골 신경(tibial nerve)와 비골신경(common peroneal nerve) 및 비복신경(sural nerve)를 확인한 후 마이크로포셉(microforcep)으로 주변 조직 및 혈관으로 부터 분리시킨 다음, 총비골신경(common peroneal nerve)은 남겨두고, 경골 신경(tibial nerve)와 비복신경(sural nerve)는 현미경 하에서 6.0 명주실(silk thread)로 결찰한 후 미세 수술 가위로 절단한다. 절개된 부위는 카나마이신(kanamycin)을 점적하고 피부를 봉합하여 회복한 후 다음 실험에 들어간다.First, anesthetize the rat with halotane, then shave the hair of the hind limb and disinfect with povidone iodine solution and isopropyl alcohol. After dissection of the skin, the tibial and common peroneal and non-sural nerves are identified from the sciatic nerve by sciatic nerve using a stereoscopic zoom microscope, and then the surrounding tissues with a microforcep. And from the blood vessels, leaving the common peroneal nerve, leaving the tibial and the nasal nerves with a 6.0 silk thread under a microscope, Cut. The incision site is recovered by dripping kanamycin and suturing the skin, and then enters the next experiment.
(2) 한약재의 주입(2) infusion of herbal medicine
오가피 300g을 정확히 평량한 후, 수욕상에서 80% 메탄올을 사용하여 3회 추출하였으며, 추출물을 감압 농축한 후 그 추출물을 동결건조(-66 , 10mmHg)시켜 분말 건조하였다. 건조시켜 얻은 오가피의 수득율은 9.69%이다.After 300 g of Ogapi was precisely weighed, the mixture was extracted three times using 80% methanol in a water bath, and the extract was concentrated under reduced pressure, and the extract was lyophilized (-66, 10 mmHg) and powder dried. Yield of dried Ogapi is 9.69%.
오가피는 생리식염수에 녹여 50mg/10ml/kg, 100mg/10ml/kg, 200mg/10ml/kg, 400mg/10ml/kg의 용량으로 구강내 주입하였다. 각 실험군은 약물 투여전의 pretest를 실시한 후, 약물을 투여하고 난 후 2시간 동안 시간경과에 따른 진통효과의 변화를 관찰하였다. 한편, 오가피를 투여하지 않은 실험군을 대조군으로 사용하였다.Ogapi was dissolved in physiological saline and injected orally at doses of 50 mg / 10 ml / kg, 100 mg / 10 ml / kg, 200 mg / 10 ml / kg, and 400 mg / 10 ml / kg. Each group underwent pretest before drug administration and observed changes in analgesic effect over time for 2 hours after drug administration. On the other hand, the experimental group that was not administered Ogapi was used as a control.
(3) 동통 반응의 관찰(3) Observation of pain reaction
신경병리성 동통에 관한 행동 검사는 수술전, 수술후 여러 차례에 걸쳐 시행하여 수술 후 2주 까지 관찰한다.Behavioral tests for neuropathic pain are performed several times before and after surgery and observed until 2 weeks after surgery.
외부 자극에 대한 철회반응(withdrawal response)을 보기 위해 실험 동물(rat)을 망으로 된 우리(cage)에 옮겨 안정시킨 후 실험을 진행한다.To see the withdrawal response to the external stimulus, the rats are transferred to a cage in a network and stabilized before the experiment.
자극은 폰 프레이 필라멘트(von Frey filament), 아세톤(acetone)을 사용하는데, 폰 프레이 필라멘트(von Frey filament)는 기계적 자극에 대한 이질통을 검사하기 위한 것으로서 낮은 강도에서 높은 강도로 자극하여 반응의 역치를 찾는다. 이는 수초 간격으로 좌우 발바닥에 각각 10회씩 자극하여, 발의 철회반응의 횟수를 얻어 백분율로 표시한다. 아세톤(acetone)은 온도자극에 대한 이질통을 검사하기 위한 것으로서, 양쪽 발에 5분 간격으로 각각 10회씩 주사기를 이용, 통각유발부위에 가하여 철회반응의 횟수를 센 다음 백분율을 자료로 삼는다.The stimulus uses von Frey filament, acetone, von Frey filament is used to test allodynia for mechanical stimulation. Find. It stimulates the left and right soles 10 times at intervals of several seconds, and obtains the number of retraction reactions of the foot, expressed as a percentage. Acetone is used to test allodynia for temperature stimulation. The acetone is measured 10 times at 5 minute intervals on each foot, and the number of withdrawal reactions is measured using a syringe.
(4) 실험절차(4) Experimental procedure
① 신경병리성 통증(neuropathic pain) 수술후 2주일째 되는 날 약물검사를 실시한다.① Neuropathic pain (2 weeks after surgery) The drug test is to be carried out.
② 실험동물을 여러 집단으로 나누고 약물은 구강에 주입한다. 대조군은 생리식염수 동일 용량을 주입한다.② Divide the test animal into several groups and inject the drug into the oral cavity. The control group is injected with the same dose of physiological saline.
③ 기계적 이질통(mechanical allodynia), 냉각 이질통(cold allodynia)를 검사한다.③ Inspect mechanical allodynia and cold allodynia.
다. 실험결과All. Experiment result
(1) 기계적 이질통에 대한 오가피의 효능(1) Effects of Ogapi on Mechanical Allodynia
도2는, 오가피의 기계적 이질통 억제에 미치는 효과 그래프이다.Figure 2 is a graph of the effect on the inhibition of mechanical allodynia of agar.
도2를 참조하면, 폰 프레이 필라멘트(von frey filament) 자극에 대한 기계적 이질통에 대한 한약재의 진통효과 검사에서 집단간 유의미한 차이를 보였다. 즉, LSD반복측정측정 결과, 60분에서 오가피 400mg/㎏집단과 통제군 사이에 유의미한 차이를 보여(p<0.05) 대조군보다 우수한 이질통 억제효과가 나타났다.Referring to FIG. 2, the analgesic effect test of the herbal medicine for mechanical allodynia on von frey filament stimulation showed a significant difference among the groups. In other words, the LSD repeat measurement result showed a significant difference between the control group and the 400 mg / kg Ogapi group at 60 minutes (p <0.05).
특히, 오가피 50mg/㎏ 집단과 오가피 100mg/㎏ 집단, 200mg/㎏ 집단은 대조군(controll)과 큰 차이를 보이지 않았으나, 오가피 400mg/㎏집단은 다른 집단들과 60분에서 유의미한 차이를 나타내었다. 따라서, 기계적 이질통 억제를 위해서 실험동물(쥐)의 경우, 오가피를 400mg/㎏ 이상 투여하여야 효과가 있다는 것을 알 수 있었다.In particular, the 50mg / kg group of Ogapi, 100mg / kg group of Ogapi, 200mg / kg group did not show a significant difference from the control group, but the 400mg / kg group of Ogapi showed a significant difference at 60 minutes with the other groups. Therefore, in order to suppress mechanical allodynia, it was found that in the case of experimental animals (rats), administration of more than 400 mg / kg of ogapi was effective.
(2) 냉각 이질통에 대한 한약재의 효능(2) Efficacy of Herbal Medicine on Cooling Allodynia
도3은 오가피의 냉각 이질통 억제에 미치는 효과 그래프이다.Figure 3 is a graph of the effect on the cooling allodynia suppression of Ogapi.
도3을 참조하면, 아세톤(acetone) 자극에 대한 냉각 이질통에 대한 한약재의 진통효과 검사에서 집단간 유의미한 차이는 보이지 않았다(F4,21=0.7, p>0.55).Referring to Figure 3, there was no significant difference between the groups in the analgesic effect test of the herbal medicine for cooling allodynia to acetone stimulation (F4, 21 = 0.7, p> 0.55).
즉, 오가피 50mg/㎏ 집단과 오가피 100mg/㎏ 집단, 200mg/㎏ 집단, 오가피 400mg/㎏집단 모두 대조군(controll)과 큰 차이를 보여 냉각 이질통에 오가피를 미량만 투여하더라도 효과가 있음을 알 수 있었다. 또한, 오가피의 냉각 이질통 억제는 투여하자마자 효과를 나타내었으며, 10분이 경과하여 그 효과가 더욱 뚜렸해 졌다.That is, the 50mg / kg group of Ogapi, 100mg / kg group of Ogapi, 200mg / kg group, and 400mg / kg group of Ogapi showed a big difference from the control group. . In addition, the cooling allodynia suppression of agar was effective immediately after administration, and the effect became more pronounced after 10 minutes.
실시예2Example 2
2.포르말린 테스트(formalin test) 동물모델2.Formalin test animal models
가.개요A. Overview
Tail-flick test와 hot-plate test와 같은 전통적인 통증 검사는 대부분 강한 강도의 자극을 일시적으로 제시한다. 이와 같은 방식으로 유발되는 통증 경험은 지속기간이 짧고, 따라서 자극 자체에 의해 개시되는 조절 기전을 평가하는 데에는 적절하지 못하다. 이에 비해 지속성 통증(tonic pain)은 일시적인 자극에 의해 유발되는 통증과는 다르게 조절될 수 있다. 포르말린 테스트(formalin test)는 일시적으로 제시되는 기계적 또는 온도 자극을 사용한 검사보다도 임상적인 통증을검사할 수 있는 보다 타당한 모델이라 할 수 있다(Dubuisson & Dennis, 1977; Abbott et al., 1981, 1982; Alreja et al., 1984).Traditional pain tests, such as the tail-flick test and the hot-plate test, often present strong intensity stimuli temporarily. Pain experiences triggered in this manner are of short duration and therefore not appropriate for assessing the regulatory mechanism initiated by the stimulus itself. In contrast, tonic pain may be controlled differently than pain caused by transient stimuli. The formalin test is a more plausible model for examining clinical pain than a temporary mechanical or temperature stimulus test (Dubuisson & Dennis, 1977; Abbott et al., 1981, 1982; Alreja et al., 1984).
포르말린(formalin)은 일찍이 통각 유발물질로 사용되어 왔으며(Lewis & Kellgren, 1939; Melzack & Melinkoff, 1974), 쥐에서 말초의 염증 반응을 연구하는 자극으로도 사용되어 왔다(Selye, 1949; Winter, 1965). 1977년 Dubuisson과 Dennis는 포르말린(formalin)으로 유발되는 행동을 자세히 기술함은 물론, 유발된 통증을 수량화하기 위한 방식을 개발하였으며, 이후 수많은 연구자들이 이 검사를 이용해 왔다.Formalin has long been used as a nociceptor (Lewis & Kellgren, 1939; Melzack & Melinkoff, 1974), and has been used as a stimulus to study peripheral inflammatory responses in mice (Selye, 1949; Winter, 1965). ). In 1977, Dubuisson and Dennis described a formalin-induced behavior, as well as a way to quantify the pain caused, and numerous researchers have since used the test.
포르말린(formalin)을 주입하면 통증 반응을 나타내는 두 가지 독특한 페이즈(phase)가 발생한다. 첫 번째 페이즈(phase)는 주입 직후 발생하는 것으로 약 5분간 지속되고, 두 번째 페이즈(phase)는 주입 후 약 20분후 시작한다(Dubbuisson & Dennis, 1977). 인간에게 포르말린(formalin)을 주입하면 국부적인 화끈거리는 통각, 박동통(poorly localized, burning, throbbing pain)을 야기하며, 그 시간경과(time course)는 동물에게서 나타나는 행동적 변화와 일치한다(Dubbuisson & Dennis, 1977). Hunskaar와 Hole의 연구(1987)에 의하면 첫 번째 페이즈(phase)는 포르말린(formalin)이 직접수용기에 작용하여 급성 통증(acute pain)을 야기하고, 두 번째 페이즈(phase)는 지속성 통증(tonic pain)으로서 염증성 통증을 일으키는 것으로 알려져 있다.Injecting formalin results in two distinct phases of pain response. The first phase occurs immediately after the injection, lasts about 5 minutes, and the second phase begins about 20 minutes after the injection (Dubbuisson & Dennis, 1977). Injecting formalin into humans causes localized localized burning, throbbing pain, and the time course coincides with behavioral changes in animals (Dubbuisson & Dennis, 1977). According to a study by Hunskaar and Hole (1987), the first phase is formalin acting directly on the receptor, causing acute pain, and the second phase is tonic pain. It is known to cause inflammatory pain.
이와 같이 포르말린 테스트(formalin test)는 급성 통증(acute pain)과 지속성 통증(tonic pain)을 동시에 반영하는 검사이기 때문에 어떤 약물이 급성통증(acute pain)을 감소시키는지 아니면 지속성 통증(tonic pain)을 감소시키는가를 알아보는 데에는 매우 적절한 검사법이라 할 수 있다.As such, the formalin test is a test that reflects both acute pain and tonic pain at the same time, which drug reduces acute pain or tonic pain. It's a very good test to see if you can reduce it.
예를 들면, Viana 등(2000)은 레몬그라스(Cymbopogon citratus)에서 추출한 정류(essential oil)가 포르말린 테스트(formalin test)에서 두 번째 페이즈(phase)를 선택적으로 억제함을 보고하였으며, Leal 등(2000)은 쿠마린(coumarin)을 함유하고 있는 브라질산 여러 약초들이 마찬가지로 포르말린 테스트(formalin test)의 두 번째 페이즈(phase)를 억제함을 보고하였다. 또한 Abdel-Fattah 등(2000)은 니겔라 오일(Nigella sativa oil)을 쥐의 구강으로 주입한 경우 포르말린 테스트(formalin test)에서 첫 번째 페이즈(phase)를 억제하였으며, 니겔라 오일(Nigella sativa oil)의 주성분인 티모퀴논(thymoquinone)을 구강, 복강, 뇌실을 통해 주입하였을 때에는 포르말린 테스트(formalin test)에서 첫 번째 뿐만 아니라 두 번째 페이즈(phase)도 억제됨을 보고하였다.For example, Viana et al. (2000) reported that essential oils extracted from lemongrass (Cymbopogon citratus) selectively inhibit the second phase in the formalin test, and Leal et al. (2000) ) Reported that several Brazilian herbs containing coumarin likewise inhibited the second phase of the formalin test. Abdel-Fattah et al. (2000) also inhibited the first phase in the formalin test when Nigella sativa oil was injected into the oral cavity of rats, and Nigella sativa oil. When injection of thymoquinone, the main component of, through the oral cavity, abdominal cavity, and ventricles, it was reported that the formalin test inhibited not only the first phase but also the second phase.
나. 실험내용I. Experiment Content
(1) 실험동물(1) experimental animals
체중 25-35g되는 ICR 마우스를 각 집단에 8-9마리씩 사용하였다. 동물은 한 우리에 4-5마리씩 집단으로 사육하였으며 먹이와 물은 자유로이 섭취하게 하였으며, 통증 검사 당일 최소한 2시간 전에 실험실로 데려와 검사 환경에 적응할 수 있게 하였다.ICR mice weighing 25-35 g were used in each group 8-9. Animals were housed in groups of four to five animals, free to feed and water, and taken to the laboratory at least two hours before the day of pain testing to allow for adaptation to the test environment.
(2) 약물의 주입(2) infusion of drugs
오가피는 생리식염수에 녹여 50mg/10ml/kg, 100mg/10ml/kg, 200mg/10ml/kg, 400mg/10ml/kg의 용량으로 통증 검사 30분전에 복강내 주입하였다. 약물을 쥐에게 주입하고 포르말린 테스트(formalin test)를 실시하였으며, 이를 정상 쥐(controll)를 사용한 포르말린 테스트(formalin test) 결과와 비교하였다.Ogapi was dissolved in physiological saline and injected intraperitoneally at a dose of 50 mg / 10 ml / kg, 100 mg / 10 ml / kg, 200 mg / 10 ml / kg, and 400 mg / 10 ml / kg. Drugs were injected into the mice and a formalin test was performed, which was compared with the formalin test results using normal mice.
(3) 동통 반응의 실험장치(3) Experimental apparatus of pain reaction
포르말린(formalin)으로 유발된 통증 반응을 관찰하기 위해 도4b와 같이 투명 아크릴을 이용하여 관찰 상자를 제작하였는데, 그 제원은 12 ×30 ×13cm이었다. 관찰 상자의 아래에 도4c와 같이 평면 반사경을 45도의 각도로 설치하고, 도4a와 같이 camcorder(JVC S-VHS)를 이용하여 기록하였다.In order to observe the pain response induced by formalin, a observation box was manufactured using transparent acrylic as shown in FIG. 4B, and the specification was 12 × 30 × 13 cm. A flat reflector was installed at an angle of 45 degrees below the observation box as shown in FIG. 4C, and recorded using a camcorder (JVC S-VHS) as shown in FIG. 4A.
(4) 실험절차(4) Experimental procedure
26-gauge needle이 달린 미세주사기(microsyringe)를 사용하여 쥐(mouse) 뒷발등 피하에 2% 포르말린(formalin)을 20㎕ 주사하였다. 주입 직후 쥐를 관찰 상자에 한 마리씩 넣고 통증 행동을 기록하였다. 이러한 통증 행동의 off-line 분석을 위해, 실험을 마친 뒤 기록된 통증 행동을 TV 모니터(TV monitor)를 이용하여 한 마리의 마우스 당 두 명의 평가자가 포르말린이 주입된 발이나 다리를 핥거나 깨무는 시간의 양을 5분 단위로 평가하였다.A microsyringe with a 26-gauge needle was used to inject 20 μl of 2% formalin in the subcutaneous back of the mouse. Immediately after injection, mice were placed one by one in the observation box and the pain behavior was recorded. For off-line analysis of these pain behaviors, the time after the experiment was recorded and the pain behavior was recorded on a TV monitor by two evaluators per mouse, licking or biting the foot or leg infused with formalin. The amount of was evaluated in 5 minute increments.
다. 실험결과All. Experiment result
정상동물에게 포르말린(formalin)을 주입한 결과 특징적인 페이즈1(phase 1)과 페이즈2(phase 2)의 통증 반응이 잘 관찰되었다. 이를 근간으로 오가피의 주입이 통증 반응에 미치는 영향을 비교하였는데 그 결과는 도5에 제시되어 있다. 도5는 포르말린(formalin) 주입 후 시간 경과에 따른 통증 행동의 변화 양상을 보여주고 있다.Injecting formalin into normal animals showed a characteristic pain response of phase 1 and phase 2. On the basis of this, the effect of the infusion of the stamens on the pain response was compared, and the results are shown in FIG. 5. Figure 5 shows a change in pain behavior over time after formalin injection.
페이즈1(Phase 1)은 포르말린(formalin) 주입 직후부터 10분까지의 반응을 합한 평균을, 페이즈2(phase 2)는 그 이후에 나타나는 반응의 합을 평균하여 제시한 것이다. 도5에서 볼 수 있는 바와 같이, 페이즈1(phase 1)에서는 오가피가 정상(normal or controll) 집단과 아무런 차이가 없었으나(Kruskal-Wallis One Way Analysis of Variance on Ranks, p>.05), 페이즈2(Phase 2)에서는 Kruskal-Wallis One Way ANOVA on Ranks 검증을 수행한 결과 통계적으로 유의미한 차가 있었다(p<0.05, at 15, 20, 25 min). 또한, Dunnett's test를 사용한 multiple comparison 결과, 오가피 집단은 정상 집단과 동일한 시간에 통계적으로 유의미한 차이가 있었다(p<0.05).Phase 1 is the average of the sum of the reactions from just after formalin injection to 10 minutes, and Phase 2 is the average of the sum of the reactions that occur after that. As can be seen in FIG. 5, in phase 1, the agar was no different from the normal or controll group (Kruskal-Wallis One Way Analysis of Variance on Ranks, p> .05). In Phase 2, the Kruskal-Wallis One Way ANOVA on Ranks test showed a statistically significant difference (p <0.05, at 15, 20, 25 min). In addition, as a result of multiple comparison using Dunnett's test, the Ogapi group showed a statistically significant difference at the same time as the normal group (p <0.05).
이러한 결과는 오가피가 페이즈1(phase 1)에는 별다른 효과가 없었으므로 급성 통증(acute pain)을 감소시키는 데에는 효과적이지 않지만, 페이즈2(phase 2)에서는 통증 억제 효과를 나타내므로 염증성 통증(inflammation pain)과 같은 지속성 통증(tonic pain)을 완화시키는데 효과적일 수 있다는 것을 시사한다.These results are not effective in reducing acute pain because of no significant effect on phase 1, but inflammation pain, as it has a pain inhibitory effect on phase 2. Suggests that it may be effective in alleviating tonic pain.
3. 기타3. Other
본 발명에 따르면, 오가피로부터 유효생리활성 성분을 추출 정제한 후, 이 추출 정제물을 편리한 연고제나 정제, 주사제 등의 제형으로 제제화하여 진통제로 사용할 수 있다.According to the present invention, after extracting and purifying the active physiologically active ingredient from Ogapi, the extract can be formulated into convenient formulations such as ointments, tablets, injections, etc. to be used as analgesics.
이때, 오가피의 유효량이나 제제화방법, 투여 방법들은 환자의 상태를 고려하여 통상적인 방법에 의하여 결정될 수 있다.At this time, the effective amount, formulation method, and administration method of agar can be determined by a conventional method in consideration of the condition of the patient.
이러한 오가피를 유효성분으로 하는 진통제는, 관절염, 근육통, 만성통과 같은 신경병리성 동통이나, 염증성 통증(inflammation pain)과 같은 지속성 통증(tonic pain)에 효과가 있을 것임은 상기 동물모델들을 통해 검증되었다.Analgesic using such a staphylococcus as an active ingredient has been verified through animal models that it will be effective in neuropathic pain such as arthritis, myalgia, chronic pain, or tonic pain such as inflammatory pain.
4. 참고문헌4. References
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이상과 같이 본 발명에 의하면, 오가피의 유효한 진통효과를 검증하기 위해 사용되어지는 행동학적 지표인 신경병리성 통증(neuropathic pain) 모델과 포르말린 테스트(formalin test))를 이용한 동물모델을 제공하는 효과가 있다.As described above, according to the present invention, there is an effect of providing an animal model using a neuropathic pain model and a formalin test, which are behavioral indicators used for verifying the effective analgesic effect of agapi. .
또한, 본 발명은, 행동학적 지표인 신경병리성 통증(neuropathic pain) 모델과 포르말린 테스트(formalin test))를 이용한 동물모델을 이용하여 오가피의 유효한 진통효과를 검증할 수 있는 효과가 있다.In addition, the present invention has an effect that can be used to verify the effective analgesic effect of the ogapi using an animal model using a neuropathic pain model and formalin test (behavioral indicators).
이와 같이, 본 발명은, 우수한 진통효과를 보일 것으로 추정되는 오가피를 정제하여 추출한 후, 신경병리성 통증(neuropathic pain) 모델에서 기계적 및 냉각 이질통(mechanical and cold allodynia)에 대한 억제효과와 포르말린 테스트(formalin test))에서 직접적 자극에 대한 통증 및 염증성 반응에 의한 통증에 대한 억제 효과를 검사하는 등의 최근 진행되는 통증에 대한 여러 가지 지표에 대한 검사를 실시하여, 오가피의 우수한 진통억제 효과를 발견하였다.As such, the present invention, after extracting and extracting agapi which is expected to exhibit an excellent analgesic effect, the inhibitory effect against mechanical and cold allodynia and formalin test (formalin) in the neuropathic pain model In the test), various indicators of recent pain, such as the pain of direct stimulation and the inhibition of pain by inflammatory response, were tested.
본 발명은 신경병리성 동통 모델과 포르말린 테스트(formalin test)에서 오가피의 진통효과를 입증함으로써, 신경손상으로 통증을 느끼는 동통환자뿐만 아니라, 일반 동통질환에도 상기 약재의 이용을 통하여 통증 완화효과를 기대해볼 수 있을 것이다.The present invention demonstrates the analgesic effect of agapi in a neuropathic pain model and formalin test, and expects a pain relief effect through the use of the medicine in general pain diseases as well as pain patients suffering from nerve damage. Could be.
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| EP2319521A4 (en) * | 2008-06-24 | 2012-06-27 | Viromed Co Ltd | Crude drug composition for cartilage regeneration, pain suppression, and edema suppression |
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