KR100842159B1 - Composition for preventing and treating acute respiratory distress syndrome and multiple organ dysfunction syndrome comprising lysophosphatidylcholine or its derivatives - Google Patents
Composition for preventing and treating acute respiratory distress syndrome and multiple organ dysfunction syndrome comprising lysophosphatidylcholine or its derivatives Download PDFInfo
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- KR100842159B1 KR100842159B1 KR1020020016029A KR20020016029A KR100842159B1 KR 100842159 B1 KR100842159 B1 KR 100842159B1 KR 1020020016029 A KR1020020016029 A KR 1020020016029A KR 20020016029 A KR20020016029 A KR 20020016029A KR 100842159 B1 KR100842159 B1 KR 100842159B1
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Abstract
본 발명은 급성 호흡곤란 증후군 및 다발성 장기부전의 예방 및 치료 효과가 우수한 약제학적 조성물에 관한 것으로, 유효성분으로서 라이소포스파티딜콜린 및 그 유사체를 포함하는 것을 특징으로 한다.The present invention relates to a pharmaceutical composition excellent in the prevention and treatment of acute respiratory distress syndrome and multiple organ failure, characterized in that it comprises lysophosphatidylcholine and its analogs as an active ingredient.
급성 호흡곤란 증후군, 다발성 장기부전, 라이소포스파티딜콜린Acute Respiratory Distress Syndrome, Multiple Organ Failure, Lysophosphatidylcholine
Description
도 1은 LPS 유발 ALI모델의 ICR 마우스들 (실험군, 대조군 및 Sham군)의 폐조직에서 미엘로퍼옥시다제 활성의 측정치를 나타내는 그래프이다. 1 is a graph showing the measurement of myeloperoxidase activity in the lung tissue of ICR mice (experimental, control and Sham group) of the LPS-induced ALI model.
도 2은 LPS 유발 내독소혈증 쇼크 모델의 ICR 마우스들 (실험군, 대조군 및 Sham군)의 폐조직에서 미엘로퍼옥시다제 활성의 측정치를 나타내는 그래프이다. FIG. 2 is a graph showing measurements of myeloperoxidase activity in lung tissue of ICR mice (experimental, control and Sham group) of LPS induced endotoxin shock model.
도 3는 CLP모델의 ICR 마우스들 (실험군, 대조군 및 Sham군)의 폐조직에서 미엘로퍼옥시다제 활성의 측정치를 나타내는 그래프이다.Figure 3 is a graph showing the measurement of myeloperoxidase activity in the lung tissue of the ICR mice (experimental, control and Sham group) of the CLP model.
도 4는 CLP모델의 ICR 마우스들 (실험군, 대조군 및 Sham군)의 혈액에서 알라닌 아미노트랜스퍼라제 수준의 측정치를 나타내는 그래프이다.4 is a graph showing measurements of alanine aminotransferase levels in the blood of ICR mice (experimental, control and Sham group) of the CLP model.
본 발명은 라이소포스파티딜콜린(lysophosphatidylcholine) 또는 그 유사체를 포함하는 급성 호흡곤란 증후군 및 다발성 장기부전의 예방 및 치료용 조성물에 관한 것이다. The present invention relates to a composition for the prevention and treatment of acute respiratory distress syndrome and multiple organ failure, including lysophosphatidylcholine or an analog thereof.
여러 연구자들의 연구 결과에 따르면, 감염, 급성 호흡곤란 증후군, 다발성 장기부전은 서로 연관되어 있다 (대한의사협회지 제45권 제2호, p198~205, 고 영관, "다발성 장기부전" 참조). Investigations have shown that infection, acute respiratory distress syndrome, and multiple organ failure are linked to each other (see Korean Society of Medical Sciences, Vol. 45, No. 2, p198–205, Koswan, “Multiple Organ Failure”).
급성 호흡곤란 증후군 (acute respiratory distress syndrome; ARDS)이란 폐포 모세혈관 장벽의 투과성이 증가되어 발생되는 폐부종에 의한 급성 저산소혈증성 호흡부전으로서 급성 폐손상 (acute lung injury; ALI)의 가장 심한 경우이다. 환자를 ARDS의 위험으로 내몰 수 있는 임상학적 상황은 외상, 출혈 또는 폐혈증으로 다양하며, 이들에 의한 전신적인 염증 반응이 조절되지 못하고 지나치게 표현되어 발생한 결과이다. 저산소증의 치료, 기관내 삽관, 기계적 환기 (mechanical ventilation)등의 치료가 이루어지고 있지만 ARDS로 인한 사망률은 50~70%에 이른다. 순환하는 염증 세포, 특히 호중구 (neutrophils)가 급성 폐 손상의 개시와 진행 (폐부종, 염증반응등)에 중요한 역활을 하는 것으로 알려져 있다. 몇몇 학자들은 ARDS 환자들에서 호중구가 폐내에 광범위하게 축적됨을 입증하였다. 이 호중구들은 일단 활성화되면 기질 금속단백분해효소를 비롯한 단백질 분해효소와 폐손상의 다른 매개체를 방출한다. 따라서 폐에서 호중구의 축적을 억제하면 급성 폐손상에 의한 급성 호흡곤란 증후군을 치료할 수 있을 것이다. Acute respiratory distress syndrome (ARDS) is an acute hypoxic respiratory failure caused by pulmonary edema caused by increased permeability of alveolar capillary barrier and is the most severe case of acute lung injury (ALI). Clinical situations that can drive a patient at risk of ARDS are diverse, including trauma, bleeding, or pulmonary disease, and are the result of uncontrolled and overexpressed systemic inflammatory responses. Treatment for hypoxia, endotracheal intubation, mechanical ventilation, etc., but mortality from ARDS is 50-70%. Circulating inflammatory cells, especially neutrophils, are known to play an important role in the initiation and progression of acute lung injury (pulmonary edema, inflammatory response, etc.). Some scholars have demonstrated extensive accumulation of neutrophils in the lungs in patients with ARDS. Once activated, these neutrophils release proteolytic enzymes, including matrix metalloproteinases, and other mediators of lung damage. Therefore, inhibiting the accumulation of neutrophils in the lung may be able to treat acute respiratory distress syndrome caused by acute lung injury.
다발성 장기부전 (multiple organ dysfunction syndrome; MODS)은 그람음성균의 내독소(endotoxin)에 대해 과도하게 전신적 반응함으로써 발생하는 패혈성 쇼크 등의 합병증으로 초래되는 질환이다. MODS의 예로서는 간경변증, 극증 간염, 급성 신부전, 폐부전, 소화관 출혈 등을 들 수 있다. 항균제와 스테로이드 제제가 사용되고 있으나 그 효과가 미미한 실정이다.Multiple organ dysfunction syndrome (MODS) is a disease caused by complications such as septic shock caused by excessive systemic reaction to endotoxin of Gram-negative bacteria. Examples of MODS include cirrhosis, extreme hepatitis, acute renal failure, lung failure, digestive tract bleeding, and the like. Antibacterial and steroidal agents are used, but their effects are insignificant.
따라서, 본 발명의 목적은 급성 호흡곤란 증후군 및 다발성 장기부전의 예방 및 치료 효과가 우수한 약제학적 조성물을 제공하는 데 있다. Accordingly, it is an object of the present invention to provide a pharmaceutical composition excellent in the prevention and treatment of acute respiratory distress syndrome and multiple organ failure.
상기 목적에 따라, 본 발명에서는 유효성분으로서 라이소포스파티딜콜린 또는 그 유도체를 포함하는 급성 호흡곤란 증후군 및 다발성 장기부전의 예방 및 치료용 조성물을 제공한다. In accordance with the above object, the present invention provides a composition for the prevention and treatment of acute respiratory distress syndrome and multiple organ failure comprising lysophosphatidylcholine or derivatives thereof as an active ingredient.
이하 본 발명을 상세히 설명한다. Hereinafter, the present invention will be described in detail.
본 발명에서 유효성분으로 사용되는 라이소포스파티딜콜린은 하기 화학식 1로 표시된다:Lysophosphatidylcholine used as an active ingredient in the present invention is represented by the following Formula 1:
상기 식에서, R1은 C4-30의 알킬이거나 하나 또는 그 이상의 이중결합을 지닌 C4-30의 알케닐이다. 바람직한 라이소포스파티딜콜린은 L-α-라이소포스파티딜콜린, 스테아로일 (L-α-Lysophosphatidylcholine, Stearoyl; Lysolecithin, stearoyl); L-α-라이소포스파티딜콜린, 팔미토일 (L-α-Lysophosphatidylcholine, Palmitoyl; Lysolecithin, palmitoyl); DL-α-라이소포스파티딜콜린, 팔미토일 (DL- α-Lysophosphatidylcholine, Palmitoyl); 및 L-α-라이소포스파티딜콜린, 올레오일 ( L-α-Lysophosphatidylcholine, Oleoyl; Lysolecithin, oleoyl)이다. Wherein R 1 is C 4-30 alkyl or C 4-30 alkenyl having one or more double bonds. Preferred Lai bovine phosphatidylcholine is L - α - Lai bovine phosphatidylcholine, days stearate (L - α -Lysophosphatidylcholine, Stearoyl; Lysolecithin, stearoyl); L - α -lysophosphatidylcholine, palmitoyl ( L - α- Lysophosphatidylcholine, Palmitoyl; Lysolecithin, palmitoyl); DL - α -lysophosphatidylcholine, palmitoyl ( DL - α- Lysophosphatidylcholine, Palmitoyl); And L - α -lysophosphatidylcholine, oleoyl ( L - α- Lysophosphatidylcholine, Oleoyl; Lysolecithin, oleoyl).
또한, 본 발명에서 유효성분은 라이소포스파티딜콜린의 유사체일 수 있고, 바람직하게는 하기 화학식 2의 라이소포스파티딜콜린의 에테르 유사체일 수 있다: In addition, the active ingredient in the present invention may be an analog of lysophosphatidylcholine, preferably an ether analog of lysophosphatidylcholine of formula (II):
상기 식에서 R2는 C4-30의 알킬이거나 하나 또는 그 이상의 이중결합을 지닌 C4-30의 알케닐이다. 더 바람직하게는 L-α-라이소포스파티딜콜린, γ
-O-알크-1-에닐 (L-α-Lysophosphatidylcholine, γ-O-Alk-1-Enyl; Lysophosphatidalcholine);
L-α-라이소포스파티딜콜린, γ-O-알킬 (L-α-Lysophosphatidylcholine, γ
-O-Alkyl; Lyso-platelet activating factor); DL-α-라이소포스파티딜콜린, γ-O-헥사데실 (DL-α- Lysophosphatidylcholine, γ-O-Hexadecyl; rac-Lyso-platelet activating factor); 및 L-α-라이소포스파티딜콜린, γ-O-헥사데실 (L-α-Lysophosphatidylcholine,
γ-O-Hexadecyl; Lyso-platelet activating factor; Lyso-PAF-C16)이다. Wherein R 2 is C 4-30 alkyl or C 4-30 alkenyl having one or more double bonds. More preferably, L - α - Lai bovine phosphatidylcholine, γ -O- alk-1-enyl (L - α -Lysophosphatidylcholine, γ -O -Alk-1-Enyl; Lysophosphatidalcholine); L - α - Lai bovine phosphatidylcholine, -O- alkyl γ (L - α -Lysophosphatidylcholine, γ -O -Alkyl; Lyso-platelet activating factor); DL - α - Lai bovine phosphatidylcholine, γ -O- hexadecyl (DL - α - Lysophosphatidylcholine, γ -O-Hexadecyl; rac-Lyso-platelet activating factor); And L-α-phosphatidylcholine small Lai, γ -O- hexadecyl-a (α -Lysophosphatidylcholine, γ -O-Hexadecyl L; Lyso-PAF-
라이소포스파티딜콜린 및 그 유사체는 상업적으로 용이하게 입수할 수 있다. 또한, 라이소포스파티딜콜린 및 그 유사체는 동물로부터 단리할 수 있고, 당업계에 잘 알려진 합성 방법으로 제조될 수도 있다. Lysophosphatidylcholine and analogs thereof are readily available commercially. Lysophosphatidylcholine and analogs thereof can also be isolated from animals and prepared by synthetic methods well known in the art.
라이소포스파티딜콜린 및 그 유사체는 포유동물의 체내에 내재성 물질이므로 안전성은 입증된 것과 다름없다.Lysophosphatidylcholine and its analogs are endogenous in the body of mammals, so safety is no less than proven.
본 발명의 약제학적 조성물은 다양한 비경구 또는 경구 투여 형태로 제형화 할 수 있다. 비경구 투여용 제형의 대표적인 것은 주사용 제형으로 등장성 수용액 또는 현탁액이 바람직하다. 또한, 경구 투여용 제형으로는 예를 들면 정제, 캅셀제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예 : 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/ 또는 글리신), 활탁제(예 : 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/ 또는 폴리에틸렌 글리콜)를 함유할 수 있다. 정제는 또한 마그네슘 알루미늄 실리케이트, 전분페이스트, 젤라틴, 트라가칸스, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다. 상기 제형은 통상적인 혼합, 과립화 또는 코팅 방법 에 의해 제조될 수 있다. The pharmaceutical compositions of the invention can be formulated in a variety of parenteral or oral dosage forms. Representative of parenteral formulations are injectable formulations, preferably aqueous isotonic solutions or suspensions. In addition, oral dosage forms include, for example, tablets, capsules, and the like, which include diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), bows in addition to the active ingredients. Turbidity such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, optionally starch, agar, alginic acid or its Disintegrants or boiling mixtures such as sodium salts and / or absorbents, colorants, flavors, and sweeteners. The formulations may be prepared by conventional mixing, granulating or coating methods.
본 발명의 약제학적 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법에 따라 제제화할 수 있다.The pharmaceutical compositions of the present invention may contain sterile and / or adjuvant such as preservatives, stabilizers, hydrating or emulsifying accelerators, salts and / or buffers for the control of osmotic pressure and other therapeutically useful substances, Can be formulated accordingly.
본 발명의 조성물의 유효성분으로서 라이소포스파티딜콜린 및 그 유사체는 인간을 포함하는 포유동물에 대해 하루에 0.01 내지 100 ㎎/㎏(체중)의 양으로 1일 1회 또는 분할하여 비경구 또는 경구적 경로를 통해 투여할 수 있다. Lysophosphatidylcholine and its analogs as active ingredients of the compositions of the present invention may be parenteral or oral routed once a day or divided into mammals, including humans, in an amount of 0.01 to 100 mg / kg body weight per day. It can be administered through.
이하 본 발명을 하기 실시예에 의하여 더욱 상세하게 설명하고자 한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이들만으로 한정되는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.
실시예Example
본 발명의 조성물의 유효성분인 라이소포스파티딜콜린이 급성 호흡곤란 증후군 및 다발성 장기부전의 예방 및 치료에 우수한 효과를 발휘함을 확인하기 위하여 LPS 유발 ALI 모델 시험, 내독소혈증 쇼크 (endotoxemia shock) 모델 및 CLP 모델 시험을 행하였다.
In order to confirm that lysophosphatidylcholine, an active ingredient of the composition of the present invention, has an excellent effect in preventing and treating acute respiratory distress syndrome and multiple organ failure, an LPS-induced ALI model test, an endotoxemia shock model, and CLP model tests were done.
참고예 1: 폐조직에서 미엘로퍼옥시다제 활성의 측정Reference Example 1 Measurement of Myeloperoxidase Activity in Lung Tissues
폐조직에서 호중구의 지표인 미엘로퍼옥시다제 (myeloperoxidase; MPO) 활성은 Goldblum et al (J. Appl. physiol. 59: 1978, 1985.)와 Parey et al (J. Immunol. 160:1007, 1998)의 방법에 따라 측정한다. 마우스를 희생하여 폐조직을 취한 후, 그 조직을 포타슘 포스페이트(potassium phosphate) 완충액에 첨가하고 균질화(homogenize)한 후, 원심분리하여 펠렛(pellets)을 얻는다. 이 펠렛을 0.5% 헥사데실트리메틸암모늄 브로마이드 (hexadecyltrimethylammonium bromide; HTAB) 함유한 포타슘 포스페이트 완충액에 첨가하고 초음파처리하여 60℃에서 120 분간 반응시킨 후, 원심분리한 다음, 그 상층액(0.02 ml)에 0.167mg/ml의 o-디아니시딘 디하이드로클로라이드(o-dianisidine dihydrochloride)와 0.0005% 과산화수소수를 함유한 포타슘 포스페이트 완충액(0.18 ml)을 첨가하고 460nm 파장에서 흡광도를 측정한다.
Myeloperoxidase (MPO) activity, an indicator of neutrophils in lung tissue, was investigated by Goldblum et al (J. Appl. Physiol. 59: 1978, 1985.) and Parey et al (J. Immunol. 160: 1007, 1998). Measure according to the method. After taking the lung tissue at the expense of the mouse, the tissue is added to potassium phosphate buffer, homogenized and centrifuged to obtain pellets. This pellet was added to potassium phosphate buffer containing 0.5% hexadecyltrimethylammonium bromide (HTAB), sonicated for 120 minutes at 60 DEG C, centrifuged, and then 0.167 in supernatant (0.02 ml). Add mg / ml o-dianisidine dihydrochloride and potassium phosphate buffer (0.18 ml) containing 0.0005% hydrogen peroxide solution and measure absorbance at 460 nm wavelength.
실시예 1: 리포폴리사카라이드(LPS) 유발 급성 폐손상(ALI) 모델 시험Example 1: Lipopolysaccharide (LPS) -induced Acute Lung Injury (ALI) Model Test
리포폴리사카라이드(LPS)를 마우스 기관지내(intratracheal)에 투여하여 직접적인 급성 폐손상(ALI)을 유발하였다. Lipopolysaccharide (LPS) was administered to the mouse bronchus (intratracheal) to cause direct acute lung injury (ALI).
35 마리의 ICR 마우스(체중 25 ~ 30 g; MJ Ltd)를 펜토바비톨로 마취시킨 후, 피부를 1㎝ 길이로 절개하여 기관지를 노출시킨 후, 7 마리씩 5개의 군 (Sham군, 실험군-1, 실험군-2, 실험군-3 및 대조군)으로 나누어, Sham군의 ICR 마우스들은 PBS (50㎕)를 기관지에 투여한 후 봉합하였고, 실험군들 및 대조군의 ICR 마우스들에는 LPS (6㎍/50㎕ PBS)를 기관지에 직접 투여한 후 봉합하였다. 그리고 나서, 실험군-1, 실험군-2 및 실험군-3의 ICR 마우스들에는 수술 2 및 14시간 후에 각각 1 회씩 지방산이 없는 1% BSA(bovine serum albumin) 용액에 녹인 L-α-라이소포스파티딜콜린 스테아로일 (Sigma)을 각각 5, 10, 20 ㎎/㎏의 양으로 피하주사로 투여하였고, 대조군의 ICR 마우스들에는 라이소포스파티딜콜린 대신 동량의 지방산이 없는 1% BSA 용액을 동일한 방식으로 투여하였다. 35 ICR mice (weight 25-30 g; MJ Ltd) were anesthetized with pentobarbitol, and the skin was cut into 1 cm lengths to expose the bronchus, and then 5 dogs of 7 each (Sham group, experimental group-1). , Experimental group-2, experimental group-3 and control group), Sham group ICR mice were sutured after administration of PBS (50 μl) to the bronchus, LPS (6 μg / 50 μl) in the experimental and control ICR mice PBS) was administered directly to the bronchus and then sutured. Then, the ICR mice of Experimental Group-1, Experimental Group-2, and Experimental Group-3 had L - α -lysophosphatidylcholine stear dissolved in 1% bovine serum albumin (BSA) solution without fatty acid once each 2 and 14 hours after surgery. Loyl (Sigma) was administered subcutaneously in amounts of 5, 10 and 20 mg / kg, respectively, and control ICR mice were dosed in the same manner with 1% BSA solution without the same amount of fatty acid instead of lysophosphatidylcholine.
수술 24시간 후에 각 군의 ICR 마우스들의 폐조직에서 호중구의 지표인 미엘로퍼옥시다제(MPO) 활성을 참고예 1에 기재된 바와 같이 측정하여, 그 평균값을 도 1에 나타내었다.Myeloperoxidase (MPO) activity, which is an indicator of neutrophils, in lung tissues of ICR mice of each group 24 hours after surgery was measured as described in Reference Example 1, and the average value thereof is shown in FIG. 1.
도 1에 도시된 바와 같이, LPS를 기관지내에 투여하였을 때, MPO 활성이 유의하게 증가하였다 (p<0.001). 실험군들(라이소포스파티딜콜린 투여군)의 ICR 마우스들은 대조군의 마우스들에 비하여 MPO 활성이 농도 의존적으로 억제되었으며, 20 mg/kg 투여량(실험군-3)일때 가장 탁월한 효과를 보였다(p<0.01).
As shown in FIG. 1, when LPS was administered intratracheally, MPO activity was significantly increased (p <0.001). ICR mice of the experimental group (lyophosphatidylcholine-administered group) had a concentration-dependent inhibition of MPO activity compared to the control mice, and showed the most excellent effect at the 20 mg / kg dose (Experimental group-3) (p <0.01).
실시예 2: 리포폴리사카라이드(LPS) 유발 내독소혈증 쇼크 모델 시험Example 2: Lipopolysaccharide (LPS) Induced Endotoxin Shock Model Test
리포폴리사카라이드(LPS)를 마우스 복강에 투여하여 내독소혈증 쇼크에 의한 간접적인 ALI를 유발하였다. Lipopolysaccharide (LPS) was administered to the mouse abdominal cavity to indirect ALI due to endotoxin shock.
35 마리의 ICR 마우스(체중 25 ~ 30 g; MJ Ltd) 7 마리씩 5개의 군 (Sham군, 실험군-1, 실험군-2, 실험군-3 및 대조군)으로 나누어, Sham군의 ICR 마우스들은 복강에 PBS(0.5 ml/100g 체중)를 투여하고, 실험군 및 대조군의 ICR 마우스들에는 복강에 LPS (1mg/kg)를 투여하였다. 그리고 나서, 실험군-1, 실험군-2 및 실험군- 3의 ICR 마우스들에는 LPS 투여 2 및 14시간 후에, 각각 1회씩 지방산이 없는 1% BSA(bovine serum albumin) 용액에 녹인 L-α-라이소포스파티딜콜린 스테아로일 (Sigma)을 각각 5, 10, 20㎎/㎏의 양으로 피하주사로 투여하였고, 대조군의 ICR 마우스들에는 라이소포스파티딜콜린 대신 동량의 지방산이 없는 1% BSA 용액을 동일한 방식으로 투여하였다. The 35 ICR mice (weight 25-30 g; MJ Ltd) were divided into five groups (Sham group, experimental group-1, experimental group-2, experimental group-3, and control group), each of which were 7 mice. (0.5 ml / 100g body weight) and experimental and control ICR mice were given LPS (1 mg / kg) intraperitoneally. Then, the ICR mice of Experimental Group-1, Experimental Group-2, and Experimental Group-3 had L - α -lyso dissolved in 1% BSA (bovine serum albumin) solution without fatty acid once and 2 hours after LPS administration, respectively. Phosphatidylcholine stearoyl (Sigma) was administered subcutaneously in amounts of 5, 10 and 20 mg / kg, respectively, and control ICR mice were dosed in the same manner with 1% BSA solution without the same amount of fatty acid instead of lysophosphatidylcholine It was.
LPS 투여 24시간 후에 각 군의 ICR 마우스들의 폐조직에서 호중구의 지표인 MPO 활성을 참고예 1에 기재된 바와 같이 측정하여, 그 평균값을 도 2에 나타내었다. 24 hours after LPS administration, MPO activity, an indicator of neutrophils, in lung tissues of each group of ICR mice was measured as described in Reference Example 1, and the average value thereof is shown in FIG. 2.
도 2에 도시된 바와 같이, LPS를 복강에 투여하였을 때 MPO 활성이 유의하게 증가하였다 (p<0.01). 실험군들(라이소포스파티딜콜린 투여군)의 ICR 마우스들은 대조군의 마우스들에 비하여 MPO 활성이 농도 의존적으로 억제되었으며, 20mg/kg 투여양일때(실험군-3) 가장 뛰어난 효과를 보였다 (p<0.01).
As shown in FIG. 2, MPO activity was significantly increased (p <0.01) when LPS was administered intraperitoneally. ICR mice of the experimental group (lyophosphatidylcholine-administered group) had a concentration-dependent inhibition of MPO activity compared to the control mice, and showed the most excellent effect at the 20 mg / kg dose (Experiment-3) (p <0.01).
실시예 3: 맹장 결찰 및 천공 (Cecal Ligation and Puncture; CLP) 모델 시험Example 3: Cecal Ligation and Puncture (CLP) Model Test
CLP 모델 (인위적으로 맹장을 결찰 및 천공하여서 복막염을 유발하여 패혈성 쇼크를 일으켜 놓은 동물)을 이용하여 패혈성 쇼크에 의한 간접적인 급성 폐손상(ALI)을 유발하였다. 패혈성 쇼크는 그 합병증으로 다발성 장기부전을 초래하는데, 그 대표적인 장기로서 폐, 간, 신장들이 손상을 받는다. Indirect acute lung injury (ALI) was caused by septic shock using the CLP model (animals that caused peritonitis by artificially ligating and puncturing the cecum). Septic shock is a complication that results in multiple organ failure, in which the lungs, liver and kidneys are damaged.
(1) 급성 호흡곤란 증후군에 대한 라이소포스파티딜의 효과 (1) Effects of Lysophosphatidyl on Acute Respiratory Distress Syndrome
30 마리의 ICR 마우스 (체중 25 ~ 30 g; MJ Ltd.)를 펜토바비탈로 마취시킨 후, 복부 오른쪽 부위를 1㎝ 길이로 절개하고 맹장을 노출시킨 다음, 10 마리의 ICR 마우스는 다시 봉합하고 (Sham 군), 나머지 20 마리의 ICR 마우스들은 회맹부 관 (ileocecal valve) 아래 부위를 결찰한 후 맹장에 21 게이지 바늘로 6개의 구멍을 내고, 복부를 다시 봉합하여 패혈성 쇼크를 유발하였다. 봉합한 지 2 및 14 시간 후에 각각 1회씩, 10 마리의 ICR 마우스에게는 지방산이 없는 1% BSA 용액에 녹인 L-α-라이소포스파티딜콜린, 스테아로일 (Sigma)을 10㎎/㎏의 양으로 피하주사로 투여하고 (실험군), 10 마리의 ICR 마우스에게는 지방산이 없는 1% BSA 용액 만을 투여하였다 (대조군). Thirty ICR mice (weight 25-30 g; MJ Ltd.) were anesthetized with pentobarbital, and then the right abdominal region was incised 1 cm long and the cecum was exposed, and then 10 ICR mice were resealed. (Sham group), the remaining 20 ICR mice were ligated under the ileocecal valve and then made six holes in the cecum with 21 gauge needles, and sutured the abdomen to cause septic shock. Once each 2 and 14 hours after closure, 10 ICR mice were subcutaneously dosed with L - α -lysophosphatidylcholine and stearoyl (Sigma) in 10% / kg dissolved in 1% BSA solution without fatty acids. Administration was by injection (experimental group) and 10 ICR mice received only 1% BSA solution without fatty acid (control).
수술 직후 그리고 4, 8, 16 시간에 각 군의 ICR 마우스의 폐조직에서 호중구의 지표인 MPO 활성을 참고예 1에 기재된 바와 같이 측정하여, 도 3에 나타내었다.Immediately after surgery and at 4, 8, and 16 hours, MPO activity, an indicator of neutrophils, in lung tissues of ICR mice of each group was measured as described in Reference Example 1, and is shown in FIG. 3.
도 3에 나타난 바와 같이, CLP 수술후 4시간부터 MPO 활성은 현저하게 증가하며 16시간까지 유지는데, 대조군에 비하여 실험군의 ICR 마우스들에서는 CLP 수술에 의해 증가한 MPO 활성이 현저하게 억제되었다.
As shown in FIG. 3, the MPO activity was significantly increased and maintained for 16 hours from 4 hours after the CLP surgery. The MPO activity of the experimental group was significantly suppressed by the CLP surgery compared to the control group.
(2) 다발성 장기부전에 대한 라이소포스파티딜콜린의 효과(2) Effect of Lysophosphatidylcholine on Multiple Organ Failure
한편, 다발성 장기부전의 하나로서 간 손상에 대한 본 발명의 라이소포스파티딜콜린의 효과를 알아보기 위해, CLP 수술 16시간 후에 각 군의 마우스로부터 혈 액을 채취하여 간독성의 지표인 알라닌 아미노트랜스퍼라제 (alanine aminotransferase; ALT)의 수준을 Reitman-Frankel법에 따라 측정하여, 그 값을 도 4에 나타내었다. 대조군에 비하여 실험군의 ICR 마우스들에서는 CLP 수술에 의해 증가된 ATP 수준이 현저하게 억제되었다.
Meanwhile, in order to determine the effect of lysophosphatidylcholine of the present invention on liver damage as one of multiple organ failures, blood was collected from each group of
라이소포스파티딜콜린 및 그 유사체는 급성 호흡곤란 증후군 및 다발성 장기부전의 예방 및 치료 효과가 우수하여, 이들 질환으로 인한 사망률을 현저히 저하시킨다.
Lysophosphatidylcholine and its analogs are excellent in the prevention and treatment of acute respiratory distress syndrome and multiple organ failure, significantly lowering mortality from these diseases.
Claims (4)
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| KR1020020016029A KR100842159B1 (en) | 2002-03-25 | 2002-03-25 | Composition for preventing and treating acute respiratory distress syndrome and multiple organ dysfunction syndrome comprising lysophosphatidylcholine or its derivatives |
| ES03745031.9T ES2536710T3 (en) | 2002-03-25 | 2003-03-25 | New therapeutic use of LPC, specific agonist ligands for the G2A receptor |
| CN038088991A CN1646138B (en) | 2002-03-25 | 2003-03-25 | Novel therapeutical use of agonist ligands specific to G2A receptor |
| CA002480429A CA2480429C (en) | 2002-03-25 | 2003-03-25 | Novel therapeutical use of agonist ligands specific to g2a receptor |
| EP03745031.9A EP1490072B1 (en) | 2002-03-25 | 2003-03-25 | Novel therapeutical use of lpc, agonist ligands specific to g2a receptor |
| PCT/KR2003/000593 WO2003080071A1 (en) | 2002-03-25 | 2003-03-25 | Novel therapeutical use of agonist ligands specific to g2a receptor |
| AU2003215954A AU2003215954B2 (en) | 2002-03-25 | 2003-03-25 | Novel therapeutical use of agonist ligands specific to G2A receptor |
| US10/509,300 US7410955B2 (en) | 2002-03-25 | 2003-03-25 | Therapeutic use of agonist ligands specific to G2A receptor |
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| WO2014142517A1 (en) | 2013-03-12 | 2014-09-18 | 주식회사 아리바이오 | Lipid nanomaterial containing lysophosphatidylcholine or derivative thereof and method for preparing same |
| KR102189490B1 (en) | 2020-04-22 | 2020-12-11 | 주식회사 아리바이오 | A composition for treating virus infection disease comprising lysophosphatidylcholine or a derivative nano formulation thereof |
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| JPS54106430A (en) | 1978-02-07 | 1979-08-21 | Toyama Chem Co Ltd | Novel preparation of lysophosphatidylcholine analog |
| JPS63152327A (en) | 1987-11-20 | 1988-06-24 | Toyama Chem Co Ltd | Immune activating agent and anticancer agent containing hemolysis preventing composition consisting of fat emulsion |
| KR20030030125A (en) * | 2001-10-08 | 2003-04-18 | 주식회사 바이오시너젠 | Composition for preventing and treating septic shock comprising lysophosphatidylcholine or its derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS54106430A (en) | 1978-02-07 | 1979-08-21 | Toyama Chem Co Ltd | Novel preparation of lysophosphatidylcholine analog |
| JPS63152327A (en) | 1987-11-20 | 1988-06-24 | Toyama Chem Co Ltd | Immune activating agent and anticancer agent containing hemolysis preventing composition consisting of fat emulsion |
| KR20030030125A (en) * | 2001-10-08 | 2003-04-18 | 주식회사 바이오시너젠 | Composition for preventing and treating septic shock comprising lysophosphatidylcholine or its derivatives |
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| WO2014142517A1 (en) | 2013-03-12 | 2014-09-18 | 주식회사 아리바이오 | Lipid nanomaterial containing lysophosphatidylcholine or derivative thereof and method for preparing same |
| KR102189490B1 (en) | 2020-04-22 | 2020-12-11 | 주식회사 아리바이오 | A composition for treating virus infection disease comprising lysophosphatidylcholine or a derivative nano formulation thereof |
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