KR20180107341A - Composition for the treatment and prevention of Leaky Gut Syndrome comprising Potassium-Competitive Acid Blocker as active component - Google Patents
Composition for the treatment and prevention of Leaky Gut Syndrome comprising Potassium-Competitive Acid Blocker as active component Download PDFInfo
- Publication number
- KR20180107341A KR20180107341A KR1020170033118A KR20170033118A KR20180107341A KR 20180107341 A KR20180107341 A KR 20180107341A KR 1020170033118 A KR1020170033118 A KR 1020170033118A KR 20170033118 A KR20170033118 A KR 20170033118A KR 20180107341 A KR20180107341 A KR 20180107341A
- Authority
- KR
- South Korea
- Prior art keywords
- leaky gut
- cab
- gut syndrome
- composition
- potassium
- Prior art date
Links
Images
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
본 발명은 장 누수 증후군 치료 및 예방용 조성물에 관한 것으로서, 더욱 상세하게는 특히 비스테로이드성 항염제(NSAID)에 의해서 유발되는 장 누수 증후군을 유용하게 예방 및 치료할 수 조성물에 관한 것이다. The present invention relates to a composition for treating and preventing intestinal leak syndrome and, more particularly, to a composition capable of effectively preventing and treating intestinal leak syndrome induced by non-steroidal anti-inflammatory drug (NSAID).
인체의 장관은 장내 세균의 저장소로서 점막 장벽기능(intestinal barrier), 면역글로불린 분비 기능, 대식세포계 등을 포함한 일련의 방어체계를 이루고 있다. 장관 내 장점막층은 장내에 존재하는 다양한 세균 및 독소 등이 혈류로 유입되는 것을 차단하는 방어벽 역할을 하며 상피세포층에 단단히 결합되어 있다. 즉 장점막은 외부물질을 차단하는 장벽인 동시에 이들을 통과, 흡수시키는 이중적인 기능을 가진다.The intestinal tract of the human body is a reservoir of intestinal bacteria and forms a series of defense systems including intestinal barrier, immunoglobulin secretion function, and macrophage system. Intestinal intestinal mucosa is a protective barrier that blocks the entry of various germs and toxins in the intestinal tract into the bloodstream and is tightly bound to the epithelial layer. That is, the intestinal membrane is a barrier for blocking external substances and has a dual function of passing and absorbing them.
장점막세포는 일정한 세포 사이의 간극을 유지하다가 소화 흡수 과정이 일어나는 동안 어떠한 자극이나 손상이 가해지면서 세포 사이의 틈으로 고분자 물질이 왕복할 수 있는 장점막 투과성이 증가되는 현상이 나타나게 된다. 이때 장벽의 기능을 제대로 하지 못하여 혈액 내 고분자 물질이 장관내 관강으로 누수되거나 관강 내의 고분자 물질이 직접 혈액으로 들어가는 현상이 초래되는데 이를 ¨새는 장〃 즉 ¨leaky gut〃의 상태라고 말한다. 이때 나타나는 증상을 총괄하여 장 누수 증후군(leaky gut syndrome: LGS)이라고 하며 노화, 알레르기, 다발성 외상, 류마티스 관절염, 염증성 대장질환, 만성피로 증후군, 과민성 증후군 등의 다양한 임상적 상태로 나타난다. 또한 장점막 투과성의 증가나 장점막의 손상으로 인해 병원체, 항원, 부패물질 등이 장점막 내로 유입되어 염증반응이 일어나고 내독소가 혈류로 유입되어 장내세균 전위(bacterial translocation), 장관내독소혈증(intestinal endotoxemia) 등을 야기하여 각종 염증반응 및 면역 반응이 나타나게 된다.The intestinal mucosa maintains a constant gap between cells, and during the digestion and absorption process, the stimulation or damage is applied, and the permeability of the mucosa through the gap between the cells increases. At this time, the barrier function is not properly performed, so that the polymer substance in the blood leaks into the intestinal canal or the polymer substance in the canal enters the blood directly. This state is referred to as a state of leleaky gut 〃. These symptoms are referred to as leaky gut syndrome (LGS), and are manifested in various clinical conditions such as aging, allergy, multiple trauma, rheumatoid arthritis, inflammatory bowel disease, chronic fatigue syndrome, and hypersensitive syndrome. In addition, increased permeability of the mucosa and damage to the mucous membrane lead to intestinal permeation of pathogens, antigens, and decayed materials, resulting in inflammatory reactions and endotoxin inflow into the bloodstream leading to intestinal bacterial translocation, intestinal endotoxemia, And various inflammatory and immune responses are produced.
이와 같은 장 누수 증후군은 다양한 원인에 의해 발생할 수 있으나 특히 비스테로이드성 항염제(nonsteroidal anti-inflammatory drug, NSAID))에 의해서도 유발되는 것으로 알려져 있다. These intestinal leak syndromes can be caused by various causes, but they are also known to be caused by nonsteroidal anti-inflammatory drugs (NSAIDs).
본 발명자들의 실험 결과에 의하면 NSAID로써 인도메타신(Indomethacin)을 투여하였을 때 정상적인 소장의 투과성(Permeability)가 증가하면서 세포 침윤(cellular infiltration) 및 융모(villi)의 손실(loss) 등을 볼 수 있으며 이는 시간이 경과함에 따라 림프여포(lymphoid follicle)를 형성하고 위장관 궤양(intestinal ulcer)를 유도하며 이는 곧 천공(perforation) 등을 거쳐 복막염(peritonitis)이 유도된다(도 1 참조). According to the experimental results of the present inventors, when indomethacin is administered as an NSAID, the permeability of the normal small intestine increases, and cellular infiltration and loss of villi are observed This forms a lymphoid follicle with the passage of time and induces an intestinal ulcer, which is followed by perforation and induces peritonitis (see FIG. 1).
이와 같은 현재 임상적인 최선의 선택으로는 양성자 펌프 억제제(Proton Pump Inhibitor(PPI))를 사용하는 것으로 알려져 있으나, 최근의 연구결과들에 의하면 Proton pump inhibitor가 오히려 NSAID에 의한 장 누수 증후군(leaky gut syndrome)을 증가시키는 것으로 알려져 있는데, 대표적 proton pump inhibitor인 에소메프라졸(esomeprazole)을 투여한 경우 소장 투과도를 측정하였을 때 시간이 경과함에 따라 십이지장 투과도가 유의성 있게 증가되는 결과를 보임에 따라 proton pump inhibitor가 미세 장염(microscopic colitis)이나 림프구성 장염(lymphocytic colitis) 등을 유도한다(Esomeprazole induces upper gastrointestinal tract transmucosal permeability increase, Mullin et al., Aliment Pharmacol Ther. 2008 Dec 1;28(11-12):1317-25 참조).Proton pump inhibitor (PPI) is known to be the best clinical choice currently available, but recent research has shown that proton pump inhibitors are more effective than NSAIDs for leaky gut syndrome ). When the esomeprazole, a representative proton pump inhibitor, was administered, the duodenal permeability was significantly increased with the passage of time, and the proton pump inhibitor (Esomeprazole induces upper gastrointestinal tract transmucosal permeability increase, Mullin et al., Aliment Pharmacol Ther 2008 Dec 1, 28 (11-12): 1317), which induces microscopic colitis or lymphocytic colitis -25).
실제로 본 발명자들의 실험에서도 Indomethacin 투여에 의하여 소장 조직 전체에 걸쳐서 출혈(bleeding) 및 부종(edema) 등을 확인할 수 있었으며 이때 proton pump inhibitor를 함께 투여한 경우 상태가 호전되기보다는 오히려 악화되는 듯한 결과를 확인하였다.In fact, the present inventors have also found that bleomycin and edema can be observed throughout the small intestine by administration of indomethacin. In this case, when the proton pump inhibitor is administered together, Respectively.
따라서 NSAID에 의한 위장관 투과도(Intestinal permeability)의 증가가 proton pump inhibitor의 투여에 의하여 오히려 더욱 증가되는 것을 보여줌으로써 새로운 약제나 물질탐색이 장 누수 증후군(Leaky gut syndrome)을 해결하기 위해 절대적으로 필요한 상황임을 알 수 있다. Therefore, it is absolutely necessary to solve the problem of Leaky gut syndrome by showing that the increase of intestinal permeability by NSAID is increased by the administration of proton pump inhibitor. Able to know.
따라서 본 발명이 해결하고자 하는 과제는 비스테로이드성 항염제(NSAID)에 의해 유발되는 장 누수 증후군(Leaky gut syndrome)을 해결할 수 있는 유용한 조성물을 제공하는 것이다.Accordingly, a problem to be solved by the present invention is to provide a useful composition capable of solving Leaky gut syndrome induced by non-steroidal anti-inflammatory drug (NSAID).
상기 기술적 과제를 달성하기 위하여 본 발명은,According to an aspect of the present invention,
칼륨 경쟁적 위산분비억제제(Potassium-Competitive Acid Blocker, p-cab)를 유효성분을 함유하는 장 누수 증후군(leaky gut syndrome) 치료 및 예방용 조성물을 제공한다.Potassium-Competitive Acid Blocker (p-cab) is a composition for treating and preventing leaky gut syndrome containing an active ingredient.
본 발명에 있어서, 상기 상기 장 누수 증후군(leaky gut syndrome)이 비스테로이드성 항염제(nonsteroidal anti-inflammatory drug, NSAID))에 의해 유발되는 것일 수 있다.In the present invention, the leaky gut syndrome may be caused by a nonsteroidal anti-inflammatory drug (NSAID).
본 발명에 있어서, 상기 칼륨 경쟁적 위산분비억제제(Potassium-Competitive Acid Blocker, p-cab)이 레바프라잔(Revaprazan), 보노프라잔(Vonoprazan), 리나프라잔( Linaprazan) 및 소라프라잔(Soraprazan)으로 이루어진 군에서 선택되는 어느 하나 이상인 것이 바람직하다.In the present invention, the Potassium-Competitive Acid Blocker (p-cab) is used in combination with Revaprazan, Vonoprazan, Linaprazan and Soraprazan, , And the like.
본 발명에 의하면 장 누수 증후군(leaky gut syndrome)을, 특히 SANID에 의해 유발되는 장 누수 증후군(leaky gut syndrome)을 치료 및 예방하는데 유용한 조성물에 제공된다.The present invention provides a composition useful for treating and preventing leaky gut syndrome, particularly leaky gut syndrome caused by SANID.
도 1은 Indomethacin 투여에 따른 소장의 변화를 나타낸 결과 도면이다.
도 2는 세포와 세포 사이의 저항성을 확인하기 위하여 TEER을 측정하여 그 결과 도면이다.
도 3은 위장관 투과도(Intestinal permeability)와 관련 있는 tight junction protein들에는 어떤 영향이 있는지 확인하고자 western blotting을 시행한 결과 도면이다.
도 4는 tight junction 과 관련성이 높은 Molecular switch인 Rho-GTPase의 활성도를 확인한 결과 도면이다.
도 5는 장 손상에 대한 Gross leisons 확인한 결과 도면이다.
도 6은 동물 조직으로 이용하여 병리학적으로 보았을 때 각 조직을 융모 손실(villi loss), 궤양(ulceration), 염증(inflammation) 기준으로 점수화한 결과 도면이다.
도 7은 실험동물 조직을 이용하여 염증과 관련한 인자들을 확인한 결과 도면이다.
도 8은 위장관 투과도(Intestinal permeability)에 영향일 미치는 inflammasome 과 관련된 인자들을 확인한 결과 도면이다.
도 9는 위장관 투과도(Intestinal permeability)의 endpoint인 tight junction과 관련한 인자들을 확인한 결과 도면이다. FIG. 1 is a graph showing the changes in intestinal length upon administration of indomethacin.
FIG. 2 is a drawing showing the result of measurement of TEER to confirm the resistance between cells and cells.
Figure 3 is a plot of western blotting to determine the effect of intestinal permeability on tight junction proteins.
FIG. 4 is a graph showing the activity of Rho-GTPase, a molecular switch having a strong relation with a tight junction.
FIG. 5 is a chart showing results of gross leishons for intestinal damage.
FIG. 6 is a view showing the result of scoring each tissue according to villi loss, ulceration, and inflammation when used as an animal tissue.
FIG. 7 is a graph showing the results of confirming factors related to inflammation using experimental animal tissues. FIG.
FIG. 8 is a plot showing the factors associated with inflammatory markers affecting intestinal permeability. FIG.
FIG. 9 is a view showing the factors related to a tight junction, which is an endpoint of intestinal permeability. FIG.
이하 본 발명을 상세하게 설명하기로 하며, 이하의 설명에서 사용되는 비스테로이드성 항염제(nonsteroidal anti-inflammatory drug, NSAID)), 위산분비억제제(Potassium-Competitive Acid Blocker(P-CAB)), 양성자 펌프 억제제(Proton Pump Inhibitor(PPI))는 예시를 위한 것뿐이며 설명에서 사용되지 않은 다른 약물을 사용하더라도 유사한 결과 및 결론을 도출할 수 있음은 당연하다.(NSAID), a potassium-competitive acid blocker (P-CAB), a proton pump (P-CAB), and the like. The present invention will now be described in detail with reference to the following non-steroidal anti-inflammatory drug Proton pump inhibitors (PPIs) are for illustration only and it is natural that similar results and conclusions can be drawn using other drugs not used in the description.
본 발명자들은 NSAID와 함께 PPI 투여 시의 위장관 투과도(Intestinal permeability)의 변화를 살펴보고 이때 PPI 대신 칼륨 경쟁적 위산분비억제제(Potassium-Competitive Acid Blocker(P-CAB))을 투여 시에 어떠한 영향이 있는지를 확인하여 본 발명의 유효성 및 효과를 입증하였다.The present inventors examined changes in gastrointestinal permeability during the administration of PPI with NSAIDs and examined the effect of potassium-competitive acid blocker (P-CAB) instead of PPI on the gastrointestinal permeability Confirming the effectiveness and effect of the present invention.
우선 세포실험으로는 Human colon carcinoma cells인 Caco-2 세포를 이용하였고 TEER기법(Trans-epithelial Electrical Resistance), RT-PCR, Westernblotting 등을 이용하였습니다. 또한 NSAID로는 인도메타신(Indomethacin) PPI로는 판토프라졸(Pantoprazole), P-CAB으로는 레바프라잔(Revaprazan)을 사용하였다. First, we used human colon carcinoma cells, Caco-2 cells, and used TEER technique (Trans-epithelial Electrical Resistance), RT-PCR and Western blotting. Pantoprazole was used as indomethacin PPI and Revaprazan was used as P-CAB for NSAIDs.
우선 세포와 세포 사이의 저항성을 확인하기 위하여 TEER을 측정하여 그 결과를 도 2에 나타냈으며, 세포와 세포 사이의 저항성을 측정함으로써 저항성이 높을수록 세포 사이의 간극이 Strong하게 연결됨을 의미합니다. In order to confirm the resistance between cells and cells, TEER was measured. The results are shown in FIG. 2, and the resistance between cells and cells was measured. The higher the resistance, the stronger the gap between cells was.
도 2의 결과를 보면 Indomethacin(IND)을 처리 한 후 세포 저항성이 현저하게 감소함을 볼 수 있으며 이때 PPI를 처리하여도 동일하게 세포 저항성이 감소되었음을 확인할 수 있습니다. 그러나 이때 P-CAB 처리 세포를 보시면 세포저항성이 유의적으로 증가함을 볼 수 있었습니다. The results of FIG. 2 show that after treatment with indomethacin (IND), the cell resistance was markedly decreased. In this case, the cell resistance was similarly decreased by treatment with PPI. However, at this time, the cell resistance of P-CAB-treated cells was significantly increased.
이어서 이 위장관 투과도(Intestinal permeability)와 관련 있는 tight junction protein들에는 어떤 영향이 있는지 확인하고자 western blotting을 시행하였고 그 결과를 도 3에 나타냈는데, 도 3을 보면 대표적인 tight junction protein인 ZO-2, occludin-1, claudin-1에서 IND 처리에 의하여 정상보다 그 발현이 감소해 있었으며 이때 PPI 처리시 더욱 발현이 감소하거나 또는 변화가 없었지만 이때 P-CAB의 처리 세포는 정상과 비교하여 비슷하거나 더 높은 수준으로 발현하는 것을 알 수 있었습니다. The results of the western blotting were shown in FIG. 3. FIG. 3 shows that the tight junction proteins ZO-2, occludin -1, and claudin-1, respectively. The expression of P-CAB was similar to or higher than that of normal cells. It was found that it expresses.
또한 이러한 tight junction 과 관련성이 높은 Molecular switch인 Rho-GTPase의 활성도를 확인하여 그 결과를 도 4에 나타냈는데, 도 4를 보면 IND 처리에 의하여 증가된 active Rho의 발현이 PPI 처리에 의하여 변화가 없음을 확인하였지만 이 때 P-CAB의 처리에 의하여 그 발현이 감소함을 확인하였습니다. FIG. 4 shows the results of confirming the activity of Rho-GTPase, which is a molecular switch related to tight junctions. FIG. 4 shows that the expression of active Rho increased by IND treatment was not changed by PPI treatment , But the expression of P-CAB decreased by this treatment.
이상의 세포실험 결과를 바탕으로 동물실험을 진행하였다. Based on the above cell test results, animal experiments were conducted.
동물은 SD RAT을 이용하였고 NSAID로써 Indomethacin을 경구 투여하였고 이와 함께 PPI로는 Pantoprazole을 정맥주사하였으며, P-CAB으로는 Revaprazan을 경구 투여하였으며, 투여 후 48시간 후에 Sacrifice 하여 gross와 pathologic index를 측정하고 molecular work을 진행하였다. Animals were treated with SD RAT and oral administration of Indomethacin as an NSAID. Pantoprazole was intravenously administered as a PPI, and Revaprazan was administered orally as P-CAB. Sacrifice was performed 48 hours after administration and gross and pathologic index were measured. work.
도 5로 나타낸 결과를 보면 gross에서 IND 투여에 의하여 소장에 출혈과 부종 등을 관찰할 수 있었으며 이때 PPI를 투여한 그룹에서도 동일한 소견을 얻을 수 있었다. 하지만 이때 P-CAB을 투여한 그룹에서는 상태가 호전되어 보이는 Gross를 확인할 수 있었다. As shown in FIG. 5, bleeding and swelling in the small intestine were observed by the administration of IND in the gross, and the same findings were obtained in the PPI-administered group. However, in the group administered P-CAB at this time, it was possible to confirm the gross that the condition improved.
또한 동물 조직으로 이용하여 병리학적으로 보았을 때 각 조직을 융모 손실(villi loss), 궤양(ulceration), 염증(inflammation) 등의 기준으로 점수화 하였고 그 결과를 도 6에 나타냈는데, IND을 단독으로 투여한 그룹에서는 심각한 vili loss, inflammation 등을 확인할 수 있으며 이때 PPI를 함께 투여한 그룹에서도 비슷한 양상의 소견을 보였습니다. 하지만 P-CAB을 투여한 그룹에서는 이러한 vili loss, inflammation 등이 좀 더 호전되는 결과를 보여주었다. The tissues were scored on the basis of criteria such as villi loss, ulceration, inflammation and the like. The results are shown in Fig. 6. IND was administered alone In one group, severe vili loss, inflammation, and other symptoms were observed. However, in the group treated with P-CAB, such vili loss and inflammation were more improved.
이상의 실험동물 조직을 이용하여 염증과 관련한 인자들을 확인하여 그 결과를 도 7에 나타냈는데, 그 결과 대표적인 pro-inflammatory cytokine 들의 발현이 IND처리 그룹과 PPI 병행 처리 그룹에서 높은 발현을 보였으며 이와 비교하여 P-CAB 처리 그룹에서는 그 발현이 감소함을 확인할 수 있었다. The results are shown in FIG. 7. As a result, the expression of representative pro-inflammatory cytokines was highly expressed in the IND treatment group and the PPI concurrent treatment group, It was confirmed that the expression was decreased in the P-CAB treatment group.
또한 위장관 투과도(Intestinal permeability)에 inflammasome의 활성이 영향을 미친다는 보고 등을 참고하여 inflammasome 과 관련된 인자들을 확인하여 그 결과를 도 8에 나타냈는데, 그 결과를 보면 IND 처리그룹에서 증가된 각 인자의 발현들이 오히려 PPI와 병행 처리시 그 발현이 더욱 증가되어 있음을 보였지만 이때 P-CAB 처리그룹에서는 그 발현 또한 감소되어 있음을 확인할 수 있었다. In addition, inflammatory factors were identified by referring to the influence of inflammatory activity on intestinal permeability, and the results are shown in FIG. 8. As a result, Expression of the P-CAB-treated group showed that the expression of P-CAB in the treatment with PPI was increased, but the expression of the P-CAB-treated group was also decreased.
마지막으로 위장관 투과도(Intestinal permeability)의 endpoint인 tight junction과 관련한 인자들을 확인하여 그 결과를 도 9에 나타냈는데, 그 결과를 보면 IND 처리에 의하여 tight junction protein의 발현이 감소되어 있음을 확인하였고 이때 PPI를 병행처리그룹에서는 그 발현이 ind 처리 그룹과 비슷하거나 오히려 더욱 감소되어 있음을 보였지만 이때 P-CAB처리 그룹에서는 Occluin-1, claudin-2 등의 발현이 증가됨을 확인할 수 있었다. Finally, the factors related to the tight junction, which is the endpoint of intestinal permeability, were identified and the results are shown in FIG. 9. The result showed that the expression of tight junction protein was reduced by IND treatment, . However, in the P-CAB treatment group, the expression of Occluin-1, claudin-2 and the like were increased in the parallel treatment group.
이상의 결과를 요약하면 NSAID에 의하여 위장관(Intestinal permeability)가 증가함을 확인할 수 있었고 이 때 PPI의 사용은 별다른 호전효과를 보이지 않았지만 P-CAB의 사용이 오히려 NSAID에 의해 유도된 Permeability 증가 및 intestinal damage를 완화시키는 효과를 보여주었고 이러한 효과들은 inflammasome을 비롯한 염증 mediator를 감소시키고 tight junction protein을 preserve 하는 효과에 기인함을 알 수 있었다. These results suggest that intestinal permeability is increased by NSAID and PPI does not show any improvement. However, the use of P-CAB increases the permeability and intestinal damage induced by NSAID These effects were shown to be due to the effect of reducing inflammatory mediators including inflammasome and preserve tight junction proteins.
결론적으로 NSAID에 의한 위장관 손상(Intestinal damage)에서 오는 장 누수 증후군(leaky gut syndrome)에서 PPI의 투여는 오히려 상태를 더욱 악화시킴을 보여줌으로써 PPI 대신 P-CAB의 사용이 장 누수 증후군(leaky gut syndrome)에 효과적으로 예방 및 치료함을 알 수 있다.In conclusion, PPI administration in patients with leaky gut syndrome resulting from intestinal damage caused by NSAIDs rather exacerbated the condition, suggesting that the use of P-CAB instead of PPI was associated with leaky gut syndrome ). ≪ / RTI >
상술한 설명에서는 P-CAB으로 레바프라잔(Revaprazan)을 예를 들어 설명을 하였으나 NSAID에 의한 장 누수 증후군(leaky gut syndrome)에 유용한 것은 P-CAB으로 본 발명이 속하는 기술 분야에 널리 알려진 것이라면 특별한 제한 없이 사용가능하며, 그 예로는 보노프라잔(Vonoprazan), 리나프라잔( Linaprazan), 소라프라잔(Soraprazan) 등을 들 수 있다. In the above description, Revaprazan has been exemplified as P-CAB. However, P-CAB is useful for the leaky gut syndrome caused by NSAID. Examples thereof include Vonoprazan, Linaprazan, Soraprazan, and the like.
Claims (3)
Potassium-Competitive Acid Blocker (p-cab) is a composition for treating and preventing leaky gut syndrome containing an active ingredient.
The method according to claim 1, wherein the leaky gut syndrome is caused by a nonsteroidal anti-inflammatory drug (NSAID), for the treatment and prevention of leaky gut syndrome Composition.
3. The method of claim 1 or 2, wherein the Potassium-Competitive Acid Blocker (p-cab) is selected from the group consisting of Revaprazan, Vonoprazan, Linaprazan, Wherein the composition is at least one selected from the group consisting of salicylic acid, soraprazan, and the like.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020170033118A KR20180107341A (en) | 2017-03-16 | 2017-03-16 | Composition for the treatment and prevention of Leaky Gut Syndrome comprising Potassium-Competitive Acid Blocker as active component |
| PCT/KR2017/010349 WO2018169153A1 (en) | 2017-03-16 | 2017-09-20 | Composition, containing potassium-competitive acid blocker as active ingredient, for treatment and prevention of leaky gut syndrome |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020170033118A KR20180107341A (en) | 2017-03-16 | 2017-03-16 | Composition for the treatment and prevention of Leaky Gut Syndrome comprising Potassium-Competitive Acid Blocker as active component |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20180107341A true KR20180107341A (en) | 2018-10-02 |
Family
ID=63522412
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020170033118A KR20180107341A (en) | 2017-03-16 | 2017-03-16 | Composition for the treatment and prevention of Leaky Gut Syndrome comprising Potassium-Competitive Acid Blocker as active component |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR20180107341A (en) |
| WO (1) | WO2018169153A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2022512813A (en) * | 2018-11-02 | 2022-02-07 | フォーディー ファーマ リサーチ リミテッド | Composition containing bacterial strain |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT202100010412A1 (en) | 2021-04-26 | 2022-10-26 | Anseris Farma S R L | COMPOSITION FOR THE TREATMENT OF IRRITABLE BOWEL AND METABOLIC SYNDROME RELATED TO INTESTINAL PERMEABILITY ALTERATIONS. |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0003048D0 (en) * | 2000-02-11 | 2000-03-29 | Dealler Stephen F | The therapeutic use of polysulphonated polyglycosides or other polyanionic compounds in autism |
| JP2003534287A (en) * | 2000-05-19 | 2003-11-18 | ユニバーシティ・オブ・メリーランド， ボルティモア | Use of a zonulin peptide antagonist for preventing or delaying the onset of diabetes |
| US7776873B2 (en) * | 2005-12-01 | 2010-08-17 | Yuhan Corporation | Method for treating damage to gastric mucosa |
| WO2013144083A1 (en) * | 2012-03-30 | 2013-10-03 | Nestec S.A. | 4-oxo-2-pentenoic acid and the health of the digestive tract |
| WO2014088982A1 (en) * | 2012-12-07 | 2014-06-12 | Albert Einstein College Of Medicine Of Yeshiva University | Gut barrier dysfunction treatment and prevention |
-
2017
- 2017-03-16 KR KR1020170033118A patent/KR20180107341A/en not_active Application Discontinuation
- 2017-09-20 WO PCT/KR2017/010349 patent/WO2018169153A1/en active Application Filing
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2022512813A (en) * | 2018-11-02 | 2022-02-07 | フォーディー ファーマ リサーチ リミテッド | Composition containing bacterial strain |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2018169153A1 (en) | 2018-09-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Kinoshita et al. | Eosinophilic gastrointestinal diseases-Pathogenesis, diagnosis, and treatment | |
| König et al. | Human intestinal barrier function in health and disease | |
| Úbeda et al. | Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats | |
| Bibi et al. | Dietary red raspberries attenuate dextran sulfate sodium-induced acute colitis | |
| Ammori et al. | Early increase in intestinal permeability in patients with severe acute pancreatitis: correlation with endotoxemia, organ failure, and mortality | |
| Han et al. | Porcine β-defensin 2 attenuates inflammation and mucosal lesions in dextran sodium sulfate–induced colitis | |
| Hatton et al. | All disease begins in the gut: Influence of gastrointestinal disorders and surgery on oral drug performance | |
| Mehrabani et al. | The effect of Calendula officinalis in therapy of acetic acid induced ulcerative colitis in dog as an animal model | |
| George et al. | In vivo cellular and molecular gastroprotective mechanisms of chrysin; Emphasis on oxidative stress, inflammation and angiogenesis | |
| KR20180107341A (en) | Composition for the treatment and prevention of Leaky Gut Syndrome comprising Potassium-Competitive Acid Blocker as active component | |
| Shah et al. | Attenuation of renal ischemia and reperfusion injury by human adrenomedullin and its binding protein | |
| Guo et al. | Protective effects of live combined B. subtilis and E. faecium in polymicrobial sepsis through modulating activation and transformation of macrophages and mast cells | |
| Ichida et al. | Randomized controlled trial for evaluation of the routine use of nasogastric tube decompression after elective liver surgery | |
| IL265761B1 (en) | Oral terlipressin compositions for use in treatment of ascites | |
| Corradi et al. | Effects of pentoxifylline on intestinal bacterial overgrowth, bacterial translocation and spontaneous bacterial peritonitis in cirrhotic rats with ascites | |
| Hung et al. | Effect of proton pump inhibitors on mortality in patients with cirrhosis and spontaneous bacterial peritonitis | |
| Ríos-Martín et al. | Approaches to the dermatopathologic diagnosis of figurate lesions | |
| Wu et al. | Gastroprotective effects of ginsenoside Rh4 against ethanol-induced gastric mucosal injury by inhibiting the MAPK/NF-κB signaling pathway | |
| Mori et al. | Suitable closure for post-duodenal endoscopic resection taking medical costs into consideration | |
| Lima et al. | Gastrointestinal motility, mucosal mast cell, and intestinal histology in rats: effect of prednisone | |
| Sun et al. | Ameliorative effect of Sargassum fusiforme polysaccharides on oxidative stress and inflammation in ethanol-induced gastric ulcer | |
| Zhang et al. | Proton pump inhibitors are not the key for therapying non-steroidal anti-inflammatory drugs-induced small intestinal injury | |
| US20150140121A1 (en) | Compositions and Methods for Tight Junction Modulation | |
| Ismail et al. | Royal jelly protects against experimentally-induced ulcerative colitis in adult male albino rats: A histological study | |
| El Zahaby et al. | Role of rebamipide and or pantoprazole in preventing dexamethasone induced gastritis in senile male albino rats |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E601 | Decision to refuse application |