KR20210042312A - 노화-관련 질환 및/또는 퇴행성 질환에 사용하는 약제학적 결합물 - Google Patents
노화-관련 질환 및/또는 퇴행성 질환에 사용하는 약제학적 결합물 Download PDFInfo
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Abstract
Description
도 1. 메트포민, 갈란타민 및 메트포민과 갈란타민 결합물의 단일 용량의 수명-연장 효과를 평가하기 위한 C. 엘레강스를 사용한 수명 분석. C. 엘레강스 생존을 측정하는 다수의 분석으로부터 풀링된 데이터가 제시된다. 치료는 성체 첫 날에 시작하였고 동물은 1회 투여되었다. 전체 수명 데이터를 표 1에 나타냈다.
도 2. 메트포민, 갈란타민 및 메트포민과 갈란타민 결합물의 반복 투여량의 수명-연장 효과를 평가하기 위한 C. 엘레강스를 사용한 수명 분석. 치료는 성체 첫 날에 시작하였고 동물은 1회 투여되었다. 전체 수명 데이터를 표 1에 나타냈다.
도 3. 갈란타민 및/또는 메트포민을 사용한 C. 엘레강스의 단일 투여는 노화 중 다중 운동 파라미터(즉, 평균 활성(a) 및 최대 활성(b)) 및 "건강한 날"의 평균 수(c)에 긍정적인 영향을 미쳤다. 후자는 동물의 활성이 치료되지 않은 대조군 조건의 평균 최대 활성의 15%보다 높은 일 수로 정의되는, 건강범위 파라미터이다(동일한 분석 이내임). 패널 a 및 b에서, 기준 활성(즉, 청색 광 자극 전)은 점선의 왼쪽에 표시되는 반면, 자극된 활성(즉, 청색 광 자극 후)은 점선의 오른쪽에 표시된다. 오차 막대는 SEM을 나타낸다. 통계적 유의 수준(및 백분율 변화)은 각 차트의 하단에 비처리 대조군에 대해 표시된다. "25 mM Met + 100 μM Gal"에 대한 통계적 유의성은 추가 선을 통해 표시된다. * p ANOVA < 0.05, ** p ANOVA < 0.01, *** p ANOVA < 0.001, NS 유의하지 않음.
도 4. 갈란타민 및/또는 메트포민을 사용한 C. 엘레강스의 반복 투여는 다중 운동 및 생식 후 성체에서 행동 파라미터에 긍정적인 영향을 미쳤다(평균 속도(a), 최대 속도(b), 분획 달리기(c), 셀 점유율(d)). 오차 막대는 SEM을 나타낸다. 통계적 유의 수준(및 백분율 변화)은 각 차트의 하단에 비처리 대조군에 대해 표시된다. "25 mM Met + 100 μM Gal"에 대한 통계적 유의성은 추가 선을 통해 표시된다. * p < 0.05, ** p < 0.01, *** p < 0.001, NS 유의하지 않음. 전체 운동 데이터를 표 2에 나타냈다.
도 5. 25 mM Met와 아세틸콜린에스터라제 억제제 Don 및 Riv 또는 아세틸콜린에스터라제 억제제-유사 화합물 Mem의 결합물은 25 mM Met와 아세틸콜린에스터라제 억제제 Gal의 결합물과 매우 유사한 운동 표현형을 유발한다(평균 속도(a), 최대 속도(b), 분획 달리기(c), 셀 점유율(d)). 통계적 유의 수준(및 백분율 변화)은 각 차트의 하단에 비처리 대조군에 대해 표시된다. * p < 0.05, NS 유의하지 않음. 전체 운동 데이터를 표 3에 나타냈다.
도 6. 세포보호 글루타티온 S-트랜스퍼라제 4(gst-4) 유전자의 전사가 상승작용 방식으로 Met 및 Gal에 의해 활성화되었다. C. 엘레강스의 생체 내 유전자 전자 분석으로부터의 데이터를 나타냈다. 각각의 원(생물학적 복제)은 다수의 동물로 구성된다. 오차 막대는 SEM을 나타낸다. 세 가지 독립적인 분석으로부터 풀링된 데이터를 나타냈다. 통계적 유의 수준(및 백분율 변화)은 각 차트의 하단에 비처리 대조군에 대해 표시된다. "25 mM Met + 100 μM Gal"에 대한 통계적 유의성은 추가 선을 통해 표시된다. *** p ANOVA < 0.001, NS 유의하지 않음.
도 7. Met 및 Gal의 결합물로 처리한 성체 C. 엘레강스는 비처리 대조군 동물에 비해 개선된 근육 형태를 나타낸다. (a) 종횡비는 근섬유 길이와 폭의 측정을 나타내는 반면, (b) 부드러움은 완벽한 근섬유 윤곽에 대한 측정을 나타낸다. 통계적 유의 수준(및 백분율 변화)은 비처리 대조군 상태에 대해 표시된다. * p ANOVA < 0.05, NS 유의하지 않음.
도 8. 메트포민과 갈란타민의 결합물로 처리된 근육 특이적 Opa1 -/- 마우스는 근육 질량을 유지하였고, 대사를 회복하였으며 간 지방증을 예방하였다.
암컷 Opa1 f/f (대조군), 타목시펜 처리 후 메트포민과 갈란타민 보충 유무에 따른 Opa1 -/- 마우스에서 측정한 (a) 체중, (b) 제지방 질량 및 (c) 지방 질량. (d)수컷 Opa1 f/f , 메트포민 및 갈란타민 보충 유무에 따른 Opa1 -/- 마우스의 백색 지방 조직(WAT: White adipose tissue) 함량. (e) 먹이 소비량. (f-h) 결합물 처리에 대한 생체 내 대사 반응. (f) 산소 소비량(VO2) (g) 이산화탄소 생성량(VCO2) (h) 에너지 소비량 (i) 골격근 IL6 염증 수치. 데이터는 평균 ± SEM, 암컷: n=2-4, 수컷: n=3, *p < 0.05, **p < 0.01, ****p < 0.0001.
도 9. 메트포민 및 갈란타민 둘 모두의 결합물은 근육 특이적 Opa1 -/- 마우스에서 신체 수행능(physical performance)을 개선하였다.
타목시펜 처리 후 60일 및 50일차에 각각 메트포민과 갈란타민 처리 유무에 따른 암컷 Opa1 -/- 마우스에서 측정한 (a) 트래드밀 수행에서 실행한 시간 및 (b) 악력. (c-f) 비복근에서 생체 내 수행한 힘-주파수 곡선. 각각 메트포민과 갈란타민 처리 유무에 따른 암컷 및 수컷 Opa1 -/- 마우스에서 강직성 수축(tetanic contraction) 동안 생성된 (c-d) 절대 힘 및 (e-f) 및 최대 특이적 힘. 데이터는 평균 ± SEM, 암컷: n = 2-4, 수컷: n=3, *p < 0.05, **p < 0.01.
도 10. 메트포민 및 갈란타민 둘 모두의 결합물은 Opa1 -/- 마우스에서 근육 질량을 부분적으로 보존하였다.
(a 내지 f) 각각 메트포민과 갈란타민 처리 보충 유무에 따른 암컷 및 수컷 대조군 (Opa1 f/f ), Opa1 -/- 마우스의 근육 중량. (a, d) 전경골근 (b, e) 비복근 (c, f) 가자미근. 메트포민과 갈란타민 처리 유무에 따른 암컷 대조군 (Opa1f/f), Opa1 -/- 마우스의 (g) 근섬유 수 및 (b) 탈신경 NCAM-양성 섬유의 정량화. 데이터는 평균 ± SEM, 암컷: n=2-4, 수컷: n=3, *p < 0.05, **p < 0.01, ***p < 0.001 및 ****p < 0.0001.
Claims (23)
- 대상의 노화-관련 및/또는 퇴행성 질환의 치료, 예방, 안정화, 발병 지연 및/또는 증상 감소에 사용하기 위한 약제학적 결합물로서, 상기 약제학적 결합물은
- 비구아니드 및/또는 이의 N-옥시드, 수화물, 약학적으로 허용되는 염 또는 용매화물, 및
- 아세틸콜린에스터라제 억제제 및/또는 이의 N-옥시드, 수화물, 약학적으로 허용되는 염 또는 용매화물을 포함하고,
상기 노화-관련 및/또는 퇴행성 질환은 신경-골격근계 질환, 노쇠, 염증성 질환, 및/또는 내분비 및 대사 장애인, 약제학적 결합물. - 제1항에 있어서, 상기 신경-골격근계 및/또는 노쇠의 노화-관련 및/또는 퇴행성 질환의 치료, 예방, 안정화, 발병 지연 및/또는 증상 감소에 사용하기 위한, 약제학적 결합물.
- 제1항 또는 제2항에 있어서, 상기 신경-골격근계의 노화-관련 및/또는 퇴행성 질환은 피라미드바깥길 및 운동 장애, 신경근 접합부 및 근육 질환, 주로 중추 신경계에 영향을 미치는 전신 위축증, 근이영양증, 뒤쉔 근이영양증, 척수성 근육 위축 및 관련 질환, 운동 신경 질환 예컨대 근위축성 측삭 경화증, 비정상적인 불수의 운동, 보행 및 이동성 이상, 운동 실조, 미토콘드리아 관련 신경근육골격 질환, 및 근육감소증을 포함하는 군으로부터 선택되는, 약제학적 결합물.
- 제1항 내지 제3항 중 어느 한 항에 있어서, 상기 신경-골격근계의 노화-관련 및/또는 퇴행성 질환은 피라미드바깥길 및 운동 장애, 신경근 접합부 및 근육 질환, 주로 중추 신경계에 영향을 미치는 전신 위축증, 근이영양증, 뒤쉔 근이영양증, 척수성 근육 위축 및 관련 질환, 운동 신경 질환 예컨대 근위축성 측삭 경화증, 비정상적인 불수의 운동, 보행 및 이동성 이상, 또는 운동 실조인, 약제학적 결합물.
- 제3항에 있어서, 상기 신경-골격근계의 노화-관련 및/또는 퇴행성 질환은 근육감소증인, 약제학적 결합물.
- 제3항에 있어서, 상기 신경-골격근계의 노화-관련 및/또는 퇴행성 질환은 미토콘드리아 관련 신경근육골격 질환; 특히 중심 핵 병 및 시신경 위축 1(OPA1) 관련 질환으로부터 선택되는 미토콘드리아 관련 신경근육골격 질환인, 약제학적 결합물.
- 제1항에 있어서, 상기 노화-관련 및/또는 퇴행성 염증성 질환은 증가된 사이토카인 수치와 관련되는 질환인, 약제학적 결합물.
- 제1항에 있어서, 상기 노화-관련 및/또는 퇴행성 내분비 및 대사 장애는 비만; 특히 근감소성 비만인, 약제학적 결합물.
- 제1항 내지 제8항 중 어느 한 항에 있어서, 상기 비구아니드는 메트포민인, 약제학적 결합물.
- 제1항 내지 제9항 중 어느 한 항에 있어서, 상기 아세틸콜린에스터라제 억제제는 갈란타민, 도네페질, 리바스티그민 및 메만틴을 포함하는 군으로부터 선택되는, 약제학적 결합물.
- 제10항에 있어서, 상기 아세틸콜린에스터라제 억제제는 갈란타민인, 약제학적 결합물.
- 노화-관련 불편사항 및/또는 퇴행성 불편사항의 예방, 안정화 및/또는 감소를 위한 약제학적 결합물의 용도로서, 상기 약제학적 결합물은
- 비구아니드 또는 이의 N-옥시드, 수화물, 약학적으로 허용되는 염 또는 용매화물, 및
- 아세틸콜린에스터라제 억제제 또는 이의 N-옥시드, 수화물, 약학적으로 허용되는 염 또는 용매화물
을 포함하는, 약제학적 결합물의 용도. - 수명 및/또는 건강 수명의 수치를 개선하기 위한 약제학적 결합물의 용도로서, 상기 약제학적 결합물은
- 비구아니드 또는 이의 N-옥시드, 수화물, 약학적으로 허용되는 염 또는 용매화물, 및
- 아세틸콜린에스터라제 억제제, 이의 N-옥시드, 수화물, 약학적으로 허용되는 염 또는 용매화물을 포함하며,
상기 수명 및/또는 건강 수명의 수치 개선은 약제학적 결합물의 투여 전 대상의 상태에 비해 또는 대조군 집단에 비해, 노화-관련 장애의 기능 개선, 노화-관련 장애 악화의 안정화, 노화-관련 불편사항의 완화 또는 안정화, 퇴행성 기능장애 및 퇴행성 불편사항의 완화 또는 안정화를 포함하는 군으로부터 선택되는, 약제학적 결합물의 용도. - 제12항 또는 제13항에 있어서, 상기 노화-관련 불편사항 및/또는 퇴행성 불편사항은 근육 약화, 근력 감소, 신경-근육 퇴행, 운동성 손상, 손상된 면역 반응, 대사 불균형, 일반적인 약화를 포함하는 군으로부터 선택되는, 약제학적 결합물의 용도.
- 제12항에 있어서, 상기 노화-관련 불편사항 및/또는 퇴행성 불편사항은 근육 약화, 근력 감소, 신경-근육 퇴행, 및 운동성 손상을 포함하는 군으로부터 선택되는, 약제학적 결합물의 용도.
- 제12항에 있어서, 상기 노화-관련 불편사항 및/또는 퇴행성 불편사항은 일반적인 약화인, 약제학적 결합물의 용도.
- 제13항에 있어서, 상기 수명 및/또는 건강 수명의 수치 개선은 콜레스테롤 수치, 트리글리세리드 수치, 고밀도 지질단백질 수치, 저밀도 지질단백질 수치, 렙틴 수치, 아디포넥틴 수치, 염증 파라미터, 및 혈압, 면역노화로 이루어진 군으로부터 선택되는 하나 이상의 파라미터의 개선을 포함하고, 여기서 상기 수명 및/또는 건강 수명의 개선은 약제학적 결합물의 투여 전의 대상의 상태에 비해 또는 대조군 집단에 비해 개선되는, 약제학적 결합물의 용도.
- 제12항 내지 제17항 중 어느 한 항에 있어서, 상기 비구아니드는 메트포민인, 약제학적 결합물의 용도.
- 제12항 내지 제18항 중 어느 한 항에 있어서, 상기 아세틸콜린에스터라제 억제제는 갈란타민, 도네페질, 리바스티그민, 및 메만틴을 포함하는 군으로부터 선택되는, 약제학적 결합물의 용도.
- 제19항에 있어서, 상기 아세틸콜린에스터라제 억제제는 갈란타민인, 약제학적 결합물의 용도.
- 제1항 내지 제11항 중 어느 한 항, 또는 제12항 내지 제20항 중 어느 한 항에 있어서, 상기 비구아니드 및 아세틸콜린에스터라제 억제제는 대상에 치료 용량 이하로 투여되는, 약제학적 결합물 또는 약제학적 결합물의 용도.
- 제1항 내지 제21항 중 어느 한 항에 있어서, 상기 대상은 인간 대상인, 약제학적 결합물 또는 약제학적 결합물의 용도.
- 제1항 내지 제22항 중 어느 한 항에 있어서, 상기 비구아니드 및 아세틸콜린에스터라제 억제제 또는 이들의 N-옥시드, 수화물, 약학적으로 허용되는 염 또는 용매화물은 약학 조성물로 개별적으로 제형화되거나 단일 약학 조성물로 제형화되는, 약제학적 결합물 또는 약제학적 결합물의 용도.
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CN120152703A (zh) | 2022-11-07 | 2025-06-13 | 再青春生物医药股份有限公司 | 二甲双胍微型片剂 |
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GB9718913D0 (en) | 1997-09-05 | 1997-11-12 | Glaxo Group Ltd | Substituted oxindole derivatives |
WO2000041540A2 (en) * | 1999-01-11 | 2000-07-20 | Atanas Russinov Djananov | Herbal supplement for increased muscle strength and endurance for athletes |
US6369087B1 (en) | 1999-08-26 | 2002-04-09 | Robert R. Whittle | Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
US20130217778A1 (en) * | 2010-07-21 | 2013-08-22 | Herman H. Vandenburgh | Methods and compositions for the improvement of skeletal muscle function in a mammal |
CN103860532B (zh) * | 2014-03-11 | 2016-02-17 | 贡岳松 | 美金刚和二甲双胍的复方药用组合物及其制备方法 |
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CN104623671A (zh) * | 2015-02-09 | 2015-05-20 | 徐云根 | 含有乙酰胆碱酯酶抑制剂和二甲双胍的复方药用组合物 |
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