초록

o 연구결과
식약청의 안전성유효성심사 그리고 약품안전과 및 중앙약사심의위원회(신약분과)를 통과하여 임상I상시험 허가를 취득하였으며, 서울대학교 병원 임상심사위원회를 무사히 통과하였습니다. 따라서 금년도에 임상I상시험을 계획대로 순조롭게 마치게될 것으로 예상합니다.

Abstract ▼

DDB(Dimethyl-4,4' -dimethoxy-5,6,5' ,6’ -dimethylene dioxybiphenyl-2,2' -dic따boxylate) is a synthetic analogue of Schisandrin C, one of the components isolated from Fructus Schisandrae which is a traditiona1 Chinese medicine. Fructus Schisandrae was found to be effective in improving liver functions

DDB(Dimethyl-4,4' -dimethoxy-5,6,5' ,6’ -dimethylene dioxybiphenyl-2,2' -dic따boxylate) is a synthetic analogue of Schisandrin C, one of the components isolated from Fructus Schisandrae which is a traditiona1 Chinese medicine. Fructus Schisandrae was found to be effective in improving liver functions and the symptoms of patients with chronic viral hepatitis B. DDB is an intermediate for the synthesis of the regioisomer of Schisandrin C. Unexpectedly, DDB was shown to protect agaist CCl₄, D-ga1actosamine, thioacetamide and prednisolone induced liver injuries in mice and rats. The toxicity of DDB was found to be very low. Since 1977, DDB has been tried c1inica11y in vira1 hepatitis B patients. The results indicate that DDB markedly improved impaired liver functions such as the elevated SGPT, bilirubin, a-feta1 protein and symptoms of the patients. However, the bioavailability of DDB tablet from the gastro-intestinal tract is only about 30% because DDB is very insoluble in water.
The objectives of this study are as the followings;
1) to synthesize a water-soluble DDB derivative (DDB-S) as an injectable drug,
2) to investigate the stabilities of DDB-S solution and powder,
3) to evaluate the preventive and therapeutic effects on the liver damage and the liver fibrosis/cirrhosis in rats induced by CCl₄ or dimethylnitrosamine,
4) to estimate various pharmacokinetic parameters of DDB-S administered intravenously to rats or rabbits,
5) to examine the antigenic potentia1 of DDB-S by active anaphylaxis (ASA), passive cutaneous anaphylaxsis (PCA) and passive hemagglutination (PHA) tests,
6) to eva1uate genotoxicity of DDB-S by in vitro Ames test using Salmonella typhimurium, chromosome aberration test using Chinese hamster lung (CHL) cells and in vivo micronuc1eus test using bone marrow cells of ddY mice,
7) to investigate the acute and subacute toxicities of DDB-S in SD rats,
8) to investigate the acute and subacute toxicities of DDB-S in Beagle dogs,
9) to study the genera1 pharmacology of DDB-S in SD rats.
10) to determine the metabolite of DDB-S in rats
11) to study the chronic toxicities of DDB-S in Beagle dogs.
The data obtained from these results demonstrate that DDB-S does not have any c1inica1 toxicities in rats or Beagle dogs and has the solubility of 39mg/mL in water. Therefore, it is concluded that these data can be utilized as the preclinica1 data for the development of injectable DDB-S.

목차 Contents

• 표지 ... 1
• 연구개발 최종보고서 ... 2
• 제출문 ... 3
• 요약문 ... 4
• 영문 요약문(SUMMARY) ... 7
• 목차 ... 8
• 제 1 장 서론 ... 9
• 제 2 장 국내.외 기술개발 현황 ... 10
• <제 1세부과제> 수용성 DDB 유도체 (DDB-S)의 합성 ... 11
• <제 2세부과제> DDB-S의 물성 및 안정성에 관한 연구 ... 34
• <제 3세부과제> DDB-S의 간염 치료효과실험 ... 54
• <제 4세부과제> DDB-S의 약동력학적 실험 ... 72
• <제 5세부과제;위탁연구보고서> DDB-S의 일반약리작용 ... 85
• <제 6세부과제> 수용정 DDB유도체 (DDB-S)의 일반독성시험연구 - 랫드에 있어서 급성정맥독성시험 ... 106
• <제 7세부과제> DDB유도체의 유전독성시험연구 ... 146
• <제 8세부과제> DDB-S(수용성 DDB 유도체)의 면역독성시험연구 ... 181
• <제 9세부과제> DDB유도체 (DDB-S)의 비글개 (Beagle Dog)에 대한 1회 정맥투여 급성독성시험 ... 218
• <제 10세부과제> DDB-S의 강제분해산물 및 랫드에서의 대사산물 확인시험 ... 271
• <제 11세부과제> 수용성 DDB-S의 독성시험에 관한 연구 ... 280
• 제 4장. 연구개발 목표 달성도 및 대외 기여도 ... 321
• 제 5장. 연구개발 결과의 활용성과 및 계획 ... 323
• 가. 계량적 성과 ... 323
• 나. 성과내용기술 ... 323
• 다. 활용계획 ... 323
• 제 6장. 기타 중요변경사항 ... 323
• 제 7장. 참고문헌 ... 324
• 최종보고서 요약 (초록) ... 325
• 끝페이지 ... 325