한약（생약）제제의 규제과학적 고찰 및 적응증 확대 연구 = Research on regulatory science and indication expansion for herbal medicine

다국어 초록 (Multilingual Abstract)

Modern regulatory science requires life-cycle safety management based on Evidence-Based Medicine （EBM）. In South Korea, 56 types of health insurance-covered herbal medicines are widely utilized based on long-standing empirical evidence from established traditional medical texts; consequently, they are exempt from non-clinical and clinical trial data submission requirements.
However, there is a significant lack of modern scientific evidence regarding their efficacy and potential drug-drug interactions （DDI）. Accordingly, this study adopts a regulatory science perspective, utilizing Hyangsapyeongwi-san （HPS） as a model to elucidate the molecular mechanism of action （MoA） for potential indication expansion and to evaluate the risk of drug-drug interactions （DDI） within clinical settings where concomitant administrations is frequent.
To evaluate the multi-target efficacy, oxidative stress was induced in HT22 cells using arachidonic acid （AA） and iron. Treatment with HPS effectively prevented Caspase-3 mediated apoptosis by inhibiting excessive reactive oxygen species （ROS） production and normalizing the impaired mitochondrial membrane potential. We confirmed that this neuroprotective effect was achieved through the direct activation of the LKB1-AMPK signaling pathway. These findings suggest that HPS possesses multi-target potential, providing a scientific rationale for indication expansion beyond conventional gastrointestinal disorders to neurological diseases.

For the safety evaluation, the expression and activity of Cytochrome P450 （CYP450） were analyzed using HepG2 cells. HPS dose-dependently inhibited the expression of CYP3A4, CYP2B6, and CYP1A2, while inducing CYP2C19. This indicates a substantial risk of pharmacokinetic interactions that could alter drug efficacy or induce toxicity when HPS is co-administered with synthetic drugs. These findings serve as essential foundational data for identifying potential DDI risks in clinical settings.
In conclusion, by elucidating the neuroprotective mechanisms and potential DDI profiles of HPS, this study provides a scientific foundation for establishing traditional medicines within the framework of EBM. The results underscore that strict clinical caution regarding pharmacokinetic interactions is mandatory, ensuring that the modernization of herbal medicine remains rooted in both efficacy and safety.

By elucidating the neuroprotective mechanism and potential drug interaction characteristics of HPS, this study provides a scientific foundation for establishing traditional medicines within the framework of evidence-based medicine （EBM）.

목차 (Table of Contents)

• 제1장 서 론 1
• 제1절 규제과학（Regulatory Science）의 이해 2
• 1. 규제과학의 정의 및 개념 2
• 2. 현대 사회에서 규제과학의 필요성 및 역할 9
• 제2절 의약품（Pharmaceutical） 규제과학 11
• 1. 의약품 개발 전주기（Life cycle）와 규제과학 11
• 2. 의약품의 과학적 평가 기준과 규제적 의사결정 14
• 제3절 천연물 의약품과 규제과학 17
• 1. 천연물 의약품의 정의 및 특수성 17
• 2. 천연물 규제과학 특징 19
• 제4절 한약제제의 분류 및 현황 21
• 1. 의약품의 분류 및 천연물 기원 의약품 21
• 2. 한약제제의 법적 정의 및 분류 체계 22
• 3. 국내 한약제제 급여 목록（56종） 및 관리 현황 23
• 제5절 연구의 필요성 및 목적 26
• 제2장 실험 재료 및 방법 28
• 1. 향사평위산（HPS）의 제조 28
• 2. 실험 재료 및 시약 29
• 3. 세포 배양 29
• 4. 세포 생존율 측정 30
• 5. 활성 산소종（ROS） 생성 측정 30
• 6. 미토콘드리아 막 전위 （MMP） 측정 31
• 7. Calcein-AM/PI 염색 31
• 8. Western blot 분석 31
• 9. 통계적 분석 33
• 제3장 실험 결과 34
• 제1절 향사평위산（HPS）의 신경보호 효과 및 기전 규명 34
• 1. 신경세포 모델에서 HPS의 세포 독성 평가 34
• 2. HPS가 AA+iron으로 유도된 세포 독성에 미치는 영향 36
• 3. AA+iron으로 유도된 산화스트레스에 대한 HPS 보호 효과 38
• 4. 활성 산소종 생성 및 미토콘드리아 기능 장애에 대한 HPS의 효과 41
• 5. HPS의 LKB1-AMPK 활성화를 통한 작용기전 확인 44
• 제2절 병용 투여 약물 상호작용（DDI） 위해성 평가 46
• 1. HPS의 CYP450 대사 효소 발현 조절 및 약물 상호작용（DDI） 평가 46
• 제4장 고 찰 48
• 제5장 결 론 53
• 참 고 문 헌 55
• ABSTRACT 60