Development of Puerarin to Reduce Alcohol Drinking

开发葛根素以减少饮酒

• 批准号: 6993082
• 负责人: Yanze Liu
• 金额: $ 89.52万
• 依托单位: NATURAL PHARMACIA INTERNATIONAL, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6993082
• 关键词: alcoholic beverage consumption; alcoholism /alcohol abuse; alcoholism /alcohol abuse chemotherapy; brain circulation; chemical synthesis; clinical research; drug design /synthesis /production; drug metabolism; drug screening /evaluation; flavones; glycosides; human subject; laboratory rat; magnetic resonance imaging; pharmacokinetics; plant extracts; psychopharmacology; radiotracer

DESCRIPTION (provided by applicant): This application is a resubmission in response to AA-04-002 from the National Institute on Alcohol Abuse and Alcoholism to continue our STTR (Phase I and II) study on the development of NPI-031G (Puerarin), an Isoflavone-C-glycoside isolated from Puerira lobota (Kudzu), as a botanical anti-craving agent for the treatment of alcohol drinking problems. In STTR Phase II, we showed that chronic oral administration of NPI-031G (150 mg/kg/day) suppressed daily alcohol drinking by almost 50 percent in animals throughout a 4-week study (see Preliminary Data Section C). Recently, we demonstrated that the extract of kudzu, which contains 20 percent NPI-031G, reduces alcohol intake significantly in heavy alcohol drinkers. In this continuing application, we propose to complete the preclinical work, including a toxicity study in year 01 and 02, a prerequisite for an IND application. In year 03, we will focus on clinical evaluation in human alcoholics. Specifically, we will conduct the following studies. Year 01: 1) Synthesis of radio-labeled NPI-031G; 2) Purification of NPI-031G (>99.0 percent) for clinical study; 3) Bioavailability and pharmacokinetic study; and 4) Toxicity studies (mutagenic, acute toxicity). Year 02: 1) Chronic toxicity study; 2) In vitro and in vivo drug metabolism studies; 3) Preparation of Drug Master File (DMF); 4) Request for IRB approval, 5) Submission of IND application; and 6) Phase I safety and alcohol challenge study in humans. Year 03: 1) Preparation of NPI-031G and placebo capsules under GMP conditions; 2) Effects on brain alcohol levels (humans); 3) Effects on cerebral blood flow in human; and 4) Human alcohol self-administration in natural setting. The proposed pre-clinical and clinical studies are necessary steps toward the commercial development of NPI-031G. NPI, Inc. has also prepared a comprehensive business plan for further development of NPI-031G as an anti-craving agent in collaboration with a pharmaceutical company in the US (Business Plan in Appendix).

描述（由申请人提供）：本申请是根据国家酒精滥用和酒精中毒研究所的 AA-04-002 重新提交的，以继续我们关于 NPI-031G（葛根素）开发的 STTR（第一阶段和第二阶段）研究，一种从葛根中分离出来的异黄酮-C-糖苷，作为植物抗渴剂，用于治疗饮酒问题。 在 STTR II 期中，我们表明，在为期 4 周的研究中，长期口服 NPI-031G（150 毫克/公斤/天）可将动物每日饮酒量抑制近 50%（参见初步数据 C 部分）。 最近，我们证明葛根提取物含有 20% NPI-031G，可显着减少酗酒者的酒精摄入量。在本次持续申请中，我们建议完成临床前工作，包括第 01 年和第 02 年的毒性研究，这是 IND 申请的先决条件。 03年，我们将重点关注人类酗酒者的临床评估。具体来说，我们将开展以下研究。 第01年：1）放射性标记的NPI-031G的合成； 2) 纯化NPI-031G（>99.0%）用于临床研究； 3）生物利用度和药代动力学研究； 4) 毒性研究（致突变、急性毒性）。 第02年：1）慢性毒性研究； 2）体内外药物代谢研究； 3）药品主档案（DMF）的准备； 4) 请求IRB批准，5) 提交IND申请； 6) 第一阶段人类安全性和酒精挑战研究。 第03年：1）在GMP条件下制备NPI-031G和安慰剂胶囊； 2）对大脑酒精水平的影响（人类）； 3）对人体脑血流量的影响； 4) 人类在自然环境下的自我饮酒。 拟议的临床前和临床研究是 NPI-031G 商业开发的必要步骤。 NPI, Inc.还与美国一家制药公司合作，为进一步开发NPI-031G作为抗渴药而制定了全面的商业计划（商业计划见附录）。