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). ? ?
| Penetar, David M; Toto, Lindsay H; Farmer, Stacey L et al. (2012) The isoflavone puerarin reduces alcohol intake in heavy drinkers: a pilot study. Drug Alcohol Depend 126:251-6 |
