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Huperzine A

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Name:Huperzine A
Synonyms: ZT-1, DEBIO 9902, Qian ceng ta, Cerebra capsule, Pharmassure Memorall capsule
Therapy Type: Small Molecule (timeline), Dietary Supplement (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Inactive)
Company: Debiopharm Group™, Neuro-Hitech, Inc.
Approved for: None

Huperzine A is an alkaloid extract derived from the Chinese club moss Huperzia serrata. Huperzine A for many years has been widely used in traditional Chinese medicine to enhance memory and to treat fever and inflammation. In the United States it is commercially available as a food supplement, but has not been approved by the FDA as a treatment for AD or other cognition disorders.

Multiple proposed mechanisms of action for huperzine A can be found in the literature. It is a selective AChE inhibitor. It also been shown to have antioxidant and neuroprotective properties counteracting glutamate-induced toxicity, possibly by interacting with NMDA receptors (Ashani et al., 1994; Ved et al., 1997; Zhang et al., 2001; Gordon et al., 2001; Bai et al., 2000).

Research on huperzine A originated with the Chinese Academy of Sciences. The Mayo Clinic, Jacksonville, Florida, generated a version of huperzine A that was tested at Georgetown University, Washington, D.C., and licensed to the biotechnology company Neuro-Hitech to develop an oral formulation for clinical development. Preclinical studies of this compound suggested blood-brain barrier penetration and good tolerability and the same mechanism of action as the original Chinese extract (Neuro Hi-Tech media release). Additional formulations of huperzine A exist, as well.

Between 2004 and 2007, Neuro-Hitech's oral formulation of huperzine A completed a Phase 2 clinical trial in the United States for the treatment of Alzheimer's disease. Conducted by the Alzheimer Disease Cooperative Study, this multicenter, four-month trial compared two doses of huperzine to placebo in 210 people with mild to moderate AD. This trial was negative on its primary endpoint, but secondary analyses indicated a trend toward cognitive improvement on the higher dose (Rafii et al., 2011). Side effects, mostly nausea and vomiting, were mild to moderate. Development of this formulation has been discontinued.

A second trial, of a sustained-release formulation developed by Shandong Luye Pharmaceutical Co., Ltd., began in 2010 and was estimated to run for two years. According to, this Phase 2/3 study was conducted at the Shanghai Mental Health Center, to compare a six-month course of two doses to placebo in 390 people with mild to moderate Alzheimer's disease. The status of this trial is unknown and data are unavailable.

The Swiss company Debiopharm tested a synthetic huperzine derivative and prodrug, ZT-1, aka DEBIO 9902. It was reported to be well-tolerated, rapidly absorbed, and converted into huperzine A, in a small Phase 1 trial in healthy Chinese volunteers ( Jia et al., 2013). However, clinical development of DEBIO 9902 has been discontinued.

Previously, clinical trials conducted in China had reported beneficial effects on cognition. These were two-week to two-month trials in 60, 103, and 160 patients with dementia, respectively (see Xu et al., 1999; Xu et al., 1995).

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