Huperzine A

Findings:

Huperzine A is described as a potent, selective, and reversible acetylcholinesterase (AChE) inhibitor used in China for Alzheimer's disease (AD) treatment. New mechanisms of action beyond AChE inhibition have also been discovered.

Authors:

BS Wang, H Wang, HZ Chen, L Zhang, YY Song, ZH Wei

Findings:

Oral administration of HupA (300-500 microg daily for 8-24 weeks) led to significant improvements in MMSE and ADL scores in patients with AD. The effect size increased over treatment time. Most adverse events were cholinergic in nature, and no serious adverse events occurred, indicating HupA is well-tolerated.

Participants:

patients with AD (Alzheimer's disease)

Dosage:

Oral administration of 300-500 microg daily for 8-24 weeks.

Study Quality Assessment:

Meta-analysis based on four randomized clinical trials comparing huperzine A (HupA) with placebo. Primary outcome measures were mini-mental state examination (MMSE) and activities of daily living scale (ADL). Data analyzed using standard meta-analysis and meta-regression methods. Treatment duration was 8-24 weeks. Adverse events were monitored.

All Effects:

Findings:

The primary analysis showed no significant cognitive effect (ADAS-Cog change at 16 weeks) for huperzine A 200 μg BID compared to placebo. Secondary analyses suggested potential cognitive benefit (ADAS-Cog and MMSE improvements) with the 400 μg BID dose, particularly at week 11 (ADAS-Cog p=0.001) and week 16 (MMSE p=0.007), though the ADAS-Cog effect at week 16 was not statistically significant (p=0.07). No significant effects were found on ADL, NPI, or CGIC at either dose. Huperzine A was generally well-tolerated.

Participants:

N=210 individuals with mild to moderate Alzheimer disease (AD), aged 50 years or older, with Mini-Mental State Examination (MMSE) scores between 10 and 24. Randomized to placebo (n=70), huperzine A 200 μg BID (n=70), or huperzine A 400 μg BID (n=70). 177 subjects completed the 16-week treatment phase.

Dosage:

Randomized to placebo, huperzine A 200 μg BID, or huperzine A 400 μg BID. Dose escalation schedule used: Group A started at 100 μg BID for 2 weeks, then 200 μg BID. Group B started at 100 μg BID for 2 weeks, then 200 μg BID for 2 weeks, then 300 μg BID for 2 weeks, then 400 μg BID.

Study Quality Assessment:

Phase II, multicenter, randomized, double-blind, placebo-controlled, 3-arm, dose-escalation trial (N=210). Duration: At least 16 weeks for primary analysis, up to 24 weeks total. Primary outcome: ADAS-Cog change at 16 weeks. Secondary outcomes: MMSE, ADCS-CGIC, ADCS-ADL, NPI. Used intention-to-treat analysis, LOCF imputation, mixed-effects modeling. Safety monitoring by Data and Safety Monitoring Board. Institutional review board approval and written informed consent obtained. Clinical trial identifier: NCT00083590. Power calculation performed (80% power for 3-point ADAS-Cog difference, deemed 'marginal statistical power'). Effectiveness of allocation concealment assessed. Funding: NIH/NIA and Neuro-Hitech, Inc. Classification of evidence: Class III evidence regarding the 200 μg BID dose.

All Effects:

Findings:

This review summarizes preclinical and clinical evidence for Huperzine A (HupA) as a neuroprotective agent for Alzheimer's disease (AD). HupA, an acetylcholinesterase inhibitor (AChEI), shows potential therapeutic benefits by modulating various molecular pathways, including reducing amyloid-β (Aβ) accumulation, promoting non-amyloidogenic APP processing, protecting mitochondria, regulating Fe2+ homeostasis, activating Wnt signaling, and reducing neuroinflammation. Some clinical trials suggest HupA improves cognition in AD and VaD patients, with reported dose and duration dependency, and is generally well-tolerated.

Participants:

The review discusses studies involving in vitro models (primary cortical neuron cultures, co-culture system of neural stem cells and microglia, primary astrocyte cultures), in vivo animal models (APPswe/PS1 mice, TgCRND8 mice, wild-type (WT) mice), and human subjects (patients with dementia including Alzheimer's disease (AD) or Vascular-associated Dementia (VaD)).

Dosage:

Mentions a small trial using 0.2 mg HupA tablets showing improvement in 58% of AD patients. A phase II trial showed cognitive enhancement with 0.4 mg HupA twice a day, tolerated for 24 weeks. Effects are described as dose-dependent (Aβ reduction in mice) and dose/duration-dependent (cognition in AD patients). Side effects noted at 'high doses'.

Study Quality Assessment:

The text describes a review summarizing findings from various studies. It mentions specific preclinical methods (e.g., proteomic analysis, specific mouse models like APPswe/PS1). For human studies, it references measurement tools (MMSE, ADAS-Cog, ADL, etc.), mentions a 'randomized clinical trial' for VaD, a 'small trial' for AD, and a 'phase II multicenter, 3-arm randomized, double-blind placebo-controlled trial' evaluated as having 'high methodological quality'. Study durations (8 weeks, 24 weeks) and side effects/tolerability are noted. Funding source (ANID grant) and conflict of interest statement (none declared) are mentioned for the review itself.

All Effects:

Findings:

Huperzine A appeared to show beneficial effects compared to placebo on cognitive function (measured by MMSE, HDS, WMS at various time points), activities of daily living (measured by ADL at various time points), and global clinical assessment (measured by CDR in one trial). However, one trial found no significant change on ADAS-Cog or ADCS-ADL. No severe adverse events were reported, and common side effects were mild (e.g., nausea, anorexia, dizziness). The authors conclude that findings should be interpreted with caution due to the poor methodological quality of the included trials.

Participants:

Systematic review included 20 RCTs involving 1823 participants with Alzheimer's disease, aged between 50 to 85 years old.

Dosage:

Dosage in included trials varied from 0.2mg to 0.8 mg daily (average ~0.37 mg daily). One trial reported tolerance up to 0.4 mg BID (twice daily).

Study Quality Assessment:

Systematic review and meta-analysis of 20 Randomized Clinical Trials (RCTs). Methodological quality assessment using Cochrane risk of bias tool found the general quality of most included trials was moderate or poor ('high risk of bias'). Specific issues noted: inadequate reporting of random sequence generation (75% unclear), allocation concealment (95% unclear), blinding (45% unclear), incomplete outcome data/attrition (most unclear), and selective outcome reporting (95% unclear). Potential publication bias suggested by asymmetrical funnel plots. Limitations acknowledged: poor methodological quality of included trials, different measurement scales used, varied treatment durations, diverse reporting methods, short treatment duration in most trials (8-12 weeks).

All Effects: