Huperizine A for the Treatment of Alzheimer’s Disease

By Georges Ramalanjaona, MD, DSc, FACEP, MBA

Alzheimer’s disease (AD) is the most common age-related dementia in U.S. adults, affecting up to 5% of the population older than age 65.1 It is characterized by progressive neurodegenerative impairment of the central nervous system (CNS) and diminished cholinergic neurotransmission. Therefore, present therapeutic strategy focuses on enhancing cholinergic activity in the CNS using acetylcholinesterase inhibitors (ACHIs) to improve cognitive deficits. However, current FDA-approved drugs, such as tacrine and donepezil, display significant side effects, including cholinergic effects and hepatotoxicity.2

Huperizine A (Hup A), a natural lycopodium alkaloid isolated from the Chinese herb Hypersia serrata, is a potent, centrally active, and selective ACHI and has been shown to improve cognitive impairment in various animal and human brain function models.3-5

The purpose of this article is to review the current clinical evidence on the role of Hup A in AD. Clinical trials suggest that Hup A may enhance short-term memory and mental status in AD patients.

Pharmacokinetics

In animal studies, purified Hup A displays a high oral bioavailability, good intestinal absorption, and an excellent penetration through the blood-brain barrier. It has a long half-life in vivo, and a longer duration of effects on acetylcholinesterase (ACHE) (3 hours) than tacrine (2 hours) and physostigmine (30 minutes).6

Mechanism of Action

Hup A acts on AD by several mechanisms:

Hup A is a reversible and selective ACHI that prevents the degradation of endogenous acetylcholine (ACH), a neurotransmitter involved in memory formation and neuronal communication.7 Brain biopsies of patients with AD have shown significant loss of presynaptic cholinergic neurons.8 Hup A appears to bind more tightly, specifically, and longer to the brain ACH than the other ACHIs. Thus, the ACHE-Hup A complex has a slower dissociative rate and more effective therapeutic index compared to other drugs.

Studies using cultures of cells derived from hippocampus and cerebellum of rat embryos have pointed out that Hup A decreases neuronal cell death induced by toxic levels of glutamate. This compound activates N-Methyl-D aspartate (NMDA) receptors and increases the flux of calcium ions into the neurons, which is neurotoxic.9

Excessive deposition of amyloid B-Peptide (AB) in the brain is the major pathological hallmark of AD. Hup A acts as a neuroprotective agent against AB-induced oxidative injury resulting from free radicals.10

Clinical Studies

Although clinical trials demonstrating the role of Hup A in AD are scarce, their results are clinically significant and deserve our attention (see Table, below).

Table

Recent randomized clinical trials of Huperizine A in the treatment of Alzheimer’s disease

Studies Patients  Treatment Duration Results
Xu et al (1995)11   103 Hup A vs. placebo 8 weeks Hup A group significantly improved in all three categories vs. placebo
Xu et al (1999)4 60 Hup A in tablets and capsules vs. placebo 8 weeks No difference between Hup A tablet and capsule
Statistically significant in all psychological evaluation before and after the six-day Hup A treatment (P < 0.01)
Mazurek et al (unpublished reports) 29 Hup A group ongoing Preliminary results show improvement in mental status in 50% of Hup A group.

 

In a prospective, double-blind, placebo-controlled study of 103 patients in China (evidence grade I in class I-III), Xu et al showed a statistically significant improvement (P < 0.01) in memory and behavioral and cognitive function in 58% of AD patients taking 200 mcg/d of Hup A compared to 36% of placebo-group patients during the eight-week period.11 Memory, cognitive function, and behavioral functions were measured by memory quotient, Mini-Mental State Examination scale, and activity of daily living scale, respectively. There was a slight increase in mild peripheral cholinergic side effects in the Hup A group compared to the placebo group. However, there was no statistically significant difference between those two groups.

In a more recent trial, Xu et al used a prospective multicenter, double-blind, randomized parallel study of 60 patients (evidence grade I) to show a clinically and statistically significant difference (P < 0.01) on all psychological tests before and after the 60-day trial of Hup A for the two treatment groups (four tablets or four capsules a day of 50 mcg).12 However, there was no significant difference between the two Hup A groups or the two placebo groups, and no clinically significant side effects in either group.

Limitations of these clinical trials include small sample size, lack of longer-term follow up, and absence of direct clinical comparison with other ACHI.

Ongoing Clinical Trials

In a preliminary study of 29 AD patients, Mazurek showed a marked improvement in mental status in more than 50% of patients taking 100 mcg/d of Hup A (unpublished reports, limited data). This preliminary trial seems promising in symptomatic improvement of AD; final results are still pending and unpublished.

Adverse Effects

In short-term trials, a slight increase in mild peripheral cholinergic side effects, such as nausea, vomiting, and diarrhea, have been reported in Hup A groups.13 These side effects are not statistically significant compared to placebo.

Contraindications and Precautions

To date, there are no reported contraindications or drug interactions of Hup A in human clinical trials. Because of insufficient reliable data, pregnant and nursing women should avoid Hup A use. No interactions are known to occur with foods or laboratory tests. Theoretically, concurrent use of anticholinergic drugs might decrease the effectiveness Hup A. Conversely, cholinergic drugs and ACHI might increase Hup A effects.

Formulation and Dosage

Hup A was first synthesized in 1991, and is commercially marketed in the United States as Cerebra in the form of dietary supplements.

In China, it has been approved as a prescription drug for symptomatic treatment of AD.

Current dosage used in clinical trials ranges from 100 to 200 mcg/d PO in divided doses.

Conclusion

Preliminary short-term studies are promising on the role of Hup A in the symptomatic treatment of AD. Specifically, patients treated with Hup A showed significant improvement in their memory and cognitive and behavioral function. Based on current trials, Hup A is possibly effective and safe in improving short-term memory and mental status in AD. Application of these results is limited due to small sample size and lack of long-term follow up.

Recommendation

Based on the scientific limitations of the data, Hup A cannot yet be recommended in AD patients. Final recommendations are awaiting the results of long-term (five-year), large clinical trials to confirm the effectiveness and safety of Hup A in AD patients.

Dr. Ramalanjaona is Associate Chairman for Academic Affairs, Department of Emergency Medicine, Seton Hall University, School of Graduate Medical Educa- tion, South Orange, NJ; and Director of Research, Division of Emergency Medicine, St. Michael’s Hospital, Newark, NJ.

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