1. •
HUPERZINE A: AN
ALKALOID WITH
COGNITIVE
ENHANCING
PROPERTIES
THE EFFECTIVENESS OF ZT-1,
A HUPERZINE A PRECURSOR, AND
DONEPEZIL IN REVERSING
SCOPOLAMINE-INDUCED COGNITIVE
IMPAIRMENT IN ELDERLY VOLUNTEERS
Andrea Zangara1
, Chris Edgar1
, Keith Wesnes1
, Pietro Scalfaro2
,
Hervé Porchet2
1
Cognitive Drug Research Ltd., Reading
2
Debiopharm SA., Lausanne

2. HUPERZINE A AND ZT-1
Huperzine A is a reversible, potent and
highly selective acetylcholinesterase inhibitor.
It demonstrated to be a safe and effective
substance for improving cognitive function.
ZT-1 represents a prodrug of huperzine A.

3. ChEIs Memory enhancement (µM/kg, p.o.) Acute LD5 (µM/kg, p.o.)
HupA 0.83 17.31
Physostigmine 1.09 6.14
Galanthamine 5.43 71.96
Tacrine 68.17 199.83
Memory enhancement (retention memory) assessed by step-down passive avoidance
performance
COMPARISON OF EFFICACY/TOXICITY
OF CHOLINESTERASE INHIBITORS IN
MICE (ZANGARA, 2003)

4. CDR SYSTEM IN ALZHEIMER’ RESEARCH
• Deterioration of central cholinergic
pathways is responsible for the cognitive
deficits seen in patients with Alzheimer's
disease (AD).
• The CDR system has been developed to
assess those domains of cognitive
function, which are influenced by the brain
cholinergic systems: attention, working
memory and episodic secondary memory.

5. HCNU
Hospitals
Contract Research
Organisations
The
Pharmaceutical
Industry
COGNITIVE DRUG RESEARCH

6. THE SCOPOLAMINE HYPOTHESIS
When scopolamine is administered to
healthy volunteers, a similar profile of
deficits is produced to that seen in AD.
This has led to the development of the
'scopolamine model', used to evaluate the
potential of novel compounds to treat the
cognitive deficits seen in AD.

7. STUDY DESIGN
This was a double-blind, randomised,
placebo and positive controlled, cross-over
study of ZT-1. In each period, 12 healthy
elderly volunteers received 0.5 mg
subcutaneous scopolamine. CDR tasks
were administered to all volunteers pre and
45 minutes post scopolamine. The
volunteers were then dosed with either
placebo, ZT-1 1.0 mg, ZT-1 1.5 mg or
donepezil 10 mg. CDR tests were re-
administered at 0.5, 2, 4.5 and 6 hours.

8. STUDY OBJECTIVES
• The aim of this study was to determine
potential actions of ZT-1, a precursor of
the alkaloid Huperzine A (a novel
cholinesterase inhibitor), in reversing
scopolamine induced cognitive and mood
decrements in healthy elderly volunteers
compared to Donepezil, the ‘lead’ drug for
Alzheimer’s Disease.
• A seconday objective was to confirm the
validity of the Scopolamine model and the
sensitivity of the CDR system to detect
the challenge.

9. RESULTS
The following graph illustrate the pattern of
change over the study day for a test of
attention, simple reaction time. For Simple
Reaction Time, statistical analysis of the
recovery scores showed a significant main
effect of treatment, with a statistically
significant benefit for ZT-1 1.5 mg over
placebo.

10. Analysis
Simple Reaction Time
Time point
-2.5 hours
-0.75 hours
1.25 hours
2.5 hours
5 hours
6.5 hours
msec
250
300
350
400
450
500
550
600
Placebo
1.0 mg ZT-1
1.5 mg ZT-1
Donepezil
Simple Reaction Time
Time point
-2.5
hours
-0.75
hours
1.25
hours
2.5
hours
5
hours
6.5
hours
msec
250
300
350
400
450
500
550
600
Placebo
1.0 mg ZT-1
1.5 mg ZT-1
Donepezil

11. Positive effects of ZT-1 were also seen in
another major domain, episodic secondary
memory. These effects are illustrated below
for Immediate Word Recall, this time
expressed in terms of the ability to reverse
the effects seen 0.75 hours after the
administration of scopolamine.

12. Immediate Word Recall - Words Correctly Recalled
Time point
-0.75
Hours
1.25
Hours
2.5
Hours
5
Hours
6.5
Hours
%
-20
-10
0
10
Placebo
1 mg ZT-1
1.5 mg ZT-1
Donepezil

13. • All three treatments were able to reduce
the impairments produced by
scopolamine. This reduction was
significant for both doses of ZT-1, as well
as donepezil.
• ZT-1 demonstrated superior power
compared to placebo, and was
comparable in direction and often
magnitude to donepezil. There were also
some indication of a better recovery
profile than donepezil.

14. CONCLUSIONS
The tasks all showed a high sensitivity to scopolamine
challenge. Both doses of ZT-1 showed indications of an
ability to reduce the impairments on tasks from the
attention, working memory, episodic secondary memory,
and motor-control domains
These data indicate further clinical research with
huperzine A and related substances, such as ZT-1, should
be undertaken
CDR system have confirmed sensitivity in the
scopolamine challenge

15. HUPERZINE A AND THE NEW EU
REGULATIONS
• Huperzine A is a highly purified substance
more similar to a drug laboratory-made
than to a plant extract. Under the new EU
directives, it is considered a herbal
medicinal product.
• Herbs previously being sold under
national food laws as food are now being
re-classified as “medicinal herbs”. Under
this new rules,a herbal medicinal product
need to respect specific requirements in
order to be approved.

16. THE NEW EU REGULATIONS ON HERBAL
PRODUCTS