•

HUPERZINE A: ANALKALOID WITH

COGNITIVEENHANCINGPROPERTIES

THE EFFECTIVENESS OF ZT-1,A HUPERZINE A PRECURSOR, AND

DONEPEZIL IN REVERSINGSCOPOLAMINE-INDUCED COGNITIVE

IMPAIRMENT IN ELDERLY VOLUNTEERSAndrea Zangara1, Chris Edgar1 , Keith Wesnes1, Pietro Scalfaro2,Hervé Porchet21Cognitive Drug Research Ltd., Reading2Debiopharm SA., Lausanne

HUPERZINE A AND ZT-1

� Huperzine A is a reversible, potent andhighly selective acetylcholinesterase inhibitor.� It demonstrated to be a safe and effectivesubstance for improving cognitive function.� ZT-1 represents a prodrug of huperzine A.

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/TOXICITYOF CHOLINESTERASE INHIBITORS IN

MICE (ZANGARA, 2003)

CDR SYSTEM IN ALZHEIMER’ RESEARCH

• Deterioration of central cholinergicpathways is responsible for the cognitivedeficits seen in patients with Alzheimer'sdisease (AD).

• The CDR system has been developed toassess those domains of cognitivefunction, which are influenced by the braincholinergic systems: attention, workingmemory and episodic secondary memory.

HCNU

Hospitals

Contract Research Organisations

The Pharmaceutical

Industry

COGNITIVE DRUG RESEARCH

THE SCOPOLAMINE HYPOTHESIS

When scopolamine is administered tohealthy volunteers, a similar profile ofdeficits is produced to that seen in AD.This has led to the development of the'scopolamine model', used to evaluate thepotential of novel compounds to treat thecognitive deficits seen in AD.

STUDY DESIGN

This was a double-blind, randomised,placebo and positive controlled, cross-overstudy of ZT-1. In each period, 12 healthyelderly volunteers received 0.5 mgsubcutaneous scopolamine. CDR taskswere administered to all volunteers pre and45 minutes post scopolamine. Thevolunteers were then dosed with eitherplacebo, ZT-1 1.0 mg, ZT-1 1.5 mg ordonepezil 10 mg. CDR tests were re-administered at 0.5, 2, 4.5 and 6 hours.

STUDY OBJECTIVES

• The aim of this study was to determinepotential actions of ZT-1, a precursor ofthe alkaloid Huperzine A (a novelcholinesterase inhibitor), in reversingscopolamine induced cognitive and mooddecrements in healthy elderly volunteerscompared to Donepezil, the ‘lead’ drug forAlzheimer’s Disease.

• A seconday objective was to confirm thevalidity of the Scopolamine model and thesensitivity of the CDR system to detectthe challenge.

RESULTS

The following graph illustrate the pattern ofchange over the study day for a test ofattention, simple reaction time. For SimpleReaction Time, statistical analysis of therecovery scores showed a significant maineffect of treatment, with a statisticallysignificant benefit for ZT-1 1.5 mg overplacebo.

AnalysisSimple Reaction Time

Time point

-2.5 hours

-0.75 hours

1.25 hours

2.5 hours

5 hours

6.5 hours

mse

c

250

300

350

400

450

500

550

600

Placebo1.0 mg ZT-11.5 mg ZT-1Donepezil

Simple Reaction Time

Time point

-2.5 hours

-0.75 hours

1.25 hours

2.5 hours

5 hours

6.5 hours

mse

c

250

300

350

400

450

500

550

600

Placebo1.0 mg ZT-11.5 mg ZT-1Donepezil

Positive effects of ZT-1 were also seen inanother major domain, episodic secondarymemory. These effects are illustrated belowfor Immediate Word Recall, this timeexpressed in terms of the ability to reversethe effects seen 0.75 hours after theadministration of scopolamine.

Immediate Word Recall - Words Correctly Recalled

Time point

-0.7

5 Hours

1.25 H

ours

2.5 H

ours

5 Hours

6.5 H

ours

%

-20

-10

0

10

Placebo1 mg ZT-11.5 mg ZT-1Donepezil

• All three treatments were able to reducethe impairments produced byscopolamine. This reduction wassignificant for both doses of ZT-1, as wellas donepezil.

• ZT-1 demonstrated superior powercompared to placebo, and wascomparable in direction and oftenmagnitude to donepezil. There were alsosome indication of a better recoveryprofile than donepezil.

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

HUPERZINE A AND THE NEW EU REGULATIONS

• Huperzine A is a highly purified substancemore similar to a drug laboratory-madethan to a plant extract. Under the new EUdirectives, it is considered a herbalmedicinal product.

• Herbs previously being sold undernational food laws as food are now beingre-classified as “medicinal herbs”. Underthis new rules,a herbal medicinal productneed to respect specific requirements inorder to be approved.

THE NEW EU REGULATIONS ON HERBAL PRODUCTS