(ZE 91019) ON THE QUANTITATIVE ...

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April 19, 2000 Eur J Med Res (2000)

139

EUROPEAN JOURNAL OF MEDICAL RESEARCH 5: 139-144

@ I. Holzapfel

PHARMACODYNAMIC EFFECTS OF VALERIAN ANp Hops COMBINATION (ZE 91019)

2000

EXTRACT

EEG

ON THE QUANTITATIVE-TOPOGRAPHICAL "

IN HEALTHY B. Vonderheid-Guthl,

Publishers

VOLUNTEERS

A. Todoroval,

A. Brattström2,

W. DimpfeP

1Pro Science Private Research Institute GmbH, Linden, Germany 2Zeller Medical AG, Romanshorn, Switzerland Ö

4J

Abstract: The aim of this investigation was to objectify the pharmacodynamic effects of different dosages of a commercially available plant extract mixture of -valerian and hops by means of the quantitative topographical EEG (qEEG) in healthy young adults in comparison to placebo. Two different dosages were applied in two single-blind, cross-over designed observation trials in 12 healthy volunteers Ost dosage: 500 mg valerian and 120 mg hops, versus placebo, first clinical trial; 2nd dosage: 1500 mg valerian and 360 mg hops, versu's placebo, second clinical trial). QEEG was recorded bipolarly from 17 surface electrodes according to the 10: 20 system and analysed using the Fast Fourier Transformation prior to, 1, 2 and 4 hours after drug intake in the recording conditions eyes open, eyes closed and under mental demand. The EEG-spectra were cut into six frequency bands. Both resting conditions (eyes open and eyes closed) were analysed together. After application of the low dosage qEEG power changes remained more or less within placebo range following the normal circadian rhythmics, except for a tendentious reduction of alpha- and beta1power 4 h after drug intake. The high dosage led to power increases in delta, decreases in alpha and a weak decrease in beta-power. Under mental performance only weak differences to placebo were seen which are not discussed. .here. In the CPT (completion of complicated additions and subtractions) the concentration and performance I

capability were hardly influenced. However, a minimal increase of me an answer time and mean OK time (time for correct answers) was observed 4 hours after intake of 2 dragees and 1 hour after 6 dragees of valerian and hopsmixture with more pronounced changes after the low dosage than the high one. In -summary, the quantitative top ographi ca I EEG was able to show slight, but clear visible effects on the CNS especially after intake of the high dosage of valerian-hops mixture Ze 91019 indicating reproducible pharmacodynamic responses of the target organ. Key words: valerian; EEG

hops;

valerian-hops

mixture;

INTRODUCTION

Extracts from valerian and hops have been used traditionally since middle ages to induce sleep and for tranquillizing effects (Hänsel, 1994). Nowadays objectivation of the pharmacodynamic effects of plant extracts is' becoming more and more important due to the increasing reminiscence of phytopharmaca in prophylaxis and therapy of different diseases. Until now predominantly the effects of valerian on sleep quality have been examined. Distinct improvement of sleep qu~lity after intake of valerian was reported by Leathwood et al. (984) and Balderer et al. (985). Faust (992) reported an efficient supplementation of psychopharmaca and psychotropic plant extracts in some cases. The lack of dang er of addicti on development in the treatment of sleep disorders with valerian in comparison to hypnotics have been pointed out by hirn. The quantitative EEG seems to be one of the seI dom used objective methods to verify the mildpharmacodynamic effects of plant extracts on CNS (Dimpfel et al., 1999). Donath et al. (995) and Schulz et al. (998) were able to show some specific changes in pharmaco-EEG after application of valerian. Therefore it is of great interest to examine the ef-

. fects of the widely used combination of valerian and hops and see whether comparable EEG power changes are measurable. METHODS Both clinical trials were performed in accordance with the German drug law and the guidelines for "Good Clinical Practice". They were approved by the local ethical committee. The volunteers gave an informed written consent to participate in the study. Insurance according to the German drug law was provided. SUBJECTS

Overall 12 healthy male volunteers aged 18 to 30 years were included in both studies. The me an age was 24.17 :!: 2.86years. The first study testing the low dosage of the plant extracts took place in

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EUROPEAN JOURNAL OF MEDICAL RESEARCH

spring, the second one in the summer time of the same year, including the same volunteers. Under consideration of defined inclusion and exclusion criteria the subjects were enrolled in the trials. All volunteers underwent a complete investigation including medical history, physical, neurological examination, standard laboratory testing, ECG and EEG. Volunteers with any kind of relevant pathological findings were excluded from the study. QEEG USING COMPUTER AIDED TOPOGRAPHICAL ELECTROENCEPHALOMETRY(CATEEM@)

QEEG was recorded bipolarly from 17 electrodes according to, the international 10:20 system. The analogue signals were digitalized (512 Hz/12 bit) and frequency-analysed using the Fast Fourier Transformation (FFT). The resulting frequency spectra were cut into six frequency bands (delta: 1.25-4.50 Hz; theta: 4.75-6.75 Hz; alphaI: 7.00-9.50 Hz; alpha2 9.75-12.50 Hz; beta1: 12.75-18.50 Hz; beta2: 18.75-35.00 Hz) using 1/4-Hz steps. Details of the recording and analysis techniques are described in Schober et al. (995). CONCENTRATION

PERFORMANCE

TEST (CPT)

The psychometfical Concentration Performance Test (CPT) according to Dueker and Lienert (965) was adapted to the CATEEM@ computer system and integrated within the Computer-AidedPsychometrical-Output (CAPO) in order to ensure a simultaneous performance of the psychometrical test and the qEEG registration. The CPT was performed over 10 minutes simultaneously to the qEEG-registration. The test was realised by fulfilme nt of definite complicated calculations (asked for on the computer screen in front of the subject) by controlling a computer mouse. It referred to difficult additions and subtJ:actions in the numerical scope of up to 100 which had to be solved without any auxiliary aid. The subjects were asked to make the correct decision by moving a mousecontrolled arrow within the correct screen field among 4 figure fields. A back report about the correctness of the answer was not given. EXPERIMENTAL

SET UP

Both studies were designed as single-blind, placebo-controlled cross-over trials. After the initial screening examination one to foul' weeks prior the first study day and a further check up for exclusion criteria on day 1, the volunteers were randomised and included into the trial. The first study included two examination days in one week wash-out interval, the second study had two main examination days with one week wash-out interval, too. In accordance with the cross-over design and following the random plan the subjects received placebo 01' 2 dragees Ze 91019. In the second trial 6 dragees Ze 91019 or placebo were given according to the random plan.

April 19, 2000

On every examination day prior to, and 1, 2 and 4 hours after application of the trial medication, the qEEG was recorded in the resting conditions "eyes closed" (5 minutes) and "eyes open" 00 minutes) and under mental demand 00 min CPT). TRIAL MEDIC~;TJON

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A commercially available extract combination Ze 91019 (IVEL@ in Germany; ReDormin@ in Switzerland) of valerian and h0pS was tested. .It was given orally as dragees whereby each dragee contained 250 mg valerian roo~ oextract (4-6: 1) and 60 mg hops extract (5-7:1). Two dragees were ap-

plied as a single dose in the low dosage design and 6 dragees as a single dose in the high'Qosage one, corresponding to a total dose of 500 01' i500 mg valerian extract resp. and 120 01' 360 mg hops extract resp. EVALUATION

AND STATISTICS

For each volunteer the qEEG data were calculated as median values of the absolute electrical power over the 17 electrodes measured under the different conditions "eyes open/eyes closed" and "concentration performance test" (CPT) within each frequency band. The qEEG-data of the first 25 minutes prior to the application of the trial medication in the respective examination day served as a baseline pre-drug value in each frequency band and were set to 100 %. All qEEG-recordings at the defined time points after drug application were expressed as percentage changes of the pre-drug baseline values. The so-called placebo-corrected drug-induced qEEG changes (in percent of the pre-drug baseline) are presented and discussed. This is the ratio of the verum and placebo values of each volunteer for a certain period of measureme nt represented in percent (verum/placebo x 100). The differences in qEEG-power changes were tested between placebo and verum and within the different dosages of the plant extracts statistical level of significance p < 0.1 using at the sign test (Sachs, 1992). In the first trial only n = 11 subject's data were available because of missing data after placebo intake in one subject. In the CPT the mean answer time (e.g. the me an time to fulfil adefinite calculation) and the mean OK time (e.g. the mean time for a correct answer) were analysed. The data of the first CPT (prior to the drug intake) served as a baseline and were set to 100 %. The CPT results obtained 1, 2 and 4 hours after drug application, were expressed as percentage changes of the pre-drug baseline values. Analogous to the analysis of the qEEG data, the placebo-corrected drug-induced changes of the me an answer time and mean OK time are presented and discussed.

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April 19, 2000

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RESULTS

The qEEG follows a common circadian rhythm which should be taken into consideration for the interpretation of drug effects. The circadian rhythm is reflected in the course of the placebo daily curves. Only comparison of the verum values (a drug-induced rise or a drop in the course of the qEEG daily changes in comparison with the pre-drug baseline values) of each volunteer with the corresponding placebo daily curve allows the exclusion of the circadian power variations in the quantitative EEG. In order to detect and to describe the pure drug effects, the so-called placebo-corrected drug-induced qEEG changes (in percent of the pre-drug baseline) are considered. Only deviations of more than 5 % of the placebo level (= 100 %) are discussed. In the low dosage trial the da ta of eleven subjects were analysed (missing placepo da ta in one case), in the second trial the da ta of all twelve volunteers were included in the analysis. Under resting conditions (eyes open/eyes closed, see Fig. 1) the low dosage of valerian and hops mixture (2 dragees) produced a slight power decrease in theta-frequency 1 hour and in betalfrequency 1 and 4 hours after drug application. A statistically significant power reduction in comparison to placebo was measured after 4 h in alphalfrequency (79.15 %, P < 0.1, sign test). A clear visible, though not statistically significant power decrease was also seen after 4 hours in alpha2-frequency. The power of beta2-frequency remained within placebo range .during the entire examination period. The high dosage (6 dragees) led to some different results than the lower dosage. A clear visible, though not statistically significant delta power increase in comparison to placebo was seen under resting conditions (see Fig.' 1) after 2 hours 016 % of placebo value). Theta power was decreased after 1 hour (90 %) and slightly increased after 2 hours 005% of placebo). A clear power decrease was seen in alphal-frequency after 1 and 2 hours (81 % resp. 90 % of placebo values). Statistically significant power decrease in comparis'Ön to placebo was only seen after 2 hours in alpha2-frequency (88 % of placebo, p < 0.05). However alpha2-power remained under placebo curve during the entire period. In betal and beta2-frequency bands a slight power reduction was seen after 1 and 2 hours. The topographical distribution of power changes in delta-, alpha2- and betal-frequency band 2 hours after application of the trial medication is presented in Figure 3. After intake of 2 dragees valerian-hops mix extract the map remains "blue-green", representing predominantly alpha2- and beta l-activity. In contrast after applica tion of 6 dragees the map displays a greater extent of red colour in the additive mixture of colours due to the power increase in delta- and decrease in alpha2- and betal-activity. Comparing the effects of the different dosages of valerian and hops mixture emder resting condi-

tions, significant differences were found especially in delta and theta frequencies, but also (after 4 hours) in alpha and betal-frequency (see Fig. 1). No significant EEG changes were measurable during CPT. In summary, at rest'the low dosage of valerian and hops (2 dragees) showed differences to placebo only 4 hours after "([r.tt$ in take in alphaI, alpha2 and betal-frequency. The high dose (6 dragees) produced a clear power increase in deltafrequency (2 and 4 h). f>.slight power decrease of alpha 1 and a more pronounced decrease of alpha2 power were visible with a maximum effect after 1 to 2 hours. A weak power reduction of beta was also seen after 1-2 hours. Under mental performance in qEEG a tendency. to power increase in delta-frequency after :2 and 4 hours was seen following the application of the high dose. No significant differences to placebo or amongst the different verum dosages were detectable during the CPT. In the CPT analysis the da ta of 10 subjects in each treatment group were taken into consideration. No significant changes in comparison to placebo were seen, except for a slight increase of the me an answer time and the me an time for correct answers 4 hours after application of 2 dragees of the valerian-hops extract and less increase of tl1'e same parameters one hour after intake of 6 dragees, possibly due to a very mild impairment of concentration. These results are presented in Figure 2.

DrscussrON Since ancient times plant extracts luve successfully been used in the therapy of different diseases. Extracts of valerian root have long been recognised for their sedative and sleep improving properties. However, with the increasing role of herbaI remedies in the pharmacotherapy, many attempts were made to objectify their effects. The quantitative EEG as an objective method reflecting the functional brain state plays an important role in providing objective criteria for the CNS effects of different CNS-active herbaI preparations. Objective characterisation of plant extracts and their mixtures by means of quantitative methods (qEEG) is needed to clarify their effects on the central nervous system and to find out whether the mix-extracts have additive effects or not in comparison to the single plant extract (e.g. valerian and hops vs. valerian). The qEEG power changes induced after application of two different dos ag es of val erian-hops mix extracts (2 resp. 6 dragees of a commercially available preparation with one dragee containing 250 mg valerian and 60 mg hops) and placebo were evaluated. The analysis was based on the da ta of two different cross-over studies including the same volunteers (n = 12). Regarding both dosages no clear differences to placebo were detected after application of 2 dragees beside slight power decreases in alpha-frequencies after 4 hours. A study schedule covering

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spring, the second one in the summer time of the same year, including the same volunteers. Under consideration of defined inclusion and exclusion criteria the subjects were enrolled in the trials. All volunteers underwent a complete investigation including medical his tory, physical, neurological examination, standard laboratory testing, ECG and EEG. Volunteers with any kind of relevant pathological findings were excluded from the study. QEEG USING COMPUTER AIDED TOPOGRAPHICAL ELECTROENCEPHALOMETRY(CATEEM@)

QEEG was recorded bipolarly from 17 electrodes according tQ the international 10:20 system. The analogue signals were digitalized (512 Hz/12 bit) and frequency-analysed using the Fast Fourier Transformation (FFT). The resulting frequency spectra were cut into six frequency bands (delta: 1.25-4.50 Hz; theta: 4.75-6.75 Hz; alpha1: 7.00-9.50 Hz; alpha2 9.75-12.50 Hz; betal: 12.75-18.50 Hz; beta2: 18.75-35.00 Hz) using 1/4-Hz steps. Details of the recording and analysis techniques are described in Schober et al. (995). CONCENTRATION

PERFORMANCE

TEST (CPT)

The psychometrical Concentration Performance Test (CPT) according to Dueker and Lienert (965) was adapted to the CATEEM@ computer system and integrated within the Computer-AidedPsychometrical-Output (CAPO) in order to ensure a simultaneous performance of the psychometrical test and the qEEG registration. The CPT was performed over 10 minutes simultaneously to the qEEG-registration. The test was realised by fulfilment of definite complicated ca1culations (asked for on the computer screen in front of the subject) by controlling a computer mouse. It referred to difficult additions and subtractions in the numerical scope of up to 100 which had to be solved without any auxiliary aid. The subjects were asked to make the correct decision by moving a mousecontrolled arrow within the correct screen field among 4 figure fields. A back report -about the correctness of the answer was not given. EXPERIMENTAL

Both studies bo-controlled ,

screening

SET Up

were designed as single-blind, placecross-over trials. After the initial

examination

one to four weeks prior

the first study day and a further check up for exclusion criteria on day 1, the volunteers were randomised and included into the trial. The first study included two examination days in one week wash-out interval, the second study had two main examination days with one week wash-out interval, too. In accordance with the cross-over design and following the random plan the subjects received placebo or 2 dragees Ze 91019. In the second trial 6 dragees Ze 91019 or placebo were given according to the random plan.

April 19, 2000

On every examination day prior to, and 1, 2 and 4 hours after application of the trial medication, the qEEG was recorded in the resting conditions "eyes closed" (5 minutes) and "eyes open" 00 minutes) and under mental demand 00 min CPT). TRIAL MEDI~'V?N