ARTICLE IN PRESS

Phytomedicine 17 (2010) 494–499

Contents lists available at ScienceDirect

Phytomedicine
journal homepage: www.elsevier.de/phymed

Double-blind, placebo-controlled, randomised study of single dose effects of

ADAPT-232 on cognitive functions
G. Aslanyan a, E. Amroyan b, E. Gabrielyan b, M. Nylander d, G. Wikman c, A. Panossian c,n
a
Department of Clinical Pharmacology, National Institute of Health, Yerevan, Armenia
b
Scientific Centre of Drug and Medical Technology Expertise, Ministry of Health, 375001 Yerevan, Armenia
c
Swedish Herbal Institute, Prinsgatan 12, SE-411 32, Gothenburg, Sweden
d
BioCare Research and Development, Stockholm, Sweden

a r t i c l e in f o a b s t r a c t

The aim of this study was to assess the effect of a single dose of ADAPT-232 (a standardised fixed
Keywords: combination of Rhodiola rosea L., Schisandra chinensis (Turcz.) Baill., and Eleutherococcus senticosus
Adaptogens Maxim) extracts on mental performance, such as attention, speed and accuracy, in tired individuals
Rhodiola rosea performing stressful cognitive tasks.
Schisandra chinensis The pilot study (phase IIa) clinical trial took the form of a double-blind, placebo-controlled,
Eleutherococcus senticosus randomised, with two parallel groups. Forty healthy females aged between 20-68 years, who claimed to
Mental performance have felt stressed over a long period of time due to living under psychologically stressful conditions
Attention
were selected to participate in the pilot study. In addition, a Stroop Colour-Word test (Stroop CW) was
Accuracy
used to exhaust/prepare the volunteers prior to the d2 test used for assessment of cognitive function of
Speed
patients.
The participants were randomised into two groups, one (n = 20) of which received a single tablet of
ADAPT-232 (270 mg), while a second (n =20) received a single tablet of placebo.
The effects of the extract were measured prior to treatment and two hours after treatment using the
d2 Test of Attention (d2). The results of the d2 test showed a significant difference (p o 0.05) in
attention, speed, and accuracy (TN-E scores) between the two treatment groups. The subjects in the
ADAPT-232 group quickly (two hours after verum was taken) gained improved attention and increased
speed and accuracy during stressful cognitive tasks, in comparison to placebo. There was also a
tendency of ADAPT-232 to reduce percentage of errors, which means better accuracy, quality of the
work, and degree of care in the volunteers under stressful conditions. No serious side effects were
reported, although a few minor adverse events, such as sleepiness and cold extremities, were observed
in both treatment groups.
& 2010 Elsevier GmbH. All rights reserved.

Introduction
A group of herbal preparations known collectively as adapto-
gens (Brekhman and Dardymov, 1969; Panossian et al., 1999;
Panossian, 2004) can increase tolerance to mental exhaustion and
may enhance attention in cases of decreased performance, such as
in fatigue and in the sensation of weakness (Olsson et al., 2009;
Panossian and Wikman, 2009; Panossian and Wikman, 2010). The
beneficial effects of multi-dose administration of adaptogens are
mainly associated with the hypothalamic-pituitary-adrenal axis, a
part of the stress-system that is believed to play a primary role in
the reactions of the body to repeated stress and adaptation
n
Corresponding author:
E-mail addresses: gayane@pharm.am (G. Aslanyan), elmira@pharm.am
(E. Amroyan), egabri@pharm.am (E. Gabrielyan), ma.n@swipnet.se (M. Nylander),
christina.holm@shi.se (G. Wikman), alexander.panossian@shi.se (A. Panossian).
(Panossian et al., 1999; Olsson et al., 2009; Panossian et al., 2007;
Panossian and Wikman, 2008; Panossian and Wikman, 2010).
A single dose application of adaptogens is important in situations,
which requires a rapid response to tension or to a stressful
situation (Panossian and Wagner, 2005). Additionally, a single
administration of these adaptogens increases mental performance
and physical working capacity in humans (Panossian and Wagner,
2005).
The use of herbal preparations derived from Rhodiola rosea L,
Schizandra chinensis (Turcz.) Baill. and Eleutherococcus senticosus
Maxim. is not generally associated with deleterious side effects. In
contrast, traditional stimulants may cause addiction, tolerance
and abuse, and give rise to negative effects on sleep structure,
thus cause rebound hypersomnolence or ’’come down’’ effects.
ADAPT-232 is a standardised fixed combination of extracts of
R. rosea, S. chinensis and E. senticosus. The aim of the present
double-blind, parallel-group, randomised, pilot (phase IIa) study
was to evaluate the effect of a single dose of ADAPT-232 on

0944-7113/$ - see front matter & 2010 Elsevier GmbH. All rights reserved.
doi:10.1016/j.phymed.2010.02.005
 ARTICLE IN PRESS
G. Aslanyan et al. / Phytomedicine 17 (2010) 494–499 495

mental performance, such as attention, speed, and accuracy, on three days was carefully explained to all volunteers. The selected
tired subjects performing stressful cognitive tasks. participants, who also accepted the trial protocol, were included
in the double-blind comparative study. Written informed consent
was obtained from each participant in accordance with the
Subjects and Methods revised declaration of Helsinki (World Medical Association
Declaration of Helsinki, 2000).
The study protocols were reviewed and approved by the
Ethics Committee of the Armenian Drug and Medical Technology
Agency of the Ministry of Health of the Republic of Armenia. Study drugs
The pilot study involved 40 patients and was carried out at the
Department of Clinical Pharmacology of the National Institute The study drugs were manufactured according to Good
of Health (Yerevan, Armenia) between January and February Manufacturing Practice (GMP) by the Swedish Herbal Institute
2008. (Gothenburg, Sweden) and presented in the form of tablets.
The ADAPT-232 (batch 1121) tablets comprised a fixed combina-
Study population tion of dried extracts from roots of R. rosea (drug extract
ratio 2.8:1; extraction solvent 70% ethanol), berries of S. chinensis
The study population included healthy female volunteers (drug extract ratio 1.4:1; extraction solvent 95% ethanol) and
(nurses, doctors and teachers), which were recruited from a roots of E. senticosus (drug extract ratio 10.5:1; extraction solvent
polyclinic, a school and a hospital close to the Department of 70% ethanol), and had been standardised with respect to
Clinical Pharmacology. The included individuals, aged between rhodioloside (0.32%), rosavin, (0.5%), tyrosol (0.05%) schizandrin
20-68 years, had experienced stress over a long period of time due (0.37%), g-schizandrin (0.24%) and eleutherosides B and E (0.15%).
to living under psychologically stressful conditions. The verum was presented as a single 420 mg tablet, which
Pregnant or breast-feeding subjects; individuals with identi- contains 270 mg of ADAPT-232.
fied medical conditions (e.g. HIV, cancer or cardiovascular, joint, The amounts of the active ingredients were determined by
liver, kidney or psychiatric diseases); those diagnosed with analytical RP-HPLC using an acetonitrile-water gradient system as
psychiatric problems; those presenting allergic reactions to herbal mobile phase. The peaks were detected by UV-PAD (Fig. 1) and the
products; those who had used adaptogens within the previous analytes were quantified at 221 nm (rhodioloside and tyrosol),
two months or corticosteroids within the previous 6 months; 252 nm (rosavin), 220 nm (eleutheroside B), and 210 nm
those misusing tranquillisers, pain killing drugs or narcotics; (eleutheroside E, schizandrin and g-schizandrin). All the
those suffering from caffeine withdrawal syndrome or were heavy analytical methods were validated for selectivity, peak purity,
coffee drinkers; and those subjects who were deemed to be precision (RSD o5%) and accuracy in the range 50 - 150% of the
unwilling to cooperate or unable to participate in the study were target amounts of analytes in accordance with International
excluded. Conference on Harmonisation (ICH) guidelines (International
The strict requirement to avoid coffee during the complete Conference on Harmonization, 1995) using Effi Validation 3
period of the trial and to abstain from alcohol and caffeine for software (version 1.03) for testing and calibration laboratories
a minimum of one day prior to the testing session on the subject to EN ISO/IEC 17 025:2001 (International Organisation for
morning of the first day of the trial and throughout the following Standardisation, 2001).

0.36 Salidroside Rt 8.38

OH
0.34
0.32 HO
O O
0.30 OH
Eleutheroside E Rt 21.63
0.28 HO
MeO HO Schizandrin Rt 51.17
OH CH3
OH
0.26 Tyrosol Rt 9.53
O O OH H OH
OH CH3O
0.24 O OH CH3
OMe
0.22 H
H
CH3O
HO MeO
0.20 CH3O
O
AU

CH3O OCH3
Triandrin Rt
0.18 HO
O
OCH3
10.43 O
HO OMe
0.16 HO OH γ-Schizandrin Rt 75.21
0.14 H
CH3
Rosavin Rt 23.56 OH
0.12 HO
O O
CH3O CH3
Eleutheroside B OH
0.10 O O
Rt 10.88 OH CH3O
0.08 MeO HO CH3O
HO CH3O OCH3
0.06 Glc-O OH OH OCH3

0.04 MeO

0.02
0.00
250.00
300.00
λ.
nm

350.00

5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 45.00 50.00 55.00 60.00 65.00 70.00 75.00 80.00
Minutes

Fig. 1. HPLC fingerprint of ADAPT-232. Rt is the retention time (min).

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496 G. Aslanyan et al. / Phytomedicine 17 (2010) 494–499

The 420 mg placebo tablets (batch 1116) contained dark

Advertising for volunteers
brown muscovado sugar and the same inactive excipients (lactose
monohydrate, microcrystalline cellulose, magnesium stearate) as
in the verum tablets. The medication was provided in blister
packs labelled ‘‘ADAPT-232/Placebo’’ followed by a code number
(1 to 40), the identification number of the participant, dosage, Medical examination and evaluation for eligibility
batch number, and expiry date. The packaging, appearance and (inclusion and exclusion parameters)
organoleptic characteristics of the verum and placebo tablets
were similar, such that they could not be distinguished. The study
drugs were stored separately at room temperature in a secure
location to prevent their use in other ways than the described
study. Randomisation

Study design
Evaluation of primary and secondary endpoints,
The selected participants were divided into two equal evaluation of the affect of learning and degree
groups (n= 20) using a simple randomisation procedure. Group of tiredness
A received tablets containing ADAPT-232, whilst the negative
control (Group B) received identical-looking tablets containing
placebo. The identification number of each participant and the
drug code number (this was encoded in a table of random
numbers, which were generated at the production site under the ADAPT Placebo
control of quality assurance personnel and kept unbroken
until the end of the study) were recorded in a protocol and in
the Case Report Form (CRF), in order to allow subsequent
identification. Information about the placebo and the verum Administration of single dose
became known to the statistician, investigators and volunteers
only after completion of the study and final statistical analysis of
the results.
On Day 1, the subjects were examined medically and assessed
for base-line primary and secondary stress-related endpoints Two hours later,
by psychometric tests conducted in the morning (9 - 10 am) evaluation of primary endpoints and single dose effect
when patients were not tired (Tm1). On day 2, the tests were
repeated in the morning (Tm2) and afternoon (  4 pm
when subjects were supposedly tired; Ta2), and the degree of
tiredness was evaluated by comparing the results of Tm2 and Ta2,
while the effects of learning were assessed by comparison of the
results of Tm1 and Tm2. In the afternoon (  4 pm) of day 3, a single Monitoring of data.
dose of the study drug (ADAPT-232) or of placebo was Analysis of results.
administered and the effects were evaluated 2 h later by Report of study.
psychometric tests (Ta3). A schematic diagram of the trial is
displayed in Chart 1. Chart 1. Schematic diagram of the design of the trial .

d2 test

Methodology
The efficacy of the treatment was evaluated by psychometric
tests, which assessed the state of functional components of
mental activity, such as short-term memory, attention (stability
and intensity), speed and accuracy. Participants were set the task
of completing forms, with a pencil, associated with the d2 Test of
Attention (d2) and the Stroop Colour-Word (Stroop CW) tests.
Stroop CW is a cognitive aspects of mental disorders such as brain
damage, attention deficit, hyperactivity disorder, dementias. It is
also used as a stressfull cognitive task for measuring stress
response, such as arterial blood pressure, heart rate, etc.
(Facchinetti et al., 2002). At the start of the test, subjects signed
their forms and were given the appropriate instructions. A strict
time limit (measured using a stop-watch) was allowed for the
completion of the tests. Subsequently, the results were checked
with the help of keys, which have scales in the upper and the
lower lines that make it possible to read numbers of processed
letters easily and quickly.
This test is a valid measure of selective attention and is
sensitive to the speed and quality of performance (Brickenkamp
and Zillmer, 1998) with following parameters:
(i) Total number of items processed (TN) – is a quantitative
measure of performance in terms of all items processed (both
relevant and irrelevant). TN is highly reliable and measures
attention, processing speed, amount of work completed, and
motivation. Keys 1 and 2 were used for scoring.
(ii) Errors of omission (E1 - under-inclusion) - occur when
relevant items (’’d’’ with two dashes) are not crossed out.
Under-inclusion is a relatively common mistake and is
sensitive to attention control, rule compliance, accuracy of
visual scanning and quality of performance. Key 1 was used
to determine the number of mistakes of omission.
(iii) Errors of commission (E2 – over-inclusion) - occur when
irrelevant letters are crossed out in contravention of the
instructions. Over-inclusion is related to ability to focus, rule
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G. Aslanyan et al. / Phytomedicine 17 (2010) 494–499 497

compliance, accuracy of visual scanning, care, and cognitive Clinical Practice (GCP) by an independent monitor that visited the
flexibility. Key 2 was used to score the errors of commission. study site on the first and third day of the trial. Thus, adherence to
(iv) Raw error score (E= E1+ E2) – represents the total number of the study protocol, performance of the psychometric tests,
errors committed and is a preliminary statistic for computing completeness and accuracy of the CRFs, and the overall conduct
other parameters. of the trial was verified.
P P
(v) Percentage of errors (E%= 100 (E1+ E2)/ N) - is a variable
measuring the qualitative aspects of performance and Statistical methods
proportion of errors made, in terms of all items processed.
The smaller the value of E%, the better is the accuracy, quality
Standard methods were used to calculate the mean, standard
of the work, and degree of care.
error of the mean and standard deviation values of the scores in
(vi) Total number of items processed minus raw error score (TN – E)
the psychometric tests. The significance of differences between
– is a highly reliable parameter that measures the amount of
groups A and B were evaluated using Student t-tests. The
work completed after a single correction for errors, in terms
significance of the differences in test scores (day 1 versus day 2;
of ability to focus, and the relationship between speed and
morning versus afternoon on day 2; day 2 versus day 3) within
accuracy.
each group, and of the mean test scores (both before and after
treatment) between groups, were determined using one-way
Stroop CW test ANOVA with Tukey multiple comparison post tests. Data manage-
ment and calculations were performed with GraphPad (San Diego,
Stroop CW is used to measure stressful cognitive tasks and CA, USA) Prism software (version 3.03 for Windows).
stress responses, such as arterial blood pressure and heart rate,
etc. (Facchinetti et al., 2002). In the present study, a test or
manual (30150M) for clinical and experimental application was Results
employed (Golden and Freshwater, 2002). This test was based on
three pages, which each contained five columns of 20 items, in A total of 40 females aged between 20 and 68 (mean age
total 100 items. The following parameters were employed: ADAPT-232: 42.7; mean age placebo: 45.4) completed the trial
and none reported adverse reactions to the medication adminis-
(i) Word score (W) - is the number of items (words) completed tered. Although, one subject from the ADAPT group reported cold
in a set time (45 s). The ‘‘word page’’ consists of the words extremities after treatment and one subject from each of the
’’RED’’, ’’GREEN’’ and ’’BLUE’’, which were arranged randomly groups claimed that treatment had caused severe sleepiness. In
and printed in black ink on a white background. The objective addition, one subject from the treatment group reported an
was to choose the word that matched the colour printed at improvement in sleep following medication.
the top of the page. All participants were submitted to stressful cognitive tasks
(ii) Colour score (C) - is the number of items (coloured symbols) (Stroop CW and d2 tests), four times over three consecutive days
completed in a set time (45 s). The ‘‘colour page’’ consists of (Day 1: in the morning when subjects were not tired; Day 2: in
100 items, all written as XXXX, printed in either red, green, or the morning when subjects were not tired and in the afternoon
blue ink on a white background. The objective was to choose when subjects were tired; Day 3: in the afternoon, two hours after
the coloured symbols that matched the word at the top of the treatment with ADAPT or placebo, when subjects were tired).
page. Repeated testing in the mornings of days 1 and 2 allowed the
(iii) Colour-word score (CW) - is the number of items (coloured effect of learning (Table 1; Fig. 2), which were subsequently
words) completed in a set time (45 s). The ‘‘colour-word excluded from the overall results. The degree of tiredness in the
page’’ consists of words from the ‘‘word page’’ printed in afternoon of day 2 was assessed by comparing these results with
colours from the ‘‘colour page’’. The objective was to choose those obtained in the morning of the same day (Table 2; Fig. 2). It
the colour in which the word at the top of the page was was seen that there was a concomitant increase in the d2 test
written, rather than the colour that the word names. score due to learning and that tiredness decreased the score in the
afternoon test. These two effects tended to neutralise each other,
Patient compliance and withdrawals
Table 1
All blister packs were collected at the end of the trial to ensure Evaluation of the efficacy of learning in the 40 participants of the phase IIa trial.
patient compliance. The lower limit for compliance was set to
Test and Time of application of test Tm1 versus Tm2p
100%. It was seen that all participants that were included in the
parameter value (statistical
study completed the observation period. significance)
1st day/morning 2nd day/morning
(Tm1) (Tm2)
Data management procedures
Stroop-CW test
All information relevant to the study, including the results of W score 35.65 7 17.13 37.15 715.98 0.3310 (ns)
the d2 and the Stroop CW tests, was entered carefully and C score 46.77 7 11.89 49.4 711.55 0.1702 (ns)
CW score 72.757 12.97 72.23 7 15.40 0.8293 (ns)
accurately into the CRF for each participant, which were
recognized by their number and trial identification. Data were d2 test
subsequently entered on a participant-by-participant basis into a TN-E score 485.4 7103.0 535.8 788.37 0.0216 (n)
TM E% score 31.83 722.00 20.73 714.89 0.0099 (nnn)
Microsoft Excels 2000 database, for further analysis.
Values are means 7 SD.
Monitoring of the study Significance of differences between means analysed by unpaired t-test is indicated
by:
n
p o 0.05, nn p o0.01, nnn po 0.001.
The trial was monitored in accordance with the ICH (Interna- ns
Indicates no significant difference (p 40.05) between the scores before and after
tional Conference on Harmonisation, 2000) guidelines for Good treatment.
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498 G. Aslanyan et al. / Phytomedicine 17 (2010) 494–499

d2 test (TN-E score) Furthermore, in an extended study of ADAPT-232 conducted at

700 the Moscow Aviation Institute on 60 volunteers, it was (Bogatova
learning effect of effect of
effect tiredness ADAPT-232 et al., 1994) demonstrated that repeated administration of
ADAPT-232 significantly increased the capacity for mental and
* physical (mainly cardiovascular) work carried out against a
600
TN-E Score

background of fatigue and/or stress (i.e. monotonous and long-

term work that simulated the environment of the Saljut and Mir
space stations).
The results obtained in a recent study (Narimanian et al., 2005)
500 indicated that adjuvant treatment of pneumonia patients with
repeated administration of ADAPT-232 has a positive effect on the
ADAPT recovery of patients by decreasing the duration of the acute phase
Placebo of the illness, by increasing mental performance of patients in the
400 rehabilitation period, and by improving their quality-of-life.
Tm1 Tm2 Ta2 Ta3 In the present study, we assessed the mental performance
test
(attention, speed and accuracy) in stressed and tired subjects on a
Fig. 2. Results of the stressful cognitive tasks applied during the phase IIa trial single dose of ADAPT-232 or placebo, whilst they performed
showing TN-E scores in the d2 test. n Indicates significant differences (p o0.05) stressful cognitive tasks (d2 test) under time pressure. The d2 test
between two groups. measures selective attention and is sensitive to the speed and
quality of performance. The results obtained in this study clearly
showed that ADAPT-232 significantly improved scores resulting
Table 2 from the psychometric test, in comparison to placebo. It was
Evaluation of the degree of tiredness in the 40 participants of the phase IIa trial. demonstrated that subjects taking ADAPT-232 increases the
amount of precise/correct work completed on the background of
Test and Time of application of test Tm2 versus Ta2p
parameter value (statistical mental fatigue. In other words, their ability to focus, processing
significance) speed and accuracy of performing specific tasks improved. These
2nt day/morning 2rd day/afternoon effects were seen already two hours after intake of ADAPT-232.
(Tm2) (Ta2) There was also a tendency that ADAPT-232 reduced percen-
Stroop-CW test
tage of errors subjects made in the stressful psychometric test, in
W score 37.15 7 15.98 37.877 16.54 0.5534 (ns) comparison to placebo. This suggests ADAPT-232 improves the
C score 49.4 7 11.55 51.777 11.23 0.0625 (ns) quality of work and degree of care in subjects under stressful
CW score 72.23 7 15.40 75.98710.9 0.0663 (ns) conditions.
d2 test In conclusion, this pilot clinical trial suggests that ADAPT-232
TN-E score 535.8 7 88.37 543.27 89.67 0.7111 (ns) efficiently and quickly improves attention, speed and accuray
E% score 20.73 7 14.89 19.787 15.61 0.7822 (ns) in situations of decreased performance caused by stress and
Values are means7 SD.
tiredness. The results confirms previous findings and is of value to
Significance of differences between means was analysed by unpaired t-test. anyone who wants to improve their mental performance in work
ns
Indicates no significant difference (p 40.05) between the scores before and after and everyday life. Further studies are required in order to find the
treatment. optimal dose level and regimen providing contineously stable
effect.

which resulted in the observed flattening of the (TN – E) curve

markedly between Tm2 and Ta2.
A significant difference (po0.05) between the two groups was
observed in respect of TN-E score - the main parameter in the d2
test where ADAPT-232 increases speed and accuracy of mental
performance improving attention, in comparison to placebo
(Fig. 2). Thus, TN-E score increased for 43 units (from 552 to
593) in ADAPR-232 group, while in placebo group the increase
was for 8 units (from 534 to 542).
Discussion
The herbal drug ADAPT-232 comprises a fixed combination of
extracts from the adaptogens R. rosea, S. chinensis and E. senticosus,
which are known to increase non-specific resistance of an
organism to stress (Panossian et al., 2008; Panossian et al., 2009).
A single dose administration of ADAPT-232 has been shown to
increase mental performance, short-term memory, the power of
comprehension and oculomotor co-ordination in Russian cosmo-
nauts undergoing training involving long periods of monotonous
work during prolonged (90 days) isolation. In complicated
psychometric tests carried out 4 h after administration of the
drug, the number of mistakes made by the trainees was
significantly reduced (Bogatova et al., 1997).
Notice of Conflict of Interest
The study was conceived by GW, the Director and a stock-
holder of SHI Research and Development. The funding sponsor,
however, had no role in any practical aspect of the study including
experimental design, data collection, management, or analysis
and interpretation of the results. The study protocol was
formulated by AP and EA, and the ethical applications were
prepared by GA and EG. GA enrolled the participants and
performed the study interventions and, together with EA,
conducted the data analysis. AP drafted the manuscript, and all
authors were involved in its critical appraisal and final approval.
AP is employed by the Sponsor on a permanent basis. GA receives
an honorarium from the sponsor for contract research carried out
on behalf of SHI Research and Development. EG and EA have no
conflicts of interest of a commercial or financial nature in respect
of this study.
Acknowledgments
The study was sponsored by the Swedish Herbal Institute (SHI)
Research and Development, Sweden, and materials were supplied
by the sponsor.
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