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The effects of repeated administration of camphor-crataegus berry extract combination on blood pressure and on attentional performance--a randomized, placebo-controlled, double-blind study.

ABSTRACT

The present study investigated the effects of repeated administration of Korodin[R], a combination of camphor and crataegus berry extract, on blood pressure and attentional functioning. This study was conducted based on a randomized, placebo-controlled, double-blind design. 54 persons participated (33 female, 21 male) with a mean age of 24.3 years. Blood pressure and body mass index were in the normal range. Participants received 20 drops of either Korodin[R] or a placebo for four times with interjacent time intervals of about 10 min. Blood pressure was measured sphygmomanometrically before and after each administration. Attentional performance was quantified by using two paper-and-pencil tests, the d2 Test of Attention and Digit Symbol Test.

Greater increases in blood pressure occurred after the four Korodin[R] administrations in comparison to the four placebo administrations. The performance in two parameters of d2 Test of Attention was consistently superior after the intake of Korodin[R]. The excellent tolerability and safety of Korodin[R], even after a total consumption of 80 drops, was confirmed.

Keywords:

Camphor

Crataegus berry

Blood pressure

Cognitive function

Complaints

Introduction

The camphor-crataegus berry extract combination, Korodin[R] Herz-Kreislauf-Tropfen, is widely used for the treatment of low blood pressure. It is applied both during transient phases of hypotension, including orthostatic hypotension, and in patients suffering from chronic hypotension. The latter form of hypotension is relatively widespread, insofar as about 3-5% of the general population is affected (Duschek and Schandry 2007).

Hypotension, including orthostatic hypotension, is associated with significant morbidity and mortality (Mukai and Lipsitz 2002). Furthermore, it has been identified as serious risk factor for stroke and coronary artery disease in the elderly (Eigenbrodt et al. 2000; Jones et al. 2012; Masaki et al. 1998; Rose et al. 2006). Fedorowski et al. (2010) reported an increased risk for cardiac events and all-cause mortality in middle-aged individuals suffering from hypotension. Mattila et al. (1988) showed higher mortality for the subgroup with the lowest blood pressure within the group of individuals above an age of 85 years. Furthermore, an association of low blood pressure in late adolescence with subsequent mortality has been reported (Sundstrom et al. 2011). Additionally, low blood pressure is associated with anxiety and depression (e.g. Hildrum et al. 2007).

Subjective symptoms typically accompany chronically low blood pressure; among these symptoms are fatigue, reduced drive, depressed mood, faintness, dizziness, headache, palpitations, and cold limbs (Weiss and Donat 1982). A considerable impact of these complaints on subjective well-being and quality of life has been shown in several large, population-based studies (e.g. Pilgrim et al. 1992).

In addition to the subjective complaints, several studies have revealed reduced cognitive performance due to chronic hypotension. Wharton et al. (2006) observed deficits in visuospatial attention tasks in persons with low blood pressure and Stegagno et al. (1996) reported reduced performance of hypotensive subjects on a short-term memory test and a mental arithmetic task. As a physiological mechanism mediating the relationship between low blood pressure and cognitive deficits, alterations in cerebral blood flow have been suggested (Owens and O'Brian 1996; Pilgrim et al. 1992).

Treatment of symptoms of low blood pressure has been shown to be effective in several studies applying chemically synthesized antihypotensiva like midodrine (Low et al. 1997) as well as the phytocombination of natural camphor and the extract from fresh crataegus berry, i.e. Korodin[R] (Belz and Loew 2003; Duschek et al. 2007; Kroll et al. 2005). For the latter compound it was demonstrated that hypotensive symptoms such as dizziness, vertigo and fatigue could be reliably reduced. In a large multicentre study including 490 patients with orthostatic hypotension Hempel et al. (2005) demonstrated a superior reduction of hypotensive complaints using the camphor-crataegus combination as compared to chemically synthesized antihypotensiva.

Various attempts have been undertaken to investigate the positive effects of pharmacological antihypotensive therapy on mental functioning (Duschek et al. 2007; Schandry and Duschek 2008; Werner et al. 2009). Duschek et al. (2007) were able to show that the application of the relatively long-acting sympathomimetics midodrine and etilefrine lead to increased attentional performance. It was demonstrated that the elevation of blood pressure through Korodin[R] was accompanied by an improvement of cognitive performance (Schandry and Duschek 2008; Werner et al. 2009).

Studies investigating the effects of antihypotensive drugs on extended time base are rare. Schandry (1999) reported a positive effect on subjective symptoms after 2 weeks of therapy with etilefrine. Hempel et al. (2005) presented data from a retrospective epidemiological cohort study, in which Korodin[R] was administered. The median of the duration of therapy was 71 days. In 70% of patients symptoms were reduced, in 23% symptoms had disappeared and in 7% symptoms were unchanged. However, because of the retrospective and observational character results of this study are of limited validity. In addition, Harder and Rietbrock (1990) investigated the long-term effects of Korodin[R] in an open multicentre trial of 4 weeks duration. Participating patients suffered from functional cardiovascular disorders. At the end of the observation period the group-mean of systolic pressure had increased by 5.8 mmHg, and of diastolic blood pressure by 3.2 mmHg. Subjective symptoms, related to the cardiovascular system, had decreased in about 90% of the patients. However, an unequivocal interpretation of the results is not possible because of the lack of randomization and a placebo group.

Relatively little is known about the effects of a repeated administration of Korodin[R]. A study where Korodin[R] was administered repeatedly on a comparatively short time basis was reported (Belz et al. 2000; Herrmann et al. 1996). The authors investigated on the basis of a placebo-controlled design the effects of cumulative doses of Korodin[R] (20, 40, 80, and 120 drops) applied in a regular interval of about 1 h between each dose step. They observed dose-dependent increases in mean arterial pressure after each Korodin[R] administration and slight rise in the base level of the mean arterial pressure. However, this design does not allow disentangling the pure repetition effect from the dose-dependent effect.

With the present study we aimed to investigate the effects of multiple Korodin[R] administrations in an unconfounded manner. Blood pressure and parameters of attentional functioning were assessed as dependent variables on the basis of a randomized, placebo-controlled, and double-blind study design.

Materials and methods

Study design

This single centre, double-blind, placebo-controlled, and randomized trial was performed in June 2012. The protocol was approved by the Ethics Committee of the Faculty of Psychology and Education of the University of Munich. The study followed the guidelines of the declaration of Helsinki and Tokyo for humans. Assessments were conducted at the Biological Psychology Research Unit of the University of Munich. The attending physician and research assistant underwent pre-study training. Participants were requested not to smoke, drink alcohol or beverages containing caffeine for 3 h prior to the experimental sessions. Furthermore, they were informed to have breakfast before participating. All participants had to give a written informed consent and received financial remuneration of 50 Euro. The session lasted for about 50 min.

Participants

54 persons, 33 female (61.1%), 21 male (38.9%) participated. Age ranged from 18 to 40 years (mean age: 24.3 years). Recruitment was accomplished by advertisements as well as by information signs posted in several university buildings. Health status of the participants was assessed by anamnestic interview and questionnaire covering diseases of the cardiovascular, respiratory, gastro-intestinal systems, thyroid, liver, as well as metabolic diseases and psychiatric disorders.

Exclusion criteria were presence of affective disorders, serious chronic diseases, history of substance abuse, severe cognitive disorder, pregnancy or breast-feeding.

Randomization and blinding

Verum (Korodin[R]) and placebo were individually prepared in small brown bottles, provided with a number. The assignments of bottle numbers to subject numbers were to be found on a separate sheet, prepared by the sponsor. Subject numbers were assigned to participants according to the sequence of their appearance. Thus, after assigning the subject number to a participant the corresponding bottle number was evident. Unblinding occurred at data analysis.

Study drugs

Participants of the verum group received four times 20 drops of Korodin[R] (being purchased in a pharmacy). Hundred grams of Korodin[R] contain 97.3 g fluid extract from fresh crataegus berries (drug-extract-ratio 1:1.3-1.5; final ethanol concentration 60 vol%), 2.5 g natural D-camphor, and 0.2 g menthol as an aromatic ingredient. One drop Korodin[R], a brown clear liquid, contains 38.62 mg crataegus berry extract and 1 mg D-camphor.

Korodin[R] heart circulation drops are a combination of D-camphor and a liquid extract from fresh hawthorn fruits (crataegi fructus recens) for oral use. The approved indication is hypotonic and orthostatic circulatory dysregulation. Korodin[R] heart circulation drops are in the current composition as an OTC medicinal product since 1962, exclusively available in pharmacies. Korodin[R] is on the market in Austria and Germany, where it was originally introduced in 1927.

In the placebo group, 20 drops of wormwood tea (prepared in the investigators lab) was administered four times. This liquid is of a bitter taste similar to Korodin[R] and is also of brown colour. Both Korodin[R] and placebo were of brown colour and dispensed on a sugar lump.

Test material

d2 Test of Attention

The d2 Test of Attention (Brickenkamp 1994) measures processing speed, rule compliance, and quality of performance, allowing for an estimation of individual attention and concentration performance. Reliability has proven to be very high, and validity of the technique has been documented by a number of research studies. Two parameters were used in the present study to quantify speed and accuracy of performance: (1) the total number of errors (TE), i.e. skipped targets and erroneously marked distractors, and (2) concentration performance (CL), i.e. number of items processed minus number of mistakes among the processed stimuli. Standard scores are used.

Digit Symbol Test

The Digit Symbol Test, a subtest of the Wechsler Adult Intelligence Scale (WAIS-R; Wechsler 1981), measures visuomotor speed and selective attention. In this task, participants are required to reproduce as many symbols as possible in blank boxes beneath randomly generated digits, according to a coding scheme, which pairs digits with corresponding symbols. The test score consists of the number of correctly assigned symbols within 120 s.

Case report form (CRF)

Anthropometric data, actual or former illnesses, concomitant medications, and adverse events were notes in the CRF. Furthermore, all blood pressure readings and results of cognitive test were recorded.

Blood pressure reading

Blood pressure was assessed sphygmomanometrically by the physician using a calibrated semi-automatic device (Omron M9 Premium, Omron Medizintechnik, Mannheim, Germany). Measurements were taken in a sitting position.

Data acquisition

Data acquisition was conducted according to the following steps:

(1) Participant reads and signs the informed consent form.

(2) Anamnestic interview and examination by the physician.

(3) After a rest period of 10 min, three blood pressure and heart rate measurements are taken in a sitting position. They are separated by rest intervals of 5 min.

(4) Instruction for the Digit Symbol Test is read.

(5) First completion of the Digit Symbol Test.

(6) Instruction for the d2 Test of Attention is read.

(7) First completion of the d2 Test of Attention.

(8) Blood pressure reading before first substance administration.

(9) First substance administration.

(10) Blood pressure reading.

(11) Second completion of the d2 Test of Attention.

(12) After 10 min rest: Blood pressure reading before second substance administration.

(13) Second substance administration.

(14) Blood pressure reading.

(15) Third completion of the d2 Test of Attention.

(16) After 10 min rest: Blood pressure reading before third substance administration.

(17) Third substance administration.

(18) Blood pressure reading.

(19) Fourth completion of the d2 Test of Attention.

(20) After 10 min rest: Blood pressure reading before fourth substance administration.

(21) Fourth substance administration.

(22) Blood pressure reading.

(23) Fifth completion of the d2 Test of Attention.

(24) Second completion of the Digit Symbol Test.

(25) Physician completes the Adverse Advents Form.

(26) Debriefing of participant. Interview and eventual reexamination by the physician.

(27) Participant receives remuneration of 50 Euro.

Data analysis

Analyses were conducted using SPSS version 21.0. Effects of Korodin[R] on blood pressure were examined by using T-test for dependent samples. Differences between verum and placebo group were evaluated using T-test for independent samples. In order to control for differences between both groups at the pre-test stage, T-tests for paired samples were computed for each of the dependent variables. A p-value of 0.05 was considered statistically significant.

Results

Sample characteristics

Due to implausible blood pressure values (caused by equipment failure), one participant (#1331, placebo group) had to be excluded from further analyses of the blood pressure data.

Table 1 shows age, body mass index (BMI), blood pressure and heart rate at baseline for the two groups.

The means of BMI, systolic blood pressure, diastolic blood pressure, mean arterial pressure (MaBP), and heart rate did not differ significantly between the two study groups (T-tests for independent samples).

Blood pressure

Table 2 shows the mean values for systolic blood pressure, diastolic blood pressure and mean arterial pressure before and after substance administration as well as the change values.

Figs. 1-3 show the change values for systolic blood pressure, diastolic blood pressure and mean arterial blood pressure for the four substance administrations.

The blood pressure changes due to the substance administrations were tested for significance. The results of the T-tests for paired samples are given in Table 3.

The differences of the change values between verum and placebo group were tested with the T-test for unpaired samples. Corresponding T- and p-values are given in Table 4.

In order to test the assumption that the height of blood pressure response after Korodin[R] may be depending on the resting blood pressure (i.e. whether lower baseline values yield in higher responses), we computed correlation coefficients between blood pressure at baseline and the blood pressure change after Korodin[R]. The respective correlation coefficients are found in Table 5. A negative sign of r denotes a higher response at lower baseline values.

The partially high correlation coefficients substantiate the fact that after the intake of Korodin[R] a significantly higher increase in blood pressure is to be expected for participants with a lower blood pressure at baseline in comparison to participants with a higher blood pressure at baseline.

Cognitive performance

Four cases had to be removed from analysis of the d2 Test of Attention scores, due to extreme values (case numbers #1349, #1308, #1338, #1323).

d2 Test of Attention, total number of errors

Changes of the total number of errors (TE) in the d2 Test of Attention are calculated as differences in TE after substance administration minus TE at baseline, i.e. before the first substance administration. Change values (i.e. improvements) of TE are displayed for the two groups and four substance administrations in Fig. 4.

d2 Test of Attention, concentration performance

Changes in concentration performance (CP) in the d2 Test of Attention are calculated as differences between CP after substance administration and CP at baseline, i.e. before the first substance administration. Values of CP are standard scores. Change values are displayed for the two groups and four substance administrations in Fig. 5.

Digit Symbol Test

In the Digit Symbol Test only marginal differences occurred in the change scores between groups, not reaching significance level.

Tolerability, complaints

In the Adverse Events Form, the physician did not report any events. Correspondingly, the additional interrogation of the participants pertaining to subjective complaints did not reveal any unwanted events.

Participants' guess about of verum or placebo administration

At the end of the session, participants had to judge whether they had received Korodin[R] or placebo. A Chi-square test showed that their judgments did not differ significantly from chance ([chi square] [1] = 2.884, p = 0.128).

Safety

The interview and re-examination by the physician showed no side effects, unknown or known effects, due to verum or placebo by any of the participants.

Discussion

Based on a randomized, placebo-controlled, and double-blind design, the present study aimed at gaining information about the effects of repeated administration of Korodin[R] on blood pressure and cognitive functions. Substances were administered four times. As main results, we observed consistently greater increases in blood pressure in response to Korodin[R] after all administrations in comparison to placebo. A similar picture appeared in cognitive functions: The performance in two parameters of the d2 Test of Attention was superior after the administration of Korodin[R].

The positive effects of a single dose of Korodin[R] on blood pressure and cognitive functions have been demonstrated earlier: Schandry and Duschek (2008) reported two placebo-controlled studies with hypotensive women, in which the administration of Korodin[R] led to an increase of blood pressure and cognitive performance. These effects were already visible within the time range of 2-5 min after substance administration. Additionally, a positive correlation between blood pressure increase and performance enhancement could be demonstrated for two cognitive tasks. In a related study, Werner et al. (2009) obtained comparable results for a sample of elderly women. Korodin[R] caused--in contrast to placebo--a short-term increase of blood pressure as well as of cognitive performance.

The results of the present study show a reduction of the blood pressure responses with repetition. Thus, accumulation of the effect of Korodin[R] with fourfold administration does not occur. This holds despite of rapid repetition rate, i.e. with intervals less than 10 min. However, looking on the pharmacokinetics of camphor (Zuccarini 2009), where peak plasma levels as late as 1 h after administration are reported, accumulation of effects would not be improbable. Considering the fast action of Korodin[R], especially pertaining to blood pressure, it seems reasonable to take more rapid ways of action into account than the one via the stomach and the blood stream. One alternative route of action could extend from the oral mucosa via the cranial nerves to the cardiovascular regulatory centres in the brain stem. From here a rapid, neurally induced constriction of peripheral small blood vessels may be triggered.

From the above mentioned finding one may infer that during the application of Korodin[R], e.g. when applied in the case of an acute drop of blood pressure, a repeated administration does not impose the risk of accumulation. Additionally, as seen in previous studies (Werner et al. 2009), the rise of blood pressure lasts only for a short period of 1-7 min.

Herrmann et al. (1996) conducted a study with repeated administration, in which the effects of Korodin[R] on blood pressure were investigated. However, in this study, concurrently with each repetition, the dose was increased (5,20,80 and finally up to 120 drops). Thus, it is easily conceivable that the observed stepwise rise of blood pressure was a consequence of the increments of doses with each step.

With the intake of any drug counter-regulatory processes, yielding a dampening of the response, have to be taken into account. During repeated substance administration these rapidly occurring counter-regulatory processes generally lead to the development of tolerance. The data as depicted, e.g. in Figs. 1 and 3, and to a minor degree in Fig. 2, suggest that blood pressure responses are governed by the development of tolerance. However, even after the fourth administration of verum the response does not decline to the placebo level. Unexpectedly, the responses of systolic and diastolic blood pressure are not coincident: reactions of systolic blood pressure are continuously decreasing; in contrast, diastolic blood pressure shows a renewed increase after the second substance administration. Presumably, this is a consequence of the different physiological control mechanisms of diastolic blood pressure, regarding e.g. the role of vascular processes.

A closer look at responses of the placebo group (cf. Figs. 1-3) reveals that the effect of intake of a drug without an active component does not decline to zero even after the fourth repetition. Compared to the active substance, the effect remains more or less constant on a low level. Obviously, habituation of the placebo effect does not occur. This confirms earlier results (Duncan et al. 2009) about the stability of the placebo effect in a slight steady rising of BP over a number of repetitions.

There is strong evidence that the elevation of blood pressure after Korodin[R] is related to the baseline value (cf. Table 5), in such as lower baseline values are accompanied by higher responses. This finding is in accordance with results of Belz and Loew (2003): Here, a dosage of 40 drops of Korodin[R] administered at a lower baseline yielded in a higher blood pressure response than 80 drops administered at a higher baseline level. The inverse relation between baseline value and the height of response could be a consequence of the physiological mechanisms governing up-regulation of blood pressure. As blood pressure is fine-tuned in a manner preventing extreme ranges (Klabunde 2011), an up-regulation of blood pressure originating from lower baseline values is less limited than it would be in the case of a higher baseline.

The positive effect of Korodin[R] on certain aspects of mental performance could be confirmed in accordance with earlier studies (Schandry and Duschek 2008; Schandry et al. 2011; Werner et al. 2009). In contrast to previous studies, however, we could not observe a positive correlation between increase of blood pressure and improvement of mental performance. Hence, other beneficial factors, acting on mental processes, besides blood pressure rise have to be considered. For instance, there is evidence that camphor acts broncho-dilating when inhaled. Our participants were instructed to breath with open mouth, while Korodin[R] was still present in the oral cavity. Thus, via a relatively direct route oxygen supply to the blood and subsequently to the brain is conceivable. In addition, a general alerting effect due to the strong gustatory sensation associated with the intake of Korodin[R] cannot be ruled out.

Tolerability and safety of a fourfold administration of Korodin has proven to be satisfactory, which is in accordance with results from Herrmann et al. (1996). Neither in the Adverse Events Form nor in the additional interrogation by the physician were any subjective complaints or unwanted events reported.

In conclusion, on the basis of this randomized, placebo-controlled, double-blind study we observed that a fourfold repeated administration of Korodin[R] consistently leads to an increase of blood pressure. However, this increase becomes weaker with repetition, but total extinction of the response does not occur. Earlier findings of a positive influence of Korodin[R] on attentional performance could be corroborated. The lack of accumulation of the blood pressure effects is ascribed to the fast acting metabolism of Camphor. Tolerability and safety of Korodin[R], even after an overall consumption of 80 drops, proved to be satisfactory.

Conflicts of interest

The authors declare that they have no conflicts of interest.

ARTICLE INFO

Article history:

Received 22 March 2014

Received in revised form 4 May 2014

Accepted 27 June 2014

http://dx.doi.org/10.1016/j.phymed.2014.06.014

Acknowledgement

This study (project number: 2012-1) was supported by Robugen GmbH (Esslingen, Germany), including financial remuneration (50 Euro) of participants.

References

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L. Erfurt, R. Schandry *, S. Rubenbauer, U. Braun

Department of Psychology, Ludwig-Maximilians-University Munich, Leopoldstr. 13, D-80802 Munich, Germany

* Corresponding author. Tel.: +49 172 8629802; fax: +49 32121011404.

E-mail address: schandry@lmu.de (R. Schandry).
Table 1
Means and standard deviations (SD) for age, body mass index (BMI),
blood pressure, and heart rate at baseline for the two groups.

                           Group

                           Korodin[R]    Placebo       Total
                           (n = 38)      (n = 15)      (N = 53)
                           Mean (SD)     Mean (SD)     Mean (SD)

Age (years)                24.4 (4.4)    24.1 (2.8)    24.3 (4.0)

BM1 (kg/[m.sup.2])         21.4 (2.7)    22.4 (2.3)    21.7 (2.6)

Systolic blood pressure    114.9 (9.8)   118.3(12.2)   115.8 (10.6)
(mmHg, baseline)

Diastolic blood pressure   75.6 (8.1)    73.1 (9.8)    74.9 (8.6)
(mmHg, baseline)

Heart rate (beats/min,     77.3 (11.3)   75.2 (13.6)   76.7(11.9)
baseline)

Table 2
Means and standard deviations (SD) for systolic blood pressure (SBP),
diastolic blood pressure (DBP), and mean arterial pressure (MaBP)
before and after each of the four substance administrations (SA), and
change values (Ch-...).

Minute   Mean of SBP (mmHg)

                          Korodin[R]     Placebo
                          n-38           n = 15

0        SBP-SA1-before   109.8 (12.1)   115.2 (14.9)
2        SBP-SA1-after    115.1 (11.9)   116.9 (15.3)
         Ch-SBP-SAl         5.3 (6.5)      1.7 (3.6)
12       SBP-SA2-before   107.1 (11.2)   113.7 (15.0)
14       SBP-SA2-after    111.7 (11.7)   113.6 (12.7)
         Ch-SBP-SA2         4.6 (5.1)     -0.1 (5.5)
24       SBP-SA3-before   107.8 (10.8)   113.9 (14.0)
26       SBP-SA3-after    110.0 (10.7)   112.4 (10.3)
         Ch-SBP-SA3         2.2 (5.5))    -1.5 (6.4)
36       SBP-SA4-before   108.6 (10.9)   113.3 (13.1)
38       SBP-SA4-after    110.5 (10.1)   114.3 (13.0)
         Ch-SBP-SA4         1.9 (6.7)      1.1 (8.3)

Minute   Mean of DBP (mmHg)

                          Korodin[R]   Placebo
                          n = 38       n = 15

0        DBP-SA1-before   73.7 (8.5)   72.1 (6.9)
2        DBP-SA1 -after   76.8 (8.1)   72.6 (9.4)
         Ch-DBP-SAl        3.1 (4.4)    0.5 (4.9)
12       DBP-SA2-before   73.3 (6.2)   70.7 (8.4)
14       DBP-SA2-after    75.0 (8.1)   71.3 (8.3)
         Ch-DBP-SA2        1.7 (6.9)    0.7 (7.7)
24       DBP-SA3-before   73.3 (7.8)   69.7 (8.8)
26       DBP-SA3-after    76.2 (8.0)   72.2 (6.6)
         Ch-DBP-SA3        2.9 (7.1)    2.5 (6.6)
36       DBP-SA4-before   71.7 (7.4)   71.7 (8.6)
38       DBP-SA4-after    74.1 (9.0)   72.5 (7.8)
         Ch-DBP-SA4        2.4 (7.4)    0.7 (4.5)

Minute   Mean of MaBP (mmHg)

                           Korodin[R]     Placebo
                           n = 38         n = 15

0        MaBP-SAl-before   85.75 (8.85)   85.38 (9.12)
2        MaBP-SAl-after    89.54 (8.43)   87.04 (9.79)
         Ch-MaBP-SAl        3.80 (3.92)    1.67 (4.50)
12       MaBP-SA2-before   85.75 (8.85)   85.38 (9.12)
14       MaBP-SA2-after    87.24 (7.82)   84.67 (9.02)
         Ch-MaBP-SA2        2.67 (5.33)     .73 (5.14)
24       MaBP-SA3-before   84.82 (7.96)   83.63 (9.57)
26       MaBP-SA3-after    87.56 (7.42)   84.73 (7.73)
         Ch-MaBP-SA3        2.74 (5.11)    1.10 (5.22)
36       MaBP-SA4-before   83.99 (7.84)   84.44 (9.50)
38       MaBP-SA4-after    86.21 (8.53)   85.69 (9.02)
         Ch-MaBP-SA4        2.22 (6.14)    1.25 (4.76)

Table 3
T-und p-values of the significance tests for changes in systolic
blood pressure (SBP), diastolic blood pressure (DBP), and mean
arterial pressure (MaBP) due to the four substance administrations
(SA1 to SA4).

                                     Korodin[R]

                                     T(37)    p (one-tailed)

SBP-SA1-before <> SBP-SA1-after      -4.981   0.000
SBP-SA2-before <> SBP-SA2-after      -5.532   0.000
SBP-SA3-before <> SBP-SA3-after      -2.518   0.008
SBP-SA4-before <> SBP-SA4-after      -1.805   0.040
DBP-SA1-before <> DBP-SA1-after      -4.248   0.000
DBP-SA2-before <> DBP-SA2-after      -1.519   0.069
DBP-SA3-before <> DBP-SA3-after      -2.472   0.009
DBP-SA4-before <> DBP-SA4-after      -1.952   0.029
MaBP-SAl-before <> MaBP-SAl-after    -5.916   0.000
MaBP-SA2-before <> MaBP-SA2-after    -4.447   0.000
MaBP-SA3-before <> MaBP-SA3-after    -3.025   0.005
MaBP-SA4-before <> MaBP-SA4-after    -2.256   0.032

                                     Placebo

                                     T(14)    p (one-tailed)

SBP-SA1-before <> SBP-SA1-after      -2.076   0.028
SBP-SA2-before <> SBP-SA2-after      -0.227   0.412
SBP-SA3-before <> SBP-SA3-after       1.009   0.165
SBP-SA4-before <> SBP-SA4-after      -0.822   0.212
DBP-SA1-before <> DBP-SA1-after      -0.894   0.193
DBP-SA2-before <> DBP-SA2-after      -0.501   0.312
DBP-SA3-before <> DBP-SA3-after      -1.529   0.074
DBP-SA4-before <> DBP-SA4-after      -0.889   0.194
MaBP-SAl-before <> MaBP-SAl-after    -1.022   0.324
MaBP-SA2-before <> MaBP-SA2-after    -0.316   0.756
MaBP-SA3-before <> MaBP-SA3-after    -0.829   0.421
MaBP-SA4-before <> MaBP-SA4-after    -0.707   0.491

Table 4
T-and p-vaiues of the significance tests for differences between
groups in change values in systolic blood pressure (SBP), diastolic
blood pressure (DBP), mean arterial pressure (MaBP).

Number of substance    SBP                      DBP
administration
                       T(51)   p (one-tailed)   T(51)   p (one-tailed)

1                      2.57    0.007            1.8     0.035
2                      2.93    0.002            0.48    0.315
3                      2.1     0.02             0.19    0.425
4                      0.41    0.34             0.96    0.215

Number of substance    MaBP
administration
                       T(51)   p (one-tailed)

1                      2.52    0.007
2                      2.02    0.024
3                      0.733   0.25
4                      0.861   0.21

Table 5
Correlation coefficients regarding the relation between blood
pressure at baseline and the blood pressure change after Korodin[R].

                             r

SBP-SAl-before: Ch-SBP-SAl   -0.259 *
SBP-SA2-before: Ch-SBP-SA2   -0.349 *
SBP-SA3-before: Ch-SBP-SA3   -0.543**
SBP-SA4-before: Ch-SBP-SA4   -0.404 **
DBP-SA1-before: Ch-DBP-SAl   -0.160
DBP-SA2-before: Ch-DBP-SA2   -0.299 *
DBP-SA3-before: Ch-DBP-SA3   -0.479 **
DBP-SA4-before: Ch-DBP-SA4   -0.283 *

Asterisks denote a significant correlation. SBP-SAx-before = systolic
blood pressure before substance administration x (x = 1,2,3,4);
DBP-SAx-before = diastolic blood pressure before substance
administration x (x = 1,2,3,4); Ch = change.

Table 6
Means, standard deviations (in parentheses) and results of T-tests
for reduction of total errors (Ch-TE) and improvement of
concentration performance (Ch-CP) in the d2 Test of Attention.
T-values and significance (p) from T-Tests for differences between
groups for substance administrations 1-4 (SA1-SA4).

            Korodin[R]     Placebo        7(52)    p (one-tailed)

Ch-TE-SAl   -4.97 (6.98)   -1.63 (4.94)   -1.950   .03
Ch-TE-SA2   -4.58 (8.97)   -2.13 (3.73)   -1.712   .04
Ch-TE-SA3   -4.87 (9.41)   -3.69 (3.39)    0.827   .21
Ch-TE-SA4   -5.82 (9.85)   -4.19 (3.57)   -1.008   .16
Ch-CP-SAl    7.84 (7.80)    6.06 (3.23)    1.185   .12
Ch-CP-SA2   11.08 (7.49)    8.19 (4.49)    1.748   .04
Ch-CP-SA3   12.55 (8.40)    9.44 (4.66)    1.737   .04
Ch-CP-SA4   15.05 (8.08)   11.81 (4.90)    1.806   .04

Fig. 1. Differences in systolic blood pressure are computed by
subtracting the pre-test value from the post-test value. Vertical
bars indicate the errors of the mean.

          Minute 0   Minute 12   Minute 24   Minute 36
          20 drops   20 drops    20 drops    20 drops

Korodin   5.30       4.60        2.20        2.00
Placebo   1.70       -0.10       -1.50       1.10

Fig. 2. Differences in diastolic blood pressure are computed by
subtracting the pre-test value from the post-test value. Vertical
bars indicate the errors of the mean.

Change Values of Diastolic Blood Pressure (mmHg)

          Minute 0   Minute 12   Minute 24   Minute 36
          20 drops   20 drops    20 drops    20 drops

Korodin   3.10       1.70        2.90        2.30
Placebo   0.50       0.70        2.50        0.70

Fig. 3. Differences in mean arterial blood pressure are computed by
subtracting the pre-test value from the post-test value. Vertical
bars indicate the errors of the mean.

Change Values of Mean Arterial Pressure (mmHg)

          Minute 0   Minute 12   Minute 24   Minute 36
          20 drops   20 drops    20 drops    20 drops

Korodin   3.62       3.28        2.17        2.45
Placebo   0.91       0.42        1.16        0.84

Fig. 4. Improvements in total number of errors (TE) in the d2 Test of
Attention are calculated as the differences in TE at baseline (i.e.
before the first substance administration) minus TE after substance
administration. Vertical bars indicate the errors of the mean.

Improvement of Total Errors

          Minute 0   Minute 12   Minute 24   Minute 36
          20 drops   20 drops    20 drops    20 drops

Korodin   4.97       4.58        4.87        5.82
Placebo   1.63       2.13        3.69        4.19

Fig. 5. The changes in concentration performance (CP, standard
scores) in the d2 Test of Attention are calculated as the diffrences
between CP after substance administration and CP at baseline, i.e.
before the first substance administration. Vertical bars indicate the
errors of the means.

Improvement of Concentration Performance

          Minute 0   Minute 12   Minute 24   Minute 36
          20 drops   20 drops    20 drops    20 drops

Korodin   7.84       11.08       12.55       15.05
Placebo   6.06       8.19        9.44        11.81
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Author:Erfurt, L.; Schandry, R.; Rubenbauer, S.; Braun, U.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Clinical report
Date:Sep 25, 2014
Words:6131
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