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  Rhythmologic Studies of Cardiodoron Given to Healthy Subjects
  

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By: Hans-Christoph Kummel, Henrik Bettermann
Studies of Cardiodoron.doc

(Original title: Ergebnisse rhythmologischer Untersuchungen von Cardiodoron an
Gesunden. Der Merkurstab 1996; 49:361-71. English by A. R. Meuss, FIL, MTA.)

(Acute subcutaneous administration of Cardiodoron 5%)

Introduction
The indication for Cardiodoron, a medicament designed by Rudolf Steiner, is "cardiac dysregulation." The pharmacology and special galenics of the medicament will not be considered in this paper. The composition, in brief, is: Onopordon, Flos dig.; Primula officinalis, Flos and Hyoscyamus, Herba.

The drug picture has been discussed in a number of papers,(1,6,11-14,21,23,34,35) Weckenmann and others have presented studies on orthostatically unstable patients,(18,19,27-33) using pulse, respiratory rate and their quotient (QPR) as parameters.

Routine analysis of 24-hour electrocardiograms makes it possible to establish interaction of respiration and heartbeat on the basis of respiratory arrhythmia, e.g. as QPR, as well as other parameters that influence heart period variability++ (We do not determine changes in cardiac frequency from the ECG but in heart period, i.e. the time interval between heart beats (R wave to R wave). This is inversely proportional to the heart frequency. Instead of the widely-used term "variable heart rate," we therefore use the
synonymous term "heart period variability.") during that 24-hour period. The duration of a heart beat is also influenced by 1) the blood pressure, which causes changes in heart period c. 6-10 times a minute, 2) the change between muscle and skin circulation that provides the basis for temperature regulation, and 3) the day and night rhythm, the influence of which is evident mainly from waking and sleeping in heart period dynamics.(2-4,24)

In accord with frequency variation, time sequence analysts refer to variability ranges (bands) as follows.

Ultra low-frequency band ULF " day and night rhythm"
High frequency band HF respiratory rhythm, respiratory sinus arrythmia
Low-frequency LF blood pressure rhythm
Very low-frequency band VLF circulatory rhythm, minute rhythm
Total frequency band TF sum of rhythms determined

The above indication and preliminary studies using Cardiodoron made us consider which frequency band might show changes under the influence of Cardiodoron. The time sequence methods of spectroanalysis seemed to suit the purpose.

Subjects and method
Subjects
From July 1995 to March 1996, 50 subjects aged 19-54 with normal cardiovascular function took part in the trial (mean age 28.6 years, standard deviation 7.6 years). Eighteen were male, 32 female, 28 nonsmokers and 22 smokers (10 of them heavy smokers). Thirteen had had prior experience of Cardiodoron. One female subject was diabetic and depended on insulin. The subjects were asked to keep exact records, to the minute, of going to sleep and waking up times. Except for two, all slept during the period from 1 to 5 a.m. One said he went to sleep at 3 a.m., the other at 2 a.m. One female subject consulted a physician on account of mental stress. None was excluded from the trial.

"Normal" everyday stress applied during the three days of the trial. It was left to the subject in each case to assess what kind of day might be called "normal."

The trial period was three days for each subject (Fig. I):
1 A baseline 24-hour ECG was recorded on the first day.
2 On the second day, the first injection of 1 ml of Cardiodoron 5% was given s.c. at 8.00 p.m. (All ampules were supplied by Weleda, having the same composition and being of the same batch. According to the manufacturers, 1 ml of Cardiodoron 5% contains Onopordon Flos 25 mg, Primula off. Flos. 25 mg, and Hyoscyamus Herba 2x 100 mg.)
3 On the third day, the second 24-hour ECG started at 8 a.m., with the second Cardiodoron 5% injection in the same dosage given at the same time. The injection was repeated at 2 p.m. and 8 p.m.

The subjects had given their written consent to take part in the trial. The trial was accepted by the ethics commission at Witten/Herdecke University.

ECG recording and analysis
Oxford Medilog FD2 instruments with solid state storage units were used. Evaluation and analysis of heart periods were done on an Oxford Excel ECG Analyzer. Variability spectra and the times for all R waves were kept on file and transferred to a personal computer for further processing.

Variability of heart periods The RR periods of all heart beats were used to calculate RR intervals as a 24-






Fig. 1. Trial design


hour sequence, dividing them into 10-minute tachograms (maximum of 144). The tachograms were put through Fast Fourier transformation (FFT), with the resulting spectra integrated within the following variation ranges (see introduction):

VLF 0.004 - 0.04 Hz = 14.4 /hour - 2.4/min
LF 0.04 -0.15 Hz = 2.4 /min - 9.0/min
HF 0.15 - 0.4 Hz = 9.0 /min - 24.0/min
TF 0.004 - 0.5 Hz = 14.4 /hour - 30.0/min

Mathematical processing was based on the method of Bigger et al.(5,22) The ULF variability referred to in the Introduction could not be determined over a 10-minute period. The periods of variation are in the range of hours.

Integration gave ms2 values for each 10-minute tachogram that corresponded to the variance in length of heart beat. We are only giving variability in ms, however, to get comparability for the standard deviation.

To concentrate the measurements, taking account of circadian variations in cardiac activity, we established mean values for all parameters for day and night: 8 a.m. - 4 p.m. (day values) and 1 a.m. - 5 a.m. (night values).

The parameters were labeled "d" and "n" respectively. We thus had eight variability parameters for every 24-h ECG.

Mean RR and pulse/respiration quotient
The mean length of beat (mean RR) was calculated after smoothing the tachograms using an Oxford Ectopia Filter for the above circadian periods. This gave the daily mean RRd and the night-time mean RRn.

The mean respiratory period was calculated using an algorithm we developed. This automatically determines the respiratory rate from the respiratory sinus arrhythmia in the ECG. It has been discussed in detail elsewhere.(9) The respiratory frequency and the mean RR within a respiratory cycle were used to determine a respiratory cycle-specific QPR. The logarithmic mean of the QPR for the above circadian periods gave QPRd and QPRn.

Statistics
All the statistical methods used are descriptive. Confirmative methods are of no real value because of the large number of parameters. To describe the results, we used the means and standard deviations of all parameters on the first and third days of the trial. We also calculated the individual differences between heart period parameters following exhibition of Cardiodoron and those from baseline recordings, determining the mean values for all subjects.

To establish the changes following exhibition of Cardiodoron, we used two methods of presentation. Histograms of individual differences - to show the frequency distribution of changes in heart period parameters - and mean error graphs, plotting untreated against treated readings. These show the changes to be dependent on the initial level. Male and female subjects were given different markers in the mean error graphs, and these also served to investigate the interdependence of individual parameters.

Results
The table shows the group means and standard deviations of all heart periods on days 1 and 3. It also includes the mean difference, its standard deviation, mean percentage change, and the number of rises and falls in all heart period parameters.


Table
: Mean values (MV) and standard deviations (SD) of baseline and Cardiodoron recordings for all subjects and Careffodoron-baseline differences (in ms, except for QPR). See also text.









The mean change from baseline was always slight. Only VLFn and TFn showed a drop by more than 5%. Following exhibition of Cardiodoron, RRn, VLFn and TFn showed a drop and QPRn a rise in more than 2/3 of subjects.

The histograms of Fig. 2 confirm that first impression. Distribution of differences between Cardiodoron and baseline readings show a remarkably high incidence of negative values especially for very low-frequency heart period variability at night (VLFn). Daytime differences are more around zero, with differences less marked than at night. This is due to the fact that variability is naturally less during the day than at night, so the differences between daytime readings are also smaller.

Fig. 3 shows mean baseline VLFn variability plotted against the corresponding Cardiodoron readings. Dots below the 45 degree line indicate a drop, those above a rise in VLFn. The graph shows no dependence of VLFn changes following exhibition of Cardiodoron on the initial VLFn reading. Nor is there a gender-dependence. These results are representative of all other parameters.

To consider the question if "normalization" of the night-time pulse-respiration quotient had occurred, we chose the same method of representation for QPR in Fig. 4. This shows a greater frequency of minor increases (compare Fig. 2, QPRn), but the change in QPR is evidently not dependent on the initial reading, so that the answer is in the negative.

In the daytime, QPR readings showed a tendency to cluster around 5, and there is a slight tendency to normalize by going towards 5 following exhibition of Cardiodoron, but this is essentially due to a decrease in extremely high individual QPR readings.

The bivariate mean error graph for differences between mean night-time heart period and night-time VLF variability provides an interesting insight into the relationship between heart period parameters. Fig. 5 shows that a rise in night-time heart rate clearly goes hand in hand with a drop in VLFn variability and vice versa. Four-field frequency (pp = 11, pn = 7, np = 8, nn = 24, with n = decrease and p = increase) also shows how differently subjects reacted. 11 reacted with a decrease in night-time heart rate coupled with an increase in very low-frequency night-time heart period variability, whereas more than twice as many subjects reacted in exactly the opposite way.

Discussion
A wide range of investigations has shown that the autonomic nervous system plays an important role in regulating heart period variability. It has been relatively well demonstrated that vagus activity (only minimally influenced by the sympathetic system) increases variability in the high-frequency range. The other ranges cannot be as clearly related;!/ it is assumed that the sympathetic system has a dominant influence in the low-frequency bands.









Fig. 2. Histograms of "Cardiodoron minus baseline" differences for all heart period parameters. Remarkably little scatter for individual daytime differences (left column, with exception of QPR) and frequency of negative differences in night-time variability, most marked in VLFn (right column).







Fig. 3. VLFn baseline v. Cardiodoron in ms. Circles = female subjects, dots = male subjects. Note increase in decreases independent of initial baseline reading (see text).


Studies with transdermal scopolamine(7,8,10,15,16,20,25,26) have shown that low doses do not block, but stimulate, vagal activity, so that there is a dose-dependent reversal of action. The effect was determined by monitoring heart period variability through an elevated high-frequency component.

We therefore expected the low dose of Hyoscyamus in Cardiodoron to increase the respiration-mediated variability component. Our findings did not show this. The results indicate that acute exhibition of Cardiodoron 5% s.c. to healthy subjects over 24 hours does not noticeably affect this area. On the other hand, and we did not expect this, the minute-rhythm VLF component was clearly reduced. This reduction goes hand in hand with a reduction in total variability (TF) and a slight reduction of heart period duration as such, i.e. the tendency is to raise the heart rate. In principle, we found all these measurable changes to occur only during the night. In the daytime, they were probably masked by changes due to the subjects' daytime activities.

Thinking in terms of the autonomic nervous system does not give sufficient clarity in assessing the results; the anthroposophical concepts are more helpful. Our hypothesis was formulated as follows: looking at the rhythmic system, its central part is the interaction of heart action and respiration. The heart rhythm itself follows as we go more towards the lower human being, and below this comes the aspect we call "circulation," which includes the blood pressure and heat exchange rhythms. The circulation










Fig. 4. QPRn baseline v. Cardiodoron. Circles = female subjects, dots = male subjects. Note increased number of minor increases independent of initial baseline reading (no normalization).


gradually imposes rhythm on the unrhythmical food stream coming from the metabolic sphere. Heat metabolism is integrated into this transition, its prime function probably being to take the liquefied food into the rhythmic processes. When the warmth process that accompanies metabolism is too active the circulatory system is taken hold of by this to a greater degree, the heart rate shows greater variation, i.e. heart period variability in very low-frequency range is enhanced. Further enhancement of metabolic activity or loss of delimitation between the systems (metabolism/rhythmic system) can evidently lead to disorders of the heart rhythm itself.

Acute exhibition of Cardiodoron can be seen to influence this transition process. Variability in heat exchange rhythm is reduced, so that less metabolic activity is transferred to the rhythmic system. In other words: Cardiodoron, in the form used, reduces the influence of -metabolic activity on the circulation, lessening the strain on it. The heart can thus be protected or freed from regulatory interference due to pathological increase in metabolic activity.










Fig. 5. “Cardiodoron minus baseline" differences of mean night-time heart period plotted against very low-frequency night-time heart period variability.


Matthiolius and Weckenmann achieved a normalizing tendency in a previously abnormal QPR when orthostatically unstable individuals were given Cardiodoron.(18,19,27-32) In our own investigations, the mean night-time QPR did not change - as one would expect - with CardiodoronCardiodoron. The daytime QPR nevertheless showed a tendency to cluster around 5, and in the present case this was minimally enhanced by the reduction in greatly elevated levels (e.g. from 9 to 7) following exhibition of Cardiodoron. The trend is marginal but does not contradict the results of earlier trials.) being in normal range before and after (mean values!) (see last column in Table). The minor changes seen in individual subjects also showed no dependence on initial readings, with relatively high readings remaining high and relatively low ones low. Our results, obtained with rhythmologic methods that have by now become highly refined, show that changes detected in the "rhythmic functional order" of healthy subjects, e.g. the "minute rhythm" at very low frequencies, are not reflected in the relatively complex pulse-respiratory rate quotient.

Conclusions and prospects
We had focused on Hyoscyamus in designing the trial and obtained an unexpected result. In healthy subjects, Cardiodoron does not change high-frequency heart period variability, which is vagally mediated, but the duration of heart beat, which is influenced by metabolism. It is evident that the Cardiodoron composition has its own sphere of action in the organism and that conclusions as to measurable effects cannot be based on the individual low-dose components. The investigations also made it possible to describe a
site of Cardiodoron action with the preparation given by injection. Further investigations are needed to confirm the site of action on oral exhibition (for 2-4: weeks) and study the state of health or quality of life of subjects. This may provide the basis for a trial with patients recording clinical data, rhyth-mologic findings and quality of life.

Prof. Hans-Christoph Kummel, MD
Henrick Bettermann, PhD
Gemeinnuetziges Gemeinschaftskrankenhaus Herdecke
D-58313 Herdecke
Germany

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Acknowledgement
We are indebted to Mr. Herbert H. Jacobi, Duesseldorf, for financial support.






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