The Mosaic of Evidence - International Academy of Homotoxicology

The Mosaic of Evidence
Multifaceted Evidence Based Research Results
in Modern Homeopathy
© IAH 2007

Objective of this Presentation
Overview of
research strategy
and practical
illustration
Presentation of
examples /
highlights in
© IAH 2007
• Main vision and goals of research
• The “evidence mosaic” concept
• Basic research
• Clinical research
2

The Vision
• In terms of an effective and well tolerable patient treatment
The vision is
© IAH 2007
To foster the unique position occupied by
Heel within medicine by building a bridge
between homeopathy and conventional
medicine
To make Heel the world leader in modern,
evidence-based natural products by
supporting and developing Heel products
and Reckeweg’s theory.
3

Main Goal of Research International
• Development of a multifaceted, synergistic evidence base for
important Heel products:
© IAH 2007
4

Further Goals of Research International
• Support and propagate the theory of homotoxicology using the
appropriate basic and clinical research models
• Improve the image of homeopathy by supporting “generic”
research in collaboration with other homeopathic companies
© IAH 2007
5

What is an Evidence Mosaic?
• A multifaceted evidence base
which is more than the sum
of its parts:
The Evidence Mosaic is based on three pillars:
Randomized Controlled Trials
Observational Studies
Basic Research
Randomized Controlled Trials
© IAH 2007
Randomized Controlled Trials (RCTs) are required to demonstrate the efficacy of a treatment. RCTs usually take place in highly selective
patient populations, in order to facilitate an unbiased comparison to placebo or another treatment. In technical terms this means that RCTs
have a high ‘internal validity’, and this is one of the main strengths RCTs. In more practical terms, investigation of efficacy in RCTs
addresses the question “can it work”?
Observational Studies
A problem with the patient populations treated in clinical trials, is that they are usually not representative of patients seen in routine practice
conditions. As a consequence, effectiveness should be demonstrated, the pragmatic benefit of the patient from the homeopathic treatment
in daily medical practice. It is therefore important to investigate the safety and effectiveness of treatments in observational studies. A study
of ‘effectiveness’ addresses the question “does it work in routine practice?”. Such studies are therefore more representative for ‘real world
clinical practice’, in more technical terms: such studies have a high external validity.
A principal strength of observational studies is that statements of safety and tolerability can be substantiated further, because for these
statements collecting of date a in a large number of patients is required, and this is usually not possible in clinical trials.
Basic Research
Basic Research intends to approach to the mode of action of the homeopathic preparation, which is unknown in many cases. For many
preparations where the efficacy and safety has been further substantiated, it is important to try to obtain information on possible
mechanism(s) of action, using the latest basic research methods and data available.
In addition, basic research can contribute to the development of possible new hypothesis, possible new indications for existing medicines, a
further understanding of homotoxicology and its principles, and last but not least to the possible development of new products.
All three types of research have possibilities and limitations. However, by combining and building on the strengths of the various
approaches, the result is more than just the sum of its parts. This involves the construction of a multifaceted, synergistic ‘Mosaic of
Evidence’.
6

Evidence mosaic for Heel top products
• Example evidence mosaic data are presented
• for Heel top products
VertigoheelTraumeel
© IAH 2007
7

Vertigoheel Evidence Mosaic
Composition of Vertigoheel ®
© IAH 2007
Tablets:
One tablet cont.: Anamirta cocculus D4 210 mg; Conium maculatum D3, Ambra
grisea D6, Petroleum rectificatum D8 30 mg each.
Drops:
100 g cont.: Anamirta cocculus D4 70 g; Conium maculatum D3, Ambra grisea
D6, Petroleum rectificatum D8 10 g each. Contains 35 vol.-% alcohol.
Injection solution:
1.1 ml cont.: Anamirta cocculus D3 7.7 μl; Conium maculatum D2, Ambra grisea
D5, Petroleum rectificatum D7 1.1 μl each.
8
8

Vertigoheel Evidence Mosaic: Clinical Studies
Homeopathic treatment of vertigo
• Two clinical trials were performed to compare Vertigoheel with
betahistine and Ginkgo biloba
• Two cohort studies were performed to compare Vertigoheel with
dimenhydrinate and betahistine
© IAH 2007
1. Clinical trial (betahistine)
Weiser M, Strösser W, Klein P. Homeopathic vs conventional treatment of vertigo. Arch
Otolaryngol Head Neck Surg 1998; 124: 879-885
2. Clinical trial (Ginkgo biloba)
Issing W, Klein P, Weiser M. The homeopathic preparation Vertigoheel versus Ginkgo
biloba in the treatment of vertigo in an elderly population: a double-blind randomized,
controlled clinical trial. Journal of Alternative and Complementary Medicine 2005, 11 (1):
155-160
1. Cohort study (betahistine)
Weiser M, Strösser W. Behandlung des Schwindels – Vergleichsstudie Homöopathikum
vs. Betahistin. Der Allgemeinarzt 2000; 22 (13): 692-694
2. Cohort study (dimenhydrinate)
Wolschner U, Strösser W, Weiser M, Klein P. Behandlung des Schwindels mit einem
modernem Homöopathikum – Ergebnisse einer referenzkontrollierten Kohortenstudie.
Biol Med 2001; 30 (4): 184-190
9

Vertigoheel Evidence Mosaic: Meta-analysis
• A meta-analysis was performed to quantitatively summarize
and evaluate four clinical studies on Vertigoheel in the treatment
of vertigo with a similar treatment aim and design
• Goal: Increasing the statistical power and thereby precision of
effect estimates
• Reference treatment: Betahistine (2x), dimenhydrinate, Ginkgo
biloba
• Total sample size: Vertigoheel N=635; reference N=753
© IAH 2007
Prof. Dr. Berthold Schneider,
Institut für Biometrie, Medizinische Hochschule Hannover (MHH)
Arzneim. –Forsch./Drug Research 2005;55 (1):23-29
10

Vertigoheel Evidence Mosaic:
Meta-analysis Results (1)
• Clinical vertigo efficacy parameter: Number of dizzy spells
Superiority of control Superiority of Vertigoheel
Study 1
Study 2
Study 3
Study 4
Meta-analysis
-3 -2 -1 0 1 2
© IAH 2007
The number of dizzy spells per day was counted and compared between
treatments. The x-axis represents differences in the number of dizzy spells.
In study 2, for instance, the mean difference between treatments was one dizzy
spell per day in favor of Vertigoheel.
Reduction in the number of dizzy spells per day compared between Vertigoheel
and reference group, at the end of the observation period (ranging from 6-8
weeks).
Vertical lines are average values, horizontal lines are 95% confidence intervals.
The 95% confidence interval indicates the precision with which the average
number of dizzy spells was estimated.
A higher number of patients will lead to a smaller confidence interval and
therefore to a more precise estimate;.
Equivalence can be argued if the left boundary of the 95% Confidence interval
does not cross the ‘inferiority limit’ of -1.
The range in the middle (-1 to 0) can be interpreted as the range of clinically
insignificant inferiority.
11

Vertigoheel Evidence Mosaic:
Meta-analysis Results (2)
• Clinical vertigo efficacy parameter: Duration of dizzy spells
Superiority of control Superiority of Vertigoheel
Study 1
Study 2
Study 3
Study 4
Meta-analysis
-1.5 -1 -0.5 0 0.5 1
© IAH 2007
The duration of dizzy spells was documented according to a 5-point rating scale:
0 = up to 2 min
1 = 2 to 10 min
2 = 11 – 60 min
3 = 1 – 6 hours
4 = more than 6 hours
The x-axis represents differences in score points with respect to the duration of
dizzy spells.
Average reduction in duration of dizzy spells (measured on an ordinal scale from
0-4) compared between Vertigoheel and reference group, at the end of the
observation period (ranging from 6-8 weeks).
Vertical lines are average values, horizontal lines are 95% confidence intervals.
The 95% confidence interval indicates the precision with which the average
number of dizzy spells was estimated. A higher number of patients will lead to a
smaller confidence interval and therefore to a more precise estimate.
Equivalence can be argued if the left boundary of the 95% Confidence interval
does not cross the ‘inferiority limit’ of -0.5.
The range in the middle (-0.5 to 0) can be interpreted as the range of clinically
insignificant inferiority.
12

Vertigoheel Evidence Mosaic:
Meta-analysis Results (3)
• Clinical vertigo efficacy parameter: Intensity of dizzy spells
Superiority of control Superiority of Vertigoheel
Study 1
Study 2
Study 3
Study 4
Meta-analysis
-1.5 -1 -0.5 0 0.5 1
© IAH 2007
The intensity of dizzy spells was documented according to a 4-point rating scale:
1 = Mild
2 = Moderate
3 = Moderate to severe
4 = Severe
The x-axis represents differences in score points with respect to the intensity of
dizzy spells
Average reduction in intensity of dizzy spells (measured on an ordinal scale from
1-4) compared between Vertigoheel and reference group, at the end of the
observation period (ranging from 6-8 weeks).
Vertical lines are average values, horizontal lines are 95% confidence intervals.
The 95% confidence interval indicates the precision with which the average
number of dizzy spells was estimated. A higher number of patients will lead to a
smaller confidence interval and therefore to a more precise estimate;.
Equivalence can be argued if the left boundary of the 95% Confidence interval
does not cross the ‘inferiority limit’ of -0.5.
The range in the middle (-0.5 to 0) can be interpreted as the range of clinically
insignificant inferiority.
13

Vertigoheel Evidence Mosaic:
Observational Studies
There are a number of observational studies available:
• “Post-marketing surveillance” studies on use of Vertigoheel in
routine practice
• Observational cohort studies comparing Vertigoheel with (for
instance) conventional treatment in routine practice
• Observational study data currently available on:
4569 patients
© IAH 2007
14

Vertigoheel Evidence Mosaic:
Observational Studies
Conclusion:
• These observational data confirm that Vertigoheel is
• safe in clinical practice
© IAH 2007
15

Vertigoheel Evidence Mosaic:
Basic Research (1)
Basic research concentrated on parameters
of microcirculation to investigate the possible
mode of action of
Vertigoheel
The following study was performed:
© IAH 2007

Vertigoheel Evidence Mosaic: Basic Research (2)
Microcirculatory effects of a homeopathic preparation
in patients with mild vertigo*
An intravital microscopic study
Dr. Rainer Klopp
Institut für Mikrozirkulation, Berlin
*Microvascular Research 2005; 69: 10-16
© IAH 2007
17

Vertigoheel Evidence Mosaic: Basic Research (3)
Study parameters (1)
• Aim: To test the possible mode of action of
Vertigoheel
• Investigation of: Influence of Vertigoheel on parameters of
microcirculation. Non-invasive intravital
microscopy (in vivo)
• Indication: Ambulant patients with vestibular vertigo
• Patients: N=32, Control: standard physiotherapy
Verum: add-on Vertigoheel 3x2 tabs/day
© IAH 2007
The publication of Klopp, Niemer and Weiser (2005) describes the effects of
Vertigoheel on variables related to microcirculation using vital microscopy
techniques in patients with vestibular vertigo.
Measurements were carried out to investigate the blood flow in arterioles (with a
mean diameter of ≥ 40 μm) of the vestibular area. It was assumed that
improvements of microcirculation in the inner ear might be a reason for the
observed symptomatic improvements with the homeopathic preparation.
Special interest was also focused on the improvement of vasomotion by effects
on vascular smooth muscle, essentially contributing to improved local blood flow.
18

Reference:
Vertigoheel Evidence Mosaic: Basic Research (4)
Study parameters (2)
• Duration: 12 weeks, assessment every 4 weeks
• Target region: cutis/subcutaneous tissue of the forearm
+ behind the ear
• Measurement: Computerized image analysis
• Functional variables: Microcirculation Q art , Q ven (arterial/venous
circulation
Reference:
Klopp R., Niemer W., Weiser M. Microcirculatory effects of a homeopathic
preparation in patients with mild vertigo: an intravital microscopic study.
Microvascular Research 2005;69:10-16.
© IAH 2007
Klopp R., Niemer W., Weiser M. Microcirculatory effects of a homeopathic
preparation in patients with mild vertigo: an intravital microscopic study.
Microvascular Research 2005;69:10-16.
19

Vertigoheel Evidence Mosaic: Basic Research (5)
Study results
2,5
2,3
2,1
1,9
Q art (µm 3 /s 10 6 ) Arteriolar flow
Arm, control
Arm, Vertigoheel
Ear, control
Ear, Vertigoheel
0 28 56 84 Days
© IAH 2007
The flow rate of erythrocytes in arterioles (arteriolar flow rate) increased on
Vertigoheel in both arterioles (ear and arm). These increases were clinically
relevant.
The differences between the treatment groups were statistically significant.
20

Vertigoheel Evidence Mosaic: Basic Research (6)
• Video
• Arteriolar/venular flow in the course of treatment
At baseline After 12 weeks of Vertigoheel
© IAH 2007
75 µm
The figure above depicts intravital micrographs showing a representative
example of the state of the vessel network in area A (cuticulum/subcuticulum of
the inside left lower arm) at baseline and after 12 weeks of treatment with
Vertigoheel. The scale bar represents 75 μm which approximately corresponds to
the diameter of a hair.
21

Vertigoheel Evidence Mosaic: Basic Research (7)
Microcirculation: Signal paths in smooth muscle cells (1)
? Role of Vertigoheel ?
G protein
NO
endothelial
β 2 Signal protein
© IAH 2007
AMP
GMP
Phosphodiesterase IV (cAMP)
Phosphodiesterase V (cGMP)
cAMP
cGMP
Adenylate cyclase
Guanylate cyclase
ATP/GTP
Abbreviations:
AMP Adenosine monophosphate
ATP Adenosine triphosphate
cAMP cyclic adenosine monophosphate
cGMP cyclic guanosine monophosphate
GMP Guanosine monophosphate
GTP Guanosine triphosphate
NO Nitric oxide
Dilation of smooth
muscle cells
It is postulated that Vertigoheel is involved in signal pathways in smooth muscle cells.
Binding to ß2 signal protein and thereby stimulation of G-protein and of the enzymes adenylate
cyclase / guanylate cyclase leads to increase of cAMP and cGMP that causes dilation of smooth
muscle cells and thus vasorelaxation.
Inhibition of the activity of phosphodiesterases IV and V reduces hydrolyses of cAMP and cGMP
to AMP and GMP. Again, the clinical consequence is vasorelaxation of peripheral vessels and
vessels of the central nervous system.
It is also postulated that Vertigoheel influences the release of NO from vascular endothelial cells.
Altogether, Vertigoheel seems to have synergistic effects on metabolism of signal paths. The
clinical consequence is reduction of tonus and thereby improvement in perfusion, vasomotion and
motillity.
22

Vertigoheel Evidence Mosaic: Basic Research (8)
Microcirculation: Signal paths in smooth muscle cells (2)
• Possible mechanism of action
• Stimulation of the synthesis of cyclic monophosphate*?
• Inhibitation of the hydrolysis of cyclic monophosphate*?
�Synergistic action?
* Studies in progress, results expected in 2007
© IAH 2007
23

Vertigoheel Evidence Mosaic: Basic Research (9)
Microcirculation: Signal paths in smooth muscle cells (3)
• Possible implications
�Increased motility of smooth vessels in arteriolar walls
• Improvement in perfusion
• Positive influence on vasomotion
© IAH 2007
24

Vertigoheel Evidence Mosaic: Basic Research (10)
Possible model for the modulatory action of Vertigoheel
© IAH 2007
Homotoxicological scheme for mode of action of Vertigoheel.
Ball = organism, position of the ball = state of health, sink = area of self-healing.
Arrows symbolise weak impulses triggered by activation of different
vasoregulative systems.
Vertigoheel pushes the ball from different directions in order that it gets back to
the area of self-healing.
A single impulse is weak but the sum of all impulses is sufficent to give the
organism enough drive to find back to self-regulation and become healthy again.
Reference:
•Köhnke, D. 2006, North American Research Conference on Complementary and
Integrative Medicine, poster, May 24-27, Edmonton, Canada; status: ongoing
25

Traumeel S ointment
Composition:
Traumeel Evidence Mosaic
© IAH 2007
Arnica montana D3 15.0
Calendula officinalis Ø 4.5
Achillea millefolium Ø 0.9
Chamomilla recutita Ø 1.5
Symphytum officinale D4 1.0
Atropa belladonna D1 0.5
Aconitum napellus D1 0.5
Bellis perennis Ø 1.0
Hypericum perforatum D6 0.9
Echinacea angustifolia Ø 1.5
Echinacea purpurea Ø 1.5
Hamamelis virginica Ø 4.5
Mercurius solubilis D6 0.4
Hepar sulfuris D6 0.25
26

Traumeel Evidence Mosaic: RCTs
© IAH 2007
Randomized Controlled Trials
Randomized Controlled Trials (RCTs) are required to demonstrate the efficacy of
a treatment. RCTs usually take place in highly selective patient populations, in
order to facilitate an unbiased comparison to placebo or another treatment. In
technical terms this means that RCTs have a high ‘internal validity’, and this is
one of the main strengths RCTs. In more practical terms, investigation of efficacy
in RCTs addresses the question “can it work”?
27

Traumeel clinical trials: Zell study (1): Design
A placebo controlled RCT in ankle sprains:
• Study design: Double-blind, randomized placebo
controlled
• Patients: 69 patients
33 Traumeel, 36 Placebo
• Dosage: 10-12 g ointment every second day with a
compression bandage, resting and cooling
• Duration of treatment: 15 days
• Evaluation of: Degree of improvement in motility, degree
of movement pain, supination (inversion
angle)
© IAH 2007
Zell J et al. Treatment of acute sprains of the ankle: A controlled double-blind trial
to test the effectiveness of a homeopathic ointment.
Biological Therapy 1989; VII(1): 1-6
28

Traumeel clinical trials: Zell study (2): Results
Improves restriction of ankle mobility:
• Significant difference of angular sums (flexion + extension) between
injured and non-injured ankles through increase in mobility of the upper
ankle (p=0.03).
0
© IAH 2007
As a primary parameter of efficacy in the Zell study the angular difference was
chosen as a measure for the degree of disease severity.
This criterion is defined as follows:
One characteristic which satisfactorily quantifies the degree of restoration of
complete joint mobility for the upper ankle (talocruralis articulation) is the
difference between the angular sum of flexion and extension for the injured and
the for the non-injured joints. The result 0 here represents equal mobility of both
ankles.
As can be seen in the figure above Traumeel was superior to placebo with
respect to this primary efficacy parameter.
29

Traumeel clinical trials: Zell study (3): Results
Superior pain reduction compared to placebo:
• Patients with no pain upon movement within two weeks after beginning
of therapy (p

Traumeel clinical trials: Zell study (4): Conclusions
• Improvement in motility was significantly better (more frequent)
with Traumeel compared to placebo (p=0.03)
• Traumeel also improved the inversion angle (supination)
considerably better and faster than placebo (p=0.13)
• Pain upon movement was significantly less with Traumeel
(p

Traumeel clinical trials: Boehmer study (1)
The efficacy of Traumeel ® S ointment versus placebo
ointment in sports injuries in athletes: a randomized
controlled trial
Prof Boehmer, Institute of Sports Medicine Committee,
Wolfgang Goethe University, Germany
Purpose:
To investigate the efficacy of Traumeel ® S versus placebo
ointment in first and second degree sprains and contusions in
athletes
© IAH 2007
Böhmer, D., Ambrus, P. Treatment of Sports Injuries with Traumeel Ointment, A
Controlled Double-Blind Study;
Biological Therapy Vol. X (4): 290-300 (1992)
32

Traumeel clinical trials: Boehmer study (2)
• Study Design: Double-blind, randomized placebo controlled
• Patients: 68 Patients
34 Traumeel, 34 Placebo
• Dosage: 10-12 g ointment 2 x/day with 30 min/bandage,
resting and cooling
• Duration
of treatment: Average of 15 days
• Evaluation of: Regression of swelling, reduction in skin
temperature, reduction in pain index, time until
resumption of training, overall evaluation of
efficacy
© IAH 2007
33

Traumeel clinical trials: Boehmer study (3)
Superior to placebo: swelling and pain
• Changes from start of treatment, in %
100
80
60
40
20
0
Reduction in
circumference
of affected
body part
(x10)*
Reduction in Reduction in
difference difference
in skin in maximum
temperature+ muscle
force+
© IAH 2007
Decrease
in pain*
Overall
efficacy rated
“good” to
“very good”
(by therapist)*
Traumeel ®
Placebo
*0.0003 < = p < =0.0214
+between affected and healthy body part
*as recorded upon conclusion of treatment
34

Traumeel clinical trials: Boehmer study (4)
Superior to placebo: return to training
• Patients treated with Traumeel ® started with training again
1.5 days earlier than with placebo
Therapy Day of final
examination
© IAH 2007
Day of
resumption
of training
Traumeel ® N= 34 14.6 12.1
Placebo N= 34 14.6 13.5
35

Traumeel clinical trials: Boehmer study (5)
Conclusions and summary
• Traumeel ® is more effective than placebo
• Traumeel ® reduced the pain index considerably and significantly
• Traumeel ® reduced circumference of effected area significantly
• Traumeel ® resulted in faster resumption of training activities
• Traumeel ® was very well tolerated
© IAH 2007
36

Traumeel clinical trials: Orizola study (1)
The efficacy of Traumeel ® S versus diclofenac and placebo
ointment in tendinous pain in elite athletes: a randomized
controlled trial*
Dr. Alejandro Orizola, orthopedic surgeon, member of the Chilean
Olympic Committee, University of Chile Clinical Hospital, Chile
© IAH 2007
*Accepted for presentation at American College of Sports Medicine Annual
Meeting, New Orleans, May 2007
37

Traumeel clinical trials: Orizola study (2)
Purpose:
• To investigate the efficacy of Traumeel ® S versus diclofenac and
placebo ointment in nontraumatic tendinous pain in elite athletes
Study population:
• Olympic team members, tennis federation, professional soccer
league.
• Number: Traumeel 89 athletes, diclofenac 87 athletes,
placebo 76 athletes
© IAH 2007
38

Traumeel clinical trials: Orizola study (3)
• Study design: Double-blind, randomized, three armed, parallel
group clinical trial
• Subjects: Chilean elite athletes with various tendinopathies
of the shoulder, elbow, knee and leg, due to
chronic microtrauma or overuse
• Treatment: Traumeel ® S ointment, diclofenac ointment or
indistinguishable placebo ointment, three times
daily for a period of at least 21 days
• Outcome 10-point visual analogue scale for pain (VAS-P),
assessment: return to sports (number of days), tolerability and
echographic assessment (measurement of
peritendinous diameter and edema by assessor
“blind” to treatment allocation).
© IAH 2007
39

Traumeel clinical trials: Orizola study (4)
• Results
Outcome parameter Traumeel Diclofenac Placebo
Pain reduction (VAS-P) 5.2* 3.6 1.4
N days return to sport 20.3 † 24.6 30.6
Peritendinous diameter/
edema (% change)
* P < 0.001 for pairwise comparisons
† P < 0.001 for pairwise comparisons with placebo
• Treatments were generally well tolerated: in total 4 patients dropped out (all in
the diclofenac group, due to allergic skin reactions)
© IAH 2007
88.2* 69.1 24.6
40

Traumeel efficacy: overall conclusions
• Traumeel has been on the market for more than 60 years
• The available trial data is promising and suggests efficacy of the
product in sports related injuries
© IAH 2007
41

Traumeel Evidence Mosaic: Observational Studies
Observational Studies
© IAH 2007
A problem with the patient populations treated in clinical trials, is that they are
usually not representative of patients seen in routine practice conditions. As a
consequence, effectiveness should be demonstrated, the pragmatic benefit of the
patient from the homeopathic treatment in daily medical practice. It is therefore
important to investigate the safety and effectiveness of treatments in
observational studies. A study of ‘effectiveness’ addresses the question “does it
work in routine practice?”. Such studies are therefore more representative for
‘real world clinical practice’, in more technical terms: such studies have a high
external validity.
A principal strength of observational studies is that statements of safety and
tolerability can be substantiated further, because for these statements collecting
of date a in a large number of patients is required, and this is usually not possible
in clinical trials.
42

Traumeel Safety data (1)
• All three studies (see references) by Zenner and Metelmann
with almost 8000 patients and all presentations of Traumeel
have confirmed the extremely high tolerability of Traumeel with
all application forms
© IAH 2007
Zenner, S., Metelmann, H. Application Possibilities of Traumeel S Injection
Solution; Biological Therapy Vol. X (4): 301-310 (1992)
Zenner, S., Metelmann, H. Therapy Experiences with a Homeopathic Ointment:
Results of Drug Surveillance Conducted on 3,422 Patients; Biological Therapy
Vol. XII (3): 204-211 (1994)
Zenner, S., Weiser, M. Oral Treatment of Traumatic, Inflammatory, and
Degenerative Conditions with a Homeopathic Remedy; Biomedical Therapy Vol.
XV (1): 22-26 (1997)
43

Traumeel Safety data (2)
• Favorable results in comparison with a topical NSAID
• Global evaluation of tolerability in the Traumeel ® and NSAID
treatment groups, respectively.
Patients (%)
100
80
60
40
20
0
Traumeel ® NSAID
Very
good
Good
© IAH 2007
Satisfactory
p

Traumeel Safety data (3)
• Local tolerability test and overall conclusion
• Patch test:
• Traumeel does not cause local irritations in a patch test
(0.0 irritability index at a score of 0-10)
• Heel, data on file
• Overall conclusion:
• Traumeel ointment has an excellent safety profile
© IAH 2007
45

Basic Research
Traumeel Evidence Mosaic: Basic Research
© IAH 2007
Basic Research intends to approach to the mode of action of the homeopathic
preparation, which is unknown in many cases. For many preparations where the
efficacy and safety has been further substantiated, it is important to try to obtain
information on possible mechanism(s) of action, using the latest basic research
methods and data available.
In addition, basic research can contribute to the development of possible new
hypothesis, possible new indications for existing medicines, a further
understanding of homotoxicology and its principles, and last but not least to the
possible development of new products.
46

Traumeel Basic Research (1)
Traumeel is an inflammation regulating drug (IRD)
Traumeel ® reduces pro-inflammatory cytokines
• in resting and activated immunocytes as well as
• in resting and activated colon epithelial cells
• The first line and mobile arm of the immune defense is activated
by Traumeel ®
• Evidence for the inflammation regulating action of
Traumeel ®
© IAH 2007
Porozov, S., Cahalon, L., Weiser, M., Branski, D., Lider, O., Oberbaum, M.
Inhibition of IL-1ß and TNF-α Secretion from Resting and Activated Human
Immunocytes by the Homeopathic Medication Traumeel S; Clinical &
Developmental Immunology Vol. 11 (2): 143-149 (2004)
47

Traumeel ® Basic Research (2)
• Results of an in vivo animal experiment in rats, a model for
inflammation
Treatment
(Results after 5 hours)
© IAH 2007
Edema Volume (%)
(n=14)
IL-6 production (%)
(n=4)
Control (Saline) 100 100
Traumeel 66* 55
P-value

Traumeel ® Basic Research (3)
Inhibition of
pro-inflammatory
cytokines
● TNF-α ▼
● IL-1β ▼
● IL-8 ▼
Immunomodulation and Inflammation Regulation
© IAH 2007
Traumeel ®
+
Stimulation of
inflammation
reducing
cytokines
● TGF-β ▲
(from reg. Th3
lymphocytes)
Abbreviations:
TNF Tumor necrosis factor
IL Interleukin
TGF Transforming growth factor
Th lymphocytes Helper T cells
49

Research on Traumeel in sports medicine:
conclusions
• Positive data on clinical efficacy
• Excellent safety profile has been proven
• Existing and ongoing basic research program on mechanism of
action:
�Indicates an influence on immunological processes
�Broad palet of ingredients indicates a potentially broad range
of actions.
© IAH 2007
50

The Evidence Mosaic Approach: Conclusions (1)
• The concept of “evidence” is not approached from a single
angle: No single piece of evidence will be convincing enough on
its own
• Evidence mosaic implies:
• A multifaceted evidence base which is more than the sum of its
parts:
SYNERGY
• A synthesis of the available information provides
ADDED VALUE
© IAH 2007
51

The Evidence Mosaic Approach: Conclusions (2)
� Research will take place within a clearly defined strategic
framework and be increasingly international
� Basic research to elicit the mechanism of action and support
the theory of homotoxicology
� More emphasis on rigorous, randomized controlled studies
© IAH 2007
52

The Evidence Mosaic Approach: Conclusions (3)
• As the first homeopathic company in the world we will be in a
position to establish a high-quality, multifaceted evidence
mosaic of key words
© IAH 2007
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© IAH 2007
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54

Hepeel: Example of Basic Research
In Vitro Study (1)
The following in Vitro Study was performed:
In Vitro Study
Hepeel ® and its Constituent Plant Tinctures
Antioxidative, Antiproliferative and Biochemical Effects in
HepG2 Cells*
*Rolf Gebhardt, Arzneimittel-Forschung / Drug Research 53,
No. 12, 823-830 (2003)
© IAH 2007
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Hepeel: Example of Basic Research
In Vitro Study (2) − Introduction (1)
Oxidative stress
Plant-derived compounds
© IAH 2007
Examples for plant-derived antioxidants:
• Key factor for many human
diseases. Reactive oxygen species
may damage nucleic acids,
proteins and biomembranes
• Well known antioxidants. Support
of regenerating mechanisms,
inhibitation of uncoordinated cell
growth during carcinogenesis
• Proven interaction with
components of detoxifying
pathways, e.g. enhancement of
glutathione (GSH)-dependent
conjugation
Polyphenols e. g. in red wine reduce the risk of arteriosclerosis.
Silibinin inhibits growth of human prostate carcinoma cells.
56

Hepeel: Example of Basic Research
In Vitro Study (3)
Aim of the study
• Evaluation of antioxidative and antiproliferative effects of Hepeel
and ist constituent plant tinctures
• Biochemical aspects of biotransformation
• Effects of serial dilutions
© IAH 2007
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Hepeel: Example of Basic Research
In Vitro Study (4)
Assays were performed by means of the human
hepatoblastoma cell line HepG2
Lipid peroxidation
• Incubation of HepG2 cells with t-butyl hydroperoxide
(t-BHP) results in enhanced lipid peroxidation which can be
quantified by measurements of malondialdehyde (MDA).
• Reduced MDA-production upon addition of Hepeel constituents
should reveal their antioxidative potential.
© IAH 2007
58

Hepeel: Example of Basic Research
In Vitro Study (5/1)
Cell proliferation
GSH activity
© IAH 2007
• Determined by incorporation of
radiolabelled [3H]-thymidine into
DNA inhibition of [3H]-thymidine
incorporation upon addition of
Hepeel constituents should reveal
their antiproliferative potential
• Determination of glutathione-Stransferase
(GSH) activity by use
of 1.2-Dichloro-4-nitrobenzene
(DCNB) enhancement of GSHactivity
upon addition of Hepeel
constituents should reveal
induction of DCNB-conjugation
with glutathione
59

Hepeel: Example of Basic Research
In Vitro Study (5/2)
Cytotoxicity
© IAH 2007
• Determined by means of the MTT
assay or alternatively by means of
LDH leakage assay
MTT: 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide
LDH: lactate dehydrogenase
60

Hepeel: Example of Basic Research
In Vitro Study (6)
MTT / LDH leakage assay
• None of the Hepeel constituents and combinations tested
showed any cytotoxic effects.
• Additional microscopical inspection of cell cultures for
morphological changes did not reveal any sign of cytotoxicity
© IAH 2007
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Hepeel: Example of Basic Research
In Vitro Study (7)
Study Results − Antioxidative Potential (1)
• Reduction of MDA-production
Carduus marianus (Silybum marianum) was most effective
• Hepeel and Carduus marianus were significantly effective
down to 0.5-times D4
• At concentrations above D4, reduction was greater than 70%
• Combinations of constituents exhibit additive antioxidative
influence
© IAH 2007
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Hepeel: Example of Basic Research
In Vitro Study (8)
Study Results − Antioxidative Potential (2)
• Effect of different dilutions of Carduus marianus on MDA-production
induced by t-BHP
© IAH 2007
Abscissa: mixed linear and logarithmic scale
Control: basal level of MDA-production
P

Hepeel: Example of Basic Research
In Vitro Study (9)
Study Results − Antioxidative Potential (3)
• Effect of different dilutions of Hepeel on MDA-production induced
by t-BHP
© IAH 2007
Abscissa: mixed linear and logarithmic scale
Control: basal level of MDA-production
P

Hepeel: Example of Basic Research
In Vitro Study (10)
Study Results – Antiproliferative Potential
[3H]-thymidine incorporation
• Colocynthis was most effective in inhibition.
• Smaller inhibition by Chelidonium, Veratrum, Carduus marianus
and Hepeel.
• China exhibited a tendency for stimulation.
• Combinations exhibited higher values; however effects did not
reflect the sum of individual values.
© IAH 2007
Additionally, cell numbers were counted (data not shown). Results were
comparable with those of [3H]-thymidine incorportion.
65

Hepeel: Example of Basic Research
In Vitro Study (11)
StudyResults–Summary(1)
• Antioxidative and antiproliferative potency of selected plant
tinctures and of Hepeel on HepG2 cells
© IAH 2007
Table 2 contains additional results for the remaining constituents.
66

Hepeel: Example of Basic Research
In Vitro Study (12)
StudyResults–Summary(2)
• Antioxidative and antiproliferative potency of selected
combination of plant tinctures on HepG2 cells
© IAH 2007
Table 3 contains additional tested mixtures which may contain more than two
constituents.
67

Highlights of Basic Research: Recent publications
Original papers, published recently
• Microcirculatory effects of a homeopathic preparation in patients
with mild vertigo: an intravital microscopic study; Klopp R,
Niemer W, Weiser M; Microvascular Research 2005, 69: 10-16
• Antiviral Activity of Engystol ® : An in vitro Analysis; Oberbaum M,
Glatthaar-Saalmüller B, Stolt P, Weiser M; Journal of Alternative
and Complementary Medicine 2005; 11 (5): 855-862
• Effects of the Homeopathic Preparation Engystol on Interferon-γ
Production by Human T-lymphocytes; Enbergs, H;
Immunological Investigations 2006; 35: 19-27
© IAH 2007
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Highlights of clinical research: Recent publications (1)
• The Effects of a Complex Homeopathic Medicine Compared
with Acetaminophenon in the Symptomatic Treatment of Acute
Febrile Infections in Children: An Observational Study; Derasse
M, Klein P, Weiser M; Explore: The Journal of Science and
Healing 2005; 1: 33-39
• Treatment of Inflammatory Diseases of the Upper Respiratory
Tract – Comparison of a Homeopathic Combination Preparation
with Xylometazoline; Ammerschläger H, Klein P, Weiser M,
Oberbaum M; Forsch. Komplementärmed. Klass. Naturheilkd
2005; 12: 24-31
© IAH 2007
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Highlights of clinical research: Recent publications (2)
• A homeopathic ointment preparation compared with 1%
diclofenac gel for acute symptomatic treatment of tendinopathy;
Schneider C, Klein P, Stolt P, Oberbaum M; Explore: The
Journal of Science and Healing 2005, 1 (6): 446-452
• Treatment of Vertigo with a Homeopathic Complex Remedy
Compared with Usual Treatments; Schneider B, Klein P, Weiser
M; Arzneim.-Forsch./Drug Res. 2005; 55 (1): 23-29
• The homeopathic preparation Engystol for the symptomatic
treatment of upper respiratory infections associated with the
common cold; an observational study; Schmiedel V, Klein P
Explore: The Journal of Science and Healing 2006; 2 (2):
109-114
© IAH 2007
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Highlights of clinical research: Recent publications (3)
• Effects of Spascupreel vs hyoscine butylbromide for
gastrointestinal cramps in children; Müller-Krampe B, Oberbaum M,
Klein P, Weiser M; in press: Pediatrics International 2007; 49 (3)
• The homeopathic anti-arthritic preparation Zeel comp. N: A review
of molecular and clinical data. Birnesser H, Stolt P; Explore: The
Journal of Science and Healing 2007 (January)
© IAH 2007
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