Wie Gelatine deinen Gelenken hilft
DecemberCite as. Since mistletoe preparations are suspected to induce production of potentially tumor promoting cytokines like interleukin IL -6, further studies on the immunological effects are of interest. In this 3-armed randomized, double blind clinical trial healthy volunteers received increasing doses of either IP strength F, 0.
Physical examination was performed weekly. Application of IP strengths G and H caused strong local reactions at the site of injection.
Stimulation of IL-6 production, CRP or relevant deviations in other laboratory parameters were not observed. Because of local reactions, IP strengths G and H were considered less tolerable than placebo. No safety concerns regarding the two mistletoe preparations have been raised by this study. EudraCT-Number Mistletoe preparations are Mistletoe für Gelenke used among cancer patients in Europe [ 12 ]. Increasing evidence exists, that Mistletoe für Gelenke preparations containing mistletoe lectins ML have beneficial effects on the quality of life of cancer patients during chemo- or radiation therapy [ 3 ].
Because they can stimulate the production of interleukin IL -6 in periphereal mononuclear cells and lymphoma cells in vitro it has been hypothesized, that they promote tumor enhancement of related malignancies [ 45 ]. IL-6 is an important growth factor for lymphoma and multiple myeloma cells in vitro and Mistletoe für Gelenke vivo [ 6 ]. However, in vitro experiments incubating mistletoe extracts with lymphoma and multiple myeloma cells have shown dose dependent apoptosis mediated growth inhibition and no stimulation [ 789 ].
Furthermore, a retrospective study of lymphoma patients who received mistletoe extracts suggested this therapy to be beneficial and revealed no hint for tumor promoting effects [ 10 ].
IP is registered for complementary cancer therapy [ 1112 ]. VM is used to reduce pain and improve mobility in patients with Mistletoe für Gelenke [ 13 ].
The study was performed in order to fulfil the requirements of the BfArM. The decisive advantage of this setup is that healthy volunteers are a comparably homogenous collective with respect to their immune system and that concomitant medication can be excluded. The Mistletoe für Gelenke was performed as a multiple dose, randomized, placebo-controlled, double blind, monocenter dose escalation clinical trial at University Medical Center Freiburg. The primary Mistletoe für Gelenke criterion was to describe the safety of IP and VM adverse events: Mistletoe für Gelenke in vital signs, physical examination and routine laboratory.
Healthy male and female volunteers between years of age with Mistletoe für Gelenke body mass index BMI between Exclusion criteria were presence or sequelae of any clinically significant disease, drug abuse, smoking more than 20 cigarettes a day, any medication in the week before inclusion, participation in another clinical trial in the 3 preceding months, previous therapy with mistletoe preparations, history of allergy to medicinal products, donation of blood in the 3 preceding months, pregnancy or breast-feeding, absence of highly effective contraception and inability to understand the nature and extent of the trial.
Only volunteers who had given written informed consent and met all the eligibility criteria were included into the study. The study had a positive vote from the ethics committee of the Faculty of Medicine at the Albert-Ludwigs University of Freiburg Germany and was carried out in compliance with the principles of Good Clinical Practice and the Declaration of Helsinki.
At baseline the subjects were randomly assigned to IP, VM or placebo. The subjects injected increasing doses of either IP strength F, 0. One ampoule of IP strength H was regarded as the maximum tolerated dose, because it was expected to cause strong local reactions [ 1415 ]. The respective medication for the next 4 weeks was Mistletoe für Gelenke out at baseline, after 4 weeks and after 8 weeks.
Clinical and safety controls physical examination, inspection of the injection site were performed weekly. Mistletoe antibodies were determined in week Safety and immunological parameters were checked again in a follow up visit 4 weeks after the last injection, The stepwise increase in dosage was performed because we hypothesized an increase of side effects and potential stimulation of the immune system with the dosage.
Mistletoe für Gelenke to this hypothesis, low dosages strength F of IP, all dosages of VM of the two mistletoe preparations should be well tolerable and cause only mild immunological changes as described in a similar study investigating a different mistletoe preparation [ 16 ]. Mistletoe für Gelenke of the high content of cytotoxic mistletoe lectin in IP strength G and H, we expected higher rates of side effects in the groups receiving IP strength G and H.
The dried plant is extracted with isotonic solution over a 14 day period without fermentation. Viscum Mali e planta tota VM is an aqueous fermented extract from fresh mistletoes growing on apple trees. Placebo was the isotonic solution that is used for the preparation of IP and VM consisting of sodium chloride, sodium bicarbonate and water for injection. Routine laboratory parameters were analyzed within less than 1 h of taking the probes by standard methods at the central laboratory of University Medical Center Freiburg according to Good Laboratory Practice GLP.
C-reactive protein CRP was determined using a turbidimetric, latex enhanced immunoassay. The Mistletoe für Gelenke analysis was done on the safety population, defined as all subjects who Mistletoe für Gelenke received at least one ampoule of the study medication and was identical to the intention to treat analysis.
All primary analysis was descriptive. For categorical variables number and percentage were calculated, for continuous variables mean, standard deviation, median, minimum and maximum were presented. Courses of laboratory parameters were analysed by generalised estimation equations GEEhereby modeling treatment group and visit number as Mistletoe für Gelenke cofactors, the respective baseline value as a linear covariate and the patient identification as the repeated measurement factor.
The correlation structure between the visits was assumed to be first-order autoregressive. Tolerability was analysed by exact two-sided Wilcoxon-Mann-Withney tests. The significance level was set to 0.
As usual for safety studies, no correction for multiple testing was performed. Randomisation was performed by the biometrical centre DatInf GmbH, Tübingen, Germany using block randomisation with variable block size. Allocation to the groups was concealed.
Blinding was performed by the manufacturer. All ampoules were identically Mistletoe für Gelenke and packed in boxes with identical appearance. All analyses and data management were performed blinded.
As this was a modified phase I dose Mistletoe für Gelenke study 20 subjects per group have been planned in analogy to similar studies with other mistletoe preparations [ 1618 ]. Because a higher drop-out rate and greater number of side effects were expected in the IP group due to high concentrations of especially mistletoe lectins ML30 subjects were chosen for this group to make sure that at least 20 could be analyzed.
One subject from the placebo group was excluded from the per protocol analysis because Mistletoe für Gelenke major protocol violations. Therefore, the per protocol analysis comprised 69 subjects and the intention to treat analysis 71 subjects. Table 1 shows the characteristics of the subjects. There were no significant differences between the groups at baseline. Significant deviations are bold typed. No differences between the groups were found for IL This increase could, at least in the IP group, possibly be related to the mistletoe preparations, because IgM also increased slightly Mistletoe für Gelenke comparison to baseline, and because antibody production, measured in week 12, was stimulated in the IP group.
In the VM-group viscotoxin and ML-antibodies were not significantly different to the placebo group. During exposure, no differences in absolute neutrophil counts, the Mistletoe für Gelenke of natural killer cells, monocytes, T-suppressor cells, B-cells, immunoglobulins A and G were found for either IP Mistletoe für Gelenke VM compared to placebo. Adverse events as percentage of subjects per group during the three treatment blocks. The difference is related to a decrease of this parameter in the placebo group and not to an increase in the IP group.
The values at baseline were not different to values after 12 weeks treatment or follow up in the IP group. The mean values were smaller in the IP group. None of the low glucose concentrations was accompanied by clinical symptoms.
The values were smaller in the VM group. Lower ALT values have no clinical relevance. The difference is related to an increase of this parameter in the placebo group rather to a decrease in the IP group. A total of 5 probands had intermittently or constantly elevated bilirubin levels 3 in the VM and 2 in the placebo group up to a maximum of 1. These elevated levels are most likely related to subjects with Gilbert's syndrome.
Clinical examinations and other parameters of the liver function prothrombin time and integrity of the liver cell ALT, AST are normal in subjects with Gilbert's syndrome and were normal in our subjects with isolated elevation of the bilirubin level.
Furthermore, at baseline, bilirubin levels in all of these 5 subjects were already close to or slightly above the upper limit of normal without any clinical or other laboratory sign of liver disease. However, there was no systematic change and values also strongly fluctuated in the placebo group. The placebo-controlled, 3-armed modified phase 1 trial presented here was planned and conducted according to all current standards. Randomization was concealed and successful: the groups were well balanced at baseline.
The number of missing Mistletoe für Gelenke is very low: all but one proband completed the study regularly. All parameters were analyzed and reported as planned in the study protocol. There was, therefore, no risk of Mistletoe für Gelenke regarding sequence generation, allocation, incomplete or Mistletoe für Gelenke outcome reporting. Mistletoe für Gelenke from the literature, partial deblinding occurred, because local reactions indicated treatment with one of the mistletoe Mistletoe für Gelenke [ 21 ].
Furthermore, all analyses of Mistletoe für Gelenke laboratory and immunological parameters were performed blinded. Therefore, partial deblinding most likely did not affect the results.
The primary aim of the study was to investigate for the first time safety and tolerability of the two mistletoe preparations IP and VM in humans to fulfil the requirements of the German regulatory authority BfArM. Therefore, the preparations were injected in a dose escalating manner. In order to achieve high internal validity the study was performed in healthy subjects.
Whether or not these data are transferable to tumor patients is a matter of debate. Because tumor patients are confronted with a life threatening disease and often experience severe side effects from conventional therapy, it can be speculated that tolerance to harmless local reactions at the Mistletoe für Gelenke of injection is higher than in healthy individuals.
This well known side effect of IP which is also mentioned in the Investigator's Brochure [ 15 ] and in a review about other mistletoe preparations [ 22 ] probably Mistletoe für Gelenke a lesser role in clinical practice than suggested from our Mistletoe für Gelenke with healthy subjects.
At least the strong local reactions and frequency of dose adjustments in our Mistletoe für Gelenke show, that we used the maximum tolerable dose and that the data are not biased by under-dosing. Our data show, that IL-6 serum levels did not increase after subcutaneous injection of the mistletoe preparations IP and VM. IL-6 was measured with highly sensitive methods and under strict adherence to the pre-analytic Mistletoe für Gelenke [ 19 ].
It was measured in parallel to the other immunological parameters and in parallel to the occurrence of local Mistletoe für Gelenke at the injection site. Therefore, the results can be regarded as valid, despite the short half-life of IL-6 in blood. This is supported by the fact that CRP, which is induced by IL-6 in the liver and has a longer half-life of 19 h, was also not increased during application of the mistletoe preparations. In multiple myeloma patients IL-6 is often synthesized by the tumor itself and by bone marrow stem cells within an autocrine Mistletoe für Gelenke loop [ 23 ].
We of course cannot rule out, that mistletoe preparations interfere in this loop, because Mistletoe für Gelenke investigated healthy probands. But we can at least conclude that no substantial amounts of IL-6 are produced from the normal immune system after application of different dosages IP or VM.