By Holger Kiesewetter, Stefan Ludwig and Oliver Planz In view of the current influenza pandemic, WHO Director General Margaret Chan urged that all options for urgently needed new diagnostic, prophylactic and therapeutic options in the fight against the epidemic be examined together . One of these options could be a medicinal plant extract, the antiviral potency - especially against influenza viruses - has been intensively researched for a few years (plant: Cistus incanus, extract name: Cystus052). in vivo, clinical). The basic experimental work on antiviral activity in cell culture experiments  and in animal models  has already been summarized in the DAZ 19/2009 .
Development of resistance
It was examined in vitro whether influenza A viruses can form virus variants resistant to Cystus052. For this purpose, the viral titers from cells treated with the plant extract were determined in a multipassaging experiment, in comparison to untreated and amantadine-treated cells (influenza viruses quickly become resistant to amantadine ). It was shown that the virus titers from amantadine-treated cells increased significantly after the fourth passage and in the fifth and sixth passages it was no longer possible to distinguish them from the titers of untreated cells due to the formation of resistant variants. In clear contrast to this was that even in the fifth passage, Cystus052 still had the same antiviral activity as in the first passage. This shows that the rock rose extract, although it initially inhibits virus replication less efficiently than amantadine, has an advantage over the adamantane derivative in later passages because it does not trigger resistant variants. Probably because the viruses cannot escape the postulated direct, non-specific, physical blockage by individual mutations.
Effect on avian and swine flu viruses
Further in vitro experiments clarified whether Cystus052 is also active against avian influenza viruses. For this purpose, the plant extract and to compare the neuraminidase inhibitor oseltamivir were tested against seven different H5N1 avian influenza viruses, which had been isolated from dead birds in Germany in 2006/2007. The treatment of virus-infected cells in the cell culture system and the concentrations of the substances used were carried out as already published [2, 3].
It became clear that the special rock rose extract Cystus052 had an antiviral effect against all H5N1 influenza viruses examined, whereas this was only the case for two strains with oseltamivir. In quantitative terms, the plant extract had an antiviral activity that was around 100 times higher than that of the neuraminidase inhibitor. The toxicity test of Cystus052 showed that the extract only damages the viability of the culture cells by 50% from a very high concentration of 1.16 ± 0.001 mg / ml (EC50). This low cell toxicity is confirmed by the clinical use of the extract (good tolerance, practically no side effects).
Recent studies have shown that the plant extract Cystus052 also has antiviral activity in vitro against the globally circulating causative agent of swine / Mexican flu, an H1N1 influenza virus. To the extent that it has already been published with regard to other influenza viruses .
Effects on epithelial cells
The decisive factor for the safety and the approval status of the rock rose extract as a medical device is the question of whether there are interactions with epithelial cell surfaces.
Cystus052 at antiviral concentrations had no negative effects on the survival of normal epithelial cells, did not affect cell growth or cell vitality, did not lead to apoptosis and did not induce receptor-mediated intracellular processes such as transcription factor activation, nor did it inhibit those induced by ligand binding to cellular surface receptors Activation of such factors . The extract did not influence the condition of epithelial cells either through physical binding or through pharmacological effects. In addition, further investigations showed that the extract did not influence the cell morphology or change the proliferation or the metabolism of the cells examined.
Antiviral effects in animal models
To analyze the antiviral Cystus052 effect against influenza viruses in vivo, Balb / c mice were infected with the Fowl Plague Virus (FPV), a highly pathogenic avian influenza virus. The previous compatibility test showed that the plant extract in a concentration of 10 mg / ml did not cause any changes in the weight course or the general health of the animals, i.e. it was free of side effects. The selected aerosol application of Cystus052 also proved to be well tolerated by mice.
The treatment three times a day with 2 ml of Cystus052 extract (10 mg / ml) resp. H2 O as a control started on the day of infection and continued for five days. Immediately after the first application, the mice were infected with FPV in a virus dose corresponding to LD50. Eight days after infection, all mice in the control group developed clinical symptoms, a significant reduction in their body weight and severe disturbances in vitality (measured using circadian temperature profiles and activity), 60% of the animals died. The mice treated with Cystus052 showed no disease-specific symptoms, only a slight decrease in body weight and no disturbance of the vitality parameters, no animal died. Oral administration of Cystus052 with the feed showed no antiviral effects after FPV infection, in contrast to aerosol treatment, which supports the hypothesis of a physical blockage of virus binding to host cells and speaks against an intracellular, systemic mechanism (contact with the nasopharynx is low when adding active ingredients as feed, but high as aerosol or lozenge).
To date, several studies have been conducted to study the effects of Cystus052. The good effectiveness of a polyphenol-rich liquid preparation (medical product: Cystus052® Sud) for painful infections in the mouth and throat was demonstrated in an application study with 53 patients . The control preparation (green tea), which is also rich in polyphenols, was significantly less effective than the special rock rose extract. In 75% of the patients in the verum group, the symptoms disappeared between the 3rd and 7th day of treatment, in the control group (green tea) only in 40% of the test subjects.
A second study with 300 patients with upper respiratory tract infections compared the use of Cystus052 as a tablet (verum) with the application of green tea (comparison) . The prospective, randomized, open-label study included 300 people with throat-verified infections. The pathogen groups were mainly distributed between bacteria (54.3%) and viruses (43.7%), about 20% of the viral infections were caused by influenza viruses. Treatment started the first time symptoms appeared, on average 2.2 days after the onset of infection. Verum therapy consisted of using two Cystus052 tablets six times a day (about 260 mg polyphenols ). The comparative therapy started on the first day of treatment by gargling and swallowing 100 ml of green tea (about 480 mg polyphenols ) eight times a day. During the following days, this dosage was halved to 100 ml of green tea four times a day. The duration of treatment and follow-up was up to seven days. The subjective complaints were recorded with a complaint score comprising five items (pain, cough intensity, cough frequency, rhinorrhea, expectoration; total score: 0 - 30).
In the verum group, the symptom score improved by 57.8% over a therapy period of 3.2 days on average. The remaining patients reported symptoms that were unchanged or worsening. The treatment results did not differ according to the pathogen group (bacteria, viruses). The comparison group showed a significantly smaller improvement in their symptoms (p <0.001, Fig. 1). The change in the complaint score between the two visits to the doctor was recorded as a further parameter of the treatment effectiveness. In the Cystus052 group the median complaint score decreased from 12 to 8, while in the comparison group it increased from 12 to 14 (difference statistically significant, p <0.001). The main side effects recorded were nausea and dizziness (Cystus052 group 14.9%, green tea group 35.3%).
The plant extract is therefore significantly more effective in reducing the duration of the illness and reducing the severity of symptoms in patients with infections of the upper respiratory tract than the use of green tea. In addition, Cystus052 has a much faster onset of action than under green tea. The observed Cystus052 effects appear to be independent of the infectious agent, which in turn supports the thesis that the highly polymeric polyphenols  contained in the rock rose extract act unspecifically through a reversible, biophysical interaction with a large number of bacteria and viruses and thus reduce their infectivity . Since these polyphenols are not absorbed or are absorbed only in negligible amounts [11, 12], a direct topical effect on bacteria and viruses in the respiratory tract must also be assumed based on these results.
In another multicentre, prospective, randomized, placebo-controlled study in a parallel group comparison design, the effectiveness of Cystus052 in infections of the upper and lower respiratory tract was demonstrated (study in publication).
Preparations from the Cystus052 cistus extract are effective and safe medical devices. Their effect can be explained purely physically because of the size of the polyphenols. In addition, the effect is local and is independent of the spectrum of pathogens. Bacteria and viruses are physically blocked, which prevents infections and reduces reinfections. There is no evidence of pharmacological, systemic effects of Cystus052. This is also supported by the lack of product-related side effects.
Taking into account the basic problems with zanamivir inhalation, the current resistance problems with oseltamivir, the extensive unsuitability of antiviral M2 blockers or the still considerable time until sufficient vaccine production begins, herbal preparations with antiviral activity, free product access beyond the Pandemic plan provided distribution channels for neuraminidase inhibitors, lack of side effects, lack of resistance development and high acceptance among users, ideal products to supplement existing concepts of influenza disease control in a meaningful and population-oriented manner.
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 Morgentau® flavored green tea. J.T. Ronnefeldt KG, 60486 Frankfurt.
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Prof. Dr. Dr. Holger Kiesewetter
Institute for Transfusion Medicine
Charité - Universitätsmedizin Berlin Charitéplatz 1, 10117 Berlin
Prof. Dr. Stephan Ludwig
Institute of Molecular Virology
University of Münster
Von-Esmarch-Str. 56, 48149 Munster
Prof. Dr. Oliver Planz
Friedrich Löffler Institute
Federal Research Institute for Animal Health Tübingen
Paul-Ehrlich-Strasse 28, 72076 Tübingen