Jörg Melzer

An Updated Systematic Review with Meta-Analysis for the Clinical Evidence of Silymarin

Background: The potential benefit of silymarin (special extract from the fruits of Silybum marianum) in the treatment of liver diseases remains a controversial issue. Methods: For this systematic review electronic databases identified 65 papers for the search terms silymarin, silibinin, silicristin or milk thistle and clinical trial. Only 19 complied with the criteria ‘double-’ or ‘single-blind’. These publications were analysed from a clinical point of view and meta-analytic calculations were performed. Results: The clinical evidence of a therapeutic effect of silymarin in toxic liver diseases is scarce. There is no evidence of a favourable influence on the evolution of viral hepatitis, particularly hepatitis C. In alcoholic liver disease, comparing with placebo, aspartate aminotransferase was reduced in the silymarin-treated groups (p = 0.01) while alkaline phosphatase was not. In liver cirrhosis, mostly alcoholic, total mortality was 16.1% with silymarin vs. 20.5% with placebo (n.s.); liver-related mortality was 10.0% with silymarin vs. 17.3% with placebo (p = 0.01). Conclusions: Based on the available clinical evidence it can be concluded - concerning possible risks / probable benefits - that it is reasonable to employ silymarin as a supportive element in the therapy of Amanita phalloides poisoning but also (alcoholic and grade Child ‘A’) liver cirrhosis. A consistent research programme, consolidating existing evidence and exploring new potential uses, would be very welcome.

Meta-analysis: phytotherapy of functional dyspepsia with the herbal drug preparation STW 5 (Iberogast)

Background : Despite a long‐standing use of herbal drugs with dyspeptic symptoms, little attention has been paid to their clinical evaluation.

An updated systematic review of the pharmacology of silymarin.

Recent years have seen an explosion of scientific papers that deal with drugs from the fruits of milk thistle and its active substances silymarin (standardized mixture of flavonolignanes), thus justifying an updated systematic review. Methods: Electronic databases identified silymarin, silibinin, silicristin or milk thistle as descriptors in >700 papers (34% published in last 5 years; 92% dealt with animal pharmacological). Only papers adequately reporting on experimental conditions, dosing, variables tested and statistics were analysed. Results: Silymarin was found to modify specifically the functions related to various transporters and receptors located in the cell membranes; that is, organic anion uptake transporter peptides (OATP), ABC transporters (P-gp), bile salt export pump, as well as TNF-a-dependent and possibly selectin-dependent phenomena. In the cytoplasm, some antioxidant properties and the inhibition of the lipoxygenase pathway seem quite selective and could concur to the antitoxic effects. Some effects like the inhibition of inducible nitric-oxide synthase, of nuclear factor κ B, and reduction of collagen synthesis are indicative of DNA/RNAmediated effects. Several studies using ‘in vitro’ and ‘in vivo’ cancer models suggest a potential of silymarin in such diseases. Topical and systemic silymarin has skin protective properties against UV-induced damage in epidermis and causes an up-regulation of tumour-suppressor genes p53- and p21CIP1. There were no data on hepatic viral replication, viremia or spontaneous tumours in the data examined. Conclusions: Data presented here do not solve the question about the complex mechanism(s) of action of the medicinal herbal drug silymarin. Silymarin may be a natural multi-functional and multi-target drug.

Efficacy and safety of mistletoe preparations (Viscum album) for patients with cancer diseases. A systematic review.

Background: Mistletoe is often used as a complementary approach in oncology. Despite experimental anti-tumour effects and several reviews there remains controversy about its clinical role. Patients and Methods: Potentially relevant trials were identified to perform a systematic review (databases: e.g. EMBASE, MEDLINE; hand search: e.g. bibliographies; search terms: e.g. mistletoe). To be included, randomised or comparative clinical trials at least had to examine mistletoe preparations standardized according to manufacturing process and to describe interventions explicitly. Additionally, cohort studies were included for reasons of external validity. Results were summarised in tables. Results: 18 clinical trials (>6,800 participants) were included. Their internal quality was mostly low. Due to heterogeneity between trials a meta-analysis was impossible. Regarding efficacy, findings were inconsistent regarding life expectancy, relation to tumour entity, dosing and treatment duration. Yet, studies indicate that quality of life (QoL) is improved. As these findings do not seem to be limited to one of the different parenteral mistletoe preparations reviewed the treatment may be summarised under the umbrella term ‘mistletoe therapy’. Regarding safety, 1 serious adverse event (AE) related to mistletoe was described; non-serious AEs were local reactions at injection site. Allergic reactions were rare. Conclusion: Supportive ‘mistletoe therapy’ seems safe and beneficial for QoL in adult patients with solid tumours. But there is an urgent need to confirm its efficacy in patient-centred care in a complex oncological setting. This has to be evaluated systematically in prospective observational trials with validated, multidimensional patient-rated QoL questionnaires and comparisons of different preparations and dosages.

Iberogast(r): Eine moderne phytotherapeutische Arzneimittelkombination zur Behandlung funktioneller Erkrankungen des Magen-Darm-Trakts (Dyspepsie, Colon irritabile) – von der Pflanzenheilkunde zur «Evidence Based Phytotherapy».Eine systematische Übersicht

Iberogast(r): A Modern Phytotherapeutic Combined Herbal Drug for the Treatment of Functional Disorders of the Gastrointestinal Tract (Dyspepsia, Irritable Bowel Syndrome) – from Phytomedicine to ‘Evidence Based Phytotherapy’. A Systematic Review Iberogast is a complex herbal preparation. As a fixed drug combination (9 constituents) it is composed of a fresh plant extract of Iberis amara and of extracts of 8 other dried herbal drugs ( Chelidonii herba, Cardui mariae fructus, Melissae folium, Carvi fructus, Liquiritiae radix, Angelicae radix, Matricariae flos, Menthae piperitae folium). The pharmacological effects as well as the therapeutic effectiveness, tolerability, and toxicity of Iberogast were experimentally and clinically recorded and documented using modern investigation tools. Both the experimental as well as the clinical studies indicated a regulatory influence of Iberogast on the whole gastrointestinal tract by a special dual action. While the included extracts of the dried herbal drugs have mainly spasmolytic properties, the fresh plant extract of Iberis amara has a tonic effect on the gastrointestinal tract. Depending on the predistension of the gastric or intestinal wall, the tonic or the spasmolytic effects of Iberogast prevail. Both the fresh plant extract of Iberis amara and the combined preparation of Iberogast were found to be toxicologically safe in therapeutically effective doses. For the estimation of the clinical effectiveness a systematic review was performed (data research: January 1970 to September 2002). As shown in controlled (according GCP standard) as well as supportive and uncontrolled clinical studies, the symptoms of functional dyspepsia and of irritable bowel syndrome (one controlled study and one observational study) could be significantly reduced by these herbal preparation in comparison to placebo. Two trials comparing Iberogast with the prokinetics metoclopramide and cisapride demonstrated a comparable therapeutic effectiveness of the herbal preparation and the prokinetics in the treatment of dyspepsia. Adverse events were rare and, with respect to frequency and spectrum, partly the same as found with placebo. Another advantage of Iberogast is that it targets only the gastrointestinal tract and the enteral nervous system, but not the central nervous system. Because of its special dual action, its clinically proven effectiveness, and its good tolerability, Iberogast may be a drug of first choice in the treatment of functional gastrointestinal diseases and their corresponding symptoms.

Open Trial to Assess Aspects of Safety and Efficacy of a Combined Herbal Cough Syrup with Ivy and Thyme

Background and Objectives: Changes in the symptoms of cough after treatment with a combined herbal preparation containing dry ivy leaf extract as main active ingredient, decoction of thyme and aniseed, and mucilage of marshmallow root (Weleda Hustenelixier, new formulation) and its tolerability were investigated in an open clinical trial (‘Anwendungsbeleg’). Patients and Methods: Between January and March 2004, 13 general practitioners recruited and treated 62 patients with a mean age of 50 years (range 16-89). The patients had irritating cough in consequence of common cold (n = 29), bronchitis (n = 20) or respiratory tract diseases with formation of viscous mucus (n = 15). The mean daily intake was 10 ml (range 7.5-15) of syrup, and the mean duration of treatment was 12 days (range 3-23 days). Treatment results were assessed on the basis of changes in the symptom scores for cough and expectoration. Safety was evaluated by means of an analysis of adverse events. In addition, efficacy and tolerability were analyzed from the judgments of the doctors and patients. Results: At the final visit, all symptom scores showed an improvement as compared to baseline. Doctors and patients assessed efficacy as good or very good in 86% and 90% of the cases, respectively. Tolerability was assessed as good or very good by 97% of the doctors and patients. Only one adverse event was reported. However, a relation to the medication was classified to be unlikely. Conclusion: Considering the traditional use of ivy leaves, thyme herb, aniseed and marshmallow root in preparations for cough, the reduction in the symptom score as well as the good tolerability the investigated combined herbal cough syrup seems to alleviate cough in consequence of common cold, bronchitis or respiratory tract diseases with formation of mucus.

Phytodolor® in Musculoskeletal Disorders: Re-Analysis and Meta-Analysis

Background: Treatment of rheumatic or musculoskeletal disorders (MD) is multi-disciplinary and includes herbal analgesics. Although already reviewed, no quantitative evaluation of efficacy and safety of the herbal combination Phytodolor® (STW1) is available. Methods: We searched in databases and contacted authors and the manufacturer to identify randomized controlled trials (RCTs) examining STW1 in patients with MD. We made a reanalysis of raw data of eligible published and unpublished RCTs and pooled the results for meta-analysis according to Cochrane guidelines and intention-to-treat. Primary outcome measure was patient global assessment of efficacy, secondary outcome measure was pain at rest and on movement. Results were stratified according to treatment groups. Results: Patient data of 11 RCTs were eligible for pooling. In the entire population, STW1 was significantly superior compared to placebo in patients’ global assessment of efficacy (group difference for rating very good/good: 20%; placebo 48.9% and STW1 69.1%; p < 0.001; OR 0.43; 95% CI 0.28–0.65) and in the subpopulation ‘other rheumatic diseases’ (placebo 45.4%; STW1 72.3%; p < 0.001; OR 0.32; 95% CI 0.2–0.52), but not in the subpopulation ‘gonarthrosis’. STW1 did not differ significantly compared to non-steroidal anti-inflammatory drugs (NSAIDs), neither in the entire population nor the subpopulations. Similar results were found for pain at rest and on movement. No serious adverse events (AE) but minor AE were reported (placebo 8.1%; STW1 14.2%; NSAIDs 18.9%). Conclusion: According to the analysed data, STW1 showed a better pain reduction than placebo in patients with pain due to MD, probably equivalent to NSAIDs, and was well tolerated.

Fixed herbal drug combination with and without butterbur (Ze 185) for the treatment of patients with somatoform disorders: randomized, placebo-controlled pharmaco-clinical trial

Herbal drugs are often used in patients with somatoform disorders yet, the available evidence is limited. The aim of the present short‐term study was to evaluate in a pharmaco‐clinical trial the additional benefit of butterbur in a fixed herbal drug combination (Ze 185 = 4‐combination versus 3‐combination without butterbur and placebo) in patients with somatoform disorders.

Aspects of Quality of Primary Care Provided by Physicians Certified in Phytotherapy in Switzerland

Background: Data on the use of phytotherapy in primary care are scarce and difficult to compare (e.g. different health-care systems, study designs). Objective: Are there differences in Switzerland regarding demographic data, practice structure, process of care and outcome/ treatment satisfaction between primary care physicians certified in phytotherapy (CAM) and physicians performing conventional primary care (COM) and their patients? Material and Methods: Subgroup analysis of the data of phytotherapy of an observational study (2 cross-sectional surveys with 3 questionnaires) which was performed as part of a nationwide evaluation program on complementary medicine (PEK). A descriptive analysis was used to compare data. Results: In survey A, 20 CAM and 191 COM physicians participated, of which 14 and 84, respectively, continued for survey B and recruited at least 276 CAM and 1,395 COM patients. Findings show that CAM physicians had less technical equipment (e.g. x-rays) than COM physicians, their consultation time was 25% longer, and they used more non-drug therapies. Whereas in the SF-36 no differences could be identified between the groups, the EUROPEP showed significant differences in favour of CAM patients. Conclusions: Preliminary data of the comparison between CAM and COM physicians indicate few differences in demographic and practice structure data. Yet, due to differences in the process of care CAM patients showed better treatment satisfaction than COM patients. This is probably due to their doctors’ communicative qualities and patient-oriented skills. To which degree this might be triggered due to phyto-pharmacosemiotic aspects needs to be investigated in a future study.

A hypericum extract in the treatment of depressive symptoms in outpatients: an open study.

Background: Extracts of Hypericum perforatum have demonstrated in randomized trials (RCTs) to be effective in mild to moderate depressive episodes. However, as their use in daily practice may differ from that in RCTs we have conducted a study to achieve a better estimate of the range and frequency of adverse drug reactions (ADR) and the efficacy. Patients and Methods: In an observational study in Germany, adult outpatients with depressive syndrome were treated with an extract of St. John’s Wort. Study duration was 12 weeks, with control visits every 4 weeks. Besides anamnestic data, the variables assessed were: evolution of ICD-10 derived symptom score, Global Clinical Impression scale (GCI), and tolerability. Results: 1,778 patients from 304 centers participated in the study (mean duration of disorder 7.3 ± 18.9 months), and 1,541 patients completed it. At the last control visit the ICD-10 sum score had dropped by 63.1% and the proportion of patients described as ‘normal to mildly ill’ (GCI-s) had increased from 21.6% at admission to 72.4%. Regarding the GCI-i, 77% of the patients had improved ‘very much’ or ‘much’ at the last visit. This was consistent with their self-assessment (76%). Lower age and shorter duration of the disorder were associated with significantly better outcomes. The incidence of ADRs was 3.54% and had been decreasing continuously from the first control visit onwards; serious ADRs did not occure. Conclusions: The herbal drug was well tolerated, and no new or serious ADR were identified. In view of the limitations inherent to the study design, it can be concluded that extracts of St. John’s Wort are effective as an antidepressant in the management of depression in daily practice.