Reto Brignoli

The Use of Silymarin in the Treatment of Liver Diseases

The high prevalence of liver diseases such as chronic hepatitis and cirrhosis underscores the need for efficient and cost-effective treatments. The potential benefit of silymarin (extracted from the seeds of Silybum marianum or milk thistle) in the treatment of liver diseases remains a controversial issue. Therefore, the objective of this review is to assess the clinical efficacy and safety of silymarin by application of systematic approach. 525 references were found in the databases, of which 84 papers were retained for closer examination and 36 were deemed suitable for detailed analysis.Silymarin has metabolic and cell-regulating effects at concentrations found in clinical conditions, namely carrier-mediated regulation of cell membrane permeability, inhibition of the 5-lipoxygenase pathway, scavenging of reactive oxygen species (ROS) of the R-OH type and action on DNA-expression, for example, via suppression of nuclear factor (NF)-κB.Pooled data from case record studies involving 452 patients with Amanita phalloides poisoning show a highly significant difference in mortality in favour of silibinin [the main isomer contained in silymarin] (mortality 9.8% vs 18.3% with standard treatment; p < 0.01). The available trials in patients with toxic (e.g. solvents) or iatrogenic (e.g. antispychotic or tacrine) liver diseases, which are mostly outdated and underpowered, do not enable any valid conclusions to be drawn on the value of silymarin. The exception is an improved clinical tolerance of tacrine. In spite of some positive results in patients with acute viral hepatitis, no formally valid conclusion can be drawn regarding the value of silymarin in the treatment of these infections.Although there were no clinical end-points in the four trials considered in patients with alcoholic liver disease, histological findings were reported as improved in two out of two trials, improvement of prothrombin time was significant (two trials pooled) and liver transaminase levels were consistently lower in the silymarin-treated groups. Therefore, silymarin may be of use as an adjuvant in the therapy of alcoholic liver disease. Analysis was performed on five trials with a total of 602 patients with liver cirrhosis. The evidence shows that, compared with placebo, silymarin produces a nonsignificant reduction of total mortality by −4.2% [odds ratio (OR) 0.75 (0.5–1.1)]; but that, on the other hand, the use of silymarin leads to a significant reduction in liver-related mortality of −7% [OR: 0.54 (0.3–0.9); p < 0.01]. An individual trial reported a reduction in the numberof patients with encephalopathy of −8.7% (p = 0.06). In one study of patients with cirrhosis-related diabetes mellitus, the insulin requirement was reduced by −25% (p < 0.01). We conclude that available evidence suggests that silymarin may play a role in the therapy of (alcoholic) liver cirrhosis.Silymarin is has a good safety record and only rare case reports of gastrointestinal disturbances and allergic skin rashes have been published. This review does not aim to replace future prospective trials aiming to provide the ‘final’ evidence of the efficacy of silymarin.

Influence of age, gender, hormonal status and smoking habits on colonic transit time

Abstract The factors that influence colonic transit time in healthy humans are not yet clearly defined. The aim of this study was therefore to determine (a) if there are differences in colonic transit time between men and women and (b) if age, female hormonal status or smoking habits are associated with alterations in these parameters. Colonic transit time was measured in 164 asymptomatic subjects (80 males, 84 females) by a radio‐opaque marker technique with one single plain abdominal X‐ray. Colonic transit time was significantly shorter in men than in women (30 ± 2 vs. 42 ± 3 h, P < 0.05). Colonic transit time in non‐smoking males was significantly shorter compared with smoking males (26 ± 2 vs. 40 ± 5 h, P < 0.05). In females only height and menstrual cycle influenced colonic transit times. We conclude that gender and smoking habits should be considered when studying colonic transit time in health and disease.

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.

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.

Systematic review of clinical data with BNO-101 (Sinupret) in the treatment of sinusitis.

Background: The herbal formula BNO-101 (containing Gentianae radix, Primulae flos, Rumicis herba, Sambuci flos and Verbenae herba; ratio 1:3:3:3:3) has been widely employed as a ‘mucoactive’ agent in Germany for 70 years for the symptoms of respiratory infections. This paper reviews the clinical evidence of BNO-101 in sinusitis. Methods: The systematic search identified 22 studies with BNO-101. Out of these, 6 controlled trials on sinusitis were reassessed according to predefined criteria. 4 trials had almost identical designs and could be examined by meta-analysis. Results: The database comprised approximately 900 patients, mostly young adult males. After 2 weeks of treatment, verum was significantly superior to placebo (2 RCTs, 159 vs. 160 patients, both add-on to antibacterial treatment). The benefit regards the patients’ assessment (‘cured’: verum = 61.1%, placebo = 34.5%), reduction of drain obstruction, headache and radiological signs (all p < 0.05). Comparing BNO-101 to ambroxol (2 RCTs, 151 vs. 150 patients, add-on to antibacterials in 13% of the cases) the patients’ assessment after 2 weeks showed no difference, although it favoured BNO-101 in chronic cases (‘cured’ BNO-101 = 37.1%, ambroxol = 12.5%; p < 0.05). It also favoured BNO-101 concerning pyorrhoea and headache (p < 0.05). No significant differences were reported in 2 open randomised trials vs. N-acetyl-cysteine and vs. the herbal product Myrtol std. Conclusions: BNO-101, combined with standard antibacterial therapy, significantly reduces the acute symptoms and signs of sinusitis. The effects are of the same order of magnitude as observed with other mucoactive agents. In the trials investigated BNO-101 had a favourable risk/benefit ratio, with an incidence of adverse events similar to placebo.

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.

Wirksamkeit und Sicherheit von Padma 28 bei peripherer arterieller Verschlusskrankheit

Hintergrund: Das komplexe pflanzliche Arzneimittel Padma 28 basiert auf einer Formel der Tibetischen Medizin und wird seit über 30 Jahren in der Schweiz zur Behandlung von Durchblutungsstörungen und Symptomen der Claudicatio intermittens (reduzierte Gehstrecke) eingesetzt. Fragestellung: Welche Evidenz liegt zur klinischen Wirksamkeit und Sicherheit dieses Arzneimittels bei Patienten mit peripherer arterieller Verschlusskrankheit (PAVK) vor? Material und Methode: Systematischer Review mit Literaturrecherche in elektronischen Datenbanken (jeweils von deren Beginn bis Herbst 2005) und den Literaturverzeichnissen der gefundenen Arbeiten. Ergebnisse: Es fanden sich 14 Artikel (6 publizierte, 1 unpublizierte und 6 doppelt publizierte Studien sowie 1 Metaanalyse). Sechs Studien untersuchten die maximale Gehstrecke, fünf davon zeigten eine signifikante Zunahme derselben. Die gepoolten Daten der Metaanalyse bestätigten eine signifikante und klinisch relevante Verlängerung der Gehstrecke um mehr als 100 m bei knapp einem Fünftel der Patienten. Die schwerwiegenden unerwünschten Ereignisse standen nicht im Zusammenhang mit dem Verum, die nicht schwerwiegenden waren gleich häufig wie unter Plazebo. Schlussfolgerungen: Die verfügbare Evidenz zeigt, dass die Multi-Target-Therapie mit Padma 28 eine statistisch signifikante und klinisch relevante Besserung von Symptomen der PAVK, d.h. eine erhöhte Gehstrecke, bewirkt.

Preliminary Data of a HAMD-17 Validated Symptom Scale Derived from the ICD-10 to Diagnose Depression in Outpatients

Background: In outpatient settings diagnostic classification of depressive symptoms is mostly descriptive based on ICD-10. Depending on clinical experience and consultation time, diagnosis can be verified by validated scales. However, physicians working in primary care are familiar with ICD-10 criteria. Therefore, the aim of the present study was to examine the feasibility of the validation of an ICD-10-derived symptom scale for depression. Methods: For this preliminary trial we generated a symptom scale derived 1:1 from the diagnostic criteria for depression given in the ICD-10 with 10 items. The Hamilton Rating Scale for Depression (HAMD-17) was used as reference in a population of 226 outpatients suffering from depressive symptoms. Correlation between scales as well as sensitivity and specificity of the ICD-10 scale were calculated. Results: The generated ICD-10 symptom scale for depression could be analyzed in 219 patients and showed a significant and strong correlation with the HAMD-17 (p < 0.0001; ρ = 0.75). The best tradeoffs between specificity and sensitivity of the ICD-10 score were found at 10 points for the lower and 14 points for the upper cut-off. Overall sensitivity and specificity was 76.7 and 88.6%. Almost two thirds (i.e. 65.3%) of the patients were correctly classified by the ICD-10 scale. Conclusion: The ICD-10 symptom scale examined in the current population was found to have fair correlation with the HAMD-17 as well as, in face of the limited variance of the patients’ condition, acceptable sensitivity and specificity. Therefore, this preliminary study showed that the ICD-10-derived symptom scale seems appropriate to be investigated in a thorough validation trial.

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.

Bedeutung von Sport und Ernährung für die körperliche Leistungsfähigkeit und Gesundheit - Ein systematischer Review

Hintergrund: Viele Menschen bewegen sich heute zu wenig und ernÄhren sich unausgewogen. Dies hat negative Auswirkungen auf das Wohlbefinden, die kÖrperliche LeistungsfÄhigkeit und ganz allgemein auf die Gesundheit. Zielsetzung: Erstellung eines systematischen Review zur Bedeutung von Sport und ErnÄhrung fÜr die Gesundheit. Methoden: Systematische Analyse und Bewertung von Humanstudien (prospektive Doppelblindstudien, epidemiologische und retrospektive Studien, kurzfristige biochemische/hÄmatologische Studien («Surrogate Markers»)) der letzten 10 Jahre aus den gÄngigen elektronischen Datenbanken sowie der Angaben von Standardwerken und publizierten Monographien. Ergebnisse und Schlussfolgerungen: SportfÖrderung stellt eine wichtige prÄventiv-medizinische Massnahme dar. Grundlage fÜr die benÖtigte kÖrperliche Bewegung ist beispielsweise die Bewegungspyramide. Zur Verbesserung sportlicher Leistung muss ein Training nach dem Prinzip der schrittweise steigenden Belastung aufgebaut sein. Die ErnÄhrung von SportlerInnen sollte – wie die ErnÄhrung von Personen, die keinen Sport betreiben – grundsÄtzlich auf der Lebensmittelpyramide basieren. Manche SportlerInnen benÖtigen zusÄtzliche NÄhrstoffe. KÖrperliche LeistungsfÄhigkeit nimmt zwar mit dem Alter ab, die LeistungsfÄhigkeit kann aber im Alter durch Training erhalten und verbessert werden. Die positive Wirkung des Trainings auf Blutfettwerte und besonders auf Herz und Kreislauf ist abhÄngig von der TrainingsintensitÄt. Schwitzen ist ein zentraler Regulationsmechanismus der durch Training oder Sport erhÖhten KÖrpertemperatur. Mit Schweiss und Verdunstung werden ausser Wasser auch Elektrolyte ausgeschieden, die wieder zu ersetzen sind. Viele SportlerInnen fragen sich, ob sie mit NahrungsergÄnzungsmitteln oder anderen – legalen! – Wirkstoffen ihre Leistung verbessern kÖnnen. Zurzeit gibt es wenige Daten Über dazu geeignete Substanzen.