Remy Meier

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in patients with toxic (e.g. solvents) or iatrogenic (e.g. antispychotic or tacrine) liver diseases, which are mostly outdated and underpowered, do not enable any valid conclusions to be drawn on the value of silymarin.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.

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.

Pharmacodynamic Effects of Sandostatin® in the Gastrointestinal Tract

Somatostatin is widely distributed throughout the human gastrointestinal system. There it is found in neurons and fibers of both the submucosal and the myenteric plexus and the pancreas as well as in the D cells of the stomach, gut and pancreatic islets. Whereas in the intestinal nervous system, in the duodenum and the pancreas, somatostatin-14 appears to be the predominant molecular form, the endocrine-type D cells of the intestine primarily contain somatostatin-28. Somatostatin peptides may act very differently at different sites, as hormones, as paracrine substances or neurotransmitters. Because of this complexity of action, very little is known about the physiological effects of somatostatin in the gastrointestinal tract. In contrast, the pharmacological actions of natural synthetic somatostatin have been thoroughly studied and have given rise to many therapeutic applications. Octreotide, an analogue with a longer half-life and higher potency, has greatly facilitated the clinical application of somatostatin. This review deals with the pharmacological effects of octreotide on different gastrointestinal functions. The somatostatin analogue exerts a long-lasting inhibitory action on gastric acid, pancreatic enzyme and bicarbonate secretion as well as on bile flow. It is also able to inhibit stimulated intestinal secretion, the release of neuropeptides from the gut and the pancreas. It can also prolong orocecum transit time and prevent gallbladder contraction. It inhibits absorption of nutrients and exerts inhibitory effects on splanchnic hemodynamics. It is because of these actions that somatostatin has attracted so much attention in the treatment of different gastrointestinal disorders.

Effect of loxiglumide, a cholecystokinin antagonist, on pancreatic polypeptide release in humans

The purpose of this study was to determine the role of cholecystokinin in the regulation of postprandial pancreatic polypeptide secretion in humans. The pancreatic polypeptide responses to modified sham feeding and gastric instillation of a test meal were first compared with the response to oral ingestion of the same meal. The experiments were repeated under cholinergic (atropine) and cholecystokinin (loxiglumide) blockade. Atropine completely abolished the pancreatic polypeptide response to sham feeding and caused significant reductions after gastric and oral food intake. Loxiglumide, on the other hand, significantly reduced pancreatic polypeptide release to oral food (51% inhibition) without affecting the response to sham feeding. In separate experiments using a duodenal perfusion system, the effects of atropine and loxiglumide on intestinal phase-stimulated pancreatic polypeptide release were examined, and both cholinergic and cholecystokinin blockade induced complete suppression. It was concluded (a) that cholecystokinin is involved in postprandial pancreatic polypeptide response, especially during the intestinal phase stimulation, and (b) that the cholinergic system is crucial and superimposed on cholecystokinin in stimulating pancreatic polypeptide release.

Germline alterations in the cyclooxygenase‐2 gene are not associated with the development of extracolonic manifestations in a large Swiss familial adenomatous polyposis kindred

Familial adenomatous polyposis (FAP) is an autosomal dominant condition leading to the development of multiple colorectal polyps and other features. Intrafamilial variation in phenotype is known to occur in FAP; despite carrying the same causing mutation in the APC gene, disease expression may considerably differ in affected individuals, likely due to the existence of modifier genes. Several lines of evidence suggest the cyclooxygenase‐2 (COX‐2) gene to be a candidate modifier in FAP. Since COX‐2 appears to be expressed in tissues prone to be affected in FAP, it might influence the occurrence of extracolonic manifestations in this disorder. Herein, we investigated whether alterations in the COX‐2 gene are involved in the development of extracolonic polyps and extragastrointestinal features. Mutational analysis using single‐strand conformation polymorphism (SSCP) in 130 members of a FAP family displaying strong phenotype variation revealed 3 polymorphic sites within the coding region of the COX‐2 gene. None of these allelic variants, however, segregated with a particular disease phenotype. In addition, expression analysis was performed in 31 family members with representative phenotypes. Neither of the two polymorphisms detected within the COX‐2 promoter was associated with a given phenotype nor was there a significant difference in quality or quantity of COX‐2 mRNA in lymphocytes as measured by reverse transcription‐ and real time quantitative reverse transcription PCR (RT‐PCR and TaqMan). In conclusion, germline alterations in the COX‐2 gene are unlikely to account for the development of extracolonic disease in FAP patients. Int. J. Cancer 87:812–817, 2000.

Efficacy of Partially Hydrolyzed Guar Gum-Added Oral Rehydration Solution in the Treatment of Severe Cholera in Adults

Background: Partially hydrolyzed guar gum (PHGG) is a water-soluble fiber if added to oral rehydration solution (ORS) and undergoes fermentation in the colon liberating short chain fatty acids (SCFAs). SCFAs potentiate the effect of ORS, reducing the severity of diarrhea. Aim: To examine the effect of PHGG-added ORS in reducing the stool output and duration of diarrhea in adult cholera. Methods: 195 male patients were studied in a randomized controlled trial: (a) 65 received ORS + 25 g PHGG; (b) 65 received ORS + 50 g PHGG, and (c) 65 received ORS alone (control). Major outcomes were stool weight and duration of diarrhea. Results: No significant differences were found in mean ± SD stool weight (g/kg b.w.) during the first and second 24 h. In the subgroup analysis (excluding very high purging patients, stool weight in the first 24 h was >10 kg), the stool weight (g/kg b.w.) was significantly reduced in the first 24 h in both groups receiving PHGG (PHGG 25 g, 136 ± 68 vs. PHGG 50 g, 144 ± 49 vs. control, 176 ± 43, p = 0.01). Conclusion: PHGG-added ORS might have a beneficial effect in moderately purging adult cholera. However, further studies are warranted to confirm the preliminary findings.

Measurement of calprotectin in ascitic fluid to identify elevated polymorphonuclear cell count

AIM To evaluate the diagnostic capability of calprotectin in ascitic fluid for detecting a polymorphonuclear (PMN) cell count > 250/μL ascites. METHODS In this prospective observational study, a total of 130 ascites samples were analysed from 71 consecutive patients referred for paracentesis. Total and differential leukocyte cell counts were determined manually with a Neubauer chamber and gentian-violet stain. Calprotectin was measured in 1 mL ascetic fluid by enzyme-linked immunosorbent assay (ELISA) and a point-of-care (POC) lateral flow assay with the Quantum Blue(®) Reader (Bühlmann Laboratories). All measurements were carried out in a central laboratory by senior personnel blinded to patient history. A PMN count > 250/μL was the primary endpoint of the study. The diagnostic value of ascitic calprotectin measurement was assessed by comparing to the final diagnosis of each patient that had been adjudicated by investigators blinded to calprotectin values. RESULTS The PMN count was > 250/μL in 19 samples (14.6%) from 15 patients (21.1%) and varied widely among the study population (range 10-19 800/mL and 1-17 820/mL, respectively). Spontaneous bacterial peritonitis (SBP) was the final diagnosis in four patients (5.6%). All patients with PMN ≤ 250/μL had negative bacterial culture. PMN count was elevated in five patients with peritoneal carcinomatosis, three with lymphoma, one with neuroendocrine carcinoma, and two with secondary peritonitis due to abdominal perforation. PMN cell counts correlated with ascitic calprotectin values (Spearmans rho; r = 0.457 for ELISA, r = 0.473 for POC). A considerable range of ascitic calprotectin concentrations was detected by ELISA [median 0.43 μg/mL, interquartile range (IQR) 0.23-1.23 (range 0.10-14.93)] and POC [median 0.38 μg/mL, IQR 0.38-0.56 (range 0.38-13.31)]. Ascitic calprotectin levels were higher in samples with PMN > 250/μL, by both ELISA [median (IQR) 2.48 μg/mL (1.61-3.65) vs 0.10 μg/mL (0.10-0.36), P < 0.001] and POC [2.78 μg/mL (2.05-5.37) vs 0.38 μg/mL (0.38-0.41), P < 0.001]. The area under the receiver operating characteristics curve for identifying an elevated PMN count was 0.977 (95%CI: 0.933 to 0.995) for ELISA and 0.982 (95%CI: 0.942 to 0.997) for POC (P = 0.246 vs ELISA). Using the optimal cut-off value for ELISA (0.63 μg/mL), ascitic calprotectin had 94.8% sensitivity, 89.2% specificity, positive and negative likelihood ratios of 8.76 and 0.06 respectively, positive and negative predictive values of 60.0% and 99.0% respectively, and 90.0% overall accuracy. Using the optimal cut-off value for POC (0.51 μg/mL), the respective values were 100.0%, 84.7%, 6.53, 0.00, 52.8%, 100% and 87.7%. Correlation between ELISA and POC was excellent (r = 0.873, P < 0.001). The mean ± SD of the difference was -0.11 ± 0.48 μg/mL with limits of agreement of + 0.8 μg/mL (95%CI: 0.69 to 0.98) and -1.1 μg/mL (95%CI: -1.19 to -0.91). CONCLUSION Ascitic calprotectin reliably predicts PMN count > 250/μL, which may prove useful in the diagnosis of SBP, especially with a readily available bedside testing device.

Probiotics: a new treatment for antibiotic-associated diarrhea?

ing 9 randomized, double-blind, placebo-controlled trials studying the effi cacy of probiotics in this setting. In these trials, 3 different probiotics ( S. boulardii, Lactobacillus spp. and Enterococcus faecium ) were used. The odds ratio for diarrhea to occur was similar for all species. The combined odds ratio was 0.37 (95% confi dence interval 0.26– 0.53; p ! 0.01) in favor of active treatment over placebo. This analysis has been criticized because of its inconsistent defi nition of diarrhea and that more than half of the studies did not analyze the data on an intention-to-treat basis. The second meta-analysis by Cremonini et al. [4] included only 7 studies with more consistent defi nitions of outcome. The results were similar. The combined relative risk was 0.39 (95% confi dence interval 0.27–0.57). According to these two meta-analyses the results infer that the use of Lactobacillus spp. and S. boulardii in the prevention of antibiotic-associated diarrhea are benefi cial. In this issue of Digestion Hawrelak et al. [5] report in a new systematic review of the effect of a single strain of L. rhamnosus GG in preventing the onset of antibioticassociated diarrhea. This report refl ects the inherent problems of this topic. Although 25 clinical trials have been published so far, only 6 placebo-controlled trials could be included. 18 trials included probiotics other than L. rhamnosus GG and one trial was not placebo-controlled. Of the 6 trials, 4 used different antibiotics in children (n = 2) and adults (n = 2). These studies were also different in sample size, duration and doses of the coAntibiotic-associated diarrhea is a frequent side effect of broad-spectrum antibiotics. The clinical presentation of diarrhea reaches from mild to fulminant pseudomembranous Clostridium diffi cile toxin-induced colitis. The frequency of antibiotic-associated diarrhea can affect as many as 25% of patients. In the last decade, there has been an increase of antibiotic-associated diarrhea of 500%. In up to 80%, the cause of diarrhea is not clear [1] . One of the mechanisms for the development of antibiotic-associated side effects seems to be related to an alteration in the intestinal fl ora. The intestinal fl ora protects the individual against enteral pathogens by multiple mechanisms: (a) production of bacteriocins; (b) competitive inhibition of binding to the mucosa; (c) enhancing synthesis of mucus, and (d) secretion of secretory IgA [2] . Probiotics (life-viable, non-pathogen microbial organisms) have been shown to have immune modulatory properties and to enhance the mucosal barrier. In fact, probiotics have anti-bacterial, anti-viral and anti-infl ammatory properties and restore the intestinal fl ora balance; they were fi rst used for the treatment or prevention of antibiotic-associated diarrhea. Several probiotics, such as Lactobacillus acidophilus, Lactobacillus caseii, Lactobacillus rhamnosus GG and the yeast Saccharomyces boulardii have been evaluated. The clear benefi ts of probiotics are still debated and the data are confl icting, since many of the trials were small and with an open-label design. D’Souza et al. [3] performed a meta-analysis includPublished online: August 17, 2005

Efficacy of L-Isoleucine Supplemented Food and Vitamin D in the Treatment of Acute Diarrhea in Children

Introduction: Antimicrobial peptides represent an important component of the innate defense of organisms ranging from plants to insects to humans. They are broad-spectrum, surface acting agents secreted by the epithelial cells of the body including intestine and respiratory tract, which kill microbes. Most such peptides possess activities against bacteria, viruses and fungi. Recently, L-isoleucine and its analogues have been found to induce antimicrobial peptides.Therefore, L-isoleucine might have therapeutic potentials in the management of infectious diarrhea. Vitamin D is another organic molecule in addition to its effect on calcium metabolism, induces antimicrobial peptides secretion through activating the toll like receptor of macrophages and leading to induction of antimicrobial peptides, and killing of bacteria. Bacterial resistance to antibiotics is a growing concern in both nosocomial and community acquired infections. Development and recommendation of newer antimicrobials are much slower than the emergence of bacterial resistance. The use of L-isoleucine and vitamin D might have beneficial effect in the treatment of acute diarrhea in children. Objectives: The objectives of this study were to examine if addition of L-isoleucine and/or vitamin D to a liquid diet reduces the stool weight and/or duration of acute diarrhea in children. Methods: This was a double blind randomized controlled clinical trial in 107 children aged 6 to 36 months attending the ICDDRB hospital with acute diarrhea: 28 children received a) Lisoleucine (2 g/d) added to milk suji(mixture of milk and rice powder, 70 Kcal/100 ml) ; b) 27 received Vitamin D 1000 IU/d added to Milk suji; c) 26 children received L-isoleucine (2g/d) plus vitamin D 1000 IU/d added to milk Suji; d) Milk suji without L-isoleucine and vitamin D. Other managements were similar in all treatment groups. The children remained in the study until recovery from diarrhea but up to a maximum of 5 days. Stool weight and time to resolution of diarrhea were the primary outcomes. Results: Baseline clinical characteristics of the children are comparable between the groups. There is a trend in stool weight (g) reduction in the groups receiving L-isoleucine and the reduction is significant on day 2 (mean ±SD; Control, 447 ± 325 vs. L-isoleucine gr, 276 ± 228 vs. L-isoleucine + Vit. D gr, 301 ± 181 vs. Vit. D gr, 386 ± 302, p=0.039) and day3 (mean ± SD, Control, 341 ± 292 vs. L-isoleucine gr, 176 ± 157 vs. L-isoleucine + Vit. D gr, 267 ± 169 vs. Vit. D gr, 321 ± 273, p=0.045). However, the duration of recovery from diarrhea was similar in four treatment groups. Conclusion: L-isoleucine supplemented food reduces stool weight in children with acute diarrhea. Further large study is recommended to establish the beneficial effect of L-isoleucine supplemented food.