Rationalising Optimal Dosing of Phytotherapeutics For Use In Children: Current Status - Potential Solutions - Actions Needed.

"Children are not small adults with respect to the treatment with medicinal products." This statement of the WHO was the basis for the initiative of the European Commission for the establishment of a paediatric regulation in 2007 to improve the health of children by facilitating the development of medicines for children and adolescents. Seventeen years later, in the field of herbal medicinal products, results are still sobering. Therefore, the Foundation Plants for Health, Society for Medicinal Plants and Natural Products Research, and German Society for Phytotherapy organised a symposium to assess the status quo for the paediatric use of herbal medicinal products (HMPs), to analyse the causes of the current situation, and to discuss strategies for establishing the proof of safe and efficacious HMPs for children.The current situation for HMPs and their use in children is not fulfilling the requirements of legislation. HMPs in paediatrics are effective and safe, but considering the needs of children is necessary. In European countries, the use, registration, and marketing of HMPs are different, depending on the respective national regulations and specific traditions. EU herbal monographs are the best common denominator for such procedures. Emerging safety discussions must be considered. New approaches with real-world data might be a solution. The regulatory framework is to be adapted. Defining rationalised dosing for HMPs can be achieved by the extrapolation of data from adults, by using existing clinical data for children, and by using RWD. Therefore, a strong need for revising restrictions for the use of HMPs in children and rationalising defined dosage regimes is obvious.

Improving the rigor and utility of botanical toxicity studies: Recommended resources.

Interest in botanicals, particularly as dietary supplement ingredients, is growing steadily. This growth, and the marketing of new ingredients and combination products as botanical dietary supplements, underscores the public health need for a better understanding of potential toxicities associated with use of these products. This article and accompanying template outline the resources to collect literature and relevant information to support the design of botanical toxicity studies. These resources provide critical information related to botanical identification, characterization, pre-clinical and clinical data, including adverse effects and interactions with pharmaceuticals. Toxicologists using these resources should collaborate with pharmacognosists and/or analytical chemists to enhance knowledge of the botanical material being tested. Overall, this guide and resource list is meant to help locate relevant information that can be leveraged to inform on decisions related to toxicity testing of botanicals, including the design of higher quality toxicological studies.

Pharmaco-epidemiological research on herbal medicinal products in the paediatric population: data from the PhytoVIS study.

In paediatrics, clinical study data are limited, especially on herbal medicinal products. To address this gap, 2063 datasets from the paediatric population were evaluated in the PhytoVIS data base. By screening for paediatric data, information on indication, gender, treatment, co-medication and tolerability were evaluated. The majority of patients was treated because of common cold, fever, digestive complaints, skin diseases, sleep disturbances and anxiety. The perceived effect of the therapy was rated in 84% of the patients as very good or good without adverse events. The data shed light on a still neglected field of phyto-pharmacotherapy by giving information on the use of herbal medicines in an unselected cohort of paediatric patients. The results confirm the good clinical effects and safety of herbal medicinal products in this patient population and show that they are widely used in Germany.What is Known:• In Germany, about 85% of children receive one or more herbal medicinal products per year.• Despite international initiatives to promote clinical research in paediatrics, there are still many gaps of knowledge in the use of drugs in paediatrics.What is New:• The PhytoVIS project evaluated 2063 data sets from the paediatric population using herbal medicinal products.• The majority of patients was treated because of common cold, fever, digestive complaints, skin diseases, sleep disturbances and anxiety, and 84% of the patients rated the therapy as very good or good without adverse events.

Phytotherapy in Functional Gastrointestinal Disorders.

BACKGROUND: Phytotherapy is an important therapeutic option in functional gastrointestinal diseases (FGID). It has a large tradition, with different approaches in different regions of the world, some of which have made their way into modern evidence-based medicine (EBM). SUMMARY: Taking into account the number of herbs in use, and also the cumulated scientific evidence on them, FGID are possibly the most important indication in phytotherapy. This does not only apply for European phytotherapy, but also for other regions, such as Asia. Within European phytotherapy, herbs active in FGID are usually classified according to their main active constituents and their activities. Typically, the herbs used in FGID are grouped into amara, aromatica, amara aromatica combining both properties, herbs stimulating gastric secretion, herbs containing spasmolytic and carminative essential oils or spasmolytic alkaloids, mucilaginosa soothing the mucosa, and flavonoid containing drugs with anti-inflammatory properties. In phytotherapy, different plants are frequently combined to maximize effectiveness and specificity of action. Very potent combination products can be developed when the mechanisms of action of the combination partners are complementary. This approach can be demonstrated by the example of STW 5. For this herbal combination product, therapeutic efficacy in FGID has been clinically proven according to the highest standards of EBM. This example also underlines that modern rational phytotherapy is definitely part of modern EBM. Key Messages: FGID is one of the most important indications in phytotherapy and rationally combined herbal preparations are established evidence-based therapeutic options.

Evaluating the Multitarget Effects of Combinations through Multistep Clustering of Pharmacological Data: the Example of the Commercial Preparation Iberogast.

Herbal combination preparations are widely used in traditional herbal medicine and are even established as modern evidence-based herbal medicinal products. The rationale behind such combinations is often questioned and assessing the contribution of each of the combination partners to overall activity is challenging. STW 5 (Iberogast) is such a combination with confirmed clinical efficacy in functional gastrointestinal disorders. It consists of nine plant extracts responsible for its multitarget function in these multifactorial diseases with their heterogeneous and overlapping pathomechanisms. This makes the combination an ideal candidate for the use of the newly described method of stepwise cluster analysis, a standardized procedure to transfer heterogeneous pharmacological data, from different models, into effect size categories. This allows for a stepwise cluster formation starting from the level of single tests up to the level of different pathomechanisms involved in the development of a certain disease, in this case functional dyspepsia subtypes and irritable bowel syndrome. In the current article, an overview on the pharmacological data on STW 5 and its single components is provided. The data are further analyzed using stepwise cluster formation, resulting in a summary of the different modes of action of STW 5 along with an evaluation of the contribution of the single constituents to the overall multitarget effects of the herbal combination preparation.

Randomized double-blind controlled clinical trials with herbal preparations of Serenoa repens fruits in treatment of lower urinary tract symptoms : An overview.

In this review, results of randomized double-blind controlled clinical trials (RCTs) with extracts of Serenoa repens fruits at a dose of 320 mg/d for the treatment of lower urinary tract symptoms (LUTS) are assessed. Of the RTCs conducted for up to 6 months, a benefit was seen in three of three RTCs with ethanolic, in eight of nine RTCs with hexane, and in one of two RTCs with CO2 extracts. Of the RTCs conducted for more than 6 months, a benefit was seen in two RTCs with hexane and in one RTC with CO2 extracts, whereas one RTC with an ethanolic, two RTCs with hexane, and one RTC with CO2 extracts did not show positive results. As LUTS are dynamic conditions with strong spontaneous fluctuation over time, the majority of patients might expect improvement of single symptoms and thus of quality of life, particularly as the extracts are well tolerated even in long-term treatment.

Modulation of gastrointestinal motility beyond metoclopramide and domperidone : Pharmacological and clinical evidence for phytotherapy in functional gastrointestinal disorders.

The prokinetic cisapride, an important therapeutic option in functional gastrointestinal (GI) disorders, was withdrawn from the market 15 years ago due to rare severe side effects. Likewise in 2014, the use of metoclopramide (MCP) and domperidone in functional GI disorders (FGID) was restricted, consequently leaving a therapeutic gap in clinical practice. A systematic review revealed that the herbal medicinal product (HMP) STW 5 presents a therapeutic option equivalent to MCP and cisapride. STW 5 is the only HMP for which efficacy has been shown in randomized controlled clinical trials (RCTs) in functional dyspepsia and irritable bowel syndrome, based on its multitarget effect on numerous etiological factors. Due to an outstanding favorable safety profile, STW 5 allows an effective and safe use in FGID without a limitation of the duration of the treatment.

Ethanol in herbal medicinal products for children : Data from pediatric studies and pharmacovigilance programs.

Herbal medicinal products are indispensable in children, e. g., in functional gastrointestinal diseases and coughs and colds, especially when available in liquid dosing forms for which dosing can be adapted ideally to different age groups. Despite being generally accepted as safe, the ethanol content of many of these products, necessary for Galenic reasons, has raised questions regarding their safety. Therefore, safety data from more than 50,000 children in noninterventional pediatric studies with these products, as well as data from routine clinical use in several million children, were assessed. No evidence of the involvement of the ethanol content in any adverse drug reactions was found. This allows us to conclude that these herbal medicinal products are safe in the age groups for which they are authorized or registered and that the present labeling is adequate to allow for their safe use in the pediatric population.

Gut Microbiome-Brain Alliance: A Landscape View into Mental and Gastrointestinal Health and Disorders.

Gut microbiota includes a vast collection of microorganisms residing within the gastrointestinal tract. It is broadly recognized that the gut and brain are in constant bidirectional communication, of which gut microbiota and its metabolic production are a major component, and form the so-called gut microbiome-brain axis. Disturbances of microbiota homeostasis caused by imbalance in their functional composition and metabolic activities, known as dysbiosis, cause dysregulation of these pathways and trigger changes in the blood-brain barrier permeability, thereby causing pathological malfunctions, including neurological and functional gastrointestinal disorders. In turn, the brain can affect the structure and function of gut microbiota through the autonomic nervous system by regulating gut motility, intestinal transit and secretion, and gut permeability. Here, we examine data from the CAS Content Collection, the largest collection of published scientific information, and analyze the publication landscape of recent research. We review the advances in knowledge related to the human gut microbiome, its complexity and functionality, its communication with the central nervous system, and the effect of the gut microbiome-brain axis on mental and gut health. We discuss correlations between gut microbiota composition and various diseases, specifically gastrointestinal and mental disorders. We also explore gut microbiota metabolites with regard to their impact on the brain and gut function and associated diseases. Finally, we assess clinical applications of gut-microbiota-related substances and metabolites with their development pipelines. We hope this review can serve as a useful resource in understanding the current knowledge on this emerging field in an effort to further solving of the remaining challenges and fulfilling its potential.

STW 5 is effective in dextran sulfate sodium-induced colitis in rats.

PURPOSE: An herbal preparation, STW 5, used clinically in functional dyspepsia and irritable bowel syndrome, has been shown to possess properties that may render it useful in inflammatory bowel disease (IBD). The present work was conducted to study its effectiveness in a rat model of IBD. METHODS: An experimental model reflecting ulcerative colitis in man was adopted, whereby colitis was induced in Wistar rats by feeding them 5 % dextran sulfate sodium (DSS) in drinking water for one week. STW 5 and sulfasalazine (as a reference standard) were administered orally daily for 1 week before colitis induction and continued during DSS feeding. The animals were then sacrificed, and the severity of colitis was evaluated macroscopically and microscopically. Colon samples were homogenized for determination of reduced glutathione, tumor necrosis factor-α, and cytokine-induced neutrophil chemoattractant-3 as well as myeloperoxidase, glutathione peroxidase, and superoxide dismutase. In addition, colon segments were suspended in an organ bath to test their reactivity towards carbachol, KCl, and trypsin. RESULTS: STW 5 and sulfasalazine were both effective in preventing the shortening of colon length and the increase in both colon mass index and total histology score as well as the changes in biochemical parameters measured except changes in dismutase activity. DSS-induced colitis led to marked depression in colonic responsiveness to the agents tested ex vivo, an effect which was normalized by both drugs. CONCLUSIONS: The findings point to a potential usefulness of STW 5 in the clinical setting of ulcerative colitis.

Medicinal Plants and Their Impact on the Gut Microbiome in Mental Health: A Systematic Review.

BACKGROUND: Various neurocognitive and mental health-related conditions have been associated with the gut microbiome, implicating a microbiome-gut-brain axis (MGBA). The aim of this systematic review was to identify, categorize, and review clinical evidence supporting medicinal plants for the treatment of mental disorders and studies on their interactions with the gut microbiota. METHODS: This review included medicinal plants for which clinical studies on depression, sleeping disorders, anxiety, or cognitive dysfunction as well as scientific evidence of interaction with the gut microbiome were available. The studies were reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: Eighty-five studies met the inclusion criteria and covered thirty mental health-related medicinal plants with data on interaction with the gut microbiome. CONCLUSION: Only a few studies have been specifically designed to assess how herbal preparations affect MGBA-related targets or pathways. However, many studies provide hints of a possible interaction with the MGBA, such as an increased abundance of health-beneficial microorganisms, anti-inflammatory effects, or MGBA-related pathway effects by gut microbial metabolites. Data for Panax ginseng, Schisandra chinensis, and Salvia rosmarinus indicate that the interaction of their constituents with the gut microbiota could mediate mental health benefits. Studies specifically assessing the effects on MGBA-related pathways are still required for most medicinal plants.

Phytohustil® and root extract of Althaea officinalis L. exert anti-inflammatory and anti-oxidative properties and improve the migratory capacity of endothelial cells in vitro.

Introduction: Althaea officinalis L.'s root extract (REA) has been used as a medicinal plant since ancient times to treat a cough. Applying REA leads to a protective film that induces a faster regeneration of the lesioned laryngopharyngeal mucosa caused by dry coughs. The buccopharyngeal mucosa is a highly vascularized tissue. In this regard, anti-inflammatory/-oxidant phytochemicals that improve the repair of the lesion site, e.g., neovascularization in the wound, are critical for promoting healing. For this reason, it is essential to investigate the effects of Phytohustil® and REA on different cellular components of the mucosa under conditions similar to those found in the injured mucosa. Thus, this in vitro study investigated the anti-inflammatory/oxidative and pro-migratory properties of Phytohustil® cough syrup on vascular endothelial cells. Methods: Human umbilical vein endothelial cells (HUVEC) were pretreated (24 h) with Phytohustil®, its excipients, or REA, followed by incubation with hydrogen peroxide (H2O2; 1 h; pro-oxidative) or with lipopolysaccharides (LPS; 3 h; pro-inflammatory). Viability and cytotoxicity were measured by PrestoBlue® assay. Intracellular reactive oxygen species (ROS) were quantified with 20-70-dichlorofluorescein diacetate (DCFDA). The release of interleukin 6 (IL6) was determined by enzyme-linked immunosorbent assay (ELISA). The migratory capacity of HUVEC was measured using a scratch assay. Results: Our results show that Phytohustil®, its excipients and REA were not cytotoxic. Pretreatment of HUVEC (24 h) with Phytohustil® or REA inhibited the LPS-activated IL6 release. Phytohustil® or REA inhibited the H2O2-induced cytotoxicity and intracellular ROS production. Phytohustil® and REA significantly stimulated wound closure compared to the control. Conclusion: Our data show that Phytohustil® and REA have anti-inflammatory/-oxidant properties and improve the migratory capacity of vascular endothelial cells. These properties may contribute to the healing characteristics of Phytohustil® and support the benefit of Phytohustil® in patient's treatment of irritated oral mucosa.

Genotoxicity of selected pyrrolizidine alkaloids in human hepatoma cell lines HepG2 and Huh6.

INTRODUCTION: Pyrrolizidine alkaloids (PAs) are found in many plant species as secondary metabolites which affect humans via contaminated food sources, herbal medicines and dietary supplements. Hundreds of compounds belonging to PAs have been identified. PAs undergo hepatic metabolism, after which they can induce hepatotoxicity and carcinogenicity. Many aspects of their mechanism of carcinogenicity are still unclear and it is important for human risk assessment to investigate this class of compounds further. MATERIAL AND METHODS: Human hepatoma cells HepG2 were used to investigate the genotoxicity of different chemical structural classes of PAs, namely europine, lycopsamine, retrorsine, riddelliine, seneciphylline, echimidine and lasiocarpine, in the cytokinesis-block micronucleus (CBMN) assay. The different ester type PAs europine, seneciphylline, and lasiocarpine were also tested in human hepatoma Huh6 cells. Six different PAs were investigated in a crosslink comet assay in HepG2 cells. RESULTS: The maximal increase of micronucleus formation was for all PAs in the range of 1.64-2.0 fold. The lowest concentrations at which significant induction of micronuclei were found were 3.2 µM for lasiocarpine and riddelliine, 32 µM for retrorsine and echimidine, and 100 µM for seneciphylline, europine and lycopsamine. Significant induction of micronuclei by lasiocarpine, seneciphylline, and europine were achieved in Huh6 cells at similar concentrations. Reduced tail formation after hydrogen peroxide treatment was found in the crosslink comet assay for all diester type PAs, while an equimolar concentration of the monoesters europine and lycopsamine did not significantly reduce DNA migration. CONCLUSION: The widely available human hepatoma cell lines HepG2 and Huh6 were suitable for the assessment of PA-induced genotoxicity. Selected PAs confirmed previously published potency rankings in the micronucleus assay. In HepG2 cells, the crosslinking activity was related to the ester type, which is a first report of PA mediated effects in the comet assay.

Effect of an herbal preparation, STW 5, in an acute model of reflux oesophagitis in rats.

A multitarget herbal preparation, STW 5, has been used clinically in different gastro-intestinal disorders including functional dyspepsia and irritable bowel syndrome. Previous studies have shown that it possesses properties that may render it useful in gastro-oesophageal reflux disease (GERD). We performed this study to test this compound in an acute model of reflux oesophagitis in rats. Oesophagitis was induced surgically by ligating the pyloric end and fore-stomach. Lower oesophageal pH was measured 3 h later in conscious animals. Five hours after surgery, animals were sacrificed and the oesophagi were examined macroscopically and histologically. Selected markers of inflammation were measured in oesophageal homogenates. STW 5 was given orally for 5 days before induction of oesophagitis. Pantoprazole was used as a reference standard. Ligated animals showed a high incidence of ulcerative lesions associated with a marked increase in myeloperoxidase, thiobarbituric acid-reactive substances, tumor necrosis factor-alpha, and interleukin-1beta. STW 5 did not affect oesophageal pH, but dose-dependently reduced the severity of the oesophageal lesions and normalized the deranged level of the inflammation markers. The beneficial effects were confirmed histopathologically. STW 5 proved to be effective in protecting against inflammatory lesions in this model of oesophagitis, thus warranting further investigation of its potential therapeutic usefulness in GERD.

Permeation characteristics of hypericin across Caco-2 monolayers in the presence of single flavonoids, defined flavonoid mixtures or Hypericum extract matrix.

OBJECTIVES: The major aim of this study was to get a detailed understanding of the exposure and fate of hypericin in the Caco-2 cell system when combined with various flavonoids, mixtures of flavonoids or Hypericum perforatum extract matrix (STW3-VI). METHODS: The permeation characteristics of hypericin in the absence or presence of quercetin, quercitrin, isoquercitrin, hyperoside and rutin were tested. Hypericin (5 µm) was mixed with single flavonoids (20 µm) or with different flavonoid combinations (each flavonoid 4 or 10 µm, total flavonoid concentration: 20 µm). Further, the uptake of hypericin (5 µm) in the presence of H. perforatum extract matrix (7.25, 29 and 58 µg/ml) was studied. KEY FINDINGS: Following application of hypericin to the apical side of the monolayer, only negligible amounts of the compound were found in the basolateral compartment. From all tested flavonoids, only quercitrin increased the basolateral amount of hypericin. Dual flavonoid combinations were not superior compared to the single combinations. The amount of hypericin in the basolateral compartment increased concentration-dependently in the presence of extract matrix (from 0 to 7.5%). CONCLUSION: Comparing the effects of various flavonoid mixtures vs the extract matrix, it can be concluded that, besides flavonoids, the extract seems to contain further compounds (e.g. phenolic acids or proanthocyanidins) which substantially improve the permeation characteristics of hypericin.

Synergy quantifications to identify individual contributions of combination partners to the overall activity - The example of STW 5.

BACKGROUND: The rationale of combinations of plant extracts is often questioned. The common argument for combinations is a higher efficacy of the combination partners by multitargeting and the elimination of adverse events. AIM: STW5, a well-known fixed herbal multicomponent preparation, is recommended in the German treatment guidelines for functional gastrointestinal diseases. The study assessed effects of STW5, its single plant components and combinations thereof on different targets to identify synergistic, additive or antagonistic effects of the combination partners. STUDY DESIGN/METHODS: STW5, its nine components and triple combinations thereof were investigated in two in vitro models - human esophageal epithelial cells (Het1A) and intestinal smooth muscle cells (HISMC) - in comparison to Omeprazole (OM) for the release of interleukin 8 (IL-8) as surrogate for inflammation and of Ca2+ as surrogate for motion, under non-inflammatory and inflammatory (Capsaicin 80 µM (CAP)) conditions. The combination index (CI) of triple combinations was calculated to assess synergistic, antagonistic and additive effects. RESULTS: In Het-1A cells, STW5 showed, under non-inflammatory as well as inflammatory conditions, releases of IL-8 (49.3 ±â€¯4.2 pg/ml, 33.7 ±â€¯2 pg/ml) comparable to the untreated control (46.3 ±â€¯4.8 pg/ml). CAP increased IL-8 releases to 85.8 ±â€¯14 pg/ml (p < 0.005). Among the single plant extracts the Iberis amara extract (IBE) induced high IL-8 releases under non-inflammatory (441 ± 177 pg/ml) and inflammatory (625± 121 pg/ml) conditions. The Silybum marianum (L.) extract (SM) reduced releases up to 20.1 ±â€¯8 pg/ml (inflammation). The CI-values of triple combinations with IBE ranged from high synergy (CI<0.03) to antagonism (CI:480). Within the triple combinations SM was the most effective combination partner to reduce IL-8. The combination of Angelica archangelica (L.)/Carum carvi (L.) was also effective. In HISMCs, STW5 induced concentration dependent higher Ca2+-releases. Only Melissa officinalis (L.) (MO) induced high Ca2+- releases in HISMCs. CONCLUSION: In Het-1A, STW5 inhibited Il-8 releases, although one of its components (IBE) stimulated IL-8 strongly. The combination partners in STW5 assured an overall marked anti-inflammatory action. In the triple combinations SM was identified as most important combination partner for the IL-8 reduction. CI-measurements can support the identification of active combination partners in a multicomponent preparation and can give directions towards the search for multitarget effects.

Anti-inflammatory effects of Phytodolor® (STW 1) and components (poplar, ash and goldenrod) on human monocytes/macrophages.

BACKGROUND: Populus tremula L. (Poplar), Fraxinus excelsior L. (ash) and Solidago virgaurea L. (goldenrod) have been used for medicinal purposes through centuries, to treat pain, fever and inflammation, but their mechanisms of action are still not fully understood. The present study was performed to investigate, whether the herbal medicinal product Phytodolor® (STW 1) and its components have anti-inflammatory effects on activated human monocytes and differentiated human macrophages to elucidate their modes of action in comparison with well-known analgesic, non-steroidal anti-inflammatory drug (NSAIDs) as diclofenac. METHODS: Adherent human monocytes obtained from peripheral blood mononuclear cells (PBMCs) were cultured in serum-free medium and pre-treated with 50-100 µg/ml of diclofenac, STW 1, their components, poplar, ash or goldenrod or its combination (0.05% to 2%). Thereafter, monocytes were activated with 0.1 or 1 µg/ml LPS for 24 h. The intracellular expressions of TNF-α or PTGS2 were determined by cell-based ELISA. Apoptotic cells were identified by YO-PRO-1 staining. Protein or total RNA were isolated to perform SDS-PAGE/Western blot and qRT-PCR analyses. PMA-differentiated human THP-1 macrophages were pre-treated with diclofenac (50 µg/ml) or STW1 (0.1%) and afterwards with LPS (1 µg/ml) and the translocation of the intracellular p62 NF-κB subunit was detected by immunofluorescence. RESULTS: STW 1 inhibited the intracellular content of TNF-α and PTGS2 protein, as well as of TNF-α and PTGS2 gene expression and induced apoptosis in LPS-activated human monocytes under serum free conditions. Furthermore, STW 1 inhibited the translocation of the p65 subunit of the redox-regulated NF-κB into the nucleus in LPS-activated human macrophages. CONCLUSION: The present in vitro investigations suggest a significant anti-inflammatory activity of STW 1 and its components by inhibiting pro-inflammatory cytokine as TNF-α and the key enzyme PTGS2 in LPS-activated human monocytes, which is, at least partly mediated through the suppression of NF-κB activation. Our results provide evidence for distinctive anti-inflammatory effects of STW 1 and its components on LPS-activated human monocytes/macrophages and, thus, for the therapeutic use of STW 1 in inflammation and pain related disorders.

STW 5 is effective against nonsteroidal anti-inflammatory drugs induced gastro-duodenal lesions in rats.

BACKGROUND: Proton pump inhibitors are often used to prevent gastro-intestinal lesions induced by nonsteroidal anti-inflammatory drugs. However, they are not always effective against both gastric and duodenal lesions and their use is not devoid of side effects. AIM: To explore the mechanisms mediating the clinical efficacy of STW 5 in gastro-duodenal lesions induced by nonsteroidal anti-inflammatory drugs (NSAIDs), exemplified here by diclofenac, in a comparison to omeprazole. METHODS: Gastro-duodenal lesions were induced in rats by oral administration of diclofenac (5 mg/kg) for 6 successive days. One group was given concurrently STW 5 (5 mL/kg) while another was given omeprazole (20 mg/kg). A day later, animals were sacrificed, stomach and duodenum excised and divided into 2 segments: One for histological examination and one for measuring inflammatory mediators (tumor necrosis factor α, interleukins-1ß and 10), oxidative stress enzyme (heme oxygenase-1) and apoptosis regulator (B-cell lymphoma 2). RESULTS: Diclofenac caused overt histological damage in both tissues, associated with parallel changes in all parameters measured. STW 5 and omeprazole effectively prevented these changes, but STW 5 superseded omeprazole in protecting against histological damage, particularly in the duodenum. CONCLUSION: The findings support the therapeutic usefulness of STW 5 and its superiority over omeprazole as adjuvant therapy to NSAIDs to protect against their possible gastro-duodenal side effects.

Variability in PXR-mediated induction of CYP3A4 by commercial preparations and dry extracts of St. John's wort.

St. John's wort (SJW, Hypericum perforatum) is a well-tolerated herbal medicine widely used for the treatment of mild and moderate depressions. In the last 5 years, SJW has been implicated in drug interactions, which are largely mediated by the induction of the drug metabolizing enzymes, especially CYP3A4. There is still some controversy regarding the exact mechanism of induction and the identity of the SJW constituents involved. We investigated in LS174T cells the induction of CYP3A4 by ten SJW extracts, six commercial preparations, and the purified SJW constituent hyperforin. The content of hyperforin among the commercial preparations of SJW varied 62-fold (range 0.49-30.57 mg/dose). The CYP3A4 induction was mediated by PXR, but not by CAR. The magnitude of the induction correlated statistically significantly with the content of hyperforin in commercial SJW preparations (R = 0.87, p = 0.004) and in dry extracts (R = 0.65, p = 0.03), but not with their content of flavonoids or hypericin. Most of the CYP3A4 induction response occurred in the hyperforin range encountered in the blood of patients treated with SJW preparations. A temperature-induced decrease in the hyperforin content of a selected dry SJW extract abolished the induction of CYP3A4. In conclusion, commercial SJW preparations still exhibit an enormous variability in CYP3A4 induction, which is mediated by hyperforin and PXR. SJW preparations with lower hyperforin content should reduce the frequency of clinical interactions involving this herbal drug.

Salicylate-based phytopharmaceuticals induce adaptive cytokine and chemokine network responses in human fibroblast cultures.

BACKGROUND: Cytokines and chemokines (CC) play a central role in immunoregulatory and inflammatory processes. Neutralising antibodies for single proinflammatory cytokines have developed into a powerful, though expensive and not always curative therapeutic strategy for severe diseases. Considering the redundancy of CC functions, network (N) rather than single target approaches are essential. Phytopharmaceuticals, common adjuvant therapies, are known modulators of a broad spectrum of CCs, but as complex mixtures with multiple targets they have not been systematically investigated. We investigated the effect of clinically established salicylate-based phytopharmaceuticals alone or in combination on CCNs under non-inflammatory and inflammatory conditions, using fibroblasts being a major source of cytokines in connective tissue diseases. METHODS: Synchronised human skin fibroblasts (HSKF) were treated for 6 h with standardised fluid plant extracts (E) of Populus tremula L. [end concentration: 0.06%, 0.1%], Solidago virgaurea L. [0.02%, 0.1%], Fraxinus excelsior L. [0.02%, 0.1%], an established combination of the three extracts-STW1 [0.05, 0.1%] and acetyl salicylic acid (ASA) [30 µg/ml], individually or in the presence of lipopolysaccharides (LPS) [10 µg/ml]. Cell lysates were profiled for 23 cytokines. Supernatants were investigated for IL-6 and IL-8 release (ELISA). Total RNA was isolated for gene-expression profiling. RESULTS: Under non-inflammatory conditions P. tremula E and ASA increased cellular proteins (P) IL-8 and IL-10; S. virgaurea E modulated IL-1α, IL-10, IL-15 and Groα (P). F. excelsior decreased IL-1α and IL-15 (P). The combination of the three extracts (STW1) modulated IL-1α, IL-3 and TNF-ß (P). LPS stimulation increased cellular IL-8, Groα, MCP-1 and RANTES (P) and increased the secretion of IL-6 and IL-8 into the medium. Under these inflammatory conditions F. excelsior reduced GMCSF, GCSF and RANTES. STW1 reduced IL-1α, IL-8, Groα, and MCP-1(P). Secretion of IL-8 and IL-6 was reduced by STW1 and ASA. Gene expression profiles supported non-additive CCN profiles. CONCLUSION: Salicylate based phytopharmaceuticals provoke cellular pro-and anti-inflammatory CCN responses under non-stress conditions, which adapt to anti-inflammatory responses after LPS-stimulation. CCN-profiles of the single extracts are not additives in combination. A simultaneous activation of cellular pro- and anti-inflammatory cytokines might heighten the immunological reactivity status of a cell.