Steigerwald Arzneimittelwerk GmbH

Darmstadt, Germany

Steigerwald Arzneimittelwerk GmbH

Darmstadt, Germany
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Jungke P.,University of Florida | Jungke P.,University of Leipzig | Ostrow G.,The Interdisciplinary Center | Li J.-L.,The Interdisciplinary Center | And 4 more authors.
Psychopharmacology | Year: 2011

Rationale: Hypericum perforatum L., known as St. John's wort (SJW), is used as a phytotherapeutic agent for the treatment of mild to moderate forms of depression. Objectives: The aim of the present study was to evaluate the effect of SJW extract (STW 3-VI; 250 and 500 mg/kg; p.o.) and fluoxetine (10 mg/kg, p.o.) on genes involved in the pathogenesis of depression using a chronic restraint stress (CRS) model in rats. Of particular interest was the assessment of similarities and differences between SJW extract and fluoxetine on the gene expression level in two different brain regions. Results: Hypothalamic and hippocampal tissues were analyzed using the Affymetrix gene chip Rat Genome 230 2.0 Array, which comprises more than 30,000 rat transcripts. Limma program and PANTHER database were used to evaluate the microarray data. Genes involved in the pathways of inflammatory processes (Mapk8), oxidative stress (Gpx3, Gstm3, Sod3) or Alzheimer's disease (Sncb, Apbb1ip) were altered by both fluoxetine and SJW extract. For all groups, several signaling pathways were identified which could provide a link between the various hypotheses of depression. Conclusion: In conclusion, microarray analysis proved to be a valuable tool to identify a large number of genes and resulting pathways that may serve as novel drug targets or predict drug responsiveness for SJW or fluoxetine. Based on our comprehensive analysis, it was possible to identify similarities and differences between SJW and fluoxetine which may help to better understand their molecular action and, in addition, help to find novel treatment strategies for stress-related depression. © 2010 Springer-Verlag.

Brierley S.M.,University of Adelaide | Brierley S.M.,Royal Adelaide Hospital | Kelber O.,Steigerwald Arzneimittelwerk GmbH
Current Opinion in Pharmacology | Year: 2011

Altered motility, discomfort and pain are common debilitating symptoms of patients with functional gastrointestinal disorders. However, these conditions represent a significant and unmet need for mainstream medical treatment, particularly after high profile therapeutic drug withdrawals due to safety concerns. As such an increasing number of sufferers are turning to alternative medicines in an effort to seek relief from their symptoms. Alternative medicines have traditionally been looked at by mainstream medicine with cynicism. However, new evidence demonstrates that the active components in natural products have actions on specific ion channels and receptors, many of which are located in sensory systems distributed throughout the body. These findings may not only explain the symptomatic benefit of these alternative medicines but also provide novel therapeutic targets for mainstream drug development. As such natural products represent a wealth of untapped potential which is waiting to be unlocked. © 2011 Elsevier Ltd. All right reserved.

Michael S.,Lowen Apotheke | Abdel-Aziz H.,Steigerwald Arzneimittelwerk GmbH | Weiser D.,Steigerwald Arzneimittelwerk GmbH | Muller C.E.,University of Bonn | And 2 more authors.
Naunyn-Schmiedeberg's Archives of Pharmacology | Year: 2012

STW 5 (Iberogast®), an established herbal combination, was effective in randomized, double blind clinical studies in functional dyspepsia and irritable bowel syndrome. Since STW 5 was found to influence intestinal motility and has anti-inflammatory properties, this study investigated the expression of adenosine receptors and characterized their role in the control of the anti-inflammatory action of STW5 and its fresh plant component STW 6 in inflammation-disturbed rat small intestinal preparations. The inflammation was induced by intraluminal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS, 0.01 M). The effects of coincubation with selective receptor agonists and antagonists, STW 5, STW 6, or combinations of these compounds on acetylcholine (ACh)- evoked contraction of ileum/jejunum preparations were tested. Adenosine receptor mRNA expression was examined by reverse transcription-polymerase chain reaction (RT-PCR). In untreated preparations, RT-PCR revealed the presence of all adenosine receptor subtypes. Suppressed expression was detected for all subtypes in inflamed tissues, except for A 2BR mRNA, which was unaffected. STW 5 reversed these effects and enhanced A 2AR expression above control levels. Radioligand binding assays confirm the affinity of STW 5 to the A 2AR, and the A 2AR antagonist was able to prevent the effect of STW 5 on TNBS-induced attenuation of the ACh contraction. Our findings provide evidence that STW 5, but not STW 6 interacts with A 2AR, which is involved in the anti-inflammatory action of STW 5. STW 6 did not contribute to adenosine A 2AR-mediated anti-inflammatory effect of STW 5. Other signaling pathways could be involved in the mechanism of action of STW 6. © 2012 Springer-Verlag.

Grundmann O.,University of Florida | Lv Y.,University of Florida | Kelber O.,Steigerwald Arzneimittelwerk GmbH | Butterweck V.,University of Florida
Neuropharmacology | Year: 2010

Chronic stress is a contributing risk factor for the development of psychiatric illnesses such as anxiety and depression disorders. The aim of the present study was to evaluate the mechanisms of action of the standardized St. John's wort extract (STW3-VI; SJW) in a chronic restraint stress model. Markers of antioxidant capacity such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) in the hippocampus and hypothalamus, and plasma levels of ACTH and corticosterone as well as the inflammatory markers IL-6 and TNF-α were determined in rats exposed to chronic restraint stress for 21 consecutive days. In addition, total body and relative organ weights as well as behavioral changes in the open field test were evaluated on the last day. The results show that stressed animals decreased in open field activity compared to unstressed animals, which could be reversed by fluoxetine (10. mg/kg, p.o.) and SJW (125-750. mg/kg, p.o.) treatment. In addition, chronic restraint stress significantly decreased thymus and spleen indices in the stressed control group. However, treating stressed rats with fluoxetine or STW3-VI produced a significant and dose dependent increase in both thymus and spleen indices compared to stressed controls. Additionally, SJW and fluoxetine significantly reduced stress-induced increases in plasma ACTH and corticosterone levels. Furthermore, the administration of SJW significantly reduced the stress-induced increase in TNF-α levels. Our data provide new evidence for the hypothesis that the mechanism of action of STW3-VI is mediated by the interrelationship between the immune, oxidative defense and neuroendocrine system. © 2009 Elsevier Ltd.

Khayyal M.T.,Cairo University | Abdel-Naby D.H.,National Center for Radiation Research And Technology | Abdel-Aziz H.,Steigerwald Arzneimittelwerk GmbH | El-Ghazaly M.A.,National Center for Radiation Research And Technology
Phytomedicine | Year: 2014

Purpose Intestinal mucositis is a common adverse effect in patients undergoing radiotherapy and constitutes a treatment-limiting condition. Since no agents are yet known that can adequately guard against its development, the search continues to find safe and effective measures. The present study was intended to investigate whether the herbal preparation, STW 5, could offer a potentially effective agent in this respect. Methods Intestinal mucositis was induced in rats by exposing them to whole body gamma-irradiation (6 Gy). Rats were treated orally with STW 5 (5 or 10 ml/kg) for five days before and two days after irradiation. One day later, rats were sacrificed and segments of small intestine were examined histologically. Intestinal homogenates and serum samples were used to assess relevant parameters for apoptosis and different markers for inflammation and oxidative stress. Results Exposure to radiation produced dose-dependent extents of intestinal injury associated with apoptotic changes with high radiation levels. Apoptosis was associated with an increase in cytosolic calcium, depletion of mitochondrial cytochrome c, B-cell lymphoma-2 and complex I. Oxidative stress parameters (reduced glutathione, thiobarbituric acid reactive substance and total nitrate/nitrite) were deranged. Inflammation markers (tumor necrosis factor and myeloperoxidase) and indices of intestinal damage (serum diamine oxidase) were increased. STW 5 protected to a large extent against histological changes and counteracted the deranged parameters. Conclusion The findings provide experimental evidence for the potential beneficial use of STW5 in protecting against the development of radiation-induced intestinal mucositis and associated changes in tissue biomarkers. © 2014 The Authors.

Weidner C.,Max Planck Institute for Molecular Genetics | Rousseau M.,Max Planck Institute for Molecular Genetics | Plauth A.,Max Planck Institute for Molecular Genetics | Wowro S.J.,Max Planck Institute for Molecular Genetics | And 3 more authors.
Phytomedicine | Year: 2015

Purpose Efficient strategies for the prevention of colon cancer are extensively being explored, including dietary intervention and the development of novel phytopharmaceuticals. Safe extracts of edible plants contain structurally diverse molecules that can effectively interfere with multi-factorial diseases such as colon cancer. In this study, we describe the antiproliferative and proapoptotic effects of ethanolic lemon balm (Melissa officinalis) leaves extract in human colon carcinoma cells. We further investigated the role of extra- and intracellular reactive oxygen species (ROS). Methods Antitumor effects of lemon balm extract (LBE) were investigated in HT-29 and T84 human colon carcinoma cells. Inhibition of proliferation was analyzed by DNA quantification. The causal cell cycle arrest was determined by flow cytometry of propidium iodide-stained cells and by immunoblotting of cell cycle regulator proteins. To investigate apoptosis, cleavage of caspases 3 and 7 was detected by immunoblotting and fluorescence microscopy. Phosphatidylserine externalization was measured by Annexin V assays. Mechanistic insights were gained by measurement of ROS using the indicator dyes CM-H2DCFDA and Cell ROX Green. Results After 3 and 4 days of treatment, LBE inhibited the proliferation of HT-29 and T84 colon carcinoma cells with an inhibitory concentration (IC50) of 346 and 120 μg/ml, respectively. Antiproliferative effects were associated with a G2/M cell cycle arrest and reduced protein expression of cyclin dependent kinases (CDK) 2, 4, 6, cyclin D3, and induced expression of cyclin-dependent kinase inhibitor 2C (p18) and 1A (p21). LBE (600 μg/ml) induced cleavage of caspases 3 and 7 and phosphatidylserine externalization. LBE-induced apoptosis was further associated with formation of ROS, whereas quenching of ROS by antioxidants completely rescued the colon carcinoma cells from LBE-induced apoptosis. Conclusions Lemon balm (Melissa officinalis) extract inhibits the proliferation of colon carcinoma cells and induces apoptosis through formation of ROS. Taken together, LBE or subfractions thereof could be used for the prevention of colon cancer. © 2015 Elsevier GmbH. All rights reserved.

Vissiennon C.,University of Florida | Vissiennon C.,University of Leipzig | Nieber K.,University of Leipzig | Kelber O.,Steigerwald Arzneimittelwerk GmbH | Butterweck V.,University of Florida
Journal of Nutritional Biochemistry | Year: 2012

Several in vivo and in vitro studies have confirmed that flavonols are metabolized by the intestinal microflora to their corresponding hydroxyphenylacetic acids. In this article, a comparison of the anxiolytic activity of the flavonols kaempferol, quercetin and myricetin in the elevated plus maze after oral (po) and intraperitoneal (ip) administration to mice in a dose range of 0.1 to 2.0 mg/kg is presented. In addition, their corresponding metabolites p-hydroxyphenylacetic acid (p-HPAA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were tested after intraperitoneal administration. Anxiolytic activity was detected for kaempferol and quercetin only after oral administration. No anxiolytic effects were observed when kaempferol and quercetin were given via the intraperitoneal administration route. The corresponding hydroxyphenylacetic metabolites p-HPAA and DOPAC showed anxiolytic effects after intraperitoneal application. In order to further test the hypothesis that flavonoids are possible prodrugs which require activation by intestinal bacteria, gut sterilization was performed using pretreatment with the antibiotic enrofloxacin (7.5 mg/day, po, for 4 days). After antibiotic treatment, the anxiolytic effect of kaempferol and quercetin disappeared, whereas it was still present for the positive control diazepam. Our results support the hypothesis that flavonoids act as prodrugs which are transformed into their active hydroxyphenylacetic acid metabolites by intestinal microflora. © 2012 Elsevier Inc..

Weidner C.,Max Planck Institute for Molecular Genetics | Weidner C.,Free University of Berlin | Wowro S.J.,Max Planck Institute for Molecular Genetics | Freiwald A.,Max Planck Institute for Molecular Genetics | And 4 more authors.
Molecular Nutrition and Food Research | Year: 2014

Over the last decades polyetiological metabolic diseases such as obesity and type 2 diabetes have emerged as a global epidemic. Efficient strategies for prevention and treatment include dietary intervention and the development of validated nutraceuticals. Safe extracts of edible plants provide a resource of structurally diverse molecules that can effectively interfere with multifactorial diseases. In this study, we describe the application of ethanolic lemon balm (Melissa officinalis) leaves extract for the treatment of insulin-resistance and dyslipidemia in mice. We show that lemon balm extract (LBE) activates the peroxisome proliferator-activated receptors (PPARs), which have key roles in the regulation of whole body glucose and lipid metabolism. Application of LBE (0.6 mg/mL) to human primary adipocytes resulted in specific peroxisome proliferator-activated receptor target gene expression. LBE treatment of insulin-resistant high-fat diet-fed C57BL/6 mice (200 mg/kg/day) for 6 weeks considerably reduced hyperglycemia and insulin resistance, plasma triacylglycerol, nonesterified fatty acids and LDL/VLDL cholesterol levels. Taken together, ethanolic lemon balm extract can potentially be used to prevent or concomitantly treat type 2 diabetes and associated disorders such as dyslipidemia and hypercholesterolemia. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Wadie W.,Cairo University | Abdel-Aziz H.,University of Munster | Zaki H.F.,Cairo University | Kelber O.,Steigerwald Arzneimittelwerk GmbH | And 2 more authors.
International Journal of Colorectal Disease | Year: 2012

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-a, and cytokineinduced 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. © The Author(s) 2012.

Although a lot of herbal medicinal products are successfully used in children since centuries, the existing documentation of their clinical application does not allways fulfill the increasing regulatory requirements. Non interventional studies may be helpful in such cases. Retrospective studies are an option making the knowledge accessible contained in the physicians patient files. Advantages are their short duration and the possibility to conduct them also in case, that regulatory limitations have already taken effect, because already existing data are used. Limitations are, however, that these studies may be conducted only in products used to a significant extent or that the quality of the available patient documentations may be limited. In these points observational studies have advantages, as the data quality can be influenced prospectively by appropriate case report forms and by monitoring. Limitations are the possibly longer duration of conduct, especially in products of seasonal use, e.g. products used in common cold. Altogether, both types of studies are an ethically valid and effective tool for the systematic collection of scientific knowledge of regulatory relevance. This is confirmed by examples from two important areas of paediatric use, i.e. gastrointestinal diseases and cough/common cold.

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