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Gut microbiota influences many aspects of host health including immune, metabolic, and gut health. We examined the effect of a fermented whey concentrate (FWC) drink rich in L-(+)-Lactic acid, consumed daily, in 18 healthy men ( n = 5) and women ( n = 13) in free-living conditions. Objective: The aims of this 6-weeks pilot trial were to (i) identify changes in the gut microbiota composition and fecal short chain fatty acid (SCFA) profile, and (ii) to monitor changes in glucose homeostasis. Results: Total fecal SCFA (mM) concentration remained constant throughout the intervention. Proportionally, there was a significant change in the composition of different SCFAs compared to baseline. Acetate levels were significantly reduced (-6.5%; p < 0.01), coupled to a significant increase in the relative amounts of propionate (+2.2%; p < 0.01) and butyrate (+4.2%; p < 0.01), respectively. No changes in the relative abundance of any specific bacteria were detected. No significant changes were observed in glucose homeostasis in response to an oral glucose tolerance test. Conclusion: Daily consumption of a fermented whey product led to significant changes in fecal SCFA metabolite profile, indicating some potential prebiotic activity. These changes did not result in any detectable differences in microbiota composition. Post-hoc analysis indicated that baseline microbiota composition might be indicative of participants likely to see changes in SCFA levels. However, due to the lack of a control group these findings would need to be verified in a rigorously controlled trial. Future work is also required to identify the biological mechanisms underlying the observed changes in microbiota activity and to explore if these processes can be harnessed to favorably impact host health. Clinical Trial Registration : www.clinicaltrials.gov, identifier NCT03615339; retrospectively registered on 03/08/2018., (Copyright © 2020 Smith, Maloney, Shaw, Horgan, Fyfe, Martin, Suter, Scott and Johnstone.)

Viral infections may predispose the airways to secondary bacterial infections that can lead to unfavorable progression of principally self-limiting illnesses. Such complicated respiratory infections include pneumonia, bronchitis, sinusitis, acute otitis media, and sepsis, which cause high morbidity and lethality. Some of the pathogenic consequences of viral infections, like the expression of bacterial adhesion receptors and the disturbance of physical barrier integrity due to inflammation, may create permissive conditions for co-infections. Influenza virus A (H3N2) is a major pathogen that causes secondary bacterial infections and inflammation that lead to pneumonia. The herbal medicine Echinacea purpurea, on the other hand, has been widely used to prevent and treat viral respiratory infections, and recent clinical data suggest that it may prevent secondary infection complications as well. We investigated the role of standardized E. purpurea (Echinaforce ® extract or EF) on H3N2-induced adhesion of live nontypeable Haemophilus influenzae (NTHi) and Staphylococcus aureus, along with the expression of bacterial receptors, intracellular adhesion molecule-1 (ICAM-1), fibronectin, and platelet activating factor receptor (PAFr), by BEAS-2B cells. Inflammatory processes were investigated by determining the cellular expression of IL-6 and IL-8 and the involvement of Toll-like receptor (TLR-4) and NFκB p65. We found that influenza virus A infection increased the adhesion of H. influenzae and S. aureus to bronchial epithelial cells via upregulated expression of the ICAM-1 receptor and, to some extent, of fibronectin and PAFr. Echinaforce (EF) significantly reduced the expression of ICAM-1, fibronectin, and PAFr and consequently the adhesion of both bacterial strains. EF also effectively prevented the super-expression of inflammatory cytokines by suppressing the expression of NFκB and possibly TLR-4. These results indicate that E. purpurea has the potential to reduce the risk of respiratory complications by preventing virus-induced bacterial adhesion and through the inhibition of inflammation super-stimulation (cytokine storms)., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Boldocynara®, a proprietary dietary supplement product consisting of the plants Cynara scolymus, Silybum marianum, Taraxacum officinale, and Peumus boldus, used to promote functions of the liver and the gallbladder. It was the aim of the present study to look from a different perspective at the product by investigating the in vitro potential of Boldocynara® as a combination product and its individual extracts on key enzymes relevant to metabolic syndrome. Peumus boldus extract exhibited pronounced inhibitory activities on α-glucosidase (80% inhibition at 100 µg/ml, IC50: 17.56 µg/ml). Silybum marianum had moderate pancreatic lipase (PL) inhibitory activities (30% at 100 µg/ml) whereas Cynara scolymus showed moderate ACE inhibitory activity (31% at 100 µg/ml). The combination had moderate to weak effects on the tested enzymes. In conclusion, our results indicate some moderate potential of the dietary supplement Boldocynara® and its single ingredients for the prevention of metabolic disorders., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Objectives: Extracts of the tubers of Harpagophytum procumbens (devil's claw, DC) inhibit different proinflammatory mediators important in the pathophysiology of osteoarthritis. Many plant-derived preparations interfere with cytochrome P450 liver enzymes, which influence their different biological activities. Therefore, the present study was designed to investigate the influence of an external metabolic activation of a DC extract on the cytotoxicity and the release of proinflammatory cytokines., Methods: A screening experiment with a panel of 12 inflammatory cytokines identified three as suitable for the study: tumour necrosis factor-α (TNF-α), interleukin (IL) IL-6 and IL-8. They were determined using enzyme-linked immunosorbent assays in lipopolysaccharide (LPS)-stimulated monocytic THP-1 cells, which were treated with rat liver S9 mix metabolically activated DC extract (DCm). For the cytotoxity experiments, a WST-1 assay was used., Key Findings: DC dose-dependently suppressed the release of TNF-α, IL-6 and IL-8 in LPS-stimulated monocytic THP-1 cells at non-cytotoxic concentrations (50-250 μg/ml). The metabolic activation of the DC extract by S9 mix did not alternate its cytotoxicity and did not diminish its inhibitory effect. This effect was improved in the case of TNF-α inhibition as reflected by their EC50 values of 116 ± 8.2 μg/ml and 49 ± 3.5 μg/ml for DC and DCm (P < 0.01)., Conclusions: Cytokines inhibitory activity of DC was not affected after its external metabolic activation. However, the amount of harpagoside and caffeic acid derivates was decreased. Other components of the extract might have contributed to its anti-inflammatory effect., (© 2014 Royal Pharmaceutical Society.)

Objectives: Preparations containing saw palmetto berries are used in the treatment of benign prostatic hyperplasia (BPH). There are many products on the market, and relatively little is known about their chemical variability and specifically the composition and quality of different saw palmetto products notwithstanding that in 2000, an international consultation paper from the major urological associations from the five continents on treatments for BPH demanded further research on this topic. Here, we compare two analytical approaches and characterise 57 different saw palmetto products., Methods: An established method - gas chromatography - was used for the quantification of nine fatty acids, while a novel approach of metabolomic profiling using (1) H nuclear magnetic resonance (NMR) spectroscopy was used as a fingerprinting tool to assess the overall composition of the extracts., Key Findings: The phytochemical analysis determining the fatty acids showed a high level of heterogeneity of the different products in the total amount and of nine single fatty acids. A robust and reproducible (1) H NMR spectroscopy method was established, and the results showed that it was possible to statistically differentiate between saw palmetto products that had been extracted under different conditions but not between products that used a similar extraction method. Principal component analysis was able to determine those products that had significantly different metabolites., Conclusions: The metabolomic approach developed offers novel opportunities for quality control along the value chain of saw palmetto and needs to be followed further, as with this method, the complexity of a herbal extract can be better assessed than with the analysis of a single group of constituents., (© 2014 The Authors. Journal of Pharmacy and Pharmacology published by John Wiley & Sons Ltd on behalf of Royal Pharmaceutical Society.)

Introduction: The authors investigated whether a new ginkgo biloba (ginkgo) fresh plant extract had a positive effect on microcirculation in the skin and liver of elderly individuals, and whether the extract had antioxidative properties in vivo., Methods: In a monocentric, controlled clinical trial with 32 elderly patients, 16 patients received three 90 mg ginkgo extract tablets twice daily for 30 days, and 16 patients acted as untreated controls. On days 0, 10, 20, and 30, microcirculatory parameters were measured using intravital microscopy in combination with reflection spectrometry, and the amount of reduced glutathione in the liver., Results: This new ginkgo fresh plant extract significantly increased the number of blood cell-perfused nodal points, the venular streaming flow, and the local hematocrit in treated participants compared to control participants and compared to values on day 0. The ginkgo preparation also increased microcirculation in the liver, and possessed antioxidative properties that resulted in significant increases in the amount of the radical scavenger glutathione in treated participants., Conclusion: The new ginkgo fresh plant extract increased the microcirculation significantly, and at the same time improved the radical scavenging capacity in elderly patients and was very well tolerated. This extract is an interesting adjuvant treatment option for patients suffering from impaired microcirculation and improves mechanisms which inhibit an accelerated expression of atherosclerosis.

Objectives: Potential interactions between herbal medicinal products and the cytochrome (CYP) P450 system are an important safety concern. We set out to develop a screening panel for assessing such interactions and use it to evaluate the interaction potential of devil's claw., Methods: The panel consisted of luminescence-based inhibition assays for CYP1A2, 2C9, 2C19, 2D6 and 3A4, and a reporter gene (luciferase) assay for pregnane X receptor (PXR) activation and CYP3A4 induction. Caftaric acid and chlorogenic acid, two compounds with strong fluorescence quenching properties, were used to demonstrate the assay's resistance to interference. We tested 10 commercial devil's claw preparations as well as harpagoside and harpagide, two important constituents of devil's claw., Key Findings: Five preparations were found to weakly inhibit CYP3A4 (IC50 124.2-327.6 µg/ml) and five were found to weakly activate PXR (EC50 10.21-169.3 µg/ml). Harpagoside and harpagide did not inhibit CYP3A4. In agreement with published data, bergamottin, a natural product known to interact with CYP3A4, was shown to inhibit CYP3A4 with an IC50 of 13.63 µm and activate PXR with an EC50 of 6.7 µm., Conclusions: Devil's claw preparations are unlikely to have a clinically relevant effect on CYP function. The assay panel proved effective in screening devil's claw preparations, demonstrating its suitability for use with plant extracts. It showed superior sensitivity and resistance to interference., (© 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.)

A major safety concern with the use of herbal medicinal products (HMP) is their interactions with conventional medicines, which are often mediated via the cytochrome P450 (CYP) system. Echinacea is a widely used over-the-counter HMP, with proven immunomodulatory properties. Its increasing use makes research into its safety an urgent concern. Previously, we showed that Echinacea extracts and its alkylamides (thought to be important for Echinacea's immunomodulatory activity) mildly inhibit the enzymatic activity of the main drug metabolising CYP isoforms, but to this date, there is insufficient work on its ability to alter CYP expression levels. We now report for the first time the effect of a commercial Echinacea extract (Echinaforce) and four Echinacea alkylamides on the transcription of the major drug metabolizing enzyme CYP3A4. HepG2 cells were exposed for 96 h to clinically relevant concentrations of Echinaforce (22, 11.6 and 1.16 μg mL(-1)) or the alkylamides (1.62 and 44 nM). CYP3A4 mRNA levels were quantified using real-time reverse transcription polymerase chain reaction (RT-PCR). Neither Echinaforce nor the alkylamides produced any significant changes in the steady-state CYP3A4 mRNA levels, under these conditions. In contrast, treatment with 50 μM rifampicin resulted in a 3.8-fold up-regulation over the vehicle control. We conclude that Echinaforce is unlikely to affect CYP3A4 transcriptional levels, even at concentrations which can inhibit the enzymatic activity of CYP3A4. Overall, our data provides further evidence for the lack of interactions between Echinacea and conventional drugs.

A sensitive LC-ESI-MS method with a solid-phase extraction was established for the determination of bilobalide, ginkgolide A and ginkgolide B in human plasma; bioavailability and pharmacokinetics of three different Ginkgo biloba L. preparations have been investigated. The preparations used in the present single-dose pharmacokinetic study were different formulations of Ginkgo biloba L. extracts (Geriaforce tincture, new Ginkgo fresh plant extract tablets and EGb 761) with various excipients. The analysis of Ginkgo terpene lactones was performed by LC-MS on a Zorbax SB-C18 column. The mobile phase consisted of water + 0.1% acetic acid and methanol 68/32 (v/v) to 49/51 (v/v) at a flow rate of 200 microL/min. Bilobalide, ginkgolide A and ginkgolide B were monitored using the selected-ion monitoring (SIM) mode at m/z of 325, 453 and 423, respectively.The amounts of the active compounds (terpene lactones) in the administered products were in the low-mg range per dose. The assay method was successfully applied to the study of the pharmacokinetics and bioavailability of bilobalide, ginkgolide A and ginkgolide B in humans. The resulting maximum concentrations (median) of bilobalide, ginkgolide A and ginkgolide B in plasma after administration of the maximum daily dose of the different Ginkgo products were 3.53, 3.62, and 1.38 ng/mL respectively after administration of Geriaforce tincture; 11.68, 7.36, and 4.18 ng/mL, respectively after taking Ginkgo fresh plant extract tablets; and 26.85, 16.44, 9.99 ng/mL, respectively after administration of EGb 761 tablets. These data are relevant to demonstrate relative bioavailabilities of different Ginkgo biloba L. preparations (Geriaforce tincture, new Ginkgo fresh plant extract tablets and EGb 761)., ((c) 2009 John Wiley & Sons, Ltd.)

ECHINACEA is a popular and widely used herbal medicinal product and consequently, studies of its interactions with conventional drugs are of particular importance. We have shown that ECHINACEA preparations and some common alkylamides weakly inhibit several cytochrome P450 (CYP) isoforms, with considerable variation in potency. We now report a detailed analysis of six commercial ECHINACEA liquid preparations, with emphasis on the metabolomic characterisation of the ECHINACEA compounds responsible for inhibiting CYP3A4. We separated each preparation into its ethanol- and water-soluble components, and then used (1)H-NMR together with multivariate data analysis and partial least square regression analysis to investigate the nature of the compounds responsible for CYP3A4 inhibition. The results implicated alkylamides in the CYP3A4 inhibitory activity of ECHINACEA. One of the commercial preparations (Echinaforce(R)) was further fractionated using solid phase extraction. Analysis by (1)H-NMR and mass spectroscopy (LC/MS, tandem MS, accurate mass) identified dodeca-2 E,4 E,8 Z,10 E/Z-tetraenoic acid (alkylamide 1) and a new compound (putative molecular formula C (18)H (36) NO (+)) as major components of the inhibitory fractions. In addition, the alkylamide content of all six preparations was determined by reverse phase HPLC. Levels of alkylamides 1 and 3 (undeca-2 E,4 E/ Z-diene-8,10-diynoic acid isobutylamide), correlated well with CYP3A4 inhibition. The acetylene tetradeca-8 Z-ene-11,13-diyn-2-one was shown to be present in the E. PURPUREA as well as the E. PALLIDA extracts. E. PURPUREA unlike E. PALLIDA was thought to not contain significant amounts of acetylenes. Our results directly confirm the role of alkylamides in the inhibition of CYP3A4 by ECHINACEA and uncovered a new compound which may also be involved. Extensive differences in the composition of the commercially available preparations were found. This will inevitably impact on the product efficacy, safety and pharmacological effects, especially since the differences involve alkylamides, an important class of ECHINACEA's active constituents. The metabolomic approach presented here may prove valuable as a screening or quality control tool., (Copyright Georg Thieme Verlag KG Stuttgart New York.)

Background: In Chinese medicine, Ginkgo biloba is used for a variety of indications. In the current study, the safety and efficacy of a traditional fresh plant extract was investigated in patients with mild cognitive impairment., Patients and Methods: 59 elderly patients were treated for 6 weeks with a twice daily tablet containing 90 mg of fresh plant Ginkgo biloba extract. The patients suffered from age-related mild cognitive impairment of the non-Alzheimer type assessed by the DemTect score and the presence of symptoms, such as forgetfulness, memory problems, and difficulties in concentration. At the end of the treatment period, safety was primarily assessed by the occurrence of adverse events and efficacy by the DemTect score, the SF-12 quality of life questionnaire, and the change in cognitive symptoms, as well as the judgment of the investigators and patients., Results: At the final visit, the SF-12 mental score had increased significantly from 48.3 +/- 10.1 to 51.3 +/- 7.9, whereas the SF-12 body score (44.5 +/- 9.2 to 45.3 +/- 8.1) and the DemTect score (15.9 +/- 2.0 to 16.0 +/- 2.3) had not changed significantly. About half of all patients experienced an improvement in their memory and their ability to concentrate, as well as a decrease in symptoms of forgetfulness. The majority of investigators and patients judged the treatment to be effective. The tablets were very well tolerated and, as a treatment for their cognitive impairment, highly accepted (90% would take them again)., Conclusion: This newly developed, holistic fresh leaf extract of Ginkgo biloba is a safe, effective, and, at least, adjuvant treatment option for patients with mild cognitive impairments., (Copyright 2009 S. Karger AG, Basel.)

Establishing the pharmacological basis for efficacy of herbal medicinal products (HMPs) is a continuous challenge. In this context, also the question of bioavailability, the elucidation of metabolic pathways and their pharmacokinetics is of major interest. These data are relevant to link results from pharmacological IN VITRO assays and clinical studies. A better understanding of the pharmacokinetics and bioavailability of phytopharmaceuticals can also help in designing rational dosage regimes. The preparations used in the present pharmacokinetic single-dose study are different ECHINACEA PURPUREA formulations (Echinaforce) with various excipients. The concentrations of the active compounds (alkamides) in the administered products have been in the low mg range per dose. Due to the expected necessary detection of ng ranges, a sensitive and selective LC-ESI-MS-based method that is capable of monitoring plasma levels of traces of active constituents in humans was developed and validated. The resulting maximum concentrations (mean +/- standard deviation) of dodeca-2 E,4 E,8 Z, 10 E/ Z-tetraenoic acid isobutylamides in plasma were 0.22 +/- 0.07 ng/mL after administration of Echinaforce tablets, 0.22 +/- 0.15 ng/mL after taking Echinaforce Junior tablets and 0.23 +/- 0.16 ng/mL after administration of an Echinacea sore throat spray. The areas under the curve were 0.22 ng/mL x h, 0.20 ng/mL x h and 0.23 ng/mL x h, respectively.

The use of topical preparations for symptom relief is common in osteoarthritis. The effects of ibuprofen (5%) and arnica (50 g tincture/100 g, DER 1:20), as gel preparations in patients with radiologically confirmed and symptomatically active osteoarthritis of interphalangeal joints of hands, were evaluated in a randomised, double-blind study in 204 patients, to ascertain differences in pain relief and hand function after 21 days' treatment. Diagnosis was according to established criteria; primary endpoints were pain intensity and hand function; statistical design was as per current regulatory guidelines for testing topical preparations. There were no differences between the two groups in pain and hand function improvements, or in any secondary end points evaluated. Adverse events were reported by six patients (6.1%) on ibuprofen and by five patients (4.8%) on arnica. Our results confirm that this preparation of arnica is not inferior to ibuprofen when treating osteoarthritis of hands.

Background: Phytotherapy is a third approach for treating lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). The lipido-sterolic extract of the fruit of Serenoa repens is one of the more widely used phytotherapeutic agents in this regard., Materials and Methods: The effect of an ethanolic extract of S. repens (10-1000 microg/ml) was tested in hormone-sensitive LNCaP, MCF-7 and hormone-insensitive DU 145, MDA MB231 prostate, breast carcinoma cell lines, renal Caki-1, urinary bladder J82, colon HCT 116 and lung A 549 cancer cells. Its cell growth inhibitory and apoptosis-inducing effects were tested using WST-1 assay and flow cytometry (Annexin V/PI stain) and/or by colorimetric assay (APOPercentage assay)., Results: The S. repens extract induced a dose-dependent antiproliferative effect on all human malignant cells tested, with GI50 values between 107 and 327 pmicro/ml. In hormone-sensitive prostate LNCaP and breast MCF-7 cell lines, the effect of extract expressed in GI50 was 2.2- and 2.5-fold more potent (p < 0.01) than in hormone-insensitive DU 145 and MDA MB231 cells. The proportion of apoptotic cells, except in A549 cells, lay between 22.5-36.3%. S. repens extract did not induce apoptosis in lung cancer A 549 cells., Conclusion: This study showed that the antiproliferative effect exerted by the ethanolic extract of S. repens is at least triggered by induction of apoptosis. These in vitro data provide some information that may be useful for clinical use and render S. repens extract an interesting tool for new applications.

This open, multicenter study investigated the tolerability and efficacy of a new tablet formulation of Echinacea purpurea extract (Echinaforce Forte; A. Vogel, Bioforce AG, Roggwil, Switzerland) in 80 subjects actively involved in sports. Most investigators (97.5%) rated the treatment as having "very good" or "good" tolerability. About 75% of patients and investigators rated its efficacy during a common cold as "very good" or "good," and 71% of subjects were free of cold episodes. This study is the first to suggest that Echinaforce is effective in the prophylaxis, as well as the treatment, of the common cold in persons who actively participate in sports.

Background: The therapeutic effectiveness of Echinacea in the treatment and the prevention of colds has been debated. Studies of naturally occurring colds are hampered by variability in time from onset of symptoms to treatment and by heterogeneity in trial design. Experimental infection studies allow for the standardization of time to initiation of treatment, virus type and dose, and immune competence of volunteers., Objective: To determine whether the negative results obtained in previous studies of Echinacea were a consequence of efficacy or of inadequate sample size, we performed a meta-analysis of experimental rhinovirus infection studies on the efficacy of Echinacea extracts to prevent symptomatic development of an experimentally induced cold., Methods: We carried out a systematic search of English- and German-language literature using the MEDLINE, EMBASE, CAplus, BIOSIS, CABA, AGRICOLA, TOXCENTER, SCISEARCH, NAHL, and NAPRALERT, databases and the search terms Echinacea, black Sampson, coneflower, and Roter Sonnenbut. Matching documents were then searched for > or = 1 of the following terms: rhinovirus, RV, inoculation, Inokulation, induced, induziert, artificial, and artifiziell. Suitable studies were identified and pooled for analysis. The primary end point was the development of symptomatic clinical colds, as defined by the authors of the original studies. Results were reported as differences in the proportion of subjects with symptomatic episodes of a common cold, expressed as odds ratios (ORs) and 95% CIs. The secondary outcome was the difference in total symptom severity scores between treatment groups (assessed daily by integrating the severity scores of 8 individual cold-related symptoms that were rated on a scale from 0 [absent] to 4 [very severe])., Results: A total of 234 articles were identified through the literature search; 231 were excluded from the analysis because they related to studies of spontaneous common colds. Three suitable studies were selected for pooling of data. Based on the analysis, the likelihood of experiencing a clinical cold was 55% higher with placebo than with Echinacea (OR, 1.55 [95% CI, 1.02-2.36]; P<0.043). The absolute difference in total symptom scores between groups was -1.96 (95% CI, -4.83 to 0.90; P=NS)., Conclusions: This meta-analysis suggests that standardized extracts of Echinacea were effective in the prevention of symptoms of the common cold after clinical inoculation, compared with placebo. Further prospective, appropriately powered clinical studies are required to confirm this finding.

Extracts from the seed of the horse chestnut (Aesculus hippocastanum L.) have traditionally been used to treat patients with chronic venous insufficiency and to alleviate its associated symptoms, including lower leg swelling. The efficacy of preparations that contain horse chestnut seed extract (HCSE) is believed to be due largely to an inhibitory effect on the catalytic breakdown of capillary wall proteoglycans. Aesculaforce is a fresh plant HCSE that is available as an oral tincture, as tablets (20 mg or 50 mg), and as topical gel. Four clinical trials in patients with chronic venous insufficiency and 1 study in patients with varicose veins demonstrated the effectiveness of these preparations through the objective measure of reduction in lower leg edema and the subjective alleviation of leg pain, heaviness, and itching. Safe, well tolerated, and acceptable to patients, the fresh plant HCSE preparation Aesculaforce offers a real alternative in the treatment of patients with mild to moderate venous insufficiency.

Echinacea plant preparations are widely used in the prevention and treatment of common cold. However, so far no molecular mechanism of action has been proposed. We analyzed the standardized tincture Echinaforce and found that it induced de novo synthesis of tumor necrosis factor alpha (TNF-alpha) mRNA in primary human monocytes/macrophages, but not TNF-alpha protein. Moreover, LPS-stimulated TNF-alpha protein was potently inhibited in the early phase but prolonged in the late phase. A study of the main constituents of the extract showed that the alkylamides dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides (1/2), trienoic (3) and dienoic acid (4) derivatives are responsible for this effect. The upregulation of TNF-alpha mRNA was found to be mediated by CB2 receptors, increased cAMP, p38/MAPK and JNK signaling, as well as NF-kappaB and ATF-2/CREB-1 activation. This study is the first to report a possible molecular mechanism of action of Echinacea, highlighting the role of alkylamides as potent immunomodulators and potential ligands for CB2 receptors.

An open study was carried out to assess, primarily, the safety and tolerability of Aesculus hippocastanum in the treatment of CVI. Patients underwent 8 consecutive weeks of treatment and were asked to take one 50 mg Aesculus hippocastanum tablet, twice daily. In total, 91 adverse events were reported, of which only 4 were rated as probably related to the study drug. Patients judged the tolerability of the study medication in the majority of the cases at visits 2 and 3 (90 and 95%, respectively) to be "good" or "fairly good." Only 2 patients rated tolerability as poor at visit 3. For each of the symptoms investigated the difference in the median value between baseline and visit 3 was found to be statistically significant and both the ankle and lower leg circumference decreased. The PPG measurements were rejected after analysis since validation measurements carried out after the trial showed that the PPG technique had an internal error of around 30%. Nevertheless, the majority of patients rated efficacy to be "very good" or "good," with only 10 patients reporting no effect by the end of the study. The results of this study indicate that Aesculaforce 50 mg tablets are a safe, well-tolerated and efficacious treatment for Widmer stage I and II CVI.

This open multicenter trial investigated the safety and efficacy of an Arnica montana fresh plant gel, applied twice daily, in 26 men and 53 women with mild to moderate osteoarthritis (OA) of the knee. After 3 and 6 weeks, significant decreases in median total scores on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were evident in the intention-to-treat and per-protocol populations (both P < .0001). Scores on the pain, stiffness, and function subscales also showed significant reductions at these timepoints. The overall local adverse-event rate of 7.6% included only one allergic reaction. Sixty-nine patients (87%) rated the tolerability of the gel as "good" or "fairly good," and 76% would use it again. Topical application of Arnica montana gel for 6 weeks was a safe, well-tolerated, and effective treatment of mild to moderate OA of the knee.