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BACKGROUND: Coronaviruses (CoVs) were long thought to only cause mild respiratory and gastrointestinal symptoms in humans but outbreaks of Middle East Respiratory Syndrome (MERS)-CoV, Severe Acute Respiratory Syndrome (SARS)-CoV-1, and the recently identified SARS-CoV-2 have cemented their zoonotic potential and their capacity to cause serious morbidity and mortality, with case fatality rates ranging from 4 to 35%. Currently, no specific prophylaxis or treatment is available for CoV infections. Therefore we investigated the virucidal and antiviral potential of Echinacea purpurea (Echinaforce®) against human coronavirus (HCoV) 229E, highly pathogenic MERS- and SARS-CoVs, as well as the newly identified SARS-CoV-2, in vitro. METHODS: To evaluate the antiviral potential of the extract, we pre-treated virus particles and cells and evaluated remaining infectivity by limited dilution. Furthermore, we exposed cells to the extract after infection to further evaluate its potential as a prophylaxis and treatment against coronaviruses. We also determined the protective effect of Echinaforce® in re-constituted nasal epithelium. RESULTS: In the current study, we found that HCoV-229E was irreversibly inactivated when exposed to Echinaforce® at 3.2 µg/ml IC50. Pre-treatment of cell lines, however, did not inhibit infection with HCoV-229E and post-infection treatment had only a marginal effect on virus propagation at 50 µg/ml. However, we did observe a protective effect in an organotypic respiratory cell culture system by exposing pre-treated respiratory epithelium to droplets of HCoV-229E, imitating a natural infection. The observed virucidal activity of Echinaforce® was not restricted to common cold coronaviruses, as both SARS-CoV-1 and MERS-CoVs were inactivated at comparable concentrations. Finally, the causative agent of COVID-19, SARS-CoV-2 was also inactivated upon treatment with 50µg/ml Echinaforce®. CONCLUSIONS: These results show that Echinaforce® is virucidal against HCoV-229E, upon direct contact and in an organotypic cell culture model. Furthermore, MERS-CoV and both SARS-CoV-1 and SARS-CoV-2 were inactivated at similar concentrations of the extract. Therefore we hypothesize that Echinacea purpurea preparations, such as Echinaforce®, could be effective as prophylactic treatment for all CoVs due to their structural similarities.
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Antivirales/farmacología , Betacoronavirus/efectos de los fármacos , Coronavirus Humano 229E/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Coronavirus/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Animales , COVID-19 , Línea Celular , Chlorocebus aethiops , Resfriado Común/tratamiento farmacológico , Resfriado Común/virología , Infecciones por Coronavirus/virología , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Pandemias , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/virología , Virus ARN/efectos de los fármacos , Ensayos Clínicos Controlados Aleatorios como Asunto , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Síndrome Respiratorio Agudo Grave/virología , Células VeroRESUMEN
BACKGROUND: Salvia officinalis has been used successfully for the treatment of hot flushes and excessive sweating during menopause. However, modes of actions have not been elucidated conclusively. We explored its pharmacology beyond any hormonal activity with a focus on neurologic impulse transmission. METHODS: A hydroalcoholic, thujone-free extract from freshly harvested Salvia officinalis leaves (A.Vogel Menosan®) was investigated in an acetylcholinesterase enzyme assay and several receptor binding assays (adrenergic alpha 2A, GABA (benzodiazepine site), GABAB; muscarinic M3, µ-opioid, serotonin 5-HT1A, serotonin 5-HT2B, serotonin 5-HT2C and serotonin transporter). The influence of the manufacturing process on additional extracts from different fresh or dry plant parts was studied. RESULTS: The Salvia officinalis extract replaced 50% of specific ligand binding to GABAA and GABAB receptors at an inhibitory concentration (IC50) of 89 and 229 µg/ml, respectively. Strong binding affinity was observed for the adrenergic α2A receptor, µ-opioid receptors, muscarinic M3 receptors, and serotonin 5-HT1A receptors, with IC50 values of 15 µg/ml, 20 µg/ml, 25 µg/ml and 19 µg/ml, respectively. Moderate interference with 5-HT2B, 5-HT2C receptors, and the human serotonin transporter was found, all with IC50 values above 32 µg/ml. Receptor binding data of Salvia extract were confirmed in native female hypothalamic tissue from two women (51 and 37 years old). Use of freshly harvested Salvia leaves resulted in 2- to 4-fold higher activity/lower IC50 values compared to extracts from dried plants or stipes. CONCLUSION: Our results suggest potent modulation of neuro-receptors and of serotonin transporters as mode of action for Salvia officinalis alcoholic extract, which may normalize thermoregulation and possibly also mental impairment during menopause.
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Sofocos/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/uso terapéutico , Salvia officinalis , Transmisión Sináptica/efectos de los fármacos , Adulto , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Persona de Mediana Edad , Extractos Vegetales/farmacologíaRESUMEN
BACKGROUND: Echinacea has antiviral activity against influenza viruses in vitro and has traditionally been used for treatment of colds and flu. OBJECTIVES: This randomized, double-blind, double-dummy, multicenter, controlled clinical trial compared a new echinacea formulation with the neuraminidase inhibitor oseltamivir, the gold standard treatment for influenza. METHODS: Following informed consent, 473 patients with early influenza symptoms (≤48 hours) were recruited in primary care in the Czech Republic and randomized to either 5 days of oseltamivir followed by 5 days of placebo, or 10 days of an Echinacea purpurea-based formulation called Echinaforce Hotdrink (A. Vogel Bioforce AG, Roggwil, Switzerland). The proportion of recovered patients (influenza symptoms rated as absent or mild in the evening) was analyzed for noninferiority between treatment groups using a generalized Wilcoxon test with significance level α = 0.05 (2-sided) and using a CI approach in the per-protocol sample. RESULTS: Recovery from illness was comparable in the 2 treatment groups at 1.5% versus 4.1% after 1 day, 50.2% versus 48.8% after 5 days, and 90.1% versus 84.8% after 10 days of treatment with Echinaforce Hotdrink and oseltamivir, respectively. Noninferiority was demonstrated for each day and overall (95% CI, 0.487-0.5265 by generalized Wilcoxon test). Very similar results were obtained in the group with virologically confirmed influenza virus infections and in a retrospective analysis during the peak influenza period. The incidence of complications was lower with Echinaforce Hotdrink than with oseltamivir (2.46% vs 6.45%; P = 0.076) and fewer adverse events (particularly nausea and vomiting) were observed with Echinaforce Hotdrink. CONCLUSIONS: Echinaforce Hotdrink is as effective as oseltamivir in the early treatment of clinically diagnosed and virologically confirmed influenza virus infections with a reduced risk of complications and adverse events. It appears to be an attractive treatment option, particularly suitable for self-care. Clinical trial identifier: Eudra-CT: 2010-021571-88. (Curr Ther Res Clin Exp. 2015; 77:66-72).
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The rhizome of ginger (Zingiber officinale) is employed in Asian traditional medicine to treat mild forms of rheumatoid arthritis and fever. We have profiled ginger constituents for robust effects on proinflammatory signaling and cytokine expression in a validated assay using human whole blood. Independent of the stimulus used (LPS, PMA, anti-CD28 Ab, anti-CD3 Ab, and thapsigargin), ginger constituents potently and specifically inhibited IL-1ß expression in monocytes/macrophages. Both the calcium-independent phospholipase A(2) (iPLA(2))-triggered maturation and the cytosolic phospholipase A(2) (cPLA(2))-dependent secretion of IL-1ß from isolated human monocytes were inhibited. In a fluorescence-coupled PLA(2) assay, most major ginger phenylpropanoids directly inhibited i/cPLA(2) from U937 macrophages, but not hog pancreas secretory phospholipase A(2). The effects of the ginger constituents were additive and the potency comparable to the mechanism-based inhibitor bromoenol lactone for iPLA(2) and methyl arachidonyl fluorophosphonate for cPLA(2), with 10-gingerol/-shogaol being most effective. Furthermore, a ginger extract (2 µg/ml) and 10-shogaol (2 µM) potently inhibited the release of PGE(2) and thromboxane B2 (>50%) and partially also leukotriene B(4) in LPS-stimulated macrophages. Intriguingly, the total cellular arachidonic acid was increased 2- to 3-fold in U937 cells under all experimental conditions. Our data show that the concurrent inhibition of iPLA(2) and prostanoid production causes an accumulation of free intracellular arachidonic acid by disrupting the phospholipid deacylation-reacylation cycle. The inhibition of i/cPLA(2), the resulting attenuation of IL-1ß secretion, and the simultaneous inhibition of prostanoid production by common ginger phenylpropanoids uncover a new anti-inflammatory molecular mechanism of dietary ginger that may be exploited therapeutically.
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Eicosanoides/farmacología , Interleucina-1beta/metabolismo , Monocitos/efectos de los fármacos , Fosfolipasas A2/metabolismo , Fosfolípidos/metabolismo , Extractos Vegetales/farmacología , Zingiber officinale/química , Ácido Araquidónico/metabolismo , Western Blotting , Células Cultivadas , Citocinas/efectos de los fármacos , Citocinas/metabolismo , Eicosanoides/metabolismo , Ensayo de Inmunoadsorción Enzimática , Humanos , Monocitos/metabolismo , Rizoma/química , Células U937RESUMEN
BACKGROUND: Acute tonsillopharyngitis or sore throat is an initial sign of viral respiratory tract infection (RTI) and an optimal indicator for early antiviral and anti-inflammatory intervention. Both of these actions have been attributed to Echinacea purpurea and Salvia officinalis. METHODS: 74 patients (age 13-69 years) with acute sore throat symptoms (<48 h) were treated with five Echinacea/Salvia lozenges per day (4,000 mg Echinacea purpurea extract [Echinaforce®] and 1,893 mg Salvia officinalis extract [A. Vogel AG, Switzerland] daily) for 4 days. Symptom intensities were recorded in a diary and oropharyngeal swab samples collected for virus detection and quantification via RT-qPCR. RESULTS: The treatment was exceptionally well tolerated, no complicated RTI developed, and no antibiotic treatment was required. A single lozenge reduced throat pain by 48% (p < 0.001) and tonsillopharyngitis symptoms by 34% (p < 0.001). Eighteen patients tested virus positive at inclusion. Viral loads in these patients was reduced by 62% (p < 0.03) after intake of a single lozenge and by 96% (p < 0.02) after 4 days of treatment compared to pre-treatment. CONCLUSIONS: Echinacea/Salvia lozenges represent a valuable and safe option for the early treatment of acute sore throats capable to alleviate symptoms and contribute to reducing viral loads in the throat.
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Echinacea , Faringitis , Salvia officinalis , Salvia , Adolescente , Adulto , Anciano , Humanos , Persona de Mediana Edad , Adulto Joven , Dolor , Faringitis/tratamiento farmacológico , Faringitis/diagnóstico , Faringitis/etiología , Carga ViralRESUMEN
Background: Echinacea purpurea has clinical antiviral activity against respiratory viruses and modulates immune functions. In this study, we compared higher doses of new Echinacea formulations with conventional formulations at lower, preventive doses for therapy of respiratory tract infections (RTIs). Methods: In this randomized, blinded, controlled trial, healthy adults (n = 409) were randomized between November 2018 and January 2019 to one of four Echinacea formulations, which were taken in case of an RTI for up to 10 days. New formulations A (lozenges) and B (spray) delivered an increased dose of 16,800 mg/d Echinacea extract during days 1-3 and 2,240-3,360 mg/d afterward; as controls, conventional formulations C (tablets) and D (drops) delivered a lower daily dose of 2,400 mg, usually taken for prevention. The primary endpoint was time to clinical remission of first RTI episodes based on the Kaplan-Meier analysis of patient-reported, investigator-confirmed, respiratory symptoms assessed for up to 10 days. In a sensitivity analysis, the mean time to remission beyond day 10 was calculated by extrapolating the treatment effects observed on days 7 to 10. Results: A total of 246 participants (median age 32 years, 78% female participants) were treated for at least one RTI. Recovery by day 10 (complete absence of symptoms) was achieved in 56 and 44% of patients with the new and conventional formulations, respectively, showing a median time to recovery of 10 and 11 days, respectively (p = 0.10 in intention-to-treat analysis, p = 0.07 in per-protocol analysis). In the extrapolated sensitivity analysis, new formulations resulted in a significantly shorter mean time to remission (9.6 vs. 11.0 days, p < 0.001). Among those with an identified respiratory virus, viral clearance until day 10 based on real-time PCR from nasopharyngeal swabs was more frequent with new formulations (70 vs. 53%, p = 0.046). Tolerability and safety (adverse events: 12 vs. 6%, p = 0.19) were good and similar between formulations. There was one severe adverse event with a potential hypersensitivity reaction in a recipient of the novel spray formulation. Conclusion: In adults with acute RTI, new Echinacea formulations with higher doses resulted in faster viral clearance than conventional formulations in prophylactic dosages. The trend for faster clinical recovery was not significant by day 10 but became so upon extrapolation. A dose increase during acute respiratory symptoms might improve the clinical benefits of orally administered Echinacea formulations. Trial registration: The study was registered in the Swiss National Clinical Trials Portal (SNCTP000003069) and on ClinicalTrials.gov (NTC03812900; URL https://clinicaltrials.gov/ct2/show/NCT03812900?cond=echinacea&draw=3&rank=14).
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Extracts from Serenoa repens are widely used for the treatment of benign prostatic hyperplasia (BPH) and traditionally for prostatitis. In the present study we evaluated the biological effects of Serenoa repens extract (Prostasan®) on prostate cells beyond its known antiandrogenic actions. Prostasan® inhibited epidermal growth factor (EGF) and lipopolysaccharide (LPS) induced proliferation of the prostatic epithelial, androgen independent cell line PC-3. At effective concentrations of 50 µg/mL, Prostasan® partly displaced EGF from EGF receptor (EGFR) but fully blocked EGF-induced cell proliferation of PC-3 cells. Similarly, Prostasan® inhibited LPS-induced proliferation of PC-3 cells without affecting LPS activation of the NFĸB pathway via toll-like receptor-4 (TLR-4). Additionally, Prostasan® reduced the constitutive secretion of monocyte chemotactic protein-1 (MCP-1), the LPS-induced secretion of IL-12 and inhibited MCP-1 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production in the presence of LPS on PC-3 cells. Taken together, our results suggest that S. repens extracts, in addition to other reported effects on BPH development and prostatitis, inhibits EGF-dependent growth and proinflammatory responses of the prostate epithelial cells.
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Proliferación Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Inflamación/patología , Extractos Vegetales/farmacología , Próstata/citología , Serenoa/química , Línea Celular/efectos de los fármacos , Citocinas/metabolismo , Factor de Crecimiento Epidérmico/antagonistas & inhibidores , Receptores ErbB/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Lipopolisacáridos , MasculinoRESUMEN
BACKGROUND: In children, up to 30% of viral respiratory tract infections (RTIs) develop into bacterial complications associated with pneumonia, sinusitis or otitis media to trigger a tremendous need for antibiotics. This study investigated the efficacy of Echinacea for the prevention of viral RTIs, for the prevention of secondary bacterial complications and for reducing rates of antibiotic prescriptions in children. METHODS: Echinaforce® Junior tablets [400 mg freshly harvested Echinacea purpurea alcoholic extract] or vitamin C [50 mg] as control were given three times daily for prevention to children 4-12 years. Two × 2 months of prevention were separated by a 1-week treatment break. Parents assessed respiratory symptoms in children via e-diaries and collected nasopharyngeal secretions for screening of respiratory pathogens (Allplex® RT-PCR). RESULTS: Overall, 429 cold days occurred in NITT = 103 children with Echinacea in comparison to 602 days in NITT = 98 children with vitamin C (p < 0.001, Chi-square test). Echinacea prevented 32.5% of RTI episodes resulting in an odds ratio of OR = 0.52 [95% CI 0.30-0.91, p = 0.021]. Six children (5.8%) with Echinacea and 15 children (15.3%) with vitamin C required 6 and 24 courses of antibiotic treatment, respectively (reduction of 76.3%, p < 0.001). A total of 45 and 216 days of antibiotic therapy were reported in the two groups, respectively (reduction of 80.2% (p < 0.001). Eleven and 30 events of RTI complications (e.g., otitis media, sinusitis or pneumonia) occurred with Echinacea and vitamin C, respectively (p = 0.0030). Echinacea significantly prevented influenza (3 vs. 20 detections, p = 0.012) and enveloped virus infections (29 vs. 47 detections, p = 0.0038). Finally, 76 adverse events occurred with Echinacea and 105 events with vitamin C (p = 0.016), only three events were reported possibly related with Echinacea. CONCLUSIONS: Our results support the use of Echinacea for the prevention of RTIs and reduction of associated antibiotic usage in children. Trial registration clinicaltrials.gov, NCT02971384, 23th Nov 2016.
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Antibacterianos , Echinacea/química , Extractos Vegetales/uso terapéutico , Infecciones del Sistema Respiratorio/prevención & control , Niño , Preescolar , Femenino , Humanos , Masculino , Infecciones del Sistema Respiratorio/patologíaRESUMEN
Animal studies suggest that ginger (Zingiber officinale Roscoe) reduces anxiety. In this study, bioactivity-guided fractionation of a ginger extract identified nine compounds that interact with the human serotonin 5-HT(1A) receptor with significant to moderate binding affinities (K(i)=3-20 microM). [(35)S]-GTP gamma S assays indicated that 10-shogaol, 1-dehydro-6-gingerdione, and particularly the whole lipophilic ginger extract (K(i)=11.6 microg/ml) partially activate the 5-HT(1A) receptor (20-60% of maximal activation). In addition, the intestinal absorption of gingerols and shogaols was simulated and their interactions with P-glycoprotein were measured, suggesting a favourable pharmacokinetic profile for the 5-HT(1A) active compounds.
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Ansiolíticos/farmacología , Catecoles/farmacología , Alcoholes Grasos/farmacología , Agonistas del Receptor de Serotonina 5-HT1 , Zingiber officinale/química , Células CACO-2 , Línea Celular , Humanos , Estructura MolecularRESUMEN
Background: Due to the frequency and severity of cold symptoms in children, and the risk of associated complications, effective treatments are urgently needed. Here we evaluated the safety profile and treatment benefits of Echinacea in children with acute cold and flu symptoms. Methods: A total of 79 children (4-12 years) were randomized to a treatment regimen of three or five times daily Echinaforce Junior tablets (total of 1200 or 2000 mg Echinacea extract, EFJ) for the prospective treatment of upcoming cold and flu episodes at first signs. Parents recorded respiratory symptoms daily during episodes in their child and physicians and parents subjectively rated tolerability. Results: EFJ was used to treat 130 cold episodes in 68 children and was very well tolerated by more than 96% positive physician's ratings. EFJ-treated cold episodes lasted 7.5 days on average, with nine out of 10 episodes being fully resolved after 10 days. Five EFJ tablets daily reduced the average episode duration by up to 1.7 days (p < 0.02) in comparison to three EFJ tablets daily regimen. Effective symptom resolution finally contributed to a low antibiotic prescription rate in this study of 4.6%. Conclusions: EFJ tablets present a valuable option for the treatment of acute cold episodes in children showing a wide safety margin and increased therapeutic benefits at five tablets daily.
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BACKGROUND: Influenza virus (IV) infections are a major threat to human welfare and animal health worldwide. Anti-viral therapy includes vaccines and a few anti-viral drugs. However vaccines are not always available in time, as demonstrated by the emergence of the new 2009 H1N1-type pandemic strain of swine origin (S-OIV) in April 2009, and the acquisition of resistance to neuraminidase inhibitors such as Tamiflu (oseltamivir) is a potential problem. Therefore the prospects for the control of IV by existing anti-viral drugs are limited. As an alternative approach to the common anti-virals we studied in more detail a commercial standardized extract of the widely used herb Echinacea purpurea (Echinaforce, EF) in order to elucidate the nature of its anti-IV activity. RESULTS: Human H1N1-type IV, highly pathogenic avian IV (HPAIV) of the H5- and H7-types, as well as swine origin IV (S-OIV, H1N1), were all inactivated in cell culture assays by the EF preparation at concentrations ranging from the recommended dose for oral consumption to several orders of magnitude lower. Detailed studies with the H5N1 HPAIV strain indicated that direct contact between EF and virus was required, prior to infection, in order to obtain maximum inhibition in virus replication. Hemagglutination assays showed that the extract inhibited the receptor binding activity of the virus, suggesting that the extract interferes with the viral entry into cells. In sequential passage studies under treatment in cell culture with the H5N1 virus no EF-resistant variants emerged, in contrast to Tamiflu, which produced resistant viruses upon passaging. Furthermore, the Tamiflu-resistant virus was just as susceptible to EF as the wild type virus. CONCLUSION: As a result of these investigations, we believe that this standard Echinacea preparation, used at the recommended dose for oral consumption, could be a useful, readily available and affordable addition to existing control options for IV replication and dissemination.
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Antivirales/farmacología , Echinacea/química , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H7N7 del Virus de la Influenza A/efectos de los fármacos , Extractos Vegetales/farmacología , Acoplamiento Viral/efectos de los fármacos , Animales , Antivirales/aislamiento & purificación , Línea Celular , Perros , Pruebas de Sensibilidad Microbiana , Extractos Vegetales/aislamiento & purificaciónRESUMEN
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).
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Antiinfecciosos/farmacología , Echinacea/química , Células Epiteliales/efectos de los fármacos , Sobreinfección/prevención & control , Receptor Toll-Like 4/antagonistas & inhibidores , Factor de Transcripción ReIA/antagonistas & inhibidores , Línea Celular , Coinfección , Células Epiteliales/citología , Células Epiteliales/microbiología , Células Epiteliales/virología , Fibronectinas/genética , Fibronectinas/inmunología , Regulación de la Expresión Génica , Haemophilus influenzae/efectos de los fármacos , Haemophilus influenzae/crecimiento & desarrollo , Haemophilus influenzae/patogenicidad , Interacciones Huésped-Patógeno , Humanos , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacos , Subtipo H3N2 del Virus de la Influenza A/crecimiento & desarrollo , Subtipo H3N2 del Virus de la Influenza A/patogenicidad , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Interleucina-8/genética , Interleucina-8/inmunología , Pulmón/citología , Pulmón/efectos de los fármacos , Pulmón/microbiología , Pulmón/virología , Extractos Vegetales/farmacología , Glicoproteínas de Membrana Plaquetaria/genética , Glicoproteínas de Membrana Plaquetaria/inmunología , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/inmunología , Transducción de Señal , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo , Staphylococcus aureus/patogenicidad , Sobreinfección/microbiología , Sobreinfección/virología , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/inmunologíaRESUMEN
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.
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Resfriado Común/prevención & control , Echinacea , Fitoterapia , Rhinovirus , Humanos , Extractos Vegetales/uso terapéuticoRESUMEN
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.
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Echinacea , Regulación de la Expresión Génica/efectos de los fármacos , Extractos Vegetales/farmacología , Receptor Cannabinoide CB2/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo , Células Cultivadas , AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Cinética , Leucocitos Mononucleares/efectos de los fármacos , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Estructura Molecular , FN-kappa B/metabolismo , Extractos Vegetales/química , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Regulación hacia Arriba , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Stimulation of T cells through the T cell receptor is insufficient for optimal T cell activation. A second activation signal is necessary, being usually provided by the costimulatory molecule CD28. Recently, additional costimulatory pathways have been identified, including inducible costimulator (ICOS) and its ligand B7RP-1. We have examined the role of the B7RP-1/ICOS costimulatory pathway on antigen presentation by B cells, using the I-Ak and I-Ek-positive CH27 B cell line and several different T cell lines. We found that CH27 expressed B7RP-1 and PD-L1 whereas the T cell lines expressed ICOS and PD-1. In the presence of HEL, the T cell hybridomas C10 and 3A9 released IL-2, which is indicative of antigen-specific T cell activation by the CH27 cells. Unexpectedly, blocking antibodies for B7RP-1 and ICOS enhanced the IL-2 response in both T cells. As expected, an increase in the production of IL-2 was seen when blocking antibodies for PD-1 were used. Blocking with antibodies for I-Ak, CD28, B7.1, and B7.2 lead to a decrease in IL-2 production. Additionally we tested a Th1 and a Th2 T cell clone. Blockade of B7RP-1/ICOS lead to an increased IFN-gamma response in Th1 cells (A.E7) and an increased IL-4 response in Th2 cells (D10.G4.1). Intracellular staining also showed an increase in cytokine production when the B7RP-1/ICOS pathway was blocked. In conclusion, the B7RP-1/ICOS pathway is negatively regulating T cell activation by B cells and may play a role similar to that of the PD-L1/PD-1 pathway.
Asunto(s)
Presentación de Antígeno , Antígenos de Diferenciación de Linfocitos T/metabolismo , Linfocitos B/metabolismo , Antígeno B7-1/metabolismo , Regulación hacia Abajo/inmunología , Animales , Presentación de Antígeno/inmunología , Antígenos de Diferenciación de Linfocitos T/fisiología , Linfocitos B/inmunología , Antígeno B7-1/fisiología , Línea Celular , Línea Celular Tumoral , Ligando Coestimulador de Linfocitos T Inducibles , Proteína Coestimuladora de Linfocitos T Inducibles , RatonesRESUMEN
Several viruses associated with upper respiratory diseases have been shown to stimulate the secretion of pro-inflammatory cytokines, including chemokines, sometimes in the absence of viral cytopathology. We evaluated the ability of a standardized preparation of the popular herbal medicine Echinacea (Echinaforce, an ethanol extract of herb and roots of E. purpurea, and containing known concentrations of marker compounds) to inhibit the viral induction of various cytokines in a line of human bronchial epithelial cells (BEAS-2B), and in two other human cell lines. All of the viruses tested, rhinoviruses 1A and 14, influenza virus, respiratory syncytial virus, adenovirus types 3 and 11, and herpes simplex virus type 1, induced substantial secretion of IL-6 and IL-8 (CXCL8), in addition to several other chemokines, depending on the virus, although only viable viruses were able to do this. In every case however Echinacea inhibited this induction. The Echinacea preparation also showed potent virucidal activity against viruses with membranes, indicating the multi-functional potential of the herb. These results support the concept that certain Echinacea preparations can alleviate "cold and flu" symptoms, and possibly other respiratory disorders, by inhibiting viral growth and the secretion of pro-inflammatory cytokines.
Asunto(s)
Antivirales/farmacología , Citocinas/antagonistas & inhibidores , Echinacea/química , Factores Inmunológicos/farmacología , Extractos Vegetales/farmacología , Virus/inmunología , Línea Celular , Citocinas/biosíntesis , Células Epiteliales/inmunología , Células Epiteliales/virología , Humanos , Mucosa Respiratoria/citologíaRESUMEN
Echinacea purpurea extracts are used in the production of standardized herbal medicines for the prevention and treatment of upper respiratory infections. Unsaturated N-alkylamide lipids, the main constituent of E. purpurea and E. angustifolia preparations capable of activating the cannabinoid receptor type-2 (CB2) have been suggested to play a role as potential anti-inflammatory and immune-modulatory principles. Here we show that ethanolic E. purpurea radix and herba extracts produce synergistic pharmacological effects on the endocannabinoid system in vitro. Superadditive action of N-alkylamide combinations was seen at the level of intracellular calcium release as a function of CB2 receptor activation. Likewise, synergism of the radix and herba tinctures was observed in experiments measuring LPS-stimulated cytokine expression from human PBMCs. While the expression of the anti-inflammatory cytokine IL-10 was significantly superstimulated, the expression of the pro-inflammatory TNF-alpha protein was inhibited more strongly upon combination of the extracts. We show that N-alkylamides act in concert and exert pleiotropic effects modulating the endocannabinoid system by simultaneously targeting the CB2 receptor, endocannabinoid transport and degradation.
Asunto(s)
Echinacea , Neutrófilos/efectos de los fármacos , Fitoterapia , Extractos Vegetales/uso terapéutico , Alcamidas Poliinsaturadas/uso terapéutico , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Calcio/metabolismo , Moduladores de Receptores de Cannabinoides/inmunología , Moduladores de Receptores de Cannabinoides/metabolismo , Cromatografía Líquida de Alta Presión , Sinergismo Farmacológico , Células HL-60 , Humanos , Interleucina-10/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/patología , Extractos Vegetales/análisis , Raíces de Plantas , Alcamidas Poliinsaturadas/química , Transporte de Proteínas , Ensayo de Unión Radioligante , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB1/inmunología , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/genética , Receptor Cannabinoide CB2/inmunología , Receptor Cannabinoide CB2/metabolismo , Infecciones del Sistema Respiratorio/inmunología , Transfección , Factor de Necrosis Tumoral alfa/metabolismo , Células U937RESUMEN
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.
Asunto(s)
Echinacea , Extractos Vegetales/farmacocinética , Alcamidas Poliinsaturadas/farmacocinética , Administración Oral , Adulto , Disponibilidad Biológica , Femenino , Humanos , Masculino , Fitoterapia , Extractos Vegetales/administración & dosificación , Alcamidas Poliinsaturadas/administración & dosificaciónRESUMEN
BACKGROUND: The interaction of the T-cell molecule PD-1 (programmed death-1) with its ligands PD-L1 and PD-L2 represents a known mechanism of T-cell inhibition. PD-1 is homologous to CD28 while the PD-1 ligands share homology with the B7 family of co-stimulatory molecules. METHODS: We have studied surface expression and transcript levels of PD-L1 and PD-L2 on murine renal tubular epithelial cells (TEC) by flow cytometric analysis and reverse transcription-polymerase chain reaction. Western blot analysis was used to confirm protein expression of PD-L1. We also tested the functional role of PD-L1 and PD-1 in antigen presentation. Furthermore, we stained mouse kidney transplants with rejection for the expression of the PD-1 ligands. RESULTS: We found that PD-L1 but not PD-L2 was weakly expressed on unstimulated TEC. Upon stimulation with IFN-gamma, a dose-dependent upregulation of PD-L1 expression was observed. Blockade of the PD-L1/PD-1 pathway with monoclonal antibodies in antigen presentation assays uncovered an inhibitory role of this ligand system in Th1 and Th2 cell activation. Staining for PD-L1 was strong in proximal and distal tubules in mouse kidney transplants with rejection, whereas staining of normal kidneys and syngenic mouse kidney transplants did not reveal PD-L1 expression. PD-L2 was not observed in normal or rejected mouse kidneys. CONCLUSIONS: These data demonstrate that PD-L1 is an inducible renal tubular epithelial antigen that negatively regulates T-cell responses elicited by IFN-gamma-stimulated TEC. We speculate that the PD-1/PD-L1 pathway may play a role in protecting the epithelium from immune-mediated tubulointerstitial injury.