RESUMO
BACKGROUND: Effects of re-supplementation of a cholesterol-enriched diet (CEDrs) on size, cholesterol content and morphology of already existing plaques are not known to date. METHODS: A group of rabbits received standard chow (SC) for 6 weeks ("negative control"; for plasma lipid measurements only). Group I-IV received 2% CED (induction) for 6 weeks; thereafter, groups II-IV have been fed a SC (= cholesterol withdrawal) for 68 weeks. Afterwards, feeding of groups II-IV was continued as follows: Group II - 10 weeks SC, group III - 4 weeks 0.5% CED (~re-supplementation), afterwards 6 weeks SC (~withdrawal again); group IV - 4 weeks 0.5% CED (re-supplementation) + atorvastatin (2.5 mg/kg body weight/day), afterwards 6 weeks SC (~withdrawal again) + atorvastatin. Plasma lipids, but also plaque size, morphology and cholesterol contents of thoracic aortas were quantified. RESULTS: After CEDrs, plasma cholesterol levels were increased. However, after withdrawal of CEDrs, plasma cholesterol levels decreased, whereas the cholesterol content of the thoracic aorta was increased in comparison with the group without CEDrs. Plaque size remained unaffected. Atorvastatin application did not change plasma cholesterol level, cholesterol content of the thoracic aorta and plaque size in comparison with the group without drug treatment. However, atorvastatin treatment increased the density of macrophages (MΦ) compared with the group without treatment, with a significant correlation between densities of MΦ (Mac-1+) and apoptotic (TUNEL+; TP53+), antigen-presenting (HLA-DR+) or oxidatively stressed (SOD2+) cells. CONCLUSIONS: In rabbits with already existing plaques, CEDrs affects plaque morphology and cellular composition, but not plaque size. Despite missing effects on plasma cholesterol levels, cholesterol content of the thoracic aorta and size of already existing atherosclerotic plaques, atorvastatin treatment transforms the already existing lesions to a more active form, which may accelerate the remodelling to a more stable plaque.
Assuntos
Aorta Torácica/efeitos dos fármacos , Doenças da Aorta/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Atorvastatina/farmacologia , Colesterol na Dieta , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Placa Aterosclerótica , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Modelos Animais de Doenças , Masculino , Coelhos , Fatores de TempoRESUMO
Willow bark extracts are used for the treatment of fever, pain and inflammation. Recent clinical and pharmacological research revealed that not only the salicylic alcohol derivatives, but also the polyphenols significantly contribute to these effects. Quantitative analysis of the European Pharmacopoeia still focuses on the determination of the salicylic alcohol derivatives. The objective of the present study was the development of an effective quantification method for the determination of as many flavanone and chalcone glycosides as possible in Salix purpurea and other Salix species as well as commercial preparations thereof. As Salix species contain a diverse spectrum of the glycosidated flavanones naringenin, eriodictyol, and the chalcone chalconaringenin, a subsequent acidic and enzymatic hydrolysis was developed to yield naringenin and eriodictyol as aglycones, which were quantified by HPLC. The 5-O-glucosides were cleaved with 11.5% TFA before subsequent hydrolysis of the 7-O-glucosides with an almond ß-glucosidase at pH 6-7. The method was validated with regard to LOD, LOQ, intraday and interday precision, accuracy, stability, recovery, time of hydrolysis, robustness and applicability to extracts. All 5-O- and 7-O-glucosides of naringenin, eriodictyol and chalconaringenin were completely hydrolysed and converted to naringenin and eriodictyol. The LOD of the HPLC method was 0.77 µM of naringenin and 0.45 µM of eriodictyol. The LOQ was 2.34 µM of naringenin and 1.35 µM for eriodictyol. The method is robust with regard to sample weight, but susceptible concerning enzyme deterioration. The developed method is applicable to the determination of flavanone and chalcone glycosides in willow bark and corresponding preparations.
Assuntos
Chalconas/análise , Flavonas/análise , Casca de Planta/química , Salix/química , Cromatografia Líquida de Alta Pressão , Indicadores e Reagentes , Limite de Detecção , Padrões de Referência , Reprodutibilidade dos TestesRESUMO
BACKGROUND: STW 5 is a combination of nine medicinal herbal extracts and used to treat functional gastrointestinal disorders including functional dyspepsia. It has a region-specific effect by relaxing the proximal and contracting the distal stomach. The research combination STW 5-II (Iberogast® Advance) lacks three herbal extracts but seems clinically as effective as STW 5. However, the action of STW 5-II on gastric motility is unknown. METHODS: In vitro circular and longitudinal muscle tone and contractility were recorded from guinea pig gastric fundus and antrum with isometric force transducers. KEY RESULTS: STW 5-II decreased concentration-dependently (64-512 µg/ml) the tone of circular and longitudinal muscle strips from the fundus. In contrast, STW 5-II increased concentration-dependently contraction amplitude in antral circular and longitudinal muscle. The effects were region-dependent but comparable in the two muscle layers. Application of 512 µg STW 5 or STW 5-II revealed comparable effects in the fundus and antrum circular and longitudinal muscle strips. CONCLUSIONS AND INTERFERENCES: STW 5-II had a region-specific effect and relaxed the proximal stomach but increased the contractility in the antrum. It was as effective as STW 5 which may explain its comparable clinical effects in treating functional dyspepsia. Impaired accommodation may be normalized through relaxation of the fundus, while the motility-promoting effects leading to an increase in antral motility may activate the gastric pump.
Assuntos
Contração Muscular/efeitos dos fármacos , Tono Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Extratos Vegetais/farmacologia , Estômago/efeitos dos fármacos , Animais , Cobaias , MasculinoRESUMO
Oxidizability of isolated low density lipoprotein (LDL) and total antioxidative capacity of plasma were measured in rabbits fed for 6 weeks a cholesterol-rich diet and for further 34 weeks a normal diet. Whereas the time to induce copper ion-mediated lipid peroxidation in LDL was prolonged during hypercholesterolemia, total antioxidative capacity as determined by a radical-trapping assay was increased at 6 weeks, but decreased during the time when the plasma cholesterol levels declined slowly to normal. Since aortic plaque progression was continued also during the first 15 weeks of normal diet, increased atherogenicity of hypercholesterolemia might be better reflected by the antioxidant capacity of plasma rather than by oxidation of isolated LDL.
Assuntos
Antioxidantes/metabolismo , Colesterol na Dieta/metabolismo , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Lipoproteínas LDL/metabolismo , Plasma/metabolismo , Túnica Íntima/metabolismo , Animais , Antioxidantes/farmacologia , Arteriosclerose/etiologia , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Colesterol na Dieta/efeitos adversos , Técnicas de Cultura , Modelos Animais de Doenças , Masculino , Oxirredução , Coelhos , Valores de Referência , Túnica Íntima/patologiaRESUMO
Functional dyspepsia (FD) is amongst the most common functional gastrointestinal disorders. Symptomatic treatment includes the use of herbal preparations whose effects on gastric motility are unclear. The present study aimed at investigating the effects of STW 5 (Iberogast), a fixed combination of hydroethanolic herbal extracts, on gastric motility in vitro. Muscle strips from guinea-pig gastric fundus, corpus and antrum were set up in organ baths either in circular or longitudinal orientation. Addition of ethanol-free STW 5 to the organ baths (32-512 microg mL(-1)) dose-dependently evoked a sustained and reversible relaxation of circular and longitudinal fundus and corpus muscle strips without changes in phasic activity. In contrast, antral muscle strips responded to STW 5 with a significant increase in the contractile force of phasic contractions without changes in tone. All effects were resistant to tetrodotoxin (0.5 micromol L(-1)), atropine (1 micromol L(-1)), omega-conotoxin GVIA (0.5 micromol L(-1)), capsaicin (1 micromol L(-1)) or L-NAME (100 micromol L(-1)), suggesting that neither nerves nor nitric oxide pathways were involved. These data demonstrate that STW 5 profoundly alters gastric motility in a region-specific but not layer-specific manner and thus implicates Iberogast in the treatment of FD patients suffering from motility disorders with impaired fundus accommodation and/or antral hypomotility.
Assuntos
Motilidade Gastrointestinal/efeitos dos fármacos , Extratos Vegetais/farmacologia , Estômago/efeitos dos fármacos , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Capsaicina/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Feminino , Cobaias , Masculino , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Técnicas de Cultura de Órgãos , Bloqueadores dos Canais de Sódio/farmacologia , Estômago/fisiologiaRESUMO
INTRODUCTION: Visceral hypersensitivity in the upper gastrointestinal tract is a potential pathomechanism of functional dyspepsia. The herbal preparation STW 5 (Iberogast) provides symptomatic relief for this condition. We aimed to investigate whether STW 5 modulates intestinal afferent sensitivity. METHODS: The herbal preparation STW 5 or vehicle (30.8% ethanol) were administered orally in male Wister rats. After 2 h animals were anaesthetized and extracellular multi-unit intestinal afferent nerve recordings were secured from the neurovascular bundle of the mesentery in the proximal jejunum. Afferent discharge to ramp distension of the intestinal loop (0-60 cm H2O) and dose-response curves for i.v. bradykinin (10, 20 and 40 microg kg(-1)) and 5-HT (5, 10, 20 and 40 microg kg(-1)) were recorded. RESULTS: Baseline discharge was not different between the vehicle and treatment group. Ramp distension was followed by a pressure dependent increase in afferent nerve discharge that was decreased following STW 5 pretreatment for all distending pressures reaching 147 +/- 8 impulses s(-1) (imp s(-1)) following STW 5 vs 171 +/- 5 imp s(-1) following vehicle at 60 cm H2O (mean +/- SEM; P < 0.05). A dose-dependent increase in afferent discharge was observed for 5-HT and bradykinin. Following STW 5 pretreatment, afferent discharge was reduced at all doses of 5-HT to 110 +/- 5 at the maximum dose after STW 5 and 128 +/- 3 imp s(-1) in controls (all P < 0.05). Afferent discharge to bradykinin was similarly reduced at 20 and 40 microg kg(-1) but not at 10 microg kg(-1) of bradykinin with a discharge rate of 176 +/- 7 imp s(-1) following STW 5 and 200 +/- 6 imp s(-1) in controls at 40 microg kg(-1) (P < 0.05). CONCLUSIONS: The preparation STW 5 reduces intestinal afferent nerve discharge following chemical and mechanical stimuli, while baseline discharge is not affected. This effect of STW 5 on afferent sensitivity may contribute to its therapeutic relief of dyspeptic symptoms.
Assuntos
Intestino Delgado/efeitos dos fármacos , Intestino Delgado/inervação , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/fisiologia , Extratos Vegetais/farmacologia , Animais , Masculino , Ratos , Ratos WistarRESUMO
INTRODUCTION: Several conventional pharmaceuticals like non-steroidal anti-inflammatory drugs (NSAIDS) or selective cyclooxygenase-2 (COX-2) inhibitors have been demonstrated to exert anti-proliferative effects and to induce apoptosis in a variety of cell lines, e.g. colon, stomach, or prostate cancer cells. STW 5 (Iberogast(®)), a combination of nine plant extracts, is widely used in the treatment of gastrointestinal disorders, including functional dyspepsia and irritable bowel syndrome for which the involvement of an inflammatory etiology is discussed. To investigate the possible anti-proliferative effects, STW 5 and its components have been tested by using the colon-carcinoma cell line HT-29. The analyses have been performed in comparison to acetylsalicylic acid (ASA) and diclofenac (Diclo), which are well-known to reduce colon carcinoma risk. RESULTS: STW 5 showed significant anti-proliferative and pro-apoptotic effects on HT-29 cancer cells, similar to NSAIDs under test. However, using the LDH assay, STW 5 revealed significantly lower cytotoxicity than Diclo at same concentrations. In contrast to NSAIDs, STW 5 induced COX-1/COX-2, caspase-3 and Bax mRNA expressions in HT-29 and blocked LPS mediated translocation of the NF-κB p65 from the cytoplasm into the nucleus in PMA-differentiated THP-1 macrophages. These effects might be relevant, e.g. for prevention of undesirable side effects like gastric erosions. CONCLUSION: Our data suggest that the pro-apoptotic effect of STW 5 on HT-29 cells is involving multiple targets and is possibly due to an activation of the caspase cascade via mitochondrial destabilization. Active concentrations of STW 5 are, in relation to therapeutic doses, comparable to those of ASA and Diclo, suggesting a similar favorable effect on colon carcinoma risk.
Assuntos
Adenocarcinoma/tratamento farmacológico , Anti-Inflamatórios não Esteroides/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Inibidores de Ciclo-Oxigenase/farmacologia , Extratos Vegetais/farmacologia , Apoptose/efeitos dos fármacos , Aspirina/farmacologia , Caspase 3/efeitos dos fármacos , Caspase 3/genética , Núcleo Celular/metabolismo , Colo/efeitos dos fármacos , Ciclo-Oxigenase 1/efeitos dos fármacos , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Citoplasma/metabolismo , Diclofenaco/farmacologia , Células HT29 , Humanos , Macrófagos/metabolismo , NF-kappa B/metabolismo , Transporte Proteico/efeitos dos fármacos , Proteína X Associada a bcl-2/efeitos dos fármacos , Proteína X Associada a bcl-2/genéticaRESUMO
STUDY OBJECTIVE: Efficacy and safety of willow bark extract for pain reduction in patients suffering from musculoskeletal disorders (MSD) has been shown in clinical short term trials. Therefore this observational study over 6 months should evaluate patterns of treatments like mono- or combinations therapy, dosage and safety during long-term treatment under pragmatic conditions with the aqueous willow bark extract STW 33-I, (Proaktiv(®); drug-extract-ratio 16-23:1). PATIENTS AND METHODS: The patients were treated with STW 33-I; comedication with other NSAIDs and opioids was allowed. An extensive case report form including pain questionnaires and patient diary was used for outcome evaluation. RESULTS: Four hundred and thirty-six patients with rheumatic pain mainly due to osteoarthritis (56.2%) and back pain (59.9%) were included. During the study the mean reductions from baseline value 58.4±22.6-31.8±22.5 after 24 weeks in the pain intensity scale (VAS 0-100mm) were significant even after 3 weeks with a reduction by 26 mm (45.6% of the baseline value) at the end of the study. The relative reductions of the weekly means of the daily patient self-rated scores of the pain (6-point Likert-scales) were between 33% and 44% of the baseline values during the course of the study. We present results of subgroups according their analgetic/antiphlogistic comedication. The distribution and specification of the main adverse events and the ratings of the treatment showed a good tolerability. No relevant drug interactions were reported. CONCLUSION: These data suggest that STW 33-I can be used as a basic treatment in the long-term therapy of painful musculoskeletal disorders and that it can be combined with NSAIDs and opioids if necessary.
Assuntos
Analgésicos/uso terapêutico , Antirreumáticos/uso terapêutico , Dor nas Costas/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Salix/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Casca de Planta/química , Pesquisa Qualitativa , Índice de Gravidade de Doença , Inquéritos e Questionários , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: A quantified aqueous Willow bark extract (STW 33-I) was tested concerning its inhibitory activity on TNF-α induced ICAM-1 expression in human microvascular endothelial cells (HMEC-1) and further fractionated to isolate the active compounds. RESULTS: At 50 µg/ml the extract, which had been prepared from Salix purpurea L., decreased ICAM-1 expression to 40% compared to control cells without showing cytotoxic effects. Further liquid-liquid partition revealed an ethyl acetate phase with potent reduction of ICAM-1 expression to 40% at 8 µg/ml. This fraction was comprehensively characterised by the isolation of flavanone aglyca and their corresponding glycosides, chalcone glycosides, salicin derivatives, cyclohexane-1,2-diol glycosides, catechol and trans-p-coumaric acid. All compounds were investigated for their activity on TNF-α induced ICAM-1 expression. The flavonoid and chalcone glycosides were not active up to 50 µM, whereas catechol and eriodictyol at the same concentration showed a significant reduction of ICAM-1 expression to 50% of control. Interestingly, other isolated flavanone aglyca like taxifolin, dihydrokaempferol and naringenin showed only weak or moderate inhibitory activity. Eriodictyol was a minor compound in the extract, whereas the catechol content in the extract (without excipients) reached 2.3%, determined by HPLC. One of the isolated cyclohexan-1,2-diol glucosides, 6'-O-4-hydroxybenzoyl-grandidentin, is a new natural compound. CONCLUSION: As catechol is quantitatively important in Willow bark extracts it can be concluded from the in vitro data that not only flavonoids and salicin derivatives, but also catechol can probably contribute to the anti-inflammatory activity of Willow bark extracts.
Assuntos
Catecóis/farmacologia , Células Endoteliais/efeitos dos fármacos , Flavonoides/farmacologia , Molécula 1 de Adesão Intercelular/metabolismo , Casca de Planta/química , Extratos Vegetais/farmacologia , Acetatos/química , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Sobrevivência Celular , Fracionamento Químico/instrumentação , Fracionamento Químico/métodos , Cromatografia Líquida de Alta Pressão , Ácidos Cumáricos/química , Células Endoteliais/metabolismo , Flavanonas/farmacologia , Humanos , Estrutura Molecular , Extratos Vegetais/química , Quercetina/análogos & derivados , Quercetina/farmacologia , Salix/química , Fator de Necrose Tumoral alfa/efeitos adversosRESUMO
BACKGROUND AND OBJECTIVE: Gene expression profiles of Sprague-Dawley (SD) rats treated with a standardized willow bark extract (WB), its salicin rich ethanol fraction (EtOH-FR) or the tricyclic antidepressant imipramine were evaluated for their potential to induce adverse events. Treatments had shown antidepressant-like effects. METHODS: Gene expression profiles (Agilent Whole Genome Array, n=4/group) obtained from the peripheral blood of male SD rats treated with WB (STW 33-I), EtOH-FR (30 mg/kg bw) or imipramine (20 mg/kg bw) were analysed comparatively by the Ingenuity Systems Programme, which allows to conduct model calculations of thresholds for theoretical potential adverse events (AE). RESULTS: The number of genes regulated by the three treatments were 1673 (WB), 117 (EtOH-FR) and 1733 (imipramine). The three treatments related to 47 disease clusters. The WB extract reached the threshold for a potential AE in one disease cluster (cardiac hypertrophy), whereas the EtOH-FR exceeded the threshold in 5 disease clusters (cardiac arteriopathy and stenosis, glomerular injury, pulmonary hypertension, alkaline phosphatase levels â). Imipramine treatment hit 13 disease clusters: tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, precipitation of congestive heart failure; urinary retention, altered liver functions. Those correspond to known potential adverse events. Glomerular injury and altered liver functions are part of the side effect profile of salicylic acid derivatives in agreement with the findings for the salicin rich EtOH-FR. CONCLUSION: There is no linear relationship between the number of constituents of a drug (preparation) and the number of different targets hit in a biological system on the gene expression level. Therefore, the number of genetic targets in a biological system does not necessarily increase with the complexity of the treatment corresponding to the non-linear behaviour of biological systems. Regarding gene expression levels AE of single treatments are not necessarily additive in combination treatments. The applied method appears to be an interesting screening tool for the prediction of potential AE. The phenomena that imipramine crossed the potential threshold for AEs several times whereas the WB extract did reach the threshold level only once, however not backed by clinical data for this AE, deserves to be further investigated. It questions the commonly assumed principle that substances with low number or without AE will have a poor efficacy.
Assuntos
Antidepressivos Tricíclicos/efeitos adversos , Perfilação da Expressão Gênica/métodos , Cardiopatias/induzido quimicamente , Imipramina/efeitos adversos , Salicilatos/efeitos adversos , Animais , Antidepressivos Tricíclicos/química , Álcoois Benzílicos/efeitos adversos , Álcoois Benzílicos/química , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Etanol/química , Regulação da Expressão Gênica/efeitos dos fármacos , Glucosídeos/efeitos adversos , Glucosídeos/química , Cardiopatias/tratamento farmacológico , Cardiopatias/patologia , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/patologia , Imipramina/química , Masculino , Nefrite/induzido quimicamente , Nefrite/patologia , Fitoterapia/efeitos adversos , Casca de Planta/efeitos adversos , Casca de Planta/química , Extratos Vegetais/efeitos adversos , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , Salicilatos/químicaRESUMO
Inflammatory processes are increasingly recognised to contribute to neurological and neuropsychatric disorders such as depression. Thus we investigated whether a standardized willow bark preparation (WB) which contains among other constituents salicin, the forerunner of non-steroidal antiphlogistic drugs, would have an effect in a standard model of depression, the forced swimming test (FST), compared to the antidepressant imipramine. Studies were accompanied by gene expression analyses. In order to allocate potential effects to the different constituents of WB, fractions of the extract with different compositions of salicyl alcohol derivative and polyphenols were also investigated. Male Sprague Dawley rats (n=12/group) were treated for 14 days (p.o.) with the WB preparation STW 33-I (group A) and its fractions (FR) (groups FR-B to E) in concentrations of 30 mg/kg. The FRs were characterized by a high content of flavone and chalcone glycosides (FR-B), flavonoid glycosides and salicyl alcohol derivatives (FR-C), salicin and related salicyl alcohol derivatives (FR-D) and proanthocyanidines (FR-E). The tricyclic antidepressant imipramine (20 mg/kg) (F) was used as positive control. The FST was performed on day 15. The cumulative immobility time was significantly (p<0.05) reduced in group A (36%), group FR-D (44%) and by imipramine (16%) compared to untreated controls. RNA was isolated from peripheral blood. RNA samples (group A, group FR-D, and imipramine) were further analysed by rat whole genome microarray (Agilent) in comparison to untreated controls. Quantitative PCR for selected genes was performed. Genes (>2 fold, p<0.01), affected by WB and/or FR-D and imipramine, included both inflammatory (e.g. IL-3, IL-10) and neurologically relevant targets. Common genes regulated by WB, FR-D and imipramine were GRIA 2 ↓, SRP54 ↓, CYP26B ↓, DNM1L ↑ and KITLG ↓. In addition, the hippocampus of rats treated (27 d) with WB (15-60 mg/kg WB) or imipramine (15 mg/kg bw) showed a slower serotonin turnover (5-hydroxyindol acetic acid/serotonin (p<0.05)) depending on the dosage. Thus WB (30 mg/kg), its ethanolic fraction rich in salicyl alcohol derivatives (FR-D) (30 mg/kg) and imipramine, by being effective in the FST, modulated known and new targets relevant for neuro- and immunofunctions in rats. These findings contribute to our understanding of the link between inflammation and neurological functions and may also support the scope for the development of co-medications from salicylate-containing phytopharmaceuticals as multicomponent mixtures with single component synthetic drugs.
Assuntos
Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Depressão , Imipramina/farmacologia , Inflamação , Ácido Salicílico/farmacologia , Salix/química , Animais , Antidepressivos/uso terapêutico , Antidepressivos Tricíclicos/farmacologia , Antidepressivos Tricíclicos/uso terapêutico , Álcoois Benzílicos/análise , Álcoois Benzílicos/farmacologia , Álcoois Benzílicos/uso terapêutico , Encéfalo/imunologia , Encéfalo/metabolismo , Citocinas/sangue , Depressão/tratamento farmacológico , Depressão/imunologia , Depressão/metabolismo , Sistemas de Liberação de Medicamentos , Flavonoides/análise , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Expressão Gênica , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Imipramina/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Masculino , Análise em Microsséries , Fitoterapia , Casca de Planta , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Ácido Salicílico/uso terapêutico , Serotonina/metabolismo , NataçãoRESUMO
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-alpha 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 (10mg/kg, p.o.) and SJW (125-750mg/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-alpha 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.
Assuntos
Hypericum , Sistemas Neurossecretores/fisiologia , Estresse Oxidativo/fisiologia , Extratos Vegetais/uso terapêutico , Estresse Psicológico/imunologia , Estresse Psicológico/metabolismo , Animais , Masculino , Sistemas Neurossecretores/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Restrição Física , Estresse Psicológico/tratamento farmacológicoRESUMO
INTRODUCTION: Willow bark extract is frequently used in the treatment of painful rheumatological diseases, such as arthritis and back pain. Its effect has been attributed to its main component salicin, but pharmacological studies have shown that the clinical efficacy of the willow bark extract cannot be explained by its salicin content alone. Therefore different modes of action have been suggested for the anti-inflammatory effect of willow bark extract. Here, we report in vitro data revelling the effect and mode of action of the aqueous willow bark extract STW 33-I as well as a water-soluble fraction (fraction E [Fr E]) in comparison with well-known non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin (ASA) and diclofenac (Diclo) on pro-inflammatorily activated human monocytes and differentiated macrophages. RESULTS: STW 33-I and the water-soluble Fr E showed concentration-dependent and significant anti-inflammatory effects in lipopolysaccharide-activated monocytes. Both inhibited the intracellular protein expression of tumour necrosis factor-alpha (TNFα) as well as the mRNA expression of TNFα and cyclooxygenase 2 (COX-2), and the release of nitric oxide (NO). In addition, apoptosis of pro-inflammatorily activated monocytes was induced. Furthermore, treatment of activated macrophages with STW 33-I inhibited the nuclear translocation of the p65 subunit of the nuclear transcription factor-kappa B (NF-κB p65). CONCLUSIONS: The present in vitro investigations suggest a significant anti-inflammatory activity of willow bark water extract STW 33-1 and of its water-soluble fraction by inhibiting pro-inflammatory cytokines (TNFα), COX-2 and nuclear translocation of the transcription factor NF-κB in pro-inflammatorily activated monocytes. Our results provide further evidence for the therapeutic use of STW 33-I in inflammation-related disorders.
Assuntos
Anti-Inflamatórios/farmacologia , Álcoois Benzílicos/farmacologia , Flavonoides/farmacologia , Glucosídeos/farmacologia , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Salix/química , Anti-Inflamatórios não Esteroides , Apoptose/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Lipopolissacarídeos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Casca de Planta , Polifenóis , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Herbal preparations are evolving as promising agents for the treatment of functional gastrointestinal disorders which are considered to be secondary to visceral hypersensitivity. We aimed to determine whether a new combination of six herbal extracts reduces the sensitivity of intestinal afferents in rat. Male Wistar rats (250-350 g, n = 6 per group) were gavaged with either vehicle or 2.5, 5 or 10 mL kg(-1) of STW 5-II, a herbal preparation which contains six extracts. Two hours later, animals were anaesthetized and extracellular multi-unit mesenteric afferent nerve recordings were obtained in the proximal jejunum in vivo. Afferent discharge to 5-hydroxy-tryptamine (5-HT) (5, 10, 20 and 40 microg kg(-1), i.v.), luminal distension (0-60 mmHg) and bradykinin (BK) (15, 30 and 60 microg kg(-1), i.v.) was recorded. At baseline, spontaneous afferent discharge was not different following pretreatment with the various doses of STW 5-II compared with vehicle. The pressure-dependent increase in afferent discharge to intraluminal ramp distension and the dose-dependent increase in afferent firing following 5-HT were also uninfluenced by STW 5-II pretreatment. In contrast, the afferent nerve responses to 15, 30 and 60 microg kg(-1) of BK were reduced following 10 mL kg(-1) STW 5-II with peaks at 106 +/- 19, 153 +/- 22 and 156 +/- 25 imp s(-1) compared with 160 +/- 15, 228 +/- 14 and 220 +/- 16 imp s(-1) following vehicle pretreatment (mean +/- SEM, P < 0.05). Intestinal afferent sensitivity to BK which plays a prime role in nociception was reduced following STW 5-II. Thus, STW 5-II may be of therapeutic use for conditions that involve neuronal hypersensitivity and the release of BK in the intestine.
Assuntos
Bradicinina/metabolismo , Intestino Delgado/efeitos dos fármacos , Preparações de Plantas/farmacologia , Fibras Aferentes Viscerais/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Eletrofisiologia , Intestino Delgado/inervação , Masculino , Mesentério/inervação , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Functional gastro-intestinal diseases as the irritable bowel syndrome are very common in the population and are characterized by a broad spectrum of symptoms which mostly are related to spastic or paralytic intestinal function without defined histopathological changes of the tissue. Due to the multifactorial pathogenesis a multifactorial therapy with multi-target action seems to be reasonable. STW 5 (Iberogast), its constituent herbal extracts and some isolated compounds were used in an in vitro model provided by intestinal samples from guinea pig in order to test their activity on histamine-induced contractions and spontaneous motility, respectively. For comparison the known spasmolyticum papaverine was used. The results show that the lytic effect of the phytotherapeuticum on histamine-induced contraction represents additively the actions of the different components and corresponds to approx. 10 microM of papaverine. Spontaneous peristaltic motion was differently modulated by the various constituent extracts. The experiments with silibinin, glycyrrhicine, chelidonine, and protopine showed that the effects of the extracts were not comparable to those of the respective chemical constituents.
Assuntos
Intestinos/efeitos dos fármacos , Parassimpatolíticos/farmacologia , Peristaltismo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Cobaias , Técnicas In Vitro , MasculinoRESUMO
A combination of ethanolic extracts from nine medicinal plants is successfully used in STW 5 (Iberogast((R))) for treatment of gastrointestinal disorders. To elucidate possible modes of action, the focus of this study is on antioxidant properties of the phytomedicine STW 5. In fact, functional gastrointestinal diseases, such as non-ulcer dyspepsia (NUD) and irritable bowel syndrome, are often initiated by or correlated to inflammatory processes, where oxidants such as reactive oxygen species (ROS) play a crucial role. Prominent in vivo sources of ROS generation are represented by the enzymes xanthine oxidase (XOD) or myeloperoxidase (MPO). Applying these enzymes in models in vitro, we show that STW 5 and its components possess strong antioxidant activities. Depending on the model investigated, even pro-oxidant activities of single components of STW 5 could be observed. Interestingly, these effects were absent in STW 5, indicating cooperation between the components. Moreover, if one of the component extracts of STW 5 is omitted, the antioxidant activity is reduced. Thus we conclude that all the single extracts combined in STW 5 are of importance for the therapeutic effect, working in concert. The component of STW 5 performing best in vitro differed with the model investigated, respectively, with ROS and ROS generators. In the XOD system, the extracts of lemon balm leaf and peppermint leaf showed the best antioxidant result, whereas concerning MPO driven chlorination reactions, bitter candy tuft extract was the most efficient antioxidant. Best protection against peroxynitrite induced oxidation of methionine like sulfur-compounds exhibited the STW 5 components lemon balm leaf, Matricaria flower and peppermint leaf.
Assuntos
Anti-Inflamatórios/farmacologia , Sequestradores de Radicais Livres/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Anti-Inflamatórios/química , Sequestradores de Radicais Livres/química , Metionina/análogos & derivados , Metionina/efeitos dos fármacos , Peroxidase/efeitos dos fármacos , Xantina Oxidase/efeitos dos fármacosRESUMO
STW 5 (Iberogast) is a fixed combination of nine medicinal plant extracts effective in the treatment of functional dyspepsia and irritable bowel syndrome. The effects of STW 5, a combination of Iberis amara fresh plant extract, and other eight plant extracts as well as single extract components including extracts from Menthae piperitae folium, Matricariae flos and Liquiritiae radix, were assayed in guinea pig ileum with or without stimulation with acetylcholine or histamine, in order to find a possible effect on the contractility of intestinal smooth muscle. STW 5 decreased acetylcholine- and histamine-induced contraction of guinea pig ileum. This was also true for extracts of Menthae piperitae folium, Matricariae flos and L. radix. Extract from I. amara, however, showed no spasmolytic action; in contrary, it increased the basal resting tone and contraction of atonic ileal segments. This was also true when STW 5 was employed. A spasmolytic action of STW 5 could also be observed in duodenum, jejunum and colon. These data are the first to show not only the spasmolytic effects of STW 5 and its component extracts in intestinal muscle but also the tonicising effects of STW 5 through its component Iberis amara extract in relaxed intestinal muscle. Thus, pharmacological evidence suggests a dual-action principle and may explain, at least in part, the clinically observed therapeutic efficacy of STW 5 (Iberogast) in both hypotonic and spastic dysmotility symptoms of functional dyspepsia and irritable bowel syndrome.
Assuntos
Intestinos/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Parassimpatolíticos/farmacologia , Extratos Vegetais/farmacologia , Animais , Cobaias , Técnicas In Vitro , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Since inflammation is a common mechanism of many gastrointestinal diseases, reactive oxygen metabolites may play an important role in their pathophysiology. Therefore it is interesting to know, whether phytopharmaceuticals known to modulate gastrointestinal motor function reveal also antioxidative properties. We tested STW 5 (Iberogast), its constituent nine different plant extracts, and some isolated compounds which are present in STW 5 for characterizing their antioxidative and radical quenching activities. The test assays consisted in pure chemical and complex cellular systems in which different types of reactive species were produced. Quantification of the effects was based on chemiluminescence reactions. The results show that all extracts contribute to the effect of the complete remedy STW 5, in the chemical systems in a strongly additive manner, in the cellular systems in a supraadditive manner. The largest contributions resulted from the extracts from peppermint and melissa leaves. Comparison of effects from isolated phytochemical compounds from the extracts with that of the extracts itself shows that usually the extract is more effective than the monosubstance which indicates also the synergism within the whole plant extracts. This means that the plant extracts present in STW 5 provide strong radical quenching activities that could also be involved in the therapeutic gastrointestinal actions.
Assuntos
Sequestradores de Radicais Livres/farmacologia , Extratos Vegetais/farmacologia , Melissa/química , Mentha piperita/química , Extratos Vegetais/química , Folhas de Planta/químicaRESUMO
To correlate the pharmacological effects of the fixed herbal combination STW 5 (Iberogast) containing nine extract components with its confirmed clinical efficacy, ex vivo/in vitro absorption tests were performed. For the investigation, the everted gut sac technique and, in a pilot study, the Caco-2-cell model were used. The absorption rate of the extracts was determined by measuring characteristic marker substances of each of the individual extracts using HPLC or GC techniques. The results allow us to conclude that the investigated substances from STW 5 possess a good bioavailability, which is in accordance with the rapid onset of the therapeutic efficacy and explains its known pharmacological effects and clinical efficacy in terms of multiple drug action and multi-target therapy, respectively.