The efficacy of goshuyuto,a typical Kampo (Japanese herbal medicine) formula,in preventing episodes of headache

ABSTRACT

Objective: The purpose of this clinical trial was to assess the efficacy of goshuyuto, a typical Kampo formula, in preventing episodes of headache in chronic headache patients.

Research design and methods: Because the treatment target of a Kampo formula is decided on a basis different to that of Western medicine, we first selected patients belonging to a subgroup that responded to goshuyuto before conducting the usual randomized controlled trial. During stage 1, the subjects were instructed to orally consume goshuyuto for 4 weeks. Only those subjects judged as responders advanced to stage 2, during which a double-blind, randomized, placebo-controlled study was conducted. The subjects consumed the same dose of goshuyuto or placebo for 12 weeks.

Results: Of the 91 subjects enrolled in stage 1, 60 were judged as responders. Of these, 53 advanced to stage 2; 28 were assigned to the goshuyuto group and 25 to the placebo group. The decrease in the number of days on which headache episodes occurred was greater in the goshuyuto group than in the placebo group (2.6 ± 3.7 vs. 0.3 ± 4.0 days, p = 0.034); no difference was observed with regard to the reduction in the frequency of consuming reliever medications (2.2 ± 4.0 vs. 1.4 ± 8.2, p = 0.672). Improvement in the associated symptoms was observed in more than 50% of the subjects in the goshuyuto group.

Conclusion: Goshuyuto is useful in preventing episodes of headache in chronic headache patients. Responder-limited design is a candidate for evaluating Kampo medicine.     

The efficacy of goshuyuto, a typical Kampo (Japanese herbal medicine) formula, in preventing episodes of headache

OBJECTIVE: The purpose of this clinical trial was to assess the efficacy of goshuyuto, a typical Kampo formula, in preventing episodes of headache in chronic headache patients. RESEARCH DESIGN AND METHODS: Because the treatment target of a Kampo formula is decided on a basis different to that of Western medicine, we first selected patients belonging to a subgroup that responded to goshuyuto before conducting the usual randomized controlled trial. During stage 1, the subjects were instructed to orally consume goshuyuto for 4 weeks. Only those subjects judged as responders advanced to stage 2, during which a double-blind, randomized, placebo-controlled study was conducted. The subjects consumed the same dose of goshuyuto or placebo for 12 weeks. RESULTS: Of the 91 subjects enrolled in stage 1, 60 were judged as responders. Of these, 53 advanced to stage 2; 28 were assigned to the goshuyuto group and 25 to the placebo group. The decrease in the number of days on which headache episodes occurred was greater in the goshuyuto group than in the placebo group (2.6 +/- 3.7 vs. 0.3 +/- 4.0 days, p = 0.034); no difference was observed with regard to the reduction in the frequency of consuming reliever medications (2.2 +/- 4.0 vs. 1.4 +/- 8.2, p = 0.672). Improvement in the associated symptoms was observed in more than 50% of the subjects in the goshuyuto group. CONCLUSION: Goshuyuto is useful in preventing episodes of headache in chronic headache patients. Responder-limited design is a candidate for evaluating Kampo medicine.     

Airway fibrosis in a mouse model of airway inflammation

BALB/c mice were sensitized to ovalbumin by systemic injection and then exposed for up to 8 weeks to ovalbumin aerosols in whole body chambers. A pattern of airway inflammation, mucous cell hypertrophy and hyperplasia, and airway remodeling with submucosal fibrosis was observed as lesions evolved over time. Larger conducting airways were removed from the lungs by microdissection. Airway fibrosis was quantified by direct assay for collagen content, which was significantly increased after 4 and 8 weeks of exposure to ovalbumin aerosol. Based upon PCR analysis of mRNA levels in the airways, most of the newly synthesized collagen was Type I. Relaxin, administered by continuous infusion over the second half of a 4-week exposure to ovalbumin, was able to inhibit the accumulation of collagen in the airways of exposed mice. Thus, stimulation of collagen degradation by an activator of collagen breakdown by matrix metalloproteinases appears to be an effective therapeutic strategy in prevention of airway fibrosis in this animal model. Whole body plethysmography of unrestrained mice indicated functional changes in airway reactivity in the lungs of exposed animals occurring in conjunction with the reported structural changes. This result indicates that the ovalbumin-exposed mouse may be a suitable model for examining structure-function relationships in the lungs of animals with a predictable time course of airway inflammation, remodeling, and fibrosis and for testing potential new drugs for treatment of asthma or chronic bronchitis at a mechanistic level.     

Mepacrine alleviates airway hyperresponsiveness and airway inflammation in a mouse model of asthma

Asthma is a multifactorial respiratory disease. Though its incidence is increasing rapidly all over the world, the available therapeutic strategies are neither sufficient nor safe for long term use. Mepacrine, a known antimalarial drug, has been shown to possess antioxidant, anti-inflammatory, platelet anti-aggregant, and PLA2 inhibitory activities. However, its possible use in asthma has not been studied yet. The objective of this study was to investigate the anti-asthmatic property of mepacrine using a mouse model of asthma. To accomplish this, male BALB/c mice were sensitized and challenged with ovalbumin and treated with increasing concentrations of mepacrine. Airway hyperresponsiveness (AHR) to methacholine was assessed using unrestrained whole body plethysmography. Mepacrine (1 mg/kg) has shown marked attenuation of AHR. Cytokines such as IL-4, IL-5, IL-13 and IFN-gamma and OVA-specific IgE levels were measured in BAL (bronchoalveloar lavage) fluid and sera, respectively. Mepacrine effectively reduced the rise in IL-4, IL-5, IL-13, and OVA-specific IgE and restored IFN-gamma levels. Mepacrine also significantly prevented the increase of sPLA2 (secretory phospholipase A2) activity in BAL fluid supernatant and Cys-LT (cysteinyl leukotrienes) in lung tissue homogenates of asthmatic mice. In addition, mepacrine treatment reduced BAL fluid eosinophilia and signs of allergic airway inflammation such as perivascular and peribronchial distribution of inflammatory cells. These findings indicate that mepacrine reduces the asthmatic features in ovalbumin induced asthma by acting on PLA2-Cys-LT axis. Thus, it could be useful for the development of better asthma therapy.     

Modulation of chemokine expression on intestinal epithelial cells by Kampo (traditional Japanese herbal) medicine, Hochuekkito, and its active ingredients

The intestinal epithelial cells sit at the interface between a lumen and a lamina propria or lymph nodes such as Peyer’s patches, where they play important roles in maintaining intestinal homeostasis through chemokine secretion. This study investigated the effect of Hochuekkito (TJ-41)—a traditional Japanese herbal (Kampo) formula used as a tonic for weakness—on chemokine expression in intestinal epithelial cells in order to explore the mechanism of its modulating effect against mucosal immunity. When cells from the rat normal small intestinal epithelial cell-line IEC-6 were stimulated with TJ-41, mRNA expression of CC chemokine ligand (CCL) 11 (eotaxin), CCL20 (MIP-3α) and CCL25 (TECK) was enhanced. Oral administration of TJ-41 to methotrexate-treated mice enhanced mRNA expression of CCL25 and keratinocyte growth factor in the jejunum with, decreasing mRNA expression of the inflammatory marker tumor necrosis factor (TNF)-α. Although oral administration of TJ-41 did not affect CCL20 mRNA expression in villus epithelium of methotrexate-treated mice, enhancement of CCL20 mRNA expression was observed in Peyer’s patches. Immunohistochemical analysis detected dense staining with anti-CCL20 antibody in the follicle-associated epithelium region of Peyer’s patches in mice administered TJ-41. Analysis of active ingredients indicates that polysaccharide-containing macromolecules in TJ-41 contribute to the enhancement of CCL20 mRNA expression through an intracellular signal cascade via nuclear factor kappa B (NF-κB) activation.     

Repression of acyl-CoA:cholesterol acyltransferase by a traditional herbal medicine (Kampo medicine), Ogi-Keishi-Gomotsu-To-Ka-Kojin.

Ogi-Keishi-Gomotsu-To-Ka-Kojin (OKGK) is a traditional herbal medicine (Kampo medicine) which has been found to ameliorate hypercholesterolemia and hypertriglyceridemia in rats and rabbits. In the present study, the effect of OKGK on acyl-CoA:cholesterol acyltransferase (ACAT) was studied in order to elucidate the mechanism of its antihypercholesterolemic action. Oral administration of OKGK to rats fed a cholesterol-enriched diet for 4 weeks markedly repressed the increase in ACAT activity in the small intestine. In contrast, OKGK did not influence hepatic ACAT activity. These results indicate that OKGK selectively inhibits ACAT activity in the small intestine relative to that in the liver, resulting in a reduction of cholesterol absorption, followed by a decrease in serum cholesterol.     

Skullcapflavone II inhibits ovalbumin-induced airway inflammation in a mouse model of asthma

Skullcapflavone II is a flavonoid derived from Scutellaria baicalensis, a widely used herbal medicine in anti-inflammatory and anticancer therapy in Korea. Skullcapflavone II antagonized the bradykinin receptor more potently than any of the other flavonoids derived from this plant. Here, we were investigated its therapeutic effects in a mouse model of ovalbumin (OVA)-induced allergic asthma. Administration of skullcapflavone II significantly reduced airway hyperresponsiveness (AHR), airway eosinophilia, Th2 cytokine production, and increased transforming growth factor-β1 (TGF-β1) levels in bronchoalveolarlavage (BAL) fluids and lungs from OVA-sensitized and -challenged mice. Skullcapflavone II administration also significantly suppressed subepithelial collagen deposition and goblet cell hyperplasia, elevated Smad7 expression and suppressed pSmad2/3 levels. Collectively, these findings indicate that skullcapflavone II, a potential bradykinin antagonist, reduced the major pathophysiological features of allergic asthma, at least in part by acting on TGF-β1/Smad signaling pathways. Thus, skullcapflavone II may have therapeutic potential for the treatment of allergic asthma.     

Narirutin inhibits airway inflammation in an allergic mouse model

1. Flavonoids are naturally occurring compounds that possess anti-allergic, anti-inflammatory, antiproliferative and anti-oxidant properties. In the present study, we investigated whether the flavonoid narirutin could reduce airway inflammation in ovalbumin (OVA)-sensitized/challenged NC/Nga mice, a model of allergic eosinophilic airway inflammation. 2. Mice were initially immunized intraperitoneally with OVA on Days 0 and 7 and then challenged with inhaled OVA on Days 14, 15 and 16. In addition, some mice received narirutin orally at doses of 0.1, 1 or 10 mg/kg bodyweight daily on Days 7-16. 3. At 10 mg/kg, but not 0.1 or 1 mg/kg, narirutin significantly diminished OVA-induced airway inflammation caused by infiltration of lung tissue with inflammatory and mucus-producing cells, as well as reduced eosinophil counts in the peripheral blood and bronchoalveolar lavage fluid (BALF), interleukin (IL)-4 levels in BALF and IgE levels in serum. 4. The mechanism of the anti-inflammatory effect of narirutin are likely to be associated with a reduction in the OVA-induced increases of IL-4 and IgE in a murine model of allergic eosinophilic airway inflammation. These findings suggest that narirutin may be an effective new tool in the treatment of bronchial asthma.     

Ultrafine carbon black particles cause early airway inflammation and have adjuvant activity in a mouse allergic airway disease model.

To gain more insight into the mechanisms of particulate matter (PM)-induced adjuvant activity, we studied the kinetics of airway toxicity/inflammation and allergic sensitization to ovalbumin (OVA) in response to ultrafine carbon black particles (CBP). Mice were exposed intranasally to OVA alone or in combination with different concentrations of CBP. Airway toxicity and inflammation were assessed at days 4 and 8. Immune adjuvant effects were studied in the lung draining peribronchial lymph nodes (PBLN) at day 8. Antigen-specific IgE was measured at days 21 and 28, whereas allergic airway inflammation was studied after OVA challenges (day 28). Results show that a total dose of 200 microg CBP per mouse, but not 20 microg or 2 microg, induced immediate airway inflammation. This 200 microg CBP was the only dose that had immune adjuvant activity, by inducing enlargement of the PBLN and increasing OVA-specific production of Th2 cytokines (IL-4, IL-5, and IL-10). The immune adjuvant activity of 200 microg CBP dosing was further examined. Whereas increased OVA-specific IgE levels in serum on day 21 confirms systemic sensitization, this was further supported by allergic airway inflammation after challenges with OVA. Our data show a link between early airway toxicity and adjuvant effects of CBP. In addition, results indicate that local cytokine production early after exposure to CBP is predictive of allergic airway inflammation. In addition this model appears suitable for studying the role of airway toxicity, inflammation and other mechanisms of particle adjuvant activity, and predicting the adjuvant potential of different particles.     

Mangosteen xanthones mitigate ovalbumin-induced airway inflammation in a mouse model of asthma

α- and γ-Mangostin, which are the major xanthones purified from a Mangosteen, Garcinia mangostana Linn., exhibit a wide range of anticancer, antioxidant, and anti-inflammatory activities. Here, we assessed their therapeutic effects in a mouse model of ovalbumin (OVA)-induced allergic asthma. Animals were treated with α- and γ-mangostins orally for 3 days at doses of 10 and 30 mg/kg daily, 1 h before the OVA challenge. Administration of α- and γ-mangostins significantly reduced the major pathophysiological features of allergic asthma, including inflammatory cell recruitment into the airway, airway hyperresponsiveness (AHR), and increased levels of Th2 cytokines. In addition, α- and γ-mangostins attenuated the increases in phosphoinositide 3-kinase (PI3K) activity, phosphorylation of Akt, and NF-κB in nuclear protein extracts after OVA challenge. In conclusion, α- and γ-mangostin may have therapeutic potential for the treatment of allergic asthma.     

Protocatechuic acid suppresses ovalbumin-induced airway inflammation in a mouse allergic asthma model

Protocatechuic acid (PCA) has been isolated from the leaves of ilex chinenses and has numerous pharmacologic effects, including anti-inflammatory and antitumoral activities. This study aims to evaluate the antiasthma activity of PCA and investigate its possible molecular mechanisms. BALB/c mice were sensitized and challenged to ovalbumin (OVA).Then mice were intraperitoneally (i.p.) injected with PCA 1 h before OVA challenge. We found that PCA treatment at 15 or 30 mg/kg significantly decreased OVA-induced airway hyper-responsiveness (AHR) to inhaled methacholine. Type 2 helper T cell (Th2) cytokines in bronchoalveolar lavage (BAL) fluid, such as interleukin-4 (IL-4), interleukin 5 (IL-5) and interleukin-13 (IL-13), and serum OVA-specific immunoglobulin E (IgE) levels, were also reduced by PCA. Moreover treatment with PCA markedly decreased the number of inflammatory cells in BALF and attenuated OVA-induced mRNA expression of CCl11, CCR3, Muc5ac, acidic mammalian chitinase (AMCase), chitinase 3-like protein 4 (Ym2) and E-selectin in lung tissues, lung histopathological studies showed that PCA inhibited inflammatory cell infiltration and mucus hypersecretion compared with the OVA-induced mice group. We then investigated the possible molecular mechanisms which might be implicated in PCA activity. Our results suggested that the protective effect of PCA might be mediated by the inhibition of the extracellular signal-regulated protein kinase (ERK), p38 Mitogen-activated protein kinase (MAPK) phosphorylation and the nuclear factor-κB (NF-κB) activation.     

Abietic acid attenuates allergic airway inflammation in a mouse allergic asthma model

Abietic acid (AA), one of the terpenoids isolated from Pimenta racemosa var. grissea, has been reported to have anti-inflammatory and immunomodulatory effects. However, the anti-allergic effects of AA remain unclear. The aim of this study was to investigate the anti-allergic effects of AA in an ovalbumin (OVA)-induced asthma murine model. The model of mouse asthma was established by induction of OVA. AA (10, 20, 40 mg/kg) was administered by oral gavage 1 h after the OVA treatment on days 21 to 23. At 24 h after the last challenge, bronchoalveolar lavage fluid (BALF) and lung tissues were collected to assess pathological changes, cytokines production, and NF-κB expression. The results showed that AA attenuated lung histopathologic changes, inflammatory cells infiltration, and bronchial hyper-responsiveness. AA also inhibited OVA-induced the nitric oxide (NO), IL-4, IL-5, IL-13, and OVA-specific IgE production, as well as NF-κB activation. In conclusion, the current study demonstrated that AA exhibited protective effects against OVA-induced allergic asthma in mice and the possible mechanism was involved in inhibiting NF-κB activation.     

Pharmacokinetic interactions between Japanese traditional medicine (kampo) and modern medicine (III). Effect of Sho-seiryu-to on the pharmacokinetics of azelastine hydrochloride in rats

Sho-seiryu-to (SST) is widely used herbal formula in Japanese traditional medicine (kampo) to treat allergic diseases. Since Japanese physicians frequently prescribe this formula combined with azelastine hydrochloride, one of anti-histamine and anti-allergic medicines, we evaluated the pharmacokinetic interactions between SST and azelastine hydrochloride in rats to obtain the drug information for the prevention from disadvantage or adverse effects by their combined therapy. Oral administration of SST did not influence the plasma concentration profile of azelastine after its intravaneous injection, suggesting that SST would not change the activities of metabolic enzymes such as cytochrome P450s. However, maximum concentration (C(max)) of azelastine after oral administration of azelastine hydrochloride was significantly reduced and mean residence time (MRT) was significantly lengthened when SST was orally administered at 20 times amount of human daily dosage. There was not significant difference in the area under the plasma concentration-time curve (AUC), suggesting that SST might delay the absorption of azelastine without affecting the extent of bioavailability. Since this delay was independent of ephedrine that is a main constituent of SST and that a suppressor for gastric transit, SST might form unsoluble complex with azelastine to reduce its absorption. At the double of human daily dose, SST did not made the absorption of azelastine delay. The possibility that SST reduce the absorption of azelastine hydrochloride could not be denied completely, however, it is suggested that SST would not cause pharmacokinetic interaction with azelastine hydrochloride clinically.     

Antioxidant and antiasthmatic effects of saucerneol D in a mouse model of airway inflammation

Chronic airway inflammation is a hallmark of asthma, which is an immune-based disease. We evaluated the ability of saucerneol D, a tetrahydrofuran-type sesquilignan isolated from Saururus chinensis, to regulate airway inflammation in an ovalbumin (OVA)-induced airway inflammation model. Furthermore, we determined whether heme oxygenase (HO)-1 was required for the protective activity of saucerneol D. The airways of OVA-sensitized mice exposed to an OVA challenge developed eosinophilia and mucus hypersecretion and exhibited increased cytokine levels. Mice were administered saucerneol D orally at doses of 20 and 40mg/kg once daily on days 26-30. Saucerneol D administered orally significantly inhibited the number of OVA-induced inflammatory cells and the production of immunoglobulin E as well as Th2-type cytokines. Histopathology studies revealed a marked decrease in lung inflammation and goblet cell hyperplasia after saucerneol D treatment. In addition, saucerneol D induced HO-1 and led to a marked decrease in OVA-induced reactive oxygen species and malondialdehyde and an increase in superoxide dismutase and glutathione in lung tissues. These antioxidant effects were correlated with HO-1 induction. In our experiments, saucerneol D treatment reduced airway inflammation and suppressed oxidative stress in an OVA-induced asthma model.