Suppression of atherosclerotic development in Watanabe heritable hyperlipidemic rabbits treated with an oral antiallergic drug, tranilast.
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BACKGROUND: Inflammatory and immunological responses of vascular cells have been shown to play a significant role in the progression of atheromatous formation. Tranilast [N-(3,4-dimethoxycinnamoyl) anthranillic acid] inhibits release of cytokines and chemical mediators from various cells, including macrophages, leading to suppression of inflammatory and immunological responses. This study tested whether tranilast may suppress atheromatous formation in Watanabe heritable hyperlipidemic (WHHL) rabbits. METHODS AND RESULTS: WHHL rabbits (2 months old) were given either 300 mg x kg-1 x d-1 of tranilast (Tranilast, n=12) or vehicle (Control, n=13) PO for 6 months. Tranilast treatment was found to suppress the aortic area covered with plaque. Immunohistochemical analysis showed that there was no difference in the percentage of the RAM11-positive macrophage area and the frequency of CD5-positive cells (T cells) in intimal plaques between Tranilast and Control. Major histocompatibility complex (MHC) class II expression in macrophages and interleukin-2 (IL-2) receptor expression in T cells, as markers of the immunological activation in these cells, was suppressed in atheromatous plaque by tranilast treatment. Flow cytometry analysis of isolated human and rabbit peripheral blood mononuclear cells showed that an increase in expression both of MHC class II antigen on monocytes by incubation with interferon-gamma and of IL-2 receptor on T cells by IL-2 was suppressed by the combined incubation with tranilast. CONCLUSIONS: The results indicate that tranilast suppresses atherosclerotic development partly through direct inhibition of immunological activation of monocytes/macrophages and T cells in the atheromatous plaque. (+info)
Tranilast suppresses vascular chymase expression and neointima formation in balloon-injured dog carotid artery.
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BACKGROUND: Activation of vascular chymase plays a major role in myointimal hypertrophy after vascular injury by augmenting the production of angiotensin (ANG) II. Because chymase is synthesized mainly in mast cells, we assumed that the chymase-dependent ANG II formation could be downregulated by tranilast, a mast cell-stabilizing antiallergic agent. We have assessed inhibitory effects of tranilast on neointima formation after balloon injury in the carotid artery of dogs, which share a similar ANG II-forming chymase with humans, and further explored the pathophysiological significance of vascular chymase. METHODS AND RESULTS: Either tranilast (50 mg/kg BID) or vehicle was orally administered to beagles for 2 weeks before and 4 weeks after balloon injury. Four weeks after the injury, remarkable neointima was formed in the carotid arteries of vehicle-treated dogs. Chymase mRNA levels and chymaselike activity of vehicle-treated injured arteries were increased 10.2- and 4.8-fold, respectively, those of uninjured arteries. Angiotensin-converting enzyme (ACE) activity was slightly increased in the injured arteries, whereas ACE mRNA levels were not. Tranilast treatment completely prevented the increase in chymaselike activity, reduced the chymase mRNA levels by 43%, and decreased the carotid intima/media ratio by 63%. In vehicle-treated injured arteries, mast cell count in the adventitia showed a great increase, which was completely prevented by the tranilast treatment. Vascular ACE activity and mRNA levels were unaffected by tranilast. CONCLUSIONS: Tranilast suppressed chymase gene expression, which was specifically activated in the injured arteries, and prevented neointima formation. Suppression of the chymase-dependent ANG II-forming pathway may contribute to the beneficial effects of tranilast. (+info)
Three distinct anti-allergic drugs, amlexanox, cromolyn and tranilast, bind to S100A12 and S100A13 of the S100 protein family.
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To investigate the roles of calcium-binding proteins in degranulation, we used three anti-allergic drugs, amlexanox, cromolyn and tranilast, which inhibit IgE-mediated degranulation of mast cells, as molecular probes in affinity chromatography. All of these drugs, which have different structures but similar function, scarcely bound to calmodulin in bovine lung extract, but bound to the same kinds of calcium-binding proteins, such as the 10-kDa proteins isolated in this study, calcyphosine and annexins I-V. The 10-kDa proteins obtained on three drug-coupled resins and on phenyl-Sepharose were analysed by reversed-phase HPLC. It was found that two characteristic 10-kDa proteins, one polar and one less polar, were bound with all three drugs, although S100A2 (S100L), of the S100 family, was bound with phenyl-Sepharose. The cDNA and deduced amino acid sequence proved our major polar protein to be identical with the calcium-binding protein in bovine amniotic fluid (CAAF1, S100A12). The cDNA and deduced amino acid sequence of the less-polar protein shared 95% homology with human and mouse S100A13. In addition, it was demonstrated that the native S100A12 and recombinant S100A12 and S100A13 bind to immobilized amlexanox. On the basis of these findings, we speculate that the three anti-allergic drugs might inhibit degranulation by binding with S100A12 and S100A13. (+info)
Ketotifen and cardiovascular effects of xamoterol following single and chronic dosing in healthy volunteers.
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AIMS: To study whether desensitization occurs after long-term administration of the 1-adrenoceptor partial agonist xamoterol and, if so, whether this can be influenced by ketotifen. METHODS: In a double-blind, randomized design 10 young, healthy males received ketotifen (2 x 1 mg day(-1) p.o.) or placebo for 3 weeks with xamoterol (2 x 200 mg day(-1) p.o.) administered concomitantly during the last 2 weeks. 'l1-adrenoceptor mediated responses were assessed as exercise-induced tachycardia and isoprenaline-induced shortening of heart rate corrected electromechanical systole (QS2c); isoprenaline-induced tachycardia was measured as a mixed beta1-/beta2-adrenoceptor-mediated effect. RESULTS: The first dose of xamoterol significantly increased resting heart rate and systolic blood pressure and significantly shortened QS2c. The last dose of xamoterol after 2 weeks of treatment still produced the same responses. Ketotifen did not influence these effects of xamoterol on resting haemodynamics. The first dose of xamoterol caused a rightward shift of the exercise- and isoprenaline-induced tachycardia (mean dose ratios+/-s.e.mean: 1.20+/-0.05 and 2.46+/-0.23) and the isoprenaline-evoked shortening of QS2c (dose ratio 3.59+/-0.68). This rightward shift was even more pronounced after 2 weeks xamoterol treatment. This additional rightward shift after 2 weeks of xamoterol was not affected by ketotifen (mean difference (95% CI) of log transformed dose ratios between placebo and ketotifen: exercise tachycardia 0.001 (-0.03; 0.04); isoprenaline tachycardia 0.03 (-0.15; 0.21); isoprenaline induced shortening of QS2c 0.13 (-0.22; 0.48)). CONCLUSIONS: In humans xamoterol is a partial beta1-adrenoceptor agonist with positive chrono- and inotropic effects at rest and antagonistic properties under conditions of beta-adrenoceptor stimulation. These effects were well maintained after chronic dosing with no signs of beta1-adrenoceptor desensitization. Ketotifen does not change the beta-adrenoceptor mediated responses of xamoterol after chronic dosing. (+info)
Comparison of intranasal triamcinolone acetonide with oral loratadine in the treatment of seasonal ragweed-induced allergic rhinitis.
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A double-blind, randomized, multicenter, parallel-group controlled study compared the efficacy and safety of intranasal triamcinolone acetonide (220 micrograms/day) and oral loratadine (10 mg/day) in patients with at least two seasons of ragweed-induced seasonal allergic rhinitis. A 28-day screening period, including a 5-day baseline period, preceded a 4-week treatment period. Reduction in rhinitis symptom scores was evident in both groups as early as day 1, with no significant between-group differences during week 1. At weeks 2, 3, and 4, patients treated with triamcinolone acetonide were significantly (P < 0.05) more improved in total nasal score, nasal itch, nasal stuffiness, and sneezing than were patients treated with loratadine. At weeks 3 and 4, rhinorrhea and ocular symptoms were significantly (P < 0.05) more improved from baseline among triamcinolone acetonide patients compared with loratadine patients. There was no significant between-group difference in relief from postnasal drip at any time point. Physicians' global evaluations significantly (P = 0.002) favored triamcinolone acetonide at the final visit, with moderate to complete relief of symptoms attained by 68% of triamcinolone acetonide patients and 59% of loratadine patients. Over the 4-week treatment period, triamcinolone acetonide patients had significantly greater improvement in total nasal score, nasal itch, nasal stuffiness, sneezing, and ocular symptoms. Both treatments were well tolerated, with headache being the most frequently reported drug-related adverse effect in both the triamcinolone acetonide (15%) and loratadine (11%) groups. These results indicate that triamcinolone acetonide is more effective than oral loratadine in relieving the symptoms of ragweed-induced seasonal allergic rhinitis. (+info)
Long term prevention of allergic lung inflammation in a mouse model of asthma by CpG oligodeoxynucleotides.
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Asthma is an inflammatory disease of the airways that is induced by Th2 cytokines and inhibited by Th1 cytokines. Despite a steady increase in the incidence, morbidity, and mortality from asthma, no current treatment can reduce or prevent asthma for a prolonged period. We examined the ability of unmethylated CpG oligodeoxynucleotides (ODN), which are potent inducers of Th1 cytokines, to prevent the inflammatory and physiological manifestations of asthma in mice sensitized to ragweed allergen. Administration of CpG ODN 48 h before allergen challenge increased the ratio of IFN-gamma to IL-4 secreting cells, diminished allergen-induced eosinophil recruitment, and decreased the number of ragweed allergen-specific IgE-producing cells. These effects of CpG ODN were sustained for at least 6 wk after its administration. Furthermore, there was a vigorous Th1 memory response to the recall Ag, inhibition of peribronchial and perivascular lung inflammation, and inhibition of bronchial hyperresponsiveness 6 wk after administration of CpG ODN. Administration of CpG ODN in IFN-gamma -/- mice failed to inhibit eosinophil recruitment, indicating a critical role of IFN-gamma in mediating these effects. This is the first report of a treatment that inhibits allergic lung inflammation in presensitized animals for a prolonged period and thus has relevance to the development of an effective long term treatment for asthma. (+info)
Adhesive explant culture of allergic nasal mucosa: effect of emedastine difumarate, an anti-allergic drug.
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Allergic reaction of the nose comprises of an immediate and a late reaction. To evaluate nasal allergic reactions, many experiments have been performed by investigators. In this study, we performed a new tissue culture technique (adhesive explant culture) to analyze the migration of cells into the culture medium from the cultured allergic nasal mucosa in response to an allergen. Basophilic cells (mast cells and basophils) and eosinophils, which were released into the culture medium after the allergen challenge, were evaluated by the analysis of histamine and eosinophil cationic protein (ECP) content in the culture medium. Histamine and basophilic cells in the culture medium were more abundant in the immediate phase (within 30 min) after challenge than in the late phase (from 30 min to 10 hr). On the other hand, ECP and eosinophils in the culture medium were more abundant in the late phase than in the immediate phase. The increase of histamine content in both phases were not inhibited by pre-treatment of emedastine difumarate (EME), an anti-allergic drug. However, the increase of ECP in the late phase was inhibited by pre-treatment with EME. Moreover, the number of EG2-positive cells was also decreased by pre-treatment with EME. These results suggest that EME might lower the activation of eosinophils in the late phase of the allergic reaction. The present study also indicates that this adhesive explant culture system is useful model for studying the cellular allergic responses to drugs ex vivo. (+info)
Effect of an orally active Th1/Th2 balance modulator, M50367, on IgE production, eosinophilia, and airway hyperresponsiveness in mice.
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We have found a novel anti-allergic agent, M50367, which suppresses IgE biosynthesis and eosinophil accumulation in vivo. In this study, we evaluated the ability of M50367 to modulate Th1/Th2 balance in Th2-background BALB/c mice and to inhibit airway hyperresponsiveness in a murine model of atopic asthma. Oral M50367 at 3-30 mg/kg/day exhibited 51 to 73% reduction of IL-4/IL-5 production and 2- to 5-fold augmentation of IFN-gamma production by Ag-stimulated cultured splenocytes of the mice sensitized with DNP-Ascaris. These alterations in Th1/Th2 cytokine production were accompanied by 55-85% suppression of plasma IgE level. Oral M50367 at a dose of 10 mg/kg/day significantly inhibited Ig-independent peritoneal eosinophilia by 54%, which was induced by repeated i.p. injections of Ascaris suum extract. To develop airway hyperresponsiveness caused by allergic airway inflammation, BALB/c mice were sensitized with i.p. OVA injections, followed three times by OVA inhalation. Oral M50367 significantly inhibited the increase in airway reactivity to acetylcholine, together with the elevation of plasma IgE level and pulmonary eosinophilia, which were observed in vehicle-treated mice 1 day after the last inhalation. Moreover, M50367 treatment reduced IL-4 and IL-5 production and tended to enhance IFN-gamma production, not only by cultured splenocytes, but also in bronchoalveolar lavage fluid. These results suggest that M50367 has a modulating ability of Th1/Th2 balance to down-regulate Th2 response in the circulating system as well as at the sites of inflammation, and may be beneficial for the treatment of allergic disorders such as atopic asthma. (+info)