Effect of AA-2414, a thromboxane A2 receptor antagonist, on airway inflammation in subjects with asthma.

BACKGROUND: Asthma is a chronic inflammatory disease of the airways. The chemokines are potent chemoattractants for eosinophils and other types of cells associated with allergic inflammation. AA-2414, a new thromboxane A2 receptor antagonist, reduces bronchial hyperresponsiveness in asthmatic subjects, but its mechanism of action is unclear. OBJECTIVE: We tested the hypothesis that the beneficial effects of AA-2414 in asthma result from reduction in the number of inflammatory cells infiltrating the airway associated with inhibition of chemokine release. METHODS: We studied bronchial biopsy specimens from 31 asthmatic subjects before and after oral treatment with AA-2414 (80 mg/day) or matched placebo for 4 months in a double-blind manner. Biopsy specimens were examined by immunohistochemistry. Each subject recorded symptom score and peak expiratory flow (PEF). Lung function and bronchial responsiveness to methacholine were measured before and after treatment. RESULTS: After treatment, significant improvements in symptom score (P <.05), PEF (P <.01), diurnal variation of PEF (P <.01), and bronchial responsiveness (P <.01) were observed in the AA-2414 group compared with the placebo group. These improvements were accompanied by a significant decrease in the number of submucosal EG2(+) eosinophils (P <.05). There was also a reduction in the number of cells expressing RANTES (P <.05) and macrophage inflammatory protein (MIP)-1alpha (P <.05) in the epithelium and of cells expressing monocyte chemotactic protein-3 (P <.01), RANTES (P <.05), MIP-1alpha (P <.01), and eotaxin (P <.01) in the submucosa in the AA-2414 treatment group. A significant correlation was found between the number of EG2(+) eosinophils and numbers of monocyte chemotactic protein-3(+) (rs = 0.52, P <.005), MIP-1alpha+ (rs = 0.34, P <.05), and eotaxin+ cells (r s = 0.47, P <.01) in the submucosa. There was a significant negative correlation between the increase in bronchial responsiveness and the change in number of submucosal EG2(+) cells (rs = -0.65, P <.001). CONCLUSIONS: These findings suggest that AA-2414 treatment of patients with asthma may inhibit activated eosinophil infiltration in part by modulating the expression of chemokines in bronchial tissues.     

Characterization of thromboxane A2 receptor and TRPV1 mRNA expression in cultured sensory neurons

Thromboxane A₂ (TxA₂) is an arachidonic acid metabolite that stimulates platelet aggregation and vasoconstriction when released from platelets and other cell types during tissue trauma. More recent research has demonstrated that TxA₂ can also stimulate vagal and spinal sensory nerves. The purpose of this study was twofold. One, we compared the expression of the TxA₂ receptor (TxA2R) in neurons from two sensory ganglia: the nodose ganglion (NG) containing cell bodies of vagal afferent nerves and the thoracic dorsal root ganglion (DRG) containing cell bodies of spinal afferent nerves. Two, we determined if TxA2R co-localizes with mRNA for the nociceptive marker, TRPV1, which is the receptor for the noxious substance capsaicin. We found a greater percentage of neurons in the NG that are positive for TxA2R expression than in the DRG. We also found that there was no correlation of expression of TxA2R with TRPV1. These data suggest that while TxA2R is expressed in both vagal and spinal neurons, TxA₂ may elicit stronger vagal or parasympathetic reflexes in the rabbit when released during tissue trauma depending on the location of release. Our data also indicate that TxA₂ is likely to stimulate both nociceptive and non-nociceptive neurons thereby broadening the types of neurons and reflexes that it may excite.     

Effect of rush immunotherapy on airway inflammation and airway hyperresponsiveness after bronchoprovocation with allergen in asthma

Background: Rush immunotherapy (RIT) has been shown to be effective in allergic asthma. Objective: We investigated the mechanisms of RIT on the basis of cytokine production by T-cell lines and airway inflammation and responsiveness. Methods: Subjects were 8 patients with house dust mite–allergic asthma treated with dust mite extract RIT for 6 months and 6 RIT-untreated control patients. IL-5 production by Dermatophagoides farinae –specific T-cell lines, eosinophil percentages, and eosinophil cationic protein (ECP) in induced sputum and airway responsiveness to allergen and histamine were evaluated before and after treatment. Changes in eosinophil percentages and ECP in induced sputum and responsiveness to histamine 24 hours after allergen inhalation were also studied. Results: After 6 months of RIT, percentages of total eosinophils (43.0% ± 6.90% to 16.8% ± 2.48%; P < .01), percentages of EG2⁺ eosinophils (32.6% ± 6.39% to 19.7% ± 4.68%; P < .01) and ECP (362.7 ± 125.3 ng/mL to 26.2 ± 5.15 ng/mL; P < .05) decreased in induced sputum, and IL-5 production by T-cell lines decreased (617 ± 93.2 pg/mL to 200.0 ± 34.1 pg/mL; P < .01). RIT decreased both early- and late-phase bronchoconstriction (early phase: 33.2% ± 3.46% to 25.4% ± 1.42%; P < .03; late phase: 16.2% ± 3.52% to 6.2% ± 1.96%; P < .03) and suppressed increases in the percentages of total (61.8% ± 4.89% to 42.0% ± 4.67%; P < .01) and EG2-positive eosinophils (55.54% ± 7.21% to 36.5% ± 6.43%; P < .01) and ECP (685.6 ± 217.0 ng/mL to 85.4 ± 23.4 ng/mL; P < .05) in induced sputum after allergen inhalation. RIT also decreased airway responsiveness to dust mite (1:303.7 ± 123.7 wt/vol to 1:65.0 ± 13.2 wt/vol; P < .03) and to histamine before (397.1 ± 206.9 μg/mL to 1391.3 ± 283.3 μg/mL; P < .03) and after allergen inhalation (139.2 ± 36.5 μg/mL to 629.1 ± 196.3 μg/mL; P < .03). Conclusion: RIT decreases airway inflammation and airway hyperresponsiveness before and after bronchial provocation with allergen, possibly by inhibiting both allergen-specific T-cell– and mast cell-dependent pathways. RIT is an effective antiinflammatory treatment in allergic asthma. (J Allergy Clin Immunol 1998;102:927-34.)     

Surface roughness mediates its effects on osteoblasts via protein kinase A and phospholipase A2

Earlier studies have shown that implant surface roughness influences osteoblast proliferation, differentiation, matrix synthesis and local factor production. Moreover, the responsiveness of osteoblasts to systemic hormones, such as 1,25-(OH)₂D₃, at the implant surface is also influenced by surface roughness and this effect is mediated by changes in prostaglandins. At present, it is not known which signaling pathways are involved in mediating cell response to surface roughness and how 1,25-(OH)₂D₃ treatment alters the activation of these pathways. This paper reviews a series of studies that have addressed this question. MG63 osteoblast-like cells were cultured on commercially pure titanium (cpTi) surfaces of two different roughnesses (R_a 0.54 and 4.92 μm) in the presence of control media or media containing 1,25-(OH)₂D₃ or 1,25-(OH)₂D₃ plus H8 (a protein kinase A inhibitor) or quinacrine (a phospholipase A₂ inhibitor). At harvest, the effect of these treatments on cell number and alkaline phosphatase specific activity was measured. Compared to cultures grown on the smooth surface, cell number was reduced on the rough surface. 1,25-(OH)₂D₃ inhibited cell number on both surfaces and inhibition of protein kinase A in the presence of 1,25-(OH)₂D₃ restored cell number to that seen in the control cultures. Inhibition of phospholipase A₂ in the presence of 1,25-(OH)₂D₃ caused a further reduction in cell number on the smooth surface, and partially reversed the inhibitory effects of 1,25-(OH)₂D₃ on the rough surface. Alkaline phosphatase specific activity was increased in cultures grown on the rough surface compared with those grown on the smooth surface; 1,25-(OH)₂D₃ treatment increased enzyme specific activity on both surfaces. Cultures treated with H8 and 1,25-(OH)₂D₃ displayed enzyme specific activity that approximated that seen in control cultures. Inhibition of phospholipase A₂ also inhibited the 1,25-(OH)₂D₃-dependent effect on the smooth surface, but on the rough surface there was an inhibition of the 1,25-(OH)₂D₃ effect as well as a partial inhibition of the surface roughness-dependent effect. The results indicate that surface roughness and 1,25-(OH)₂D₃ mediate their effects through phospholipase A₂, which catalyzes one of the rate-limiting steps in prostaglandin E₂ production. Further downstream, prostaglandin E₂ activates protein kinase A.     

Differential distribution of γ-aminobutyric acidA, receptor subunit (α1, α2, α3, α5 and β2+3) immunoreactivity in the medial prefrontal cortex of the rat

A detailed mapping of the γ-aminobutyric acid (GABA)_A receptor subunits (α₁, α₂, α₃ and β₂₊₃) in the infralimbic/ventral prelimbic region (IL/vPL) of the rat frontal cortex was carried out using subunit-specific antibodies. The α₁ and β₂₊₃ subunit antibodies immunostained all layers of the IL/vPL region. Layers II and III displayed immunostaining of cell bodies whereas I, V and VI showed predominantly neuropil staining. The size of the α₁-positive cell bodies corresponded to that of small interneurons (range, 20–55 μm²; mean ± SEM, 37 ± 5.5 μm²) as well as pyramidal cells or large interneurons (range, 87–135 μm²; mean ± SEM, 103.4 ± 9.7 μm²). However, β₂₊₃ antibody immunostained only small cell bodies. Immunoreactivity for α₂ was restricted to layers I and II, whereas α₃ and α₅ subunit expression was seen only in layer VI. The antibody to the α₂ subunit immunostained small cell bodies (range, 29–63 μm²; mean ± SEM, 32 ± 4.5 μm²) in layer II, resembling interneurons. Conversely, both α₃ and α₅ antibodies immunostained large cell bodies (range, 94–151 gmm²; mean ± SEM, 115.7 ± 13.4 μm²), consistent with pyramidal cell labelling in layer VI.     

IL-6 release from mouse glia caused by MeHg requires cytosolic phospholipase A2 activation

Methylmercury is a potent neurotoxin that causes severe neurological disorders in fetuses and young children. Recent studies indicated that MeHg could alter levels of immune mediators produced by cells of the central nervous system. Results from this study indicated that MeHg could greatly induce IL-6 release from primary mouse glial cultures. This property was not shared by other cytotoxic heavy metals, such as CdCl₂ or HgCl₂. MeHg was known to induce cytosolic phospholipase A₂ (PLA₂) activation and expression, and this enzyme was required for IL-6 induction in some experimental systems. Further experiments using structurally distinct pharmacological agents were performed to test the hypothesis that MeHg induced PLA₂ activation was necessary for MeHg induced IL-6 release. Results indicated that AACOCF₃ (≥10 μM), MAFP (≥0.625 μM) and BEL (≥0.625 μM) significantly reduced MeHg induced IL-6 release in glia. However, these PLA₂ inhibitors did not block MeHg induced GSH depletion. These results suggested that PLA₂ activation was required for MeHg to induce glial IL-6 release.     

Effect of ketanserin, a new blocking agent of the 5-HT2 receptor, on airway responsiveness in asthma

Most of the antihypertensive drugs have a liability for adverse effects in asthma. Since there are few available data on the effect of ketanserin, a new antihypertensive drug which is a type-2 serotonin receptor antagonist, on human respiratory function, we have tested whether this drug can modify bronchial hyperresponsiveness to methacholine in asthmatic patients. The protective effect of intravenous ketanserin (0.14 mg/kg) was small, but significant.     

腺苷A2a受体在红景天苷调节大鼠低氧性肺动脉高压中的作用

 目的：探讨腺苷A_2a受体（A_2aAR）对低氧性肺动脉高压大鼠的保护作用及红景天苷对大鼠低氧性肺动脉高压的调控作用及其机制。方法：将SD大鼠60只随机分为6组：正常组、低氧组、低氧+红景天苷低剂量组、低氧+红景天苷中剂量组、低氧+红景天苷高剂量组、低氧+A_2aAR激动剂（CGS-21680）组。测定各组大鼠平均肺动脉压（mPAP）、平均颈动脉压（mCAP）和右心室(RV)/（左心室+室间隔）(LV+S),观察各组肺细小动脉显微结构变化;用免疫组化法和原位杂交法测定肺细小动脉管壁A_2aAR含量的变化;用实时荧光定量PCR法和Western blotting法测定肺组织匀浆A_2aAR mRNA和蛋白含量的变化。结果：（1）低氧组大鼠mPAP明显高于正常对照组,A_2aAR激动剂组和红景天苷高剂量组可以明显降低mPAP,红景天苷中、低剂量组mPAP虽有下降趋势,但差异无统计学意义。（2）低氧组大鼠RV/(LV+S)显著高于正常组,A_2aAR激动剂组和红景天苷中、高剂量组RV/(LV+S)显著低于低氧组,红景天苷低剂量组较低氧组有减低趋势,但差异无统计学意义。（3）低氧组大鼠肺细小动脉重构显著, A_2aAR激动剂组及红景天苷低、中、高剂量组肺血管重构较低氧组明显减轻。（4）低氧组肺血管和肺组织A_2aAR mRNA和蛋白表达均明显高于正常组,A_2aAR激动剂组和红景天苷高剂量组肺血管和肺组织A_2aAR mRNA和蛋白水平均较低氧组进一步升高。结论：A_2aAR对低氧性肺动脉高压大鼠具有保护作用;红景天苷能够上调低氧性肺动脉高压大鼠肺血管和肺组织A_2aAR的表达,该通路可能是其减轻低氧性肺动脉高压和肺血管重建的重要机制。     

Role of phospholipase A2 in prepulse inhibition of the auditory startle reflex in rats

High levels of calcium-independent phospholipase A₂ (iPLA₂) are present in the striatum and cerebral cortex [W.Y. Ong, J.F. Yeo, S.F. Ling, A.A. Farooqui, Distribution of calcium-independent phospholipase A₂ (iPLA₂) in monkey brain, J. Neurocytol. 34 (2005) 447–458], and several clinical investigations have suggested a possible role of altered iPLA₂ activity in neurodegenerative and psychiatric disorders. The present study was carried out to elucidate a possible effect of PLA₂ on prepulse inhibition (PPI) of the acoustic startle reflex. Rats that received intraperitoneal injection of the non-specific PLA₂ inhibitor, quinacrine, showed significantly decreased PPI at 76, 80, and 84 dB, compared to saline injected controls. In addition, rats that received intrastriatal injection of antisense oligonucleotide to iPLA₂ showed significant reduction in PPI at prepulse intensities of 76 and 84 dB compared to scrambled sense injected controls. Together, these findings point to a role of PLA₂ in PPI of the auditory startle reflex and sensorimotor gating.     

Negative crosstalk between M1 and M2 muscarinic autoreceptors involves endogenous adenosine activating A1 receptors at the rat motor endplate

At the rat motor nerve terminals, activation of muscarinic M₁ receptors negatively modulates the activity of inhibitory muscarinic M₂ receptors. The present work was designed to investigate if the negative crosstalk between muscarinic M₁ and M₂ autoreceptors involved endogenous adenosine tonically activating A₁ receptors on phrenic motor nerve terminals. The experiments were performed on rat phrenic nerve-hemidiaphragm preparations loaded with [³H]-choline (2.5 μCi/ml). Selective activation of muscarinic M₁ and adenosine A₁ receptors with 4-(N-[3-clorophenyl]-carbamoyloxy)-2-butyryltrimethylammonium (McN-A-343, 3 μM) and R-N⁶-phenylisopropyladenosine (R-PIA, 100 nM), respectively, significantly attenuated inhibition of evoked [³H]-ACh release induced by muscarinic M₂ receptor activation with oxotremorine (10 μM). Attenuation of the inhibitory effect of oxotremorine (10 μM) by R-PIA (100 nM) was detected even in the presence of pirenzepine (1 nM) blocking M₁ autoreceptors, suggesting that suppression of M₂-inhibiton by A₁ receptor activation is independent on muscarinic M₁ receptor activity. Conversely, the negative crosstalk between M₁ and M₂ autoreceptors seems to involve endogenous adenosine tonically activating A₁ receptors. This was suggested, since attenuation of the inhibitory effect of oxotremorine (10 μM) by McN-A-343 (3 μM) was suppressed by the A₁ receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (2.5 nM), and by reducing extracellular adenosine with adenosine deaminase (0.5 U/mL) or with the adenosine transport blocker, S-(p-nitrobenzyl)-6-thioinosine (NBTI, 10 μM). The results suggest that the negative crosstalk between muscarinic M₁ and M₂ autoreceptors involves endogenous adenosine outflow via NBTI-sensitive (es) nucleoside transport system channelling to the activation of presynaptic inhibitory A₁ receptors at the rat motor endplate.     

Inhibition of calcium-independent phospholipase A2 prevents inflammatory mediator production in pulmonary microvascular endothelium

Inhalation of allergens can result in mast cell degranulation and release of granule contents, including tryptase, in the lung. Injury to human pulmonary microvascular endothelial cells (HMVEC-L) can also result in activation of the coagulation cascade and thrombin generation. We hypothesize that these proteases activate calcium-independent phospholipase A₂ (iPLA₂), in HMVEC-L, leading to the production of membrane phospholipids-derived inflammatory mediators. Both thrombin and tryptase stimulation of HMVEC-L increased iPLA₂ activity that was inhibited by pretreatment with the iPLA₂ selective inhibitor bromoenol lactone (BEL). Arachidonic acid and prostaglandin I₂ (PGI₂) release were also increased in tryptase and thrombin stimulated cells and inhibited by BEL pretreatment. Pretreating the endothelial cells with AACOCF₃ a cytosolic PLA₂ inhibitor did not inhibit tryptase or thrombin induced arachidonic acid and PGI₂ release. In addition thrombin and tryptase also increased HMVEC-L platelet activating factor (PAF) production that significantly contributes to the recruitment and initial adherence of polymorphonuclear neutrophils (PMN) to the endothelium. Tryptase or thrombin stimulated increase in PMN adherence to the endothelium was inhibited by pretreatment of HMVEC-L with BEL or pretreatment of PMN with CV3988, a PAF receptor specific antagonist. Collectively, these data support our hypothesis that iPLA₂ activity is responsible for membrane phospholipid hydrolysis in response to tryptase or thrombin stimulation in HMVEC-L. Therefore selective inhibition of iPLA₂ may be a pharmacological target to inhibit the early inflammation in pulmonary vasculature that occurs as a consequence of mast cell degranulation or acute lung injury.     

Oral administration of a dominant T-cell determinant peptide inhibits allergen-specific TH1 and TH2 cell responses in Cry j 2–primed mice

Background: Oral immunotherapy with a peptide for allergic immune responses is theoretically a promising therapy but has not been established yet. Objective: To evaluate immune suppressive efficacy of oral administration of an immunodominant peptide, we investigated changes in T-cell proliferation, T_H1 - and T_H2 -cytokine production, and T_H1 - and T_H2 -mediated antibody production in mice after oral administration of a peptide. Methods: Peptide p246-259, containing a dominant T-cell determinant of Cry j 2, which is the major allergen in Japanese cedar pollen, was used in this study. Groups of mice received p246-259 or PBS alone before or after they were primed intranasally with Cry j 2 and cholera toxin. In another experiment mice were primed intraperitoneally with Cry j 2 and alum. Proliferative response and cytokine production by nasal-associated lymph node cells against Cry j 2 were investigated. Amounts of systemic anti-Cry j 2 IgE and IgG antibodies were also measured. Results: Oral administration of the peptide to mice before, or even after, the sensitization induced oral tolerance in T-cell responses against the allergen; the tolerance was associated with decreased production of T_H1 (IFN-γ and IL-2) and T_H2 (IL-4) cytokines. Allergen-specific T_H1 -mediated (IgG2a and IgG2b) and T_H2 -mediated (IgG1 and IgE) antibody responses were also inhibited. Conclusions: Oral administration of a dominant T-cell determinant peptide induces immunologic tolerance in both T_H1 and T_H2 cell responses against the whole protein allergen. Our study is the first, to our knowledge, to demonstrate the potential for peptide-based oral immunotherapy in order to treat allergic immune responses. (J Allergy Clin Immunol 1998;102:961-7.)     

Effect of acyclovir on bronchoconstriction and urinary leukotriene E4 excretion in aspirin-induced asthma

Background: Acyclovir (9-[2-hydroxyethoxymethyl] guanine), an inhibitor of the DNA polymerase of the herpes virus, has been reported to exhibit pharmacologic activity other than antiviral activity, including antiasthmatic effects. Objective: This study was designed to investigate the protective effect of acyclovir on airway responsiveness to the sulpyrine provocation test and to investigate whether this protective activity is associated with a reduction in aspirin-induced excretion of urinary leukotriene E₄ (u-LTE₄ ), a marker of cysteinyl leukotriene (LT) overproduction that participates in the pathogenesis of aspirin-induced asthma. Methods: We assessed the effects of pretreatment with acyclovir on bronchoconstriction precipitated by inhalation of sulpyrine in 16 adult patients with mild or moderate aspirin-induced asthma; those who were in stable clinical condition and were hyperresponsive to the sulpyrine provocation test were allocated to this study. A double-blind, randomized, cross-over design was used. u-LTE₄ was measured by a combined reverse-phase HPLC enzyme immunoassay. Results: Acyclovir protects against aspirin-induced attacks of asthma through mechanisms unrelated to its bronchodilator property but related to the improvement of bronchial hypersensitivity to sulpyrine; protection was nearly complete in all patients (P < .0001). By contrast, after acyclovir, the maximum level of u-LTE₄ in patients was significantly lower than that in control subjects (P < .01). Conclusion: Our results suggest that acyclovir is not only an antiviral drug but also an inhibitor of analgesic-induced bronchoconstriction, probably acting by inhibiting the release of cysteinyl LTs. (J Allergy Clin Immunol 1998;102:909-14.)     

Ultrastructural analysis of TiO2 nanotubes with photodecomposition of water into O2 and H2 implanted in the nude mouse

To analyze the biocompatibility and O2 generation of TiO2 nanotubes via photodecomposition of water into O2 and H2 in vivo, samples were implanted under the inguinal skin of the nude mouse. Venous oxygen saturation (SvO2) of the inguinal skin over the implanted region was measured with a tissue oximeter and the ultrastructures were examined with an electron microscope. Four weeks after the implantation, SvO2 of the inguinal skin of the groups with TiO2 nanotubes was 30-40% higher than that of the opposite control region (54%). SvO2 of the other groups, comprising splenic autografts, fetal cardiac tissue transplantation and surgical procedure without TiO2 nanotubes, was roughly the same as that of controls. Ultrastructurally, TiO2 nanotubes were phagocytized by the macrophage and promoted filament formation in its cytoplasm. Neither death of the cell nor destruction of the tissue was recognized. These findings indicate excellent biocompatibility and O2 generation of TiO2 nanotubes in vivo.     

The effect of a specific thromboxane A2 antagonist, AA-2414 on airway hyperresponsiveness induced by ozone exposure in dogs]

To determine whether thromboxane A2 (TxA2) is involved in airway hyperresponsiveness induced by ozone exposure, we studied the effect of a specific TxA2 antagonist, AA-2414 on ozone-induced airway hyperresponsiveness in seven dogs. Airway responsiveness to inhaled methacholine was determined by modified Astograph (7 Hz oscillation method), and numbers of neutrophils in the peripheral blood, neutrophil counts in bronchoalveolar lavage fluid (BALF), the levels of TxB2 and 6-keto-Prostaglandin F1 alpha (6-keto-PGF1 alpha) in BALF were measured before and after ozone exposure, and after ozone exposure with pretreated AA-2414. Ozone exposure was carried out for 2 hr at an ozone level of 3.06 +/- 0.06 ppm (mean +/- SE). Airway responsiveness to inhaled methacholine increased significantly after ozone exposure (p less than 0.01), and the hyperresponsiveness induced by ozone exposure was inhibited significantly by pretreated AA-2414 (p less than 0.01). Numbers of neutrophils in the peripheral blood and neutrophil counts in BALF increased after ozone exposure, and these increase were not inhibited by pretreated AA-2414. There was no apparent change in the levels of TxB2 in BALF after ozone exposure and after ozone exposure with pretreated AA-2414, however the levels of 6-keto-PGF1 alpha in BALF decreased after ozone exposure and after ozone exposure with pretreated AA-2414 (p less than 0.1). These results suggest that TxA2 plays an important role in the development of airway responsiveness after ozone exposure in dogs, and ozone-induced airway hyperresponsiveness may not be associated with the hyperproduction of TxA2 but with the relative increase of TxA2 due to the decrease of PGI2.     

House dust mite avoidance for children with asthma in homes of low-income families

BACKGROUND: Home exposure to high levels of house dust mite allergen has been shown to aggravate airways reactivity and asthma. OBJECTIVE: The purpose of this study was to determine whether specific house dust mite control measures could reduce exposure levels and asthma severity. METHODS: This double-blinded, randomized trial compared asthma progression over 1 year in children whose homes received standard environmental control intervention with those whose homes received aggressive intervention for dust mite elimination. The primary end point was doubling in PD20 methacholine. RESULTS: Symptom scores and quality-of-life scores were similar for the standard and aggressive intervention groups. PD20 methacholine doubling occurred in 9 members of the aggressive intervention group vs 4 control patients (P <.05). Dust mite levels decreased in the aggressive intervention homes compared with the standard intervention homes (P <.05). CONCLUSION: Aggressive dust mite intervention decreased dust mite levels and improved bronchial hyperresponsiveness.     

Effects of KP-496, a novel dual antagonist of leukotriene D4 and thromboxane A2 receptors on nasal blockage in guinea pig models of allergic rhinitis

OBJECTIVE AND DESIGN: KP-496 is a novel dual antagonist for leukotriene (LT) D(4) and thromboxane (TX) A(2) receptors. We investigated effects of KP-496 on antigeninduced nasal blockage in 2 guinea pig models of allergic rhinitis. SUBJECTS: Male Hartley guinea pigs were used. TREATMENT: Animals were actively sensitized with ovalbumin (OVA) or Japanese cedar pollen, and were then repeatedly challenged with OVA or pollen, respectively. KP-496 (0.003 %-0.05 %) was intranasally administered 0.5 or 1 h before and 2 h after an antigen challenge. METHODS: As an indicator of nasal blockage, specific airway resistance was measured using a double-flow plethysmograph system. Statistical analyses were performed with Dunnett's test (OVA model) or t-test (pollen model). RESULTS: Although early phase response was not affected by even a high dose (0.03 %) of KP-496, late phase nasal blockage (1.68 +/- 0.26) was inhibited by 0.01 % (0.87 +/- 0.19; p <0.05) and 0.03 % (0.44 +/- 0.12; p <0.01) of KP-496 in the OVA model. On the other hand, both early (5.60 +/- 0.77) and late phase responses (7.90 +/- 1.70) were inhibited by 0.05 % KP-496 to 2.68 +/- 0.84 (p <0.05) and 2.71 +/- 0.83 (p <0.05), respectively, in the pollen model, in which nasal hyperresponsiveness had been acquired by multiple challenges. CONCLUSIONS: KP-496 may be clinically effective for nasal blockage in allergic rhinitis.