Venom immunotherapy (VIT) is proven to be curative for insect allergy, but the mechanisms and the biomarkers associated with clinical efficacy remain elusive. We report herein the discovery of a leading candidate biomarker, osteopontin (OPN), for VIT. From cDNA microarray and clustering analyses, an increased expression of OPN was found in patients who completed 5—6 years of VIT and discontinued therapy for 3—6 years as compared with the untreated group. A significantly higher level of serum OPN was found in the completed treatment group as compared with the untreated group. Following VIT, kinetically increased levels of OPN associated with reduced venom specific IgE levels were noted in subjects with large local allergic reactions to venom. These findings together with the fact that OPN is involved in Th1-associated immune response strongly suggest a role of OPN as a functional biomarker for VIT.

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Bronchial asthma is a complicated and diverse disorder affected by genetic and environmental factors. It is widely accepted that it is a Th2-type inflammation originating in lung and caused by inhalation of ubiquitous allergens. The complicated and diverse pathogenesis of this disease yet to be clarified. Functional genomics is the analysis of whole gene expression profiling under given condition, and microarray technology is now the most powerful tool for functional genomics. Several attempts to clarify the pathogenesis of bronchial asthma have been carried out using microarray technology, providing us some novel biomarkers for diagnosis, therapeutic targets or understanding pathogenic mechanisms of bronchial asthma. In this article, we review the outcomes of these analyses by the microarray approach as applied to this disease by focusing on the identification of novel biomarkers.

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Respiratory viral infections profoundly influence the disease activity of wheezing illnesses and asthma in early childhood. Viral bronchiolitis shares many features with asthma and a subset of children develop recurrent wheezing after their initial illness. Recently mechanisms for virus-induced exacerbations of childhood asthma are beginning to be focused on and defined. Viruses cause systemic immune activation and also produce local inflammation. These factors are likely to affect airway pathogenesis leading to airway narrowing, an increase in mucus production, and eventually bronchospasm, and airway obstruction. These new insights related to the pathogenesis and disease activity are likely to provide new targets for the therapy and prevention of early asthma in childhood.

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Background: Approximately 16.2% of the Japanese population suffer from cedar pollinosis, with various manifestations such as ophthalmic, laryngo-pharyngeal and skin symptoms in addition to nasal symptoms. Thus, the annual pollen season is an agonizing period for patients. No study has reported symptoms and their clinical courses after conjunctival provocation with purified cedar pollen allergen Cry j1 as well as suppression of these allergen-induced ocular symptoms by antihistamine eye drops.
Methods: Nine patients with Japanese cedar pollinosis who had no nasal or ocular symptoms were included in the present study, after obtaining informed consent in writing. 1) Purified cedar pollen allergen Cry j1 was instilled in the left eye and phosphate-buffered saline (PBS) in the right eye as a control. 2) Levocabastine hydrochloride ophthalmic suspension and ketotifen fumarate ophthalmic solution were respectively instilled in the left and right eyes, which were then challenged with the allergen. Ocular symptoms after provocation with the allergen were recorded through the clinical course.
Results: Pollen allergen-induced ocular symptoms were itching and hyperemia of the palpebral conjunctiva, and itching lasted for more than 5 hours. Moreover, preadministration of antihistamine eye drops suppressed the increases in the ocular symptom scores, eliminating itching within 1 hour. Allergen provoked not only ocular symptoms but also nasal symptoms in 77.8% of patients.
Conclusions: Preadministration of antihistamine eye drops suppressed the symptoms induced by the allergen, which suggests that this is an effective early therapy for Japanese cedar pollinosis, if it is started before the pollen season. However, self-protection by patients using a mask may not be effective enough to suppress nasal symptoms during the pollen season, requiring them to additionally wear glasses to avoid exposure to the allergen.

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Background: Seasonal allergic rhinitis (SAR) induced by Japanese cedar pollen is a substantial problem in Japan. Omalizumab, a novel humanized monoclonal anti-immunoglobulin E (IgE) antibody, has already been proven to reduce symptoms associated with SAR. We investigated the safety and efficacy of omalizumab in the treatment of patients with Japanese cedar pollen-induced SAR compared to placebo.
Methods: A randomized, placebo-controlled, double-blind study was conducted in 100 Japanese patients with a history of moderate-to-severe SAR induced by Japanese cedar pollens. Omalizumab (150, 225, 300, or 375mg) or placebo was administered subcutaneously every 2 or 4 weeks based on serum total IgE and body weight at baseline. The primary efficacy variable was the mean of daily nasal symptom medication scores (sum of the daily nasal symptom severity score and daily nasal rescue medication score) during the treatment period. Secondary efficacy variables included the daily ocular symptom medication score and related variables.
Results: Primary and all secondary efficacy variable scores were significantly lower in the omalizumab group than in the placebo group (P < .01). Serum free IgE levels markedly decreased in the omalizumab group and were associated with clinical efficacy. The overall incidence of injection site reactions was higher in the omalizumab group than in the placebo group; however, the adverse reaction profile was similar between the two groups when excluding injection site reactions. No anti-omalizumab antibodies were detected.
Conclusions: Omalizumab was effective and safe in the treatment of SAR induced by Japanese cedar pollen.

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Background: The clinical efficacy of combination therapy comprising a long acting β₂-agonist (LABA) and corticosteroid is widely recognized for the treatment of adult asthma. Here we examine the effect of salmeterol xinafoate (SX) and fluticasone propionate (FP) alone and in combination on the immunological activation of human cultured mast cells (HCMC)in vitro.
Methods: HCMC were passively sensitized with IgE antibody and then activated by challenging with anti-IgE antibody. The effect of drugs on the activation of mast cells was examined by measuring the amount of released chemical mediators (histamine, leukotrienes (LT) and prostaglandin D₂ (PGD₂)) and granulocyte macrophage colony stimulating factor (GM-CSF).
Results: The release of each chemical mediator was inhibited by 10^-9—10^-8M SX but not by 10^-10—10^-7M FP. The production of GM-CSF was inhibited by a concentration of 10^-8M in both drugs and the inhibition was augmented by combined treatment with 10^-11M of each drug.
Conclusions: The immunological release of chemical mediators (histamine, LT, PGD₂) from HCMC was inhibited by SX but not by FP. SX and FP inhibited the production of GM-CSF by HCMC and both drug showed synergistic inhibition in the production of GM-CSF.

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Background: Theophylline is a useful drug for the treatment of asthma. The Asthma Prevention and Management Guidelines (JGL) recommend use of sustained-release theophylline products as controllers and of injectable aminophylline products as relievers. The Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention, the NHLB/WHP Workshop Report 1995 (GINA, 1995) and guidelines in Western countries recommend sustained-release theophylline, but not as positively as in the JGL. The aim of this survey was to determine the occurrence of serious adverse reactions.
Methods: The survey was conducted in 66 institutions staffed by physicians certified by the Japanese Society of Allergology (JSA). The target diseases were asthma and COPD including chronic bronchitis and pulmonary emphysema, which are indications for use of sustained-release theophylline products in Japan.
Results: 3,921 patients were included in the safety evaluation. No serious adverse reactions were observed among the patients in this survey, although 54 patients (1.38%) exhibited non-serious adverse reactions. The incidence of adverse reactions was found to be high in patients who had begun use of sustained-release theophylline products at the time of registration in this survey, and in patients who were concomitantly taking macrolide antibiotics.
Conclusions: The present survey demonstrates that sustained-release theophylline is safe, as long as used appropriately, although adverse reactions tend to develop early after initiation of administration.

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Background: A dry powder inhaler of KP-496 is currently in clinical development in Japan as an anti-asthmatic agent. The aim of this study was to evaluate the in vitro pharmacological profile of KP-496.
Methods: The antagonistic activities of KP-496 for leukotriene (LT) D₄ and thromboxane (TX) A₂ receptors were examined using the LTD₄- and U46619-induced contractions of the isolated guinea pig trachea. The selectivity of KP-496 was examined using various agonist-induced contractions in the isolated guinea pig trachea.
Results: KP-496 produced parallel rightward shifts of the LTD₄ and U46619 concentration-response curves in a concentration-dependent manner. Schild plot analyses of the antagonistic activities of KP-496 demonstrated that it is a competitive antagonist for LTD₄ and TXA₂ receptors with pA₂ values of 8.64 and 8.23, respectively. The LTD₄ antagonistic activity of KP-496 was comparable to that of pranlukast and zafirlukast but was more potent than that of montelukast. The TXA₂ antagonistic activity of KP-496 was comparable to that of seratrodast. KP-496 and seratrodast also inhibited the prostaglandin (PG) D₂- and PGF_2α-induced contractions of the isolated guinea pig trachea. KP-496 had no effect on the histamine-, acetylcholine-, serotonin- and substance P-induced contractions of the isolated guinea pig trachea.
Conclusions: These results indicate that KP-496 is a selective dual antagonist for LTD₄ and TXA₂ receptors. LTD₄ and TXA₂ play important roles in asthma, and antagonists for these mediators are being used for the treatment of asthma. Thus, KP-496 is expected to become a novel potent therapeutic agent for asthma.

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Background: We report a case of an urticarial reaction after drinking alcohol beverages. The patient was a 47-year-old man suffering urticarial and anaphylactoid reaction to alcohol for two years. These reactions were observed at every alcohol beverages intake.
Case Summary: We performed a prick test with diluted ethanol, alcohol beverages and their metabolites (acetaldehyde, acetic acid). Only acetic acid showed a positive result. Oral challenge test with diluted-ethanol caused pruritus and swelling of his lips. An oral challenge test with 8% diluted Shochu (Japanese distilled alcohol from rice or wheat) caused wheals on his upper back.
Discussion: Only acetic acid, a metabolite of alcohol, induced a positive prick test in the patient with alcohol-induced urticaria. This result was not observed in normal volunteers. An oral challenge test with diluted-alcohol or Shochu showed a positive wheal reaction in a dose dependent-manner which suggests that urticaria seen in this patient might be induced by alcohol-intolerance. However possible allergic reaction to acetaldehyde could not be excluded.

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