title: Safety evaluation of standardized allergen extract of Japanese cedar pollen for sublingual immunotherapy.
abstract: Japanese cedar (JC) pollinosis is caused by Japanese cedar pollen (JCP) and most common seasonal allergic disease in Japan. Subcutaneous immunotherapy (SCIT) with allergen extract of JCP (JCP-allergen extract) is well established for JC pollinosis treatment with improvement of symptoms. However, major drawbacks for SCIT are repeated painful injections, frequent hospital visits and anaphylactic risk. Currently, sublingual immunotherapy (SLIT) has received much attention as an advanced alternative application with lower incidence of systemic reactions because the liquid or tablet form of allergen is placed under the tongue. The aim of this study was safety evaluation of standardized JCP-allergen extract currently developed for SLIT in JC pollinosis. JCP-allergen extract showed no potential genotoxicity. No systemic effects were observed in rats administered JCP-allergen extract orally for 26 weeks followed by 4-week recovery period. Mild local reactions such as hyperplasia and increased globule leukocytes resulting from vehicle (glycerin)-induced irritation were observed in stomach. No-observed-adverse-effect level was greater than 10,000 JAU/kg/day for systemic toxicity, equivalent to 300-fold the human dose. No local irritation was found in rabbits oral mucosae by 7-day sublingual administration. These results demonstrate the safe profile of standardized JCP-allergen extract, suggesting it is suitable for SLIT in JC pollinosis.
authors.affiliation: Research Laboratory, Torii Pharmaceutical Co., Ltd., 2183-1 Teranosaku, Ota, Sakura, Chiba 285-0808, Japan; Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan. Electronic address: yuko.mitobe@torii.co.jp.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Mitobe
authors.affiliation: Toxicology Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 23-Naganuki, Hadanoshi, Kanagawa 257-0014, Japan.
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Yokomoto
authors.affiliation: Research Laboratory, Torii Pharmaceutical Co., Ltd., 2183-1 Teranosaku, Ota, Sakura, Chiba 285-0808, Japan.
authors.forename: Katsuyo
authors.initials: K
authors.lastname: Ohashi-Doi
mesh_terms: D000284:Administration, Oral; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D032485:Cryptomeria / Q000276:immunology*; D004269:DNA, Bacterial / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007271:Injections, Intradermal; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced; D015162:Micronucleus Tests; D009061:Mouth Mucosa / Q000187:drug effects; D009154:Mutation; D019055:No-Observed-Adverse-Effect Level; D010323:Passive Cutaneous Anaphylaxis; D011058:Pollen / Q000276:immunology / Q000633:toxicity*; D011817:Rabbits; D017207:Rats, Sprague-Dawley; D006255:Rhinitis, Allergic, Seasonal / Q000188:drug therapy* / Q000276:immunology; D018570:Risk Assessment; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D063729:Sublingual Immunotherapy / Q000009:adverse effects* / Q000379:methods; D013997:Time Factors
chemical_list: D000485:Allergens; D004269:DNA, Bacterial
keywords: Allergen extract; Allergen specific immunotherapy; Genotoxicity; Japanese cedar pollen; Oral mucosal irritation; Repeated toxicity; Safety evaluation; Sublingual immunotherapy