g 0.06mg 100g 7mg 3 SD Zn 6,608,000cpm/ mg 10mg/kg Zn γ 65 Zn mM 1 2 /

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1 ( ) - Koji Yoshinaga, Takao Tanaka, Hiroki Hamano, Runa Eta, Takayuki Horii, Yoshihiro Kawabata, Shigeru Furuta, Mineo Takei Zeria Pharmaceutical Co.Ltd., Central Research Laboratories To clarify the effect of polaprezinc (a chelate compound consisting of zinc ion and L-carnosine) on taste disorder, we investigated the effect of polaprezinc on zinc-deficient (Zn( )) diet-induced hypogeusia model in rats. After four weeks on the Zn( ) diet feeding, polaprezinc (1, 3 or 10 mg/kg) for four weeks or [ 65 Zn] polaprezinc (10 mg/kg) for two weeks were administered orally once a day. Zn( ) rats increased the preference rate for quinine hydrochloride solution, while polaprezinc repaired the increased taste preference rate. We also evaluated the proliferation of taste bud cells in the circumvallate papilla using 5-bromo-2 -deoxyuridine (BrdU). The incorporation of BrdU into taste bud cells in Zn( ) rats was reduced as compared with that in zinc-sufficient (Zn(+)) rats and polaprezinc at doses of 3 and 10 mg/kg improved the reduced incorporation of BrdU into taste bud cells. The zinc concentration in the lingual epithelium was markedly decreased in Zn( ) rats as compared with Zn(+) rats. After administration of polaprezinc to Zn( ) rats at doses of 1, 3 and 10 mg/kg, zinc concentration in the lingual epithelium significantly increased. Moreover, after administration of [ 65 Zn] polaprezinc, the 65 Zn radioactivity was mainly detected in the epithelium of the tongue in Zn( ) rats. These findings are indicating that the altered taste preferences by zinc deficiency is induced by the delayed proliferation of taste bud cells, and the restoration of zinc contents by polaprezinc in the lingual epithelium repaired the increased taste preference rate by improving the delay of cell proliferation. The results demonstrate the significance of zinc and the therapeutic efficacy of polaprezinc for taste disorder. : Zinc deficiency ; hypogeusia ; polaprezinc ; distribution ; taste buds proliferation TEL : FAX: kouji-yoshinaga@zeria.co.jp L-

2 g 0.06mg 100g 7mg 3 SD Zn 6,608,000cpm/ mg 10mg/kg Zn γ 65 Zn mM 1 2 / mg/kg mg/kg Bromo-2 deoxyuridine BrdU mg/kg BrdU BrdU BrdU / mg/kg PBS1 ml 4mg 1mg 1mg ICP-MS Fig. 1 Effect of polaprezinc on the preference for quinine hydrochloride in Zn( ) rats. (A) Changes of the preference rate for quinine hydrochloride versus water in Zn(+) rats and Zn ( ) rats. Values are means, n = 12-48, ***p < : significantly different from the Zn(+) group. (B) Values are means, n = 10-12, *p < 0.05, **p < 0.01, ***p < : significantly different from Zn(+) : vehicle group (t-test), # p <0.05, ## p<0.01, significantly different from Zn( ) : vehicle group (Dunnett s test). 8)

3 ( ) mg/kg mg/kg 3mg/kg 10mg/kg Fig.1 BrdU vs : vs p<0.001 BrdU 1mg/kg 3 10mg/kg :Vehicle, 1mg/kg, 3mg/kg, 10mg/kg : p< p <0.001Table 1 Table 1 Group BrdU incorporation rate (%) n Zn(+) Vehicle 52.8 ± Zn( ) Vehicle 43.9 ± 1.2 * 12 Zn( ) Polaprezinc (1 mg/kg) 43.8 ± Zn( ) Polaprezinc (3 mg/kg) 50.2 ± 1.1 # 12 Zn( ) Polaprezinc (10 mg/kg) 51.3 ± 0.8 # 12 vs : 133 1vs83 1µg/g p< mg/kg 3 10mg/kg :Vehicle, 1mg/kg, 3mg/kg, 10 mg/kg : p< p< p<0.001 µg/gfig.2 Effect of polaprezinc on BrdU incorporation into taste bud cells in Zn( ) rats. *p<0.001 compared with Zn(+) vehicle group (t-test), # p< compared with Zn( )vehicle group (Dunnett s test). 9) 65 Zn Zn 3 Fig.3A Zn 2 Fig. 2 Effect of polaprezinc on the zinc concentration in the lingual epithelium of Zn( ) rats. The zinc concentration in lingual epithelium was measured by ICP-MS. Zn( ) rats were orally administered the vehicle or polaprezinc (1, 3, or 10 mg /kg) once a day, while Zn(+) rats were only administered the vehicle. Values are represented as the mean ± standard error (n = 5). ** p<0.01 compared with Zn(+) vehicle (t-test), # p<0.05, ### p<0.001 compared with Zn(-) vehicle (Dunnett s test). 9) 2.97µg/g µg/g µg/g µg/g Fig.3B 65 Zn 65 Zn 65 Zn 65 Zn Fig.4

味覚障害に対する亜鉛製剤ポラプレジンクの作用 Fig. 4 Fig. 3 Serum and lingual radioactivity following repeated oral administration of 65Zn-radiolabeled polaprezinc to Zn(+) and Zn( ) rats.

Values are represented as the mean ± standard error (n = 4-5).

4 味覚障害に対する亜鉛製剤ポラプレジンクの作用 Fig. 4 Fig. 3 Serum and lingual radioactivity following repeated oral administration of 65Zn-radiolabeled polaprezinc to Zn(+) and Zn( ) rats. Following oral administration of [65Zn] polaprezinc to rats for 14 days, serum (A) and lingual (B) radioactivity were measured by gamma counting. Values are represented as the mean ± standard error (n = 4-5). 文献 9)より引用 217 Microautoradiography of the tongue following repeated oral administration of 65Zn-radiolabeled polaprezinc to Zn(+) (A) and Zn( ) (B) rats. Tongues were prepared after administration of [65Zn] polaprezinc for 14 days. Scale bars at the bottom right corner of each image equal 100 µm. 文献 9)より引用亜鉛欠乏による味蕾の味細胞の増殖遅延や味覚障害に対する改善効果に寄与しているものと推測された Scheme 1 味覚障害患者での臨床試験においてプラセボとの比較によりポラプレジンク投与による味覚障害の改善効果が報告 10 されている今回得られたこれらの結果は臨床試験でのポラプレジンクの効果を裏付ける結果でありその作用機序を考える上で多くの情報を与えてくれる以上の結果から亜鉛製剤であるポラプレジンクは味覚障害の治療薬として非常に有用であると考えられた参考文献 Schema 1 1) Henkin RI, Graziadei PPG, Bradley DF : The molecular basis of taste and its disorders. Ann Int Med 71 : , 1969.

5 ( ) - 2) Hamada N, Endo S, Tomita H : Characteristics of 2278 patients visiting the Nihon University Hospital Taste Clinic over a 10-year period with specific reference to age and sex distributions. Acta Otolaryngol(Suppl. 546) : 7-15, ) Ikeda M, Hirai R, Shigihara S, Ikui A : Taste disorders and zinc deficiency. Int J Oral-Med Sci 6 : , ) Hasegawa H, Tomita H : Assessment of taste disorders in rats by simultaneous study of the two-bottle preference test and abnormal ingestive behavior. Auris-Nasus Larynx (Tokyo)13 (Suppl. I) : S33-S41, ) Kobayashi T, Tomita H : Electron microscopic observation of vallate taste buds of zinc-deficient rats with taste disturbance. Auris Nasus Larynx (Tokyo) 13 (Suppl. I) : S25-S31, ) Komai M, Goto T, Suzuki H, Takeda T, Furukawa Y: Zinc deficiency and taste dysfunction : Contribution of carbonic anhydrase, a zinc-metalloenzyme, to normal taste sensation. Biofactors 12 : 65-70, ) turnover. 49: , ) Hamano H, Yoshinaga K, Eta R, Emori Y, Kawasaki D, Iino Y, Sawada M, Kuroda H, Takei M: Effect of polaprezinc on taste disorders in zincdeficient rats. Biofactors 28 : , ) Hamano H, Yoshinaga K, Tanaka T, Eta R, Horii T, Kawabata Y, Furuta S, Takei M : Polaprezinc, a zinc compound, is distributed to the lingual epithelium and increases its zinc concentration in zincdeficient rats. Life Sci 85 : , ) Sakagami M, Ikeda M, Tomita H, Ikui A, Aiba T, Takeda N, Inokuchi A, Kurono Y, Nakashima M, Shibasaki Y, Yotsuya O : A zinc-containing compound, polaprezinc, is effective for patients with taste disorders : randomized, double-blind, placebocontrolled, multi-center study. Acta Oto-Laryngologica 26 : 1-6, 2008.

CHEMOTHERAPY Fig. 1 Body weight changes of pregnant mice treated orally with AM- 715 Day of sestation

CHEMOTHERAPY CHEMOTHERAPY Fig. 1 Body weight changes of pregnant mice treated orally with AM- 715 Day of sestation CHEMOTHERAPY Table 1 Preliminaly test of AM- 715 1): Mean } SD *: Significant difference