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Ặ ྡ ᒣ ᮏ ♸ ኴ ᮁ
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ච⤌⧊Ꮫἲ䛻䜘䜛పศᏊ་⸆ရ䛾⸆≀ືែ◊✲
ㄽᩥ䛾せ᪨
㻌 ୍⯡䛻⸆≀ືែ䛿䠈⸆≀⾑୰⃰ᗘ䜢䝟䝷䝯䞊䝍䞊䛸䛧䛶◊✲䛥䜜䛶䛚䜚䠈䛭䛾䝕䞊䝍䛿⮫ᗋ䛷 Ᏻ䛛䛴ຠᯝⓗ䛻⸆≀⒪ἲ䜢⾜䛖ୖ䛷㠀ᖖ䛻㔜せ䛷䛒䜛䚹䛧䛛䛧䠈⸆≀䛾స⏝㒊䜔స⏝䛾
Ⓨ⌧㒊䛾ゎ᫂䜔⸆≀䛾ຠᯝ䜔స⏝䛾ᶵᗎゎ᫂䛺䛹䛾䛯䜑䛻䛿䠈⾑୰⃰ᗘ䜢 ᐃ䛧䛯䛰䛡 䛷䛿༑ศ䛸䛿ゝ䛘䛺䛔䛣䛸䜒ᐇ䛷䛒䜚䠈⸆≀ືែ䛾䜘䜚ṇ☜䛺ᢕᥱ䛾䛯䜑䛻䛿䠈⤌⧊䞉⣽⬊䝺䝧 䝹䛷䛾⸆≀ᒁᅾ䛸䛭䛾㛫⤒㐣䛻䜘䜛ኚ䜢ㄪ䜉䜛ᚲせ䛜䛒䜛䚹⤌⧊䞉⣽⬊䝺䝧䝹䛷䛾⸆≀ື
ែ䛾ゎᯒἲ䛸䛧䛶ᚑ᮶⏝䛔䜙䜜䛶䛔䛯䜰䜲䝋䝖䞊䝥ᶆ㆑⸆≀䜢⏝䛔䜛 autoradiography ἲ䜔㏆ᖺ 㛤Ⓨ䛥䜜䛯Imaging Mass Spectrometry (MS)ἲ䛺䛹䛜Ꮡᅾ䛩䜛䛜䠈䛣䜜䜙䛻䛿䠈ᨺᑕᛶ≀㉁䜢ྲྀ
䜚ᢅ䛖䛯䜑䛾≉ู䛺༊⏬䜢タ⨨䛩䜛ᚲせ䛷䛒䛳䛯䜚䠈㧗㢠䛺ᶵჾ䛜ᚲせ䛷䛒䛳䛯䜚䛸䛔䛳䛯ᵝ䚻 䛺▷ᡤ䛜Ꮡᅾ䛧䠈୍⯡䛾◊✲ᐊ䛻ᬑཬ䛧䛶䛔䜛䛸䛿ゝ䛔㞴䛔䚹䛣䜜䜙䛻ẚ䜉䛶䛂⸆≀䜢䝍䞊䝀䝑䝖 䛸䛩䜛ච⤌⧊Ꮫἲ䛃䛿䠈⡆౽䠈Ᏻ౯䠈Ᏻ䛷䛒䜚䠈ྠ➼௨ୖ䛾ṇ☜ᛶ䠈≉␗ᛶ䜢ᣢ䛴ゎᯒἲ 䛷䛒䜚䠈䛣䜜䜎䛷✀䚻䛾⸆≀䛻䛴䛔䛶⤌⧊䞉⣽⬊䝺䝧䝹䛷䛾⸆≀ືែ䜢ሗ࿌䛧䛶䛔䜛䚹
ᮏ◊✲䛷䛿, ᮍ䛰⤌⧊䞉⣽⬊䝺䝧䝹䛷䛾⸆≀ືែ䛻㛵䛩䜛ヲ⣽䛺䝕䞊䝍䛜ᚓ䜙䜜䛶䛔䛺䛔⸆
≀䜢◊✲ᑐ㇟䛸䛧䛶, 䛭䜜䜙䛾⤌⧊䞉⣽⬊ෆືែ䜢ච⤌⧊Ꮫⓗ᪉ἲ䛻䜘䜚ゎᯒ䛧䛯䚹 㻌 㻌
1䠊2✀㢮䛾ᢠMRSA⸆Teicoplaninཬ䜃Daptomycin䛾䛭䜜䛮䜜䛻ᑐ䛩䜛≉␗ᢠయ䜢స〇 䛧䠈䛭䜜䜙䜢⏝䛔䛯ච⤌⧊Ꮫἲ䛻䜘䜚ྛ⸆≀䛾⤌⧊䞉⣽⬊䝺䝧䝹䛷䛾ືែゎᯒ䜢⾜䛳 䛯䚹䛭䛾⤖ᯝ䠈䐟Teicoplanin䛿㏆ᒀ⣽⟶ୖ⓶⣽⬊䛾ᚤ⤧ẟ䜘䜚άⓎ䛻྾䛥䜜䛶䛔䜛 䛣䛸䠈ᢞᚋ24㛫䛷䜋䜌⭈⮚䛛䜙ฟ䛥䜜䛶䛚䜚䠈ᢞᚋ8᪥䛷䜒ከ㔞䛻✚䛧䛶䛔䛯 Vancomycin䛻ẚ䜉䛶✚ᛶ䛜ప䛔䛣䛸䜢♧䛧䛯䚹Teicoplanin䛜Vancomycin䛻ẚ䜉䛶స
⏝䛾䝸䝇䜽䛜ప䛔䛾䛿䠈䛣䛾✚ᛶ䛾ᕪ䛻㉳ᅉ䛧䛶䛔䜛ྍ⬟ᛶ䛜♧䛥䜜䛯䚹䛣䛾✚ᛶ䛾ᕪ 䛿䠈ྠ䛨䜾䝸䝁䝨䝥䝏䝗⣔ᢠ⏕≀㉁䛷䛒䛳䛶䜒ྛ⸆≀䛾ᒀ⣽⟶䛛䜙䛾྾䛸ศἪ䛻㛵䛩 䜛䝖䝷䞁䝇䝫䞊䝍䞊䛾✀㢮䛸Ⓨ⌧䝺䝧䝹䛻㐪䛔䛜䛒䜛ྍ⬟ᛶ䜢♧၀䛧䛶䛔䜛䚹
䐠Daptomycin䛿㏆ᒀ⣽⟶ୖ⓶⣽⬊䛾ᚤ⤧ẟᇶ㒊䛻䝸䞁䜾≧䛾㝧ᛶᛂ䛜☜ㄆ䛥䜜䠈䜶䞁
䝗䝃䜲䝖䞊䝅䝇⤒㊰䛻䜘䜚⸆≀䛜⣽⬊ෆ䛻ྲྀ䜚㎸䜎䜜䛶䛔䜛䛣䛸䜢☜ㄆ䛧䛯䚹䜎䛯䠈ᢞᚋ24 㛫䛷䛿㏆ᒀ⣽⟶ୖ⓶⣽⬊୰䛾᰾䛸䝸䝋䝋䞊䝮୰䛻Daptomycin䛜ᒁᅾ䛧䛶䛔䛯䛜䠈ᢞᚋ7
᪥䛷䛿⭈⮚䛛䜙ἥ䛥䜜㛗ᮇ㛫✚䛧䛺䛔䛣䛸䜢᫂䜙䛛䛻䛧䛯䚹䛧䛛䛧䠈ᢞᚋ24㛫䛷䛿㏆
ᒀ⣽⟶ୖ⓶⣽⬊୰䛾䝸䝋䝋䞊䝮䛻Daptomycin䛜✚䛧䛶䛔䛯䛣䛸䛛䜙䠈⮫ᗋ䛻䛚䛔䛶ᩘ㐌 㛫㐃⥆ᢞ䛥䜜䛯ሙྜ䠈Daptomycin䛜䝸䝋䝋䞊䝮䛻✚䛧䠈䛭䜜䛜స⏝䛷䛒䜛⭈ẘᛶ䛾ཎ ᅉ䛾1䛴䛸䛺䜛ྍ⬟ᛶ䛜♧၀䛥䜜䛯䚹
2. 2ᆺ⢾ᒀ⒪⸆䛷䛒䜛Alogliptin䛻ᑐ䛩䜛≉␗䝰䝜䜽䝻䞊䝘䝹ᢠయ䜢⏝䛔䛯ච⤌⧊Ꮫ ἲ䛻䜘䜚⭈⮚ཬ䜃⫢⮚䛷䛾Alogliptin䛾ᒁᅾ䜢ゎᯒ䛧䛯䚹䛭䛾⤖ᯝ䠈⸆≀ᢞᚋ1㛫䛾⭈
⮚䛷䛿䠈㏆ᒀ⣽⟶S3ศ⠇䛾ୖ⓶⣽⬊య䛜ᰁⰍ䛥䜜䛯䛜䠈S1, S2ศ⠇䛿ୖ⓶⣽⬊䛾ᚤ⤧
ẟ䛾䜏䛜ᰁⰍ䛥䜜䛶䛔䛯䚹䜎䛯䠈㐲ᒀ⣽⟶䜔㞟ྜ⟶䛻䜒㝧ᛶ⣽⬊䛜ほᐹ䛥䜜䛯䚹ᢞᚋ24
㛫䛾⭈⮚䛷䛿, ㏆ᒀ⣽⟶S3ศ⠇䛻䛿୰➼ᗘ䛾㝧ᛶᛂ䛜ㄆ䜑䜙䜜䛯䛜䠈䛾㡿ᇦ䛿䜋 䛸䜣䛹ᰁⰍ䛥䜜䛺䛛䛳䛯䚹⫢⮚䛷䛿䠈ᢞᚋ1㛫䛷䠈⸆≀௦ㅰ㓝⣲䜢㧗ᗘ䛻Ⓨ⌧䛧䛶䛔䜛⫢
ᑠⴥ䛾䝌䞊䞁III䛾⫢⣽⬊䛻䝌䞊䞁I䛾⫢⣽⬊䜘䜚䜒ᙉ䛔ᰁⰍ䛜ㄆ䜑䜙䜜䛯䛜䠈ᢞᚋ24㛫 䛷䛿䜋䜌ᾘኻ䛧䛶䛔䛯䚹䛣䜜䜙䛾⤖ᯝ䛿䠈Alogliptin䛾⭈⮚䛷䛾྾䛸⫢⣽⬊䛷䛾ྲྀ䜚㎸䜏 䛜㒊䛻䜘䛳䛶␗䛺䛳䛶䛚䜚䠈䛣䜜䜙䛾䝥䝻䝉䝇䛻1䛴䜎䛯䛿」ᩘ䛾䝍䜲䝥䛾䝖䝷䞁䝇䝫䞊䝍䞊䛜 㛵䛧䛶䛔䜛ྍ⬟ᛶ䜢♧၀䛧䛶䛔䜛䚹䛥䜙䛻䠈Alogliptin䛿㛗ᮇ㛫䛾⏝䛻䜘䜚䠈⸆≀䛜S3䝉䜾 䝯䞁䝖䛻✚䛧䛶⾜䛝䠈స⏝䜢ᘬ䛝㉳䛣䛩ྍ⬟ᛶ䛜♧䛥䜜䛯䚹୍᪉䠈 ⫢⮚䛷䛾స⏝䛿䠈⸆
≀䛾✚௨እ䛾⌮⏤䛻䜘䜛䜒䛾䛷䛒䜛ྍ⬟ᛶ䛜♧၀䛥䜜䛯䚹
3.䛜䜣⣽⬊䛻ከ䛟ฟ⌧䛧䛶䛔䜛EGFR䛻ඹ᭷⤖ྜ䜢⏕䛨, ᢠ⭘⒆ຠᯝ䜢♧䛩2✀㢮䛾ศᏊᶆⓗ
⒪⸆Afatinibཬ䜃Dacomitinib䛻ᑐ䛩䜛ච⤌⧊Ꮫἲ䛾㛤Ⓨ䛸, 䛣䜜䜢⏝䛔䛯䝷䝑䝖ᑠ⭠
ཬ䜃⓶䛻䛚䛡䜛⸆≀ືែゎᯒ䜢⾜䛳䛯䚹୍⯡ⓗ䛻ච⤌⧊Ꮫἲ䛾᳨ฟᑐ㇟䛷䛒䜛ᢠཎ≀
㉁䠄䝍䞁䝟䜽㉁䠈1⣭䜰䝭䝜ᇶ䜢ᣢ䛴పศᏊྜ≀䛺䛹䠅䛿䠈䝩䝹䝬䝸䞁䜔Glutarualdehyde䛺䛹䛾
ᯫᶫ䜢⏝䛔䛶ᢠཎ䛾䜰䝭䝜ᇶ䛸⤌⧊ෆ䝍䞁䝟䜽㉁䛾䜰䝭䝜ᇶ䜢⤖ྜ䛥䛫⤌⧊ෆ䛻ᅛᐃ䛩䜛䚹䛧 䛛䛧䠈Afatinib䛸Dacomitinib䛿1⣭䜰䝭䝜ᇶ䜢ᣢ䛯䛺䛔䛯䜑ᯫᶫ䜢⏝䛔䛶䜒⤌⧊䛻ᅛᐃ䛩䜛 䛣䛸䛿䛷䛝䛺䛔䚹䛧䛛䛧䠈୧⸆䛿α, β-㣬䜿䝖䞁㒊ศ䜢᭷䛧䛶䛔䜛䛾䛷⏕యෆ䛷ErbB䝣䜯䝭䝸 䞊ཷᐜయ䜔䛾䝍䞁䝟䜽㉁䛸䝬䜲䜿䝹ຍᛂ䛻䜘䜚ඹ᭷⤖ྜ䜢ᙧᡂ䛩䜛䚹䛣䛾䜘䛖䛻䛧䛶ᙧᡂ 䛥䜜䛯Afatinib or Dacomitinib-protein conjugate䛿䠈ᯫᶫ䛻䜘䜚⤌⧊ෆ䛷䛾ᅛᐃ䛜ྍ⬟䛷䛒 䜛䚹䛭䛣䛷ᢠAfatinibᢠయ䜢⏝䛔䛶Afatinib or Dacomitinib- protein conjugate䛾ᒁᅾ䜢ゎᯒྍ
⬟䛺ච⤌⧊Ꮫἲ䜢㛤Ⓨ䛧䠈䝷䝑䝖⭠⟶ཬ䜃⓶䛻䛚䛡䜛Afatinib or Dacomitinib-protein
conjugate䛾ᒁᅾ䜢ゎᯒ䛧䛯䚹ᮏ◊✲䛾⤖ᯝ䜘䜚䠈⭠⟶ཬ䜃⓶䛻䛚䛡䜛Afatinib or
Dacomitinib-protein conjugate䛾ᒁᅾ䛿䠈ྛ⤌⧊䛾EGFRⓎ⌧㒊䛸䜋䜌୍⮴䛧䛶䛔䜛䛣䛸䛜
᫂䜙䛛䛸䛺䛳䛯䚹ᮏ◊✲䛿䠈䝷䝑䝖䛾⭠⟶⣔ཬ䜃⓶䛻䛚䛡䜛Afatinib or Dacomitinib-protein conjugate䛾ᒁᅾ䜢ゎ᫂䛧䛯᭱ึ䛾䜒䛾䛷䛒䜚䠈Afatinib䜔Dacomitinib䛻䜘䜛ㄏⓎᛶୗ⑩䜔⓶
ẘᛶ䛾䝯䜹䝙䝈䝮䜢ゎ᫂䛩䜛䛖䛘䛷᭷⏝䛷䛒䜛䛸ᛮ䜟䜜䜛䚹
