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〆 Fⅵ ﾕ{ﾂｨ逢 ｺﾋちM ﾕZﾅ ﾃ|ﾀﾀｯ Zﾆｻ ﾖﾅZﾌｳ P限ｻ Z]

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〆 Fⅵ ﾕ{ﾂｨ逢 ｺﾋちM ﾕZﾅ ﾃ|ﾀﾀｯ Zﾆｻ ﾖﾅZﾌｳ P限ｻ Z] YfY Õ{¨§ ºË¿M ÕZÅÃ|ÀÀ¯ ZÆ» ÖÅZ̳ PÀ» Z] Âa ÄmYÂy ¾Ë}M ,½ZÌËZ¨ ̷ָ f¯{ ½ZƨY Ê°a ¹Â¸ ÃZ´¿Y{ É·¯Z»Z§ ÃÁ³ ¿ Y ½ZÅZ̳ Õ´·Z]£ .|À//Z] Ö» ZÅ ¾Ì¿ÂaZ// į |ÀfÅ ÖËZÅ ºË¿MÁËY ZÅYf//Y Õ{¨//§ Ä] |¿YÂe Ö» YfY Õ{¨//§ Ö³|ÀÀ¯ZÆ» dÌ·Z § ַ¸ Ön¿ZÌ» {Y» Y ÕY Äf//{ ½|// µZ §Ì£ ®¼¯ Ã| {Y|¿ZfY Ö¿Z»{ ÕZÅ Ã{ÁY§ f³ .|ÀÀ¯ Ö» //Ì·ZeZ¯ Y Õ¬¸u ÕZ//Å|Ìe¸¯Â¿ Ö//À Ë |Ë|m cZ^̯e dyZ ÕY] Õ|Ë|m ]ZÀ» ZË Á |À¯ ÕZÅÖ³ËÁ ¶Ì·{ Ä] YfY Õ{¨§ ÕZÅÃ|ÀÀ¯ ZÆ» .|ËZ¼¿ {ZnËY Õ ZÆ» iY ¾ËY Z] ÕZÅ ÕZ¼Ì] ½Z//»{ dÆm {Â//y ®//Ë·¯Z»Z§ ,Ö¿§ÁÌ°Y ,½ÂÀm ,Ö³{//§Y ĸ¼m Y ÖÂÀf» (PDEs) ZÅYfY Õ{¨§ ¾»» {Y|¿Y ÕZ¼Ì] ,ºM ,\¸« Ö¿Z¬fuY ÖËZZ¿ |Àf//Å ZÅ ºË¿M Y ÃÁ³ ZÅYf//Y Õ{¨//§ ,ËÁ¸°//Y ¶bÌf·Z» ,|ÌËÂeZ»Á dËeM ,ÕÂ//Ë ¾Ë¿{M { fY Õ{¨//§ |¿ÂÌa Ì·Á|ÌÅ Z] į { ÕÂË ½ÂÌ¿ZebÌÅ Á ½Y{» { Ö//Àm Ö¿YÂeZ¿ cZ¨§ÂÀ» ¾Ë¿Y³ Á (cAMP) Õ¬¸u cZ¨§ÂÀ» ÌyY ÕZÅ µZ { .|¿Y Äf§³ Y« ÄmÂe {» ½Y{Y¿ ÕZÅ |Ìe¸¯Â¿ ¾ËY ÄËne hZ] (cGMP) ÕÂ//¬¸u Õ̳ ºq  Ä] ÃZ̳ PÀ» Z] ÕZÅÁY{ Ä] ¶ËZ¼e Z] ZÅYfY Õ{¨§ Á ¾ËY Y .|¿Â// Ö» Õ¬¸u ®Ë·¯Z»Z§ µZ § {Y» Öy] .dY Äf§ZË ËY§Y ,Õ¬¸u ÕZÅ |Ìe¸¯Â¿ ¾ËY iY ¹YÁ{ Á d¸£ ºÌÀe Ä̸ ÕZÆ» dÌ·Z § ,|ÀËMÖ» d{ Ä] ½ZÅZ̳ Y į į |¿Y{ ַ¸// {°¸¼ µfÀ¯ { ּƻ ¬¿ Ã|¼ Á |ÀÅ{ Ö» ½Z¿ {Ây Y ZÅYfY Õ{¨//§ Õ³ Ön¿ZÌ» ÄË¿Zi ÕZÅ ½Z// ¹ZÌa ¾ËY ªË Y Á ZÅ|ÌË¿ÁÁÔ§ ,ZÅ|ÌË·Z°·M ÃÁ³ Ä//] ª¸ f» ZÅ ½M ÉY 9 4 Ìe . 4 ÃZ¼ . º Á dÌ] µZ 304 Êa{ Êa 13 269 ÖÅZ̳ PÀ» Z] YfY Õ{¨§ ºË¿M ÕZÅ Ã|ÀÀ¯ ZÆ» (PDEIs) YfY Õ{¨§ ÕZÅ Ã|ÀÀ¯ ZÆ» .(1 ¶°//) {Â//Ö» ÕYY{ ZÅYf//Y Õ{¨//§ ÕZ//Å Ã|ÀÀ¯ ZÆ» Ö·YÂe Z//Y] Yf//Y Õ{¨//§ ÕZÅ ºË¿M ĸ¼m Y |À//Z] Ö» ÖÂÀf» ®Ë·¯Z»Z§ cY//iY ½{Â//] Ö//ZfyY ,ZfyZ// ,Ä//ÀÌ»M ÕZÅ|Ì//Y ,\//¸« Ä//¸ Ö//Z^¬¿Y c|//« Ã|//ÀÅ{ ËY§Y Ä] dÌ//Zu ,ּ˿M ÕZ//Å Ö³ËÁ ,Ã{Z//» Ìa ,¥Z Ä//¸ Ã|ÀÀ¯ ¶// ,©Á// Ã|ÀÀ¯ //f» 11 Ä] Öf§Z] //ËÂe Á Ö//]Zzf¿Y ÕZ//Å Ã|ÀÀ¯ZÆ» ,¿Á] Ã|ÀÀ¯ //f» ,{Z//¬ ¿Y| ,Ö³{//§Y| Ö ] .(PDE1-PDE11) |¿Â Ö» ºÌ//¬e Ã{Y¿Zy Ã|//ÀÅ{ ËY§Y Á ½Y|Ì//¯Y Öf¿M ,[Z//Æf·Y| ÖZfyY ZÌ] cAMP ÕY] ZÅYf//Y Õ{¨§ Ä] .ħZu Á Õ̳{ZË Ä¸¼m Y Ö¯Y{Y ÕZÅ dÌ·Z § ´Ë{ Öy] ,(PDE8, PDE7, PDE4 |À¿Z») |ÀfÅ Õ{¨§ ÕZÅÃ|ÀÀ¯ZÆ» Y ½YÂeÖ» cYiY ¾ËY ¶Ì·{ PDE9 |À¿Z») Ã{Â] ÖZfyY ZÌ//] cGMP ÕY] ĸ¼m Y ÖÂÀf» ÕZÅÕZ¼Ì] ½Z»{ dÆm ZÅYfY Á{ Š¸z» c Ä] Ä//̬] Á (PDE6 , PDE5 Ö¿Z¬fuY ÖËZZ¿ ,Ö¿§ÁÌ°//Y ,½ÂÀm ,Ö³{§Y ĸ¼m Y) |ÀÀ¯ Ö» //Ì·Á|ÌÅ Y Õ¬¸u |//ÌeÂX¸¯Â¿ dËeM ,ÕÂË ¾»» {Y|//¿Y ÕZ¼Ì] ,º//M ,\¸« Ã|ÀÀ¯|¯ ÕZŽ .(PDE11, PDE10 ,PDE3 ,PDE2 ½Á¯ ÕZ¼Ì] ,ËÁ¸°//Y ¶bÌf·Z» ,|//ÌËÂeZ»Á ½ZÌ] ZÅ d§Z] Ö»Z¼e { Z^ˬe0 ZÅYf//Y Õ{¨//§ ½ÂÌ¿ZebÌÅ Á ½Y{» { ÖÀm Ö¿YÂeZ¿ ,(Crohn) ÕÁ ZÅ ºË¿M Y Äf{ ¾ËY ¶Ì·{ ¾Ì¼Å Ä] Á { ֻ .{¼¿ Ã{Z¨fY ½Y{Y¿ { ÕÂË ,|ÀfÅ Y~³iY ®Ë·ÂȨ̈ ÕZÅ{°¸¼ Y ÕZÌ] Ö¸Y ÃÁ³ Á{ Ä] YfY Õ{¨§ ÕZÅÃ|ÀÀ¯ ZÆ» ,¥Z ĸ ZeY ,Ö^¸« ĸ ÕË~aZ^¬¿Y Ì¿ Ö]Zzf¿YÌ£ ÕZÅ Ã|ÀÀ¯ZÆ» / 1 :|¿Â// Ö» ºÌ¬e Á cZ ËZ» Zf¼Š,ÖËZÀÌ] {°¸¼ ,Öf¯Ôa ¼ne ÖËZÅ Ã|ÀÀ¯ ZÆ» / 2 Á ZÅYf//Y Õ{¨§ dÌ·Z § .(1) ÖÀ¼ËY ÕZÅ xZa ÕYf] Z] Á (A) Ö^¸« ĸ { cAMP ÖZfyY ÕYf] Z] YfY Õ{¨§ ÕZÅ ºË¿M Y ÖËZŠĿ¼¿ / 1 ¶° (B) ©Á ¥Z ĸ { cGMP ÖZfyY 304 Êa{ Êa 94 Ìe . 4 ÃZ¼ . º Á dÌ] µZ ÉY 270 14 Âa ÄmYÂy ¾Ë}M ,½ZÌËZ¨ ̷ָ f¯{ µÁZf¸̯ .|¿Â Ö» Ã{Z¨fY Ö^¸« ÖËZZ¿ { į ZÅYfY Õ{¨§ Y ÖZy ÕZź˿MÁËY ÕY] į į d//Y PDE3 Ã|ÀÀ¯ZÆ» ®Ë Ì¿ (Cilostazol) ÕZÅ Ö³ËÁ Ö//y] Ä] ¶Ë} { .|Àf//Å Ö//]Zzf¿Y Y« FDA |ÌËPe {» [ÁZÀf» ´À· ½Z»{ dÆm Ö//¿Z»{ ÕZ//Å{]Z¯ Á PDE Ã{YÂ//¿Zy Â// 11 .dY Äf§³ :{ÂÖ» ÃZY ÄÔy  Ä] ZŽM ÕZÅÃ|ÀÀ¯ZÆ» j¯Y { \·Z£ ºË¿MÁËY Á cAMP PDE ®Ë PDE4 Öy] Ä//¯ {Y{ Ö//¿YÁY§ ÕZ//Å ¹§ÁËY PDE1 ,ÖËYÂÅ Ì» { PDE ¾ËY .dY Ö]ZÆf·Y ÕZÅ µÂ¸ ¶ËZ¼e ´Ë{ Ö//y] Á cGMP ÕY] f//Ì] ¶ËZ¼e ½ZÌ] Ä̸¯ Á Ö«Á / Ö^¸« d§Z] ,¤» ,¥Z ĸ { PDE1 ÕZÅ ºË¿MÁËY .|¿Y{ cAMP ÕY] fÌ] |ÀeZ^ ½M ¥|Å ÕZÅ ÕZ¼Ì] ,¾ËY]ZÀ] .{Â// Ö» ĸ Á ÄË ,Ä̸¯ ,\¸« ,Õ¯» Ö^ ºf//Ì ,ÕÂË ¾»» {Y|//¿Y ÕZ¼Ì] ,®Ë·M d//ÌÀË :Y ¥Y|ÅY ,PDE1 ÕZÅ Ã|ÀÀ¯ZÆ» .{Y{ {Â//mÁ ¥Z ,Ö³{//§Y ,ËÁ¸°//Y ¶bÌf·Z» ,ËZËÂ//a ħZu ¾f§ d{ Y Á ½ÂÀm ÕY] ¶¼fv» Ö¿Z»{ ,ħZu ¾f§ d{ Y ,Ö¿§ÁÌ°Y ,¼ËY·M ÕZ¼Ì] ªf» ®Ë (Vinpocetine) ¾ÌfÂa ¾ËÁ .|ÀZ]Ö» ÕZÅÃ|ÀÀ¯ZÆ» ½ZÌ» Y .|Z]Ö» dÌeZ»{ Á ½Z ] ÕZÆ» iY Z] Z°ÀËÁ ÕZÅ|ÌË·Z°·M Y ÖZÀ ļ̿ ½Z»{ dÆm (Apremilast) d//ÔÌ»aM ,PDE4 {» ¤» ½Ây ½ZËm {Â^Æ] dÆm į dY PDE1 (Roflumilast) d//Ô̻¸§Á Á ËZËÂ//a .{̳ Ö» Y« Ã{Z¨fY //Âe ÕÂË ¾»» {Y|//¿Y ÕZ¼Ì] ½Z»{ dÆm ZÅd¯Ôa Á |^¯ ,ÄË ,\¸« ,µZ¿{M Ã|£ { PDE2 d//ÔË{Â^ËY .|¿Y Äf§³ Y//« |//ÌËZe {Â//» FDA ÕZÅYf] Á{Å cGMP Á cAMP .{ ֻ d§ZË ¿Á] Ã|ÀÀ¯ f» cYiY ¶Ì·{ Ä] Ì¿ (Ibudilast) ÕY] Ö¿Z»{ ¥Y|ÅY į ÖËZÅÕZ¼Ì] .|ÀfÅ PDE2 Õ¤» ÕZÅÄf° Á ºM { Ö¿Á¿ Ã|ÀÀ¯d§Zv» Á Ìb :Y |ÀeZ^ |ÀfÅ PDE2 ÕZÅ Ã|ÀÀ¯ZÆ» dÆm Ì¿ (Cilomilast) d//Ô̻¸̯ .{Y{ {]Z¯ .{Zu Ö¨Àe m ¹Á|À Á į ÕÂË ¾»» {Y|¿Y ÕZ¼Ì] Ä] ½ZËÔf^» ½Z»{ ÄËZ¬» { cAMP ÕY] Õf//Ì] ¶ËZ¼e PDE3 {» d«Â»  Ä] ,|ÀÅ{ Ö¼¿ xZa µÂ»ZeÂ^·Z Ä] { Ze|¼0 Yf//Y Õ{¨//§ ¾ËY .{Y{ cGMP Z//] .dY Äf§³ Y« |ÌËPe ,ZÅ d¯Ôa ,|^¯ ,ÖËYÂÅ Ì» ,Ö¿Z ½Ây ºfÌ ÕYf//] Z] Yf//Y Õ{¨//§ ®//Ë PDE5 .{Y{ {Â//mÁ Ö]ZÆf·Y ÕZÅ µÂ¸// Á Ö//]q d//§Z] Á ZÅ d¯Ôa ,ÄË { Ä//¯ d//Y cGMP ÖZfyY Ö¿Z»{ ¥|Å ®Ë ½YÂÀ Ä] PDE3 ÕZÅ Ã|ÀÀ¯ ZÆ» ÕZÅ Ã|ÀÀ¯ZÆ» .{Â// Ö» ½ZÌ] ©Á ¥Z ĸ ÄfyZÀ ºM Á Ö«Á / Ö^¸« ÕZÅÕZ¼Ì] { ì·Z] ©Á ¥Z ĸ Z//eY hZ] |À¿YÂe Ö» PDE5 Ì¿ Y Ì·ÂbÌ· Á Ã| ZÅ d¯Ôa ¼ne ¿Z» Á |¿Y Ã| ¥Y|ÅY PDE5 ÕZ//Å Ã|ÀÀ¯ZÆ» ,¾//ËY]ZÀ] .|¿Â// Ì¿ ZÅ ¾Ìf¿Y³ ¶Ìf» Á ¾ËÁZaZa .|ÀÀ¯ Ö» ®Ëve ,Ö«Á / Ö^¸« ÕZ//Å ÕZ¼Ì] { ¶¼fv» Ö//¿Z»{ .|ÀfÅ PDE3 ÕZÅ Ã|ÀÀ¯ZÆ» µÁY ¶¿ ¾Ì¸Ì§ÂXe ,ZÅ º¿Zy { Ö//Àm µÔfyY ,ÕÂË ½ÂÌ//¿ZebÌÅ (Enoximone) ½Â¼Ì//¯Â¿Y Á ½ÂÀ˸̻ ,½ÂÀË»M Ä̸¯ ÖËZ//Z¿ Á Ö¼¯Â· ,Äf°// , {Á µY//¿Y |Àf//Å ºË¿MÁËY ¾ËY ÕZÅ Ã|ÀÀ¯ZÆ» ĸ¼m Y Ì¿ ÉY 9 4 Ìe . 4 ÃZ¼ . º Á dÌ] µZ 304 Êa{ Êa 15 271 ÖÅZ̳ PÀ» Z] YfY Õ{¨§ ºË¿M ÕZÅ Ã|ÀÀ¯ ZÆ» Á Ã{Â] ÖZfyY cGMP ÕY] c| Ä] PDE9 ,(Sildenafil) ¶Ì§Z¿|¸Ì Zu µZu { .|À//Z] Ö» ,µZv ,Ä̸¯ ,¤» ĸ¼m Y ¦//¸fz» ÕZÅ d§Z] { (Vardenafil) ¶Ì§Z¿{YÁ Á (Tadalafil) ¶//̧Z¿Y{Ze ½ZÌ] Ã{f//³  Ä] Ã{Á Á ½Â//·Â¯ ,cZf//Áa ½Z»{ dÆm Ä//¯ |Àf//Å PDE5 ÕZÅ Ã|ÀÀ¯ZÆ» Ö]Zzf¿Y Ã|ÀÀ¯ ZÆ» ®Ë BAY 73-6691 .{Â// Ö» .|¿Ì³Ö» Y« Ã{Z¨fY {» ½ZËZ«M { {Á µY¿Y Ìa Ö]ZËY dve į d//Y PDE9 ÕY] |Ë|m Á { Á {Y{ ÄÌ°^ { Y d¸£ ¾Ëf//Ì] PDE6 .|Z] Ö» ¼ËY·M ÕZ¼Ì] ½Z»{ ÕY] ÖÀÌ·Z] PDE ¾Ëe½YÁY§ ÄÌ°^ ÕZÅÂfbÂf§ Ö¸yY{ Z£ Á cAMP Ì·Á|ÌÅ { Ä^¿Zm Á{ dÌ·Z § PDE10 Ö¼ÔaÂfÌ t PDE6 ,ÄÌuZ¿ ¾ËY { .|Z] Ö» º//m { §Á Ä] Á |Å{ Ö» ½Z//¿ {Ây Y cGMP ÖmZy ÖÁz» Á ÕY Ä¿YÂfY d¼« { Y cGMP Ã|ÀÀ¯ZÆ» ®Ë ¾ËÁZaZa .{ ֻ ½ZÌ] ¤» z» ÖËZÀÌ] { ÖeZÌu ¬¿ Á Ã{Y{ ÅZ¯ ¿ Ä] xZa { Õ{°¸¼ //ËZ¬¿ {Â^Æ] { Ä//¯ d//Y PDE10 Á PDE5 ®ÌfÌ·ZeZ¯ ÕZÅÃZ´ËZm į ÖËZm½M Y .{Y{ ZÆ» ,¾ËY]ZÀ] Á |Z] Ö» iR» Ö¿§ÁÌ°Y Y ÖZ¿ fÌ] ,|ÀfÅ ºÅ Ä]Z//» ÁY{ Ä] µZeY { PDE6 ½Z»{ { |Ë|m Õ{//°ËÁ d//Y ¾°¼» PDE10 ½Z¼Å Z//] //Ì¿ Y PDE5, PDE6 ÕZ//Å Ã|ÀÀ¯ZÆ» .|Z] ½ÂÀm ÕZ¼Ì] { µÔfyY h//Z] ,¾ËY]ZÀ] Á Ã{//¯ ZÆ» c|//« Á{ Å ÕÁ į dY ÕYfY Õ{¨§ ,PDE11 .|¿Â Ö» ÖËZÀÌ] Õ|ÅY .|À¯ Ö» ¶¼ cGMP Á cAMP |ÌeÂX¸¯Â¿ ÕY] ÖZfyY Yf//Y Õ{¨//§ ®Ë PDE7 ,cZfÁa ,Öf¸°Y ĸ { ºË¿M ¾ËY ½ZÌ] ] ÖÀ^» ÕZÅ µÂ¸ { Ã{f//³  Ä] į d//Y cAMP PDE11 {°¸¼ .{Y{ {Â//mÁ Ö«Y] {|£ Á Ä//Ì] ÕZÅÁY{ .{Â// Ö» ½ZÌ] Ö//]ZÆf·Y Ìa Á Ö//À¼ËY Ä] į {Y{ {ÂmÁ Ö¯Y|» Z»Y dY ÄfyZÀ//Z¿ ÂÀÅ ½YÂÀ Ä] į |¿Y{ Y ¶Ì¿Zfa ¾ËY PDE7 Ã|ÀÀ¯ZÆ» ÃZY ½Y{» ¶j» |Ì·Âe { ºË¿M ¾ËY Ö·Z¼fuY ¬¿ µZu{ .|¿Â {ZÆÀ//Ìa [ZÆf·Y| |Ë|m ÕZÅÁY{ .(2,3) |À¯ Ö» Ä] PDE7 ÕY//] Ö]Zzf¿Y Ã|ÀÀ¯ZÆ» p//ÌÅ Zu Ö ] ¬§ Á {Y|¿ {ÂmÁ Ã| |ÌËPe ÕÁY{ c YfY Õ{¨§ Ö Ì^ ÕZÅ Ã|ÀÀ¯ZÆ» t// { PDE7 Ö]Zzf¿Y ZÆ» ÖËZ¿YÂe Z] cZ^̯e Ä] ÃZ̳ PÀ» Z] ÕZÅÁY{ Ä] Ä«Ô ,ÌyY ÄÅ{ { .|¿Y Ã| Y³ ÃZ´ËZ»M {Y» Y ÕZÌ] .dY Äf§ZË ËY§Y ÕÌ´¼q  ÕY] ÖZfyY ÕZÅ ºË¿M Y ÕY Ã{Y¿Zy PDE8 ,|¿YÃ|»M d{ Ä] ½ZÅZ̳ Y į ®Ë·¯Z»Z§ µZ § ÕZÅ|ÀËM§ Y ÕZÌ] { ּƻ ¬¿ Á Ã{Â] cAMP |ÀÅ{ Ö» ½Z¿ {Ây Y YfY Õ{¨§ ZÆ» dÌ·Z § |Ì·Âe ,T ÕZÅ µÂ¸ ÕZ µZ § ĸ¼m Y Ö°Ë·ÂÌ] :{{³ Ö» ÃZY ZÅ ½M Ä] ¶Ë} { į {°¸¼ Á µZ°Ìe¯¿{M ÕÔabÌÅ 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