ラウリン酸ナトリウム誘発モルモット末梢動脈閉塞モデル に対する抗血小板薬pamicogrel の作用 ࡥ༖᪾Бᴧ1ᴩ˧ ޤ ႏ ޖᴧ2ᴩࠞՠᯚխᴧ3 ႎᐖˢᴧ3ᴩๅӏటޔࢶᴧ2ᴩձǽᔐपᴧ1
ᚌಃඨᚌᝒ 16(2):212~221ᴩ 2005
◆ේޓ⪺◆ᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡᛡ
ラウリン酸ナトリウム誘発モルモット末梢動脈閉塞モデル に対する抗血小板薬pamicogrel の作用 ࡥ༖᪾бᴧ1ᴩ˧ ޤ ႏ ޖᴧ2ᴩࠞՠᯚխᴧ3 ႎᐖˢᴧ3ᴩๅӏటޔࢶᴧ2ᴩՁǽᔐपᴧ1
ʬʑʵȾߦȬɞ pamicogrelᴥ KBT3022ᴦ Ɂผჵӛɥ೫ڸǽʳɰʴʽᥣᄉʬʵʬʍʒఞಷӦᑩᩐ ᒈᄠᒑຣ࣊Ɂ۾ᒈӦᑩюੵ˫ऻɁᄠᒑ༆ძɁࠕՒɆ۾ȬɞᄻᄑȺᴩʳɰʴʽᥣʔʒʴɰʪɁ Ͳ˩ȾߦȬɞͽႊɥ೫Ȫᴩticlopidine, acetylsalicylic acidᴥ ASAᴦ ȝɛɆ cilostazol ɁͽႊȻᢎȪȲᴫ و Pamicogrelᴥ 0.1, 0.3 ȝɛɆ 1 mg/kg, p.o.ᴦ ɂʳɰʴʽᥣʔʒʴɰʪӦᑩюੵ˫ 1 ᩖऻɛɝ 1 ஓ 1 ᄑȾѿᏚϫऻᑆɁᄠᒑ༆ძɁࠕɥੱސᩖጽՠੵ˫ȬɞȦȻȾɛɝ໎ݨੵ˫ᏰȻᢎȪȹႊᦀΗ 2 ᒈᄠᒑຣɁͲ˩ɥ pamicogrel۾ҤȪȲᴫɑȲᴩʳɰʴʽᥣʔʒʴɰʪੵ˫ 1 ȝɛɆ 3 ஓऻɁѿᏚϫ ɂ 1 mg/kg ੵ˫ᏰȾȝȗȹȾੱҤȪȲᴫTiclopidineᴥ 100 ȝɛɆ 300 mg/kg, p.o.ᴦ ɕպറȾ໎ݨੵ ˫ᏰȻᢎȪȹႊᦀΗސᄑȾᄠᒑ༆ძɁࠕɥੱҤȪȲᴫˢᴩticlopidine ɂʳɰʴʽᥣʔʒʴɰʪ ᒈᄠᒑຣɁͲ˩ɥȾੱҤȪȲȟᴩ3 ஓऻȝɛɆ 300۾ੵ˫ 1 ஓऻȾ 100 mg/kg ɁႊᦀȾȝȗȹ mg/kg ɁႊᦀȾȝȗȹɂɜȞȽͽႊɥᇉȨȽȞȶȲᴫASA ɂᄠᒑ༆ძɁࠕɥ 10 mg/kg Ⱦȝȗȹ ʳɰʴʽᥣʔʒʴɰʪੵ˫ 3 ஓऻȾᴩ30 mg/kg Ⱦȝȗȹ 3, 7 ȝɛɆ 10 ஓऻȾ໎ݨੵ˫ᏰȻᢎȪȹ ᒈᄠᒑຣɂ ASA 30 mg/kg۾মȨȮȲȟᴩ100 mg/kg ɁႊᦀȺɂɜȞȽͽႊɥᇉȨȽȞȶȲᴫۄȾ ೫ȪȲႊᦀȾوऐȨȮȲᴫCilostazolᴥ 10 ȝɛɆ 30 mg/kg, p.o.ᴦ ɂ̾ۄɁ 3 ஓऻɁɒȾͲ˩ɥ ᒈᄠᒑຣȾߦȪȹ໎ݨੵ˫ᏰȻᢎȪȹɜȞȽͽႊɥᇉȨȽȞȶȲᴫ۾ȝȗȹᄠᒑ༆ძȝɛɆ ʬʑʵȾȝȗȹᕻȽผჵڸǽ͏˨ɁፀȞɜᴩpamicogrel ɂʳɰʴʽᥣᄉʬʵʬʍʒఞಷӦᑩᩐ ӛɥᇉȬȦȻȟɜȞȻȽȶȲᴫ
Key words: áîôéðìáôåìåô äòõç¬ áòôåòéáì ïããìõóéöå äéóåáóå¬ çõéîåá ðéç¬ ðáíéãïçòåì¬ óëéî ôåíðåòáôõòå
ȸȗȹȗɞᴫˢᴩASA ɂȰɁ COX1 ᩼ژ 緒 言 ͽႊȾɛɝᚌከюᄠጯᑛȞɜɁprostacyclin
ǽᚌߴɁ๊ॴԇɂӦᑩᚌಃდȽȼɁგৰȾȝ ᴥPGI2ᴦ ႇႆɕੱҤȬɞᴫPGI2 ɂऐӌȽᚌከછ ȺȕɝᴩȨɜȾᚌߴѼᪿੱҤɥȬɞފىȗȹᛵȽमҾɥȫȹȗɞȦȻȞɜᴩ ए acetylsalicylic acidᴥ ASAᴦ ɥֆɓሗȁɁᚌߴ ȦȻȞɜ ASA ȾɛɞᚌಃढɁੱҤͽႊȟນ ᗧȟᩒᄉȨɟᚌಃდɁผჵȾࢿȢΈႊȨɟȹ ऍȨɟɞȦȻȟଊȨɟȹȗɞ1)ᴫȨɜȾᴩ ȗɞᴫASA ɁᚌߴͽႊɂᚌߴɁ ASA ɂᑑᒅከȾȝȤɞ COX1 ɥ᩼ȬɞȦȻ cyclooxgenase1ᴥ COX1ᴦ ੱҤͽႊȾɛɝऐӌ Ⱦɛɞ prostaglandinᴥ PGᴦ ႇႆɁੱҤՒɆ ASA Ⱥȕɞ ɁᑑዯᒒɋɁᄽᄑȽҨ༜Ⱦɛɝᑑᒅከ᪩ȝފىȽᚌߴ๊ॴԇՒɆᚌከՖ᎔ 2) 3) thromboxan A2ᴥ TxA2ᴦ ɁႇႆɥੱҤȬɞͽႊȾ ɛɆҋᚌɥᄉးȬɞȦȻȟᅺɜɟȹȗɞ ᴫ
ផ࣋ȐȎ 502-8585 ࠢ᩵ࢍ˧ႎ฿ూ 5-6-1ȑޙފႆͶൡᑤґޙ۾ǽ 1 ࠢ᩵ᗧᇼ ǽ 1 Department of Biofunctional Molecules, Gifu Pharmaceutical University,Ȑ5-6-1 Mitahora-higashi, Gifu 502-8585 Japanȑ Tel: 058-237-3931ǽFax: 058-237-5979ǽe-mail: [email protected] ࡀɬʚʽʀ 14Fȑڛࡀ 1-6-20ǽڛ᩸ࢍԈԖ۾ ǽ 2 ஓటɴʵɶʘʽಊࣻ͢ᇋᗧ̜ᗧҤటȐȎ 530-0003 ǽ 2 Nippon Organon K.K., Regulatory AffairsȐDojima Avanza 14F 1-6-20 Dojima, Kita-ku Osaka 530-0003 Japanȑ ࡀɬʚʽʀ 14Fȑڛࡀ 1-6-20ǽڛ᩸ࢍԈԖ۾ ǽ 3 ஓటɴʵɶʘʽಊࣻ͢ᇋԗᗧᩒᄉటȐȎ 530-0003 ǽ 3 Nippon Organon K.K., Clinical DevelopmentȐDojima Avanza 14F 1-6-20 Dojima, Kita-ku Osaka 530-0003 Japanȑ ՙ͇ᴷ2004 ࢳ 12 ఌ 24 ஓǽՙျᴷ2005 ࢳᴮఌ 29 ஓ ʬʑʵȾߦȬɞᚌߴᗧ pamicogrel Ɂͽႊ 213ڸࡥ༖ᴩɎȞᴷʳɰʴʽᥣʔʒʴɰʪᄉʬʵʬʍʒఞಷӦᑩᩐ
᩸ᴦ ȝɛɆ cilostazolᴥஓటɴʵɶʘ۾ȦɟɜɁȦȻȞɜᴩɛɝᤣᄑȾᚌߴɁ бጠᗧᴩ ᩸ᴦ ɂ 0.5ᴢ ʧʴɴɷʁɲʋʶʽʇʵʝ۾COX ɥ᩼Ȫᴩᑑዯᒒ᪩ɥᄉးȪȽȗᚌ ʽᴩ ۾ߴᗧɁᩒᄉȟఖɑɟȹȗɞᴫ ʉʽʬʘɴʶɲ˂ʒᴥ Tw e e n 8 0 ᴩ֪бጠᗧᴩ ǽEthyl 2[4, 5bisᴥ4methoxyphenylᴦthiazol2 ᩸ᴦ ໎Ⱦੵ˫ᦀȟ 5 ml/kg ȾȽɞɛșȾਰ yl] pyrrol1ylacetateᴥpamicogrel; KBT3022ᴦ ༝ȪȲᴥ̓ᦷȺੵ˫߁ᦀɁ Tween 80 ȻȻɕȾ ॴӦᑩᆕԇდᴥ ASOᴦ ȬɝȷɉȪᴩᖘႡ෩Ⱥఊጶ༟࣊ɥ 0.5ᴢ ȻȪڸდ [ ᩐڸɂ৻ॴӦᑩᩐ ȝɛɆ Burger გᴥ TAOᴦ ] ผჵᗧᩒᄉɥᄻᄑȾ ȲᴦᴫCollagenᴥʬʴʮႇഈᴩూ̱ᴦ ȝɛɆ ADP ᩒᄉȨɟȲȾնȨɟȲᚌߴᗧȺȕ ᴥɲʪˁʁ˂ˁʫʑɭɵʵᴩూ̱ᴦ ɂȰɟȱɟ ȾںɞᴫPamicogrel ȻȰɁ˿ᛵ๊ॴ͍ព࿎ desethyl ͇ࠖɁ SKF ʚʍʟɫ˂ȝɛɆႆျᄑ᭥ pamigogrel ɂ COX ȝɛɆ5lipoxygenase ᩼ ໎ᜓȪȲᴫᚱ᮷ᗧɑȲɂ໎ݨ ᴥ 0.5ᴢ Tween 80 ͽႊɥȪᴩ pamicogrel ɂጽՠੵ˫Ⱦɛɝᚌከ ໎ᴦ Ɂጽՠੵ˫ɂʳɰʴʽᥣʔʒʴɰʪੵ˫
ɁوɁ PGI2 ɛɝɕᤣᄑȾᚌߴɁ TXA2 ႇႆ 1 ᩖऻɛɝᩒܿȪᴩȰɁஓȞɜ 1 ஓˢے ɥੱҤȪᴩȨɜȾԚґȽᚌߴͽႊՒɆᚌ ᩖ᪣Ⱥ 14 ஓᩖੵ˫ȪȲᴫ ȠȞȶȲȲɔȾ۾Ɂᝁ᮷ɂ᮷ൌȟوಃͽႊȟᝓɔɜɟɞੵ˫ᦀȾȝȗȹ ASA Ⱦᝓ ǽ̾ Experiment 1ᴥ Exp. 1ᴦ ՒɆExperiment 2] و ɔɜɟɞɛșȽᑑᒅከ᪩ɥමȼᇉȨȽȗȦȻ 2 Ȩɟȹȗɞ4)6)ᴫȨɜȾ pamicogrel ɂሗȁ ᴥExp. 2ᴦ ] ȾґȤȹஃȪȲᴫिȶȹᴩ Exp. 1֖ڨȟ ɁӦ࿎ሗȾȝȤɞӦᑩᚌಃʬʑʵȾȝȗȹᚌಃ ՒɆ Exp. 2 ɁȰɟȱɟȾߦྃᏰɥᜫȤȲᴫȨ Ȩɟȹȗɞ7)9)ᴫɑ ɜȾᴩ Exp. 2 ȾɂॴߦྃȻȪȹ pamicogrel 1֖ڨढɥੱҤȬɞȦȻȟ ȲᴩʬʵʬʍʒɁᠣᚌ္۰ढᑤᴩᚌዯ࣊ՒɆ mg/kg, p.o. ੵ˫ᏰɥጸɒоɟȲᴫ ڨȬɞȦȻȟױᚌ༲ᤈᑤȽȼᚌํӦॴɥ ȸȠᴩ 2．ラウリン酸誘発モルモット末梢動脈閉塞ژȨɟȹȗɞ10)ᴫȦɟɜɁͽႊȾ֖ pamicogrel ɂͅɁᚌߴᗧɛɝɕऐȗᚌಃ モデル ͽႊȟఙशȨɟɞᴫȪȞȪᴩ pamicogrel Ɂ৻ॴ ǽʬʵʬʍʒɥʤʽʒʚʵʝʉ˂ʵᲽᥖ˩ᴥʗ /ʬʑʵȾߦȬɞผჵӛȾȷȗȹɂ೫ ʽʠʉ˂ʵᴩɬʦʍʒʳʦʳʒʴ˂ʄᴩ40 mgڸӦᑩᩐ ᒈӦᑩɥ۾ȨɟȹȗȽȗᴫ kg, i.p.ᴦ ȺίຣʛʍʓȾِްȪᴩծ ᒈӦᑩɁ˹ϫɥ۾დȾߦȬ ϾȷȤȽȗɛșȾҋȨȮڸǽȰȦȺᴩ pamicogrel Ɂ৻ॴӦᑩᩐ ɞผჵӛɥɜȞȾȬɞᄻᄑȺʳɰʴʽᥣ ɹʶʽʫȺඨɔᚌํɥϦඨȨȮᴩȰɁఞಷϫȾ ʬʑʵȾߦȬɞ าߪᦉɥᬲᚐॴȾҨоȪʳɰʴʽᥣʔʒʴɰʪڸᄉʬʵʬʍʒఞಷӦᑩᩐ pamicogrel ɁผჵӛȾȷȗȹ೫Ȫᴩ ᴥ10 mg/ml in saline, 0.1 ml at 37Ƈᴦ ɥੵ˫ȪȲ ticlopidine, ASA ȝɛɆ cilostazol ɁͽႊȻᢎ ᴥFig. 1AᴦᴫาߪᦉҨоͱɂɬʷʽɬʵʟɫ ೫ȪȲᴫ ᴥూ̧նಊࣻ͢ᇋᴦ Ⱦɛɝᩐȫᴩʳɰʴʽᥣ ʔʒʴɰʪੵ˫Ɂ 5 ґऻȾɹʶʽʫɥ۶Ȫѓ ۾ᩒᣮȨȮȲᴫఊऻȾҒᩒɥ᎓նȪஓɛɝ 実験材料および方法 ᒈɁᄠᒑຣ࣊ɥຣ࣊ʅʽɿ˂ᴥ THR Dᴩᓱ๕ 1．使用薬物 ފᛏͽᴦ ɥΈႊȪ Animal Blanket Controller ǽʳɰʴʽᥣʔʒʴɰʪᴥూ̱ԇᴩూ̱ᴦ ɂ ᴥATB1100ᴩஓటбᴦ ɥ̿ȪȹጽᄑȾᜊߔ ᛏᗧᴩोࡀᴦ ɥӏțᴩ 37Ƈ ȪȲᴫᄠᒑ༆ძɁࠕɂɴʤऻ 3, 7, 10 ȝɛɆڷ۾ᴥںႆျᄑ᭥ ȾӏຣȪȹ໎ᜓȨȮ 10 mg/ml ȻȪȲᴫPamicogrel 14 ஓᄻȾʑʂʉʵɵʫʳᴥ PowerShot 600, ᩸ᴦ ᴩticlopidineᴥஓటɴ Canonᴦ ɥႊȗȹќᅊଟफᴥࡿծᴩ႐ȝɛɆᚾ۾ᴥஓటɴʵɶʘʽᴩ ᩸ᴦᴩacetylsalicylic acidᴥ ASAᴩ֪ տɁ 4 ኙଟफᴦ ɥᚐȗᴩпȹɁᝁ᮷ጶ̘۾ʵɶʘʽᴩ 214 ஓటᚌಃඨᚌޙ͢ᝒǽቼ 16 ࢊǽቼ 2 հ
A) B)
9 or 10 7 or 8 5 or 6 3 or 4 1 or 2 SodiumSodium lauratelaurate (i.a.) (i.a.)
Saphenous artery
Femoral artery
Fig. 1ǽShematic diagram of laurate injection into femoral artery (A) and criteria for lesion score of whole paw and lower leg (B) in guinea pig.
A D
B E
C
Fig. 2ǽǽReprisentative photographs of ischemic lesion 14 days after sodium laurate injection.ǽA: Sham, B: Vehicle, C: Pamicogrel at 0.3 mg/kg/day, p.o., D: Pamicogrel at 1 mg/kg/day, p.o., E: Ticlopidine at 300 mg/gk/day, p.o. ʬʑʵȾߦȬɞᚌߴᗧ pamicogrel Ɂͽႊ 215ڸࡥ༖ᴩɎȞᴷʳɰʴʽᥣʔʒʴɰʪᄉʬʵʬʍʒఞಷӦᑩᩐ
ऻȾʠʳɮʽʓȺ 3 ̷ɁҜްᐐȟҝȁȾќᅊ ᪿᑤລްᚽᏚ˹Ⱥ 37Ƈᴩ1 ґᩖɮʽɷʯʣ˂ʁ նᴩȰɁҜްፀ ʱʽȪᴩɽʳ˂ɼʽᴥ 10 µg/mlᴦ ɑȲɂ ADPᴥ 2کҜްȪᴩ2 ̷͏˨ˢᒵȪȲ µMᴦ ɥຍӏȪᴩᚌߴѼᪿɥৎᠭȨȮȲᴫ5 ґ کɥႊȪȲᴫɑȲᴩ3 ̷ȻɕˢᒵȪȽȞȶȲ ᣥᤈ࣊ɥᚌ۾նɂȰɁ˹ᩖɁʃɽɬɥҜްፀȻȪȲᴫᄠᒑ ᩖລްɥᚐȗȰɁȻȠीɜɟȲఊ ໄɂ˩ᜤɁȻȝɝᴩ༆ძɁࠕɁ ߴɁѼᪿလȻȪȲᴫژ༆ძɁҜް ࣊նȗɥ 11 ᪡Ⱦґ᭒ȪȲᴥ Fig. 1Bᴦᴫ 4．血小板数，血球数およびヘマトクリット Grade 0 : ۰ԇȽȪᴫ 値の測定 Grade 1 : ྲɁ۰ᓨȟྲȕɞȗɂᠴɁࠈȾ᪅ ǽᚌߴѼᪿᑤɁᚌȾӦᑩႡᏚᦉɛɝ ࠈȨɟɞᴫ EDTAe2K ᚌከȾ 2 ml ᚌȪʷ˂ʴʽɺʩɷ Grade 2 : ྲɁᑱᕶᴫ ɿ˂ȺɛȢઌȪȲᴫඒȾᒲӦᚽᏚᴥూ̦ ᴩAD241ᴦ ɥႊȗȹᚌɥᴥూފGrade 3 : ᄠᒑɁ۰ᓨȟȾȝɛɉᴫ ԗႊ ᴩʅʵʛʍɹ CPK310Aᴦ ȺȪފඳȝɛɆᑱᕶᴫ ̦ԗႊەGrade 4 : Ɂ Grade 5 : ᄠᒑɁ۰ᓨȟᠴᡡɁ˹ᠴᯏɑȲɂȰ Ȳᴫᄌᚌ္ລްႊɂˢ᪡ᴥ 500 ςᴦᴩᠣᚌ ɁఞಷȾȝɛɉᴫ ္ᴩᚌߴȝɛɆʢʨʒɹʴʍʒϏລްႊɂˢ ඳ ᪡ᴥ 500 ςᴦ ऻȨɜȾ̝᪡ᴥ 100ەGrade 6 : ᠴᡡɁ˹ᠴᯏɑȲɂȰɁఞಷɁ ȝɛɆᑱᕶᴫ ςᴦ ȪȲᴫᄌᚌ္ລްႊȾɂ໎ᚌҷᴥɹɮʍɹ ᴦ 3 ɥ˩ȪᴩઌऻފGrade 7 : ᄠᒑɁ۰ᓨȟᠴпͶᴥ whole pawᴦ Ⱦ ʳɮʀᴩూ̦ԗႊ ȝɛɉᴫ 30 ᇽ͏˨ᏚȪᴩᒲӦᚌ္ລްᚽᏚᴥూ̦ԗႊ ᴩF800ᴦ ɥႊȗȹᚌ္ୣᴩᚌߴୣȝɛފඳȝ ەGrade 8 : ᠴпͶᴥ whole pawᴦ Ⱦȝɛɉ ɛɆᑱᕶᴫ ɆʢʨʒɹʴʍʒϏɥລްȪȲᴫ Grade 9 : ᄠᒑɁ۰ᓨȟᑬᴥ legᴦ Ⱦȝɛɉᴫ ඳȝɛɆᑱᕶȟᑬȾȝɛɉᴫ 5．統計処理ە : Grade 10 ᒈᄠᒑ۾ǽᄠᒑຣ࣊ɂᴩʳɰʴʽᥣѿᏚϫɁ 3．血小板凝集能 ຣ࣊ȻՕߦϫɁᄠᒑຣ࣊ɁࢃȺ᚜Ȫᴩʳɰʴʽ ǽᄠᒑ༆ძɁᜊߔఙᩖɁఊጶஓɁᗧ࿎ੵ˫ 3 ᥣʔʒʴɰʪੵ˫ऻɁյᩖȾȝȗȹȰɟȱɟ ໎ݨੵ˫ᏰȻϯѿᏚᏰɂˢЫᥓᏚґୠґऻᴩ ۾ᩖऻȾʬʵʬʍʒɥɲ˂ʐʵᲽᥖ˩Ⱦᒆ ӦᑩȾӦᑩႡᏚᦉɥષоȪᴩȰȦȞɜ 1/10 ߁ t ೫ްɥᴩ໎ݨੵ˫ᏰȻյᚱ᮷ᗧੵ˫ᏰɂȰɟ 3.8ᴢ ɹɲʽᥣʔʒʴɰʪ໎ɁоȶȲᚌከ ȱɟˢЫᥓᏚґୠґऻᴩDunnett ೫ްɥᚐȶ Ⱦ 9/10 ߁ɁᚌɥȪȲᴫȰɁɹɲʽᥣӏ ȲᴫᚌߴѼᪿᑤȝɛɆᚌʛʳʫ˂ʉ˂ɕպ ᚌɥຣȺ 100 ą gᴩ10 ґᩖᤕ॑Ȫ۹ᚌߴᚌ റȾ໎ݨੵ˫ᏰȻϯѿᏚᏰɂˢЫᥓᏚґୠґ ᴥ platelet rich plasma ; PRPᴦ ɥीȲᴫȰɁฉ ऻᴩt ೫ްɥᴩ໎ݨੵ˫ᏰȻյᚱ᮷ᗧੵ˫Ᏸɂ ພɥȨɜȾ 1500 ą gᴩ10 ґᩖᤕ॑Ȫ̈ᚌߴ ȰɟȱɟˢЫᥓᏚґୠґऻᴩDunnett ೫ްɥ ᚌᴥ platelet poor plasma ; PPPᴦ ɥीȲᴫीɜ ᚐȶȲᴫᄠᒑ༆ძɁҜްȾȷȗȹɂ໎ݨੵ˫Ᏸ ɟȲ PRP ɂ PPP ɥႊȗȹᚌߴୣȟ 5 ą 108 Ȼյᚱ᮷ᗧੵ˫ᏰȺȰɟȱɟᎱɝᣌȪລްɁґ cells/ml ȻȽɞɛșȾȪȲᴫ ୠґɥᚐȶȲᴫȰɁፀᴩȺȕɞȻȽ ǽᚌߴѼᪿᑤɁລްɂᴩBorn Ɂ༝ศȾि ȨɟȲᗧ࿎ᏰȾȷȗȹɂᴩȨɜȾյᩖȾȝȗ ȶȹᚌߴѼᪿᑤລްᚽᏚᴥ NBS Hematracer 1 ȹȰɟȱɟˢЫᥓᏚґୠґऻᴩDunnett ೫ް PAT4Aᴦ ɥႊȗȹᣥᤈॴɁ۰ԇɥລްȬɞȦ ɥᚐȶȲᴫ෩ໄɂ 5ᴢ ఝɥȻȪᴩ5ᴢ ȻȾɛɝᚐȶȲᴫȬȽɢȴᴩPRP ɥᚌߴѼ ȝɛɆ 1ᴢ ఝȾґȤȹ᚜ᇉȪȲᴫ 216 ஓటᚌಃඨᚌޙ͢ᝒǽቼ 16 ࢊǽቼ 2 հ
Table 1ǽEffects of pamicogrel, ticlopidine, ASA and cilostazol on the progression of sodium laurateinduced arterial occlusive disease in guinea pigs Dose Grade of lesion Drugs (mg/kg, p.o.) n 3rd 7th 10th 14th day Experiment 1 Sham - 12 0.0 – 0.0 0.0 – 0.0 0.0 – 0.0 0.0 – 0.0
Control - 12 5.1 – 0.8 6.7 – 0.9 8.0 – 0.9 8.3 – 1.0
Pamicogrel 0.1 12 2.7 – 0.7 * 3.5 – 0.8 * 4.2 – 1.0 * 4.5 – 1.0 * 0.3 12 1.3 – 0.5 ** 1.8 – 0.7 ** 2.8 – 1.0 ** 3.4 – 1.0 ** 1.0 12 0.3 – 0.3 ** 0.5 – 0.5 ** 0.7 – 0.7 ** 0.7 – 0.7 **
Ticlopidine 100 12 2.8 – 0.8 3.7 – 0.9 * 4.3 – 1.0 * 4.8 – 1.1 * 300 12 1.3 – 0.6 ** 3.0 – 0.9 * 3.4 – 1.1 ** 3.6 – 1.2 **
Experiment 2 Control - 12 3.3 – 0.5 6.2 – 0.5 7.3 – 0.6 8.1 – 0.5
ASA 10 12 5.1 – 0.4 * 7.1 – 0.3 8.3 – 0.4 8.8 – 0.5 30 12 5.3 – 0.3 * 8.0 – 0.3 * 9.3 – 0.3 * 9.5 – 0.2 100 12 2.8 – 0.7 5.0 – 0.8 6.8 – 0.8 7.3 – 0.8
Cilostazol 10 12 4.7 – 0.6 7.4 – 0.7 8.5 – 0.6 9.1 – 0.5 30 12 3.7 – 0.6 6.3 – 0.7 8.2 – 0.6 8.6 – 0.4
Pmicogrel 1 12 1.9 – 0.7 2.8 – 1.0 ** 3.1 – 1.1 ** 3.4 – 1.3 ** Drugs were orally administered 1 hr and once a day for 14 days after sodium laurate injection. Data were expressed as mean ± S.E. * P < 0.05, ** P < 0.01 vs control (one-way ANOVA followed by Dunnett's test). In the two-way ANOVA with repeated measures, there was significant difference between control and pamicogrel groups, between control and ticlopidine groups, and between control and ASA groups. However, there was no significant difference between control and cilostazol groups.
ࠕȾߦȪȹ໎ݨੵ˫ᏰȻᢎȪȹɜȞȽͽ 成 績 ႊɥᇉȨȽȞȶȲᴫˢᴩʳɰʴʽᥣʔʒʴɰ ɥӦᑩюੵ˫ȪȲϯں皮膚潰瘍に対する作用 ʪɁ͍ɢɝȾႆျᄑ᭥．1 ǽFig. 2 ȝɛɆ Table 1 ȾᇉȬɛșȾᴩ໎ݨੵ ਖ਼ᚓᴥ shamᴦ ᏰɁऻᑆɁᄠᒑȾɂпȢ۰ԇɂᝓ ˫ᏰȾȝȗȹʳɰʴʽᥣʔʒʴɰʪੵ˫ऻᩖ ɔɜɟȽȞȶȲᴫ ጽᤈȾͧȶȹᄠᒑ༆ძგ۰Ɂᚐȟᝓɔɜɟᴩ ȰɁგ۰Ɂᚐɂ 10 ஓऻȾɎɏʡʳʒ˂Ⱦᤎ 2．皮膚温に対する作用 ᒈɁᄠᒑຣ࣊ɂ໎ݨੵ˫ᏰȾȝȗȹʳɰ۾ȪȲᴫȰɟȾߦȪȹ pamicogrelᴥ 0.1, 0.3 ȝɛɆ ǽ 1 mg/kg, p.oᴦ ੵ˫ᏰɂႊᦀΗސᄑȾᄠᒑ༆ძɁ ʴʽᥣʔʒʴɰʪѿᏚϫȟՕߦϫȻᢎȪȹ 1 ࠕɥੱҤȪȲᴫ Ticlopidineᴥ 100 ȝɛɆ 300 ȝɛɆ 3 ஓऻȾȝȗȹͲϏɥᇉȪȲᴥ Table mg/kg, p.o.ᴦ ੵ˫ᏰɕպറȾႊᦀΗސᄑȾᄠᒑ 2ᴦᴫȰɁᄠᒑຣɁͲ˩ɂ 7 ஓ͏᪃Ⱦɂ sham Ɂ ȪȲᴫ Pamicogrelᴥ 0.1, 0.3 ȝɛɆेو༆ძɁࠕɥੱҤȪȲᴫ ASA ɂᄠᒑ༆ძɁ ෩ໄɑȺ ࠕɥ 10 mg/kg Ⱦȝȗȹʳɰʴʽᥣʔʒʴɰʪ 1 mg/kg, p.o.ᴦ ੵ˫Ᏸɂ໎ݨੵ˫ᏰȻᢎȪȹ ੵ˫ 3 ஓऻȾᴩ 30 mg/kg Ⱦȝȗȹ 3, 7 ȝɛɆ ʳɰʴʽᥣʔʒʴɰʪѿᏚ 1 ȝɛɆ 3 ஓऻɁ মȨ ᄠᒑຣɁͲ˩ɥੱҤȪᴩ 1 mg/kg ੵ˫ᏰȾȝȗۄஓऻȾ໎ݨੵ˫ᏰȻᢎȪȹȾ 10 ȮȲȟᴩ 100 mg/kg ɁႊᦀȺɂɜȞȽͽႊɥ ȹࢃȟᝓɔɜɟȲᴫ Ticlopidineᴥ 100 ȝɛ ᇉȨȽȞȶȲᴫ Cilostazolᴥ 10 ȝɛɆ 30 mg/kg, Ɇ 300 mg/kg, p.o.ᴦ ੵ˫ᏰɕպറȾᄠᒑຣɁͲ ೫ȪȲႊᦀȾȝȗȹᄠᒑ༆ძɁ ˩ɥੱҤȬɞϿտȟᝓɔɜɟȲȟᴩ 100 mg/kgوp.o.ᴦ ɂ̾ ʬʑʵȾߦȬɞᚌߴᗧ pamicogrel Ɂͽႊ 217ڸࡥ༖ᴩɎȞᴷʳɰʴʽᥣʔʒʴɰʪᄉʬʵʬʍʒఞಷӦᑩᩐ
Table 2ǽEffects of pamicogrel, ticlopidine, ASA and cilostazol on the skin temperature of the thigh in guinea pigs Dose Skin temperature of the thigh ( C) Drugs (mg/kg, p.o.) 1st 3rd 7th 10th 14th day Experiment 1 Sham - -0.13 – 0.04 ** -0.13 – 0.05 ** -0.15 – 0.04 -0.13 – 0.04 -0.07 – 0.05
Control - -0.71 – 0.13 -0.49 – 0.08 -0.19 – 0.08 -0.11 – 0.07 -0.10 – 0.05
Pamicogrel 0.1 -0.40 – 0.10 -0.30 – 0.09 -0.18 – 0.07 -0.28 – 0.05 -0.14 – 0.07 0.3 -0.49 – 0.10 -0.25 – 0.08 -0.07 – 0.07 -0.25 – 0.07 -0.26 – 0.04 1.0 -0.24 – 0.05 ** -0.22 – 0.06 * -0.20 – 0.04 -0.13 – 0.04 -0.16 – 0.05
Ticlopidine 100 -0.27 – 0.12 * -0.28 – 0.06 -0.14 – 0.05 -0.16 – 0.06 -0.10 – 0.07 300 -0.32 – 0.13 -0.28 – 0.07 -0.17 – 0.09 -0.16 – 0.06 -0.22 – 0.07
Experiment 2 Control - -1.26 – 0.13 -0.60 – 0.10 -0.28 – 0.11 -0.04 – 0.07 -0.01 – 0.07
ASA 10 -1.42 – 0.16 -0.81 – 0.12 -0.46 – 0.10 -0.15 – 0.07 -0.13 – 0.05 30 -1.51 – 0.15 -1.08 – 0.12 * -0.36 – 0.09 -0.03 – 0.08 -0.07 – 0.08 100 -1.43 – 0.19 -0.76 – 0.19 -0.48 – 0.07 -0.13 – 0.05 -0.13 – 0.05
Cilostazol 10 -1.26 – 0.17 -0.99 – 0.13 -0.48 – 0.10 -0.07 – 0.05 -0.07 – 0.06 30 -1.54 – 0.19 -0.98 – 0.17 -0.35 – 0.11 -0.09 – 0.08 -0.06 – 0.06
Pamicogrel 1 -0.77 – 0.14 * -0.34 – 0.08 -0.35 – 0.09 -0.08 – 0.06 -0.13 – 0.06 Drugs were orally administered 1 hr and once a day for 14 days after sodium laurate injection. Data were expressed as mean –S.E. n=12, * P < 0.05, ** P < 0.01 vs control (one-way ANOVA followed by Dunnett’s test or t-test).
ੵ˫ᏰɁ 1 ஓऻȾࢃȟᝓɔɜɟȲɁɒȺ ᪿȾɂɜȞȽͽႊɥᇉȨȽȞȶȲᴫ ASA ɂ ȕȶȲᴫASA ɂ 30 mg/kg ੵ˫ᏰɁ 3 ஓऻɁɒ 100 mg/kg, p.o. ੵ˫ᏰȾȝȗȹ collagen Ѽᪿɥ ऐͽႊȟᝓɔɜɟȲᴫ ȾੱҤȪȲȟᴩ ADP ѼᪿȾɂɜȞȽͽۄ˩ȽᄠᒑຣͲ ೫ȪȲو೫ ႊɥᇉȨȽȞȶȲᴫ Cilostazol ɂ̾وCilostazolᴥ 10 ȝɛɆ 30 mg/kg, p.o.ᴦ ɂ̾ ᒈᄠᒑຣȾߦȪȹ໎ݨੵ ႊᦀȾȝȗȹ collagen ȝɛɆ ADP ѼᪿȾߦȪ۾ȪȲႊᦀȾȝȗȹ ΈوᏰȻᢎȪȹɜȞȽͽႊɥᇉȨȽȞȶ ȹɜȞȽͽႊɥᇉȨȽȞȶȲᴫɑȲᴩ̾˫ Ȳᴫˢᴩ sham ᏰɂѿᏚϫȟՕߦϫɛɝɕͲ ႊȪȲᗧ࿎ɂᣵஓੵ˫ 2 ᩖऻȾȝȗȹᚌߴ ȗϿտɥᇉȪȲȟȰɁ۰ԇɂɢȭȞȽɕɁȺȕ ୣᴩᠣᚌ္ୣᴩᄌᚌ္ୣȝɛɆʢʨʒɹʴʍ ȶȲᴫ ʒϏȾпȢफᬭɥ˫țȽȞȶȲᴫ
3．血小板凝集能に対する作用 考 案 ǽʳɰʴʽᥣʔʒʴɰʪੵ˫ 14 ஓऻɁᚌʛ ʳʫ˂ʉ˂ȝɛɆᚌߴѼᪿᑤȾߦȬɞ ǽPamicogrel ɂሗȁɁᚌಃʬʑʵȾȝȗȹࢠ pamicogrel, ticlopidine, ASA ȝɛɆ cilostazol Ɂ ȾऐӌȽᚌಃͽႊɥᇉȬȦȻȟɜȞȻȽȶ फᬭɥ Table 3 ȾᇉȬᴫ Pamicogrel ɂ collagen ȹȗɞ7)9)ᴫȪȞȪᴩȰɟɜɁͽႊɂпȹ̙᩻ ᴥ10 µg/mlᴦ Ѽᪿɥ 1 mg/kg, p.o. ੵ˫ᏰȾȝȗȹ ӛȺȕɝᴩผჵӛȾȷȗȹɂпȢ೫Ȩɟ დڸ໎ݨੵ˫ᏰȻᢎȪȹȾੱҤȪȲᴫˢᴩ ȹȗȽȗᴫ࿑ȾᴩᒱࣂȾȝȗȹ৻ॴӦᑩᩐ ADP ѼᪿȾȷȗȹɂɜȞȽͽႊɥᇉȨȽȞ Ɂผჺӛɂᗧ࿎ɁӛɥҜްȬɞ˨ȺᛵȽ ໄȺȕɞȦȻȞɜӦ࿎᮷ȾȝȗȹఞಷژȶȲᴫTiclopidine ɂ ADP Ѽᪿɥ 300 mg/kg, p.o. Ҝް ʬʑʵȾȝȤɞผჵӛɥ೫Ȭɞ॒ڸੵ˫ᏰȾȝȗȹȾੱҤȪȲȟᴩ collagen Ѽ Ӧᑩᩐ 218 ஓటᚌಃඨᚌޙ͢ᝒǽቼ 16 ࢊǽቼ 2 հ
Table 3ǽEffects of pamicogrel, ticlopidine, ASA and cilostazol on the hematological parameter and the platelet aggregation in guinea pigs Platelet aggregation (%) Dose Platelets Erythrocytes Leukocytes Hematocrit Collagen ADP Drugs (mg/kg, p.o.) ( 104cells/mm3)(104cells/mm3)(102cells/mm3) (%) 10 g/ml 2 M Experiment 1 Sham - 67.4 – 2.7 522.8 – 14.0 65.8 – 6.8 43.9 – 1.1 76.4 – 1.6 69.8 – 1.7 (n=12) (n=12) (n=12) (n=12) (n=12) (n=12) Control - 77.1 – 4.1 502.9 – 26.1 60.4 – 6.5 44.1 – 2.1 74.0 – 2.2 67.8 – 2.6 (n=12) (n=12) (n=12) (n=12) (n=11) (n=11) Pamicogrel 0.1 75.5 – 4.6 480.9 – 17.8 59.5 – 6.0 41.4 – 1.2 78.7 – 1.1 67.0 – 2.5 (n=12) (n=12) (n=12) (n=12) (n=12) (n=12) 0.3 80.6 – 4.7 486.5 – 12.3 59.9 – 5.3 41.3 – 0.9 77.2 – 1.7 67.9 – 2.1 (n=12) (n=12) (n=12) (n=12) (n=10) (n=10) 1.0 76.6 – 3.9 508.3 – 13.3 68.7 – 6.6 43.1 – 0.9 56.4 – 7.3 * 69.0 – 1.8 (n=12) (n=12) (n=12) (n=12) (n=12) (n=12) Ticlopidine 100 75.0 – 3.7 451.4 – 19.5 67.9 – 7.4 40.6 – 1.1 75.9 – 2.1 61.2 – 3.1 (n=12) (n=12) (n=12) (n=12) (n=12) (n=12) 300 81.4 – 3.5 470.0 – 19.0 59.8 – 5.2 41.3 – 1.1 75.0 – 1.5 49.8 – 1.8 ** (n=12) (n=12) (n=12) (n=12) (n=12) (n=12)
Experiment 2 Control - 82.1 – 2.5 462.0 – 17.6 41.8 – 3.2 40.1 – 0.9 76.7 – 1.8 73.6 – 2.9 (n=12) (n=12) (n=12) (n=12) (n=12) (n=12) ASA 10 84.5 – 5.0 476.3 – 17.2 39.3 – 3.0 40.8 – 1.0 74.5 – 1.5 70.6 – 1.5 (n=12) (n=12) (n=12) (n=12) (n=12) (n=12) 30 75.6 – 3.3 474.3 – 9.6 43.3 – 5.4 40.2 – 0.7 74.5 – 2.0 70.1 – 2.5 (n=12) (n=12) (n=12) (n=12) (n=11) (n=11) 100 81.9 – 3.8 452.0 – 16.0 38.8 – 2.2 40.2 – 1.1 60.9 – 4.1 ** 67.9 – 2.3 (n=11) (n=11) (n=11) (n=11) (n=12) (n=12) Cilostazol 10 77.3 – 4.9 455.8 – 16.3 39.5 – 3.1 39.0 – 1.3 74.2 – 1.1 75.5 – 1.9 (n=12) (n=12) (n=12) (n=12) (n=11) (n=11) 30 84.3 – 4.3 476.3 – 27.4 47.5 – 3.7 40.8 – 1.9 73.2 – 1.4 71.5 – 2.0 (n=12) (n=12) (n=12) (n=12) (n=12) (n=12) Pamicogrel 1 73.2 – 5.5 467.7 – 18.0 40.3 – 3.8 39.9 – 1.1 63.9 – 2.4 ** 69.4 – 1.8 (n=12) (n=12) (n=12) (n=12) (n=11) (n=11) Drugs were orally administered 1 hr and once a day for 14 days after sodium laurate injection. Data were expressed as mean – S.E. * P < 0.05, ** P < 0.01 vs control (one-way ANOVA followed by Dunnett’s test or t-test).
ʬʑʵɥႊȗȲڸᛵȟȕɞᴫ ʬʵʬʍʒఞಷӦᑩᩐ ʬʑʵɂᴩ˿ȾʳʍʒȾȝȗȹ pamicogrel ɁผჵӛȾȷȗȹ ticlopidine, ASAڸǽఞಷӦᑩᩐ ʳɰʴʽᥣɑȲɂ̓ᥣɁӦᑩюੵ˫ʬʑʵȝɛ ȝɛɆ cilostazol ɥߦྃᗧȻȪȹ೫ȪȲᴫ Ȩɟȹȗ ǽ໎ݨੵ˫ᏰȾȝȗȹʳɰʴʽᥣʔʒʴɰʪӦ֖ڨɆᥙᥣɁᄠюੵ˫ʬʑʵȟ ɞ11)13)ᴫʬʵʬʍʒȾȝȗȹɕʳʍʒȻպറȾ ᑩюੵ˫ऻᴩᩖጽᤈȾͧȶȹᄠᒑ༆ძგ۰Ɂ ᚐȟᝓɔɜɟȲᴫˢᴩʳɰʴʽᥣʔʒʴɰ ڨᒈӦᑩюੵ˫Ⱦɛɞʬʑʵȟ۾ʳɰʴʽᥣɁ ɥੵ˫ȪȲ sham ᏰںȨɟȹȗɞ14)ᴫʳɰʴʽᥣɂ᪒ɮɴʽॴႜᬂ ʪɁ͍ɢɝȾႆျᄑ᭥֖ ᒈӦᑩɛɝᬲᚐॴȾੵ˫Ȭɞ Ⱥɂ 14 ஓᩖɁᜊߔఙᩖ˹ȾȝȗȹѿᏚϫऻᑆ۾ॴҷȺȕɝᴩ๊ ᒈɁᄠᒑ۾ȦȻȾɛɝੵ˫ͱɛɝఞಷɁᚌከюᄠጯᑛɥ Ⱦგ۰ɂпȢᝓɔɜɟȽȞȶȲᴫ ϾȨȮᴩ৻ॴᄑȽैၥ᪩ɥᄉȦȻȟȺȠ ຣ࣊ɂ໎ݨੵ˫ᏰȾȝȗȹʳɰʴʽᥣʔʒʴɰ ᒈɁᄠᒑຣ࣊ ʪѿᏚϫȟՕߦϫȻᢎȪȹ 1 ȝɛɆ 3 ஓऻ۾ɞᴫȦɁఞಷैၥ˪пȾɛɝ ȺɂͲϏɥᇉȪȲᴫȰɁᄠᒑຣɁͲ˩ɂᩖጽ ەɁͲ˩ᴩऻᑆɁैၥ˪пȾɛɞ۰ᓨȾፖȠᴩ ȬɞϿտɥᇉȪȲᴫˢᴩ shamेوඳᑱᕶȟᠭȦɞᴫȦɟɜɁგৰɂᚌከюᄠጯᑛ ᤈȾͧȗ ϾȻȰɟȾͧșᚌߴѼᪿɛɞᚌಃढȾɛ ᏰȺɂȰɁᄠᒑຣͲ˩ɂЁȞȺȕȶȲᴫȪȲȟ ɝৎᠭȨɟɞȦȻȞɜᴩߵȽȢȻɕґᄑȾʜ ȶȹᴩటᝁ᮷ȾȝȤɞʳɰʴʽᥣʔʒʴɰʪੵ ᒈᄠᒑຣ࣊۾დɁგৰȻ᭒ͬȬɞȻᐎțɜ ˫Ⱦɛɞᄠᒑ༆ძɁࠕȝɛɆڸʒɁ৻ॴӦᑩᩐ ɟᴩᗧ࿎Ɂӛॴɥ̙ລȬɞȲɔȾႊȽʬʑ ɁͲ˩ɂਖ਼ᚓኄȾɛɞ᪩ȺɂȽȢʳɰʴʽᥣ ᴩ ʔʒʴɰʪɁੵ˫ȾɛɞȻᐎțɜɟɞᴫوʵɁˢȷȺȕɞȻᐎțɜɟɞ11)ᴫȰȦȺ̾ ʬʑʵȾߦȬɞᚌߴᗧ pamicogrel Ɂͽႊ 219ڸࡥ༖ᴩɎȞᴷʳɰʴʽᥣʔʒʴɰʪᄉʬʵʬʍʒఞಷӦᑩᩐ
ɛɝऍȞȶȲɁɂΈႊ֖ڨᄑȾᄠᒑ༆ძɁࠕɥ ҤͽႊȟȦɟɑȺɁސǽPamicogrel ɂႊᦀΗ ੱҤȪȲᴫɑȲᴩpamicogrel ɂ 1 ȝɛɆ 3 ஓऻ ȪȲɽʳ˂ɼʽ༟࣊ȟᯚȞȶȲȲɔȺȕɞȻᐎ ᒈᄠᒑຣ࣊ɁͲ˩ɥੱҤȬɞϿտɥᇉȪ țɜɟɞᴫˢᴩᄠᒑ༆ძȾߦȬɞӛɂ۾Ɂ 1 mg/kg ੵ˫ᏰȾȝȗȹ 1 ȝɛɆ 3 ஓऻɁᄠᒑ pamicogrel ȟȽί឴ͽႊɥᇉȪȲɁȾߦȪ ຣ࣊ɁͲ˩ɥȾੱҤȪȲᴫ Pamicogrel ɂ ȹᴩASA ɂིӛȕɞȗɂˢɁႊᦀȺȽ মͽႊɥᇉȪȲᴫȦɁፀɂᴩ 1ᴦ pamicogrelۄ collagen ѼᪿɥੱҤȪȲȦȻȞɜᴩȦɁ pamicogrel ɁͽႊȾɂᚌߴȝɛɆᚌಃͽ ȟᚌߴɁ cyclooxygenaseᴥ COXᴦ ɥᚌከюᄠ ႊȟᩜ˫ȬɞȻᐎțɜɟɞᴫ ጯᑛɁCOX ɛɝɕᤣᄑȾੱҤȬɞ6)ᴩ2ᴦ ᄑȾᄠᒑ༆ძɁ pamicogrel ȟᚌํӦॴՒɆᠣᚌ္۰ढᑤɥސǽTiclopidine ɕպറȾႊᦀΗ Ȭɞ10) Ƚȼ ASA Ⱦɂིȗ pamicogrel Ɂ࿑ॴױ ˩ᒈᄠᒑຣ࣊ɁͲ۾ࠕɥੱҤȪȲᴫɑȲᴩ ȨɟɞᴫȨɜȾᴩ ASAדȬɞȦȻȟᇉىȾᩜȪȹɕպറȾੱҤȬɞϿտɥᇉȪȲȟᴩ Ⱦᠭ ʬʑʵȾȝȗȹผჵڸmg/kg ੵ˫ᏰɁ 1 ஓऻɁɒȺȕȶȲᴫ ɂʬʵʬʍʒఞಷӦᑩᩐ 100 Ȩɟȹȝɝ14)ᴩ֖ڨʬʑ ӛɥᇉȨȽȗȦȻȟஒȾڸTiclopidine ɂஒȾʬʵʬʍʒఞಷӦᑩᩐ Ȩɟȹȝ టᆅሱȾȝȗȹ ASA ɁͲႊᦀȾɛɝᄠᒑ༆ძ֖ڨʵȾȝȗȹผჵӛɥᇉȬȦȻȟ ɁȻɎɏˢᒵȬɞɕɁ ɁࠕɥȨȮȲൡࣃȾȷȗȹɂɜȞȺɂوɝᴩȰɁͽႊɂ̾ ȺȕȶȲ11)ᴫTiclopidine ɂ ADP ѼᪿɥੱҤȪ ȽȗȟᴩᯚႊᦀɁ 100 mg/kg, p.o. ੵ˫ᏰȾᩜȪ ȲȦȻȞɜᴩటʬʑʵȾȝȤɞ ADP ѼᪿɁᩜ ȹɂ໎ݨੵ˫ᏰȻᢎȪȹɜȞȽͽႊȟᝓɔ ȻˢᒵȬ֖ڨȨɟɞᴫ ɜɟȽȞȶȲȦȻȞɜᴩȰɁדȟᇉ˫
ǽASA ɂ 10 mg/kg, p.o. ੵ˫ᏰȾȝȗȹ 3 ஓऻ ɞᴫˢᴩthromboxan A2ᴥ TXA2ᴦ ՙ߁Ͷઞᗧ ʬʑʵȾȝȗȹᕻڸȾᴩ30 mg/kg, p.o. ੵ˫ᏰȾȝȗȹ 3, 7 ȝɛɆ ɂʬʵʬʍʒఞಷӦᑩᩐ ȨɟȹȗɞȦȻȞ֖ڨஓऻȾ໎ݨੵ˫ᏰȻᢎȪȹᄠᒑ༆ძგ۰ ȽผჵӛɥᇉȬȦȻȟ 10
মȨȮȲȟᴩ 100 mg/kg, p.o. ੵ˫ᏰȾȝȗ ɜᴩటʬʑʵȾȝȗȹ TXA2 ȟᛵȽमҾɥۄɥ ȹɂɜȞȽࢃɂᝓɔɜɟȽȞȶȲᴫɑȲᴩ ȲȪȹȗɞȻᐎțɜɟɞ11) 14)ᴫȪȲȟȶȹᴩ ASA ɂ 30 mg/kg, p.o. ੵ˫ᏰȾȝȗȹᄠᒑຣ࣊ ASA ȟటʬʑʵȾȝȗȹིӛȺȕɞျႏȻȪ ऐȨȮȲᴫȦɟɂ ASA ȟպ ȹɂɬʃʞʴʽʂʶʽʨȻለȨɟɞᚌከюᄠጯۄɁͲ˩ɥȾ ႊᦀȾȝȗȹᄠᒑ༆ძɥমԇȨȮȲፀȻˢᒵ ᑛюɁ cyclooxygenase1ᴥ COX1ᴦ ɥੱҤȬɞ
ȪȲᴫటᝁ᮷Ⱦȝȗȹ Exp. 1 ՒɆ Exp. 2 Ȱɟ ȦȻȾɛɞ prostacyclinᴥ PGI2ᴦ ɁႇႆੱҤȾɛ ऐȪȹȪۄȱɟȾߦྃᏰɁ᪩ɁጽᤈȟႱȽȶȹȗȲᴫɑ ɝᚌከՖ᎔ȝɛɆᚌߴѼᪿɥᣡȾ ȲᴩExp. 2 ȾȝȤɞ pamicogrel 1 mg/kg Ɂᄠᒑ ɑȶȲፀȾɛɞȞɕȪɟȽȗᴫPamicogrel ɂ ༆ძȾߦȬɞፀɂࢃɂᝓɔɜɟȲȟ ASA ȻպറȾ COX ᩼ͽႊɥȬɞȟᴩȰɁ
Exp. 1 ɁፀɛɝߵȪऍȞȶȲᴫȦɁᤏȗɁՁ ͽႊɂᚌߴᤣᄑȺȕɞȦȻȞɜ TXA2 ՙ߁ ɂɜȞȺɂȽȗȟᴩஃȪȲఙɑȲɂ ͶઞᗧȻպറȽᕻȽผჵӛȟीɜɟȲɕى ҝȁɁఙȾоᔸȪȲӦ࿎ɁՕख़ॴɁᤏȗȾɛ ɁȻᐎțɜɟɞ4)ᴫ ೫ȪȲႊᦀȾȝȗوɞժᑤॴȟᐎțɜɟɞᴫ ǽˢᴩ cilostazol ɂ̾ ᒈᄠᒑຣ࣊ȾߦȪ۾ǽటᝁ᮷ȾȝȗȹASAᴥ 100 mg/kg, p.o.ᴦ Ȼ ȹᄠᒑ༆ძɁࠕȝɛɆ pamicogrelᴥ 1 mg/kg, p.o.ᴦ Ɂ collagen ᄉᚌߴ ȹɜȞȽͽႊɥᇉȨȽȞȶȲᴫ Cilostazol ɂ ѼᪿȾߦȬɞੱҤͽႊɂɎɏպኄȺȕȶȲᴫ 14 ஓऻɁᚌߴѼᪿɥੱҤȪȽȞȶȲȦȻȞ ೫ȪȲᗧ࿎ɁႊᦀȟͲȞȶȲȞᴩȕوȨɟ ɜᴩ֖̾ڨȦɟɜɁፀɂ Yokota ɜȾɛɝஒȾ ȹȗɞፀȻˢᒵȬɞɕɁȺȕȶȲ5)ᴫȪȞȪᴩ ɞȗɂӦ࿎ሗࢃȟᐎțɜɟɞᴫ Ɂ೫Ⱥ collagen ѼᪿȾߦȬɞ˵ᗧҷɁੱ ǽ͏˨ɁፀȞɜᴩ pamicogrel ɂʬʵʬʍʒఞو̾ 220 ஓటᚌಃඨᚌޙ͢ᝒǽቼ 16 ࢊǽቼ 2 հ
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Effect of pamicogrel, a new antiplatelet drug, on the progression of sodium laurate-induced arterial occlusive disease in guinea pigs
Masamitsu SHIMAZAWA＊1, Yuki MIYAKE＊2, Takafumi YAMAGUCHI＊3 Koichi YOKOTA＊3, Takayuki SUKAMOTO＊2, Hideaki HARA＊1
Key words: antiplatelet drug, arterial occlusive disease, guinea pig, pamicogrel, skin temperature
ǽWe examined the protective effect of pamicogrel, a new antiplatelet drug, on the sodium laurate induced peripheral arterial occlusive disease of posterior limb in the guineapig, and compared its effect with those of acetylsalicylic acid, ticlopidine and cilostazol. In the control group given saline alone, the sodium laurate injection at 1mg/leg into the right femoral artery caused an ischemic change in the peripheral posterior limb followed by apprearance of violet color around the whole paw, edema, gangrene, mummification and falling off of fingers, whole paw and lower leg after 3 to 14 days. Decrease of the skin temperature at the site of sodium laurate injection was significantly inhibited as compared with that of the control group on days 1 and 3. Oral administration of pamicogrel (0.1, 0.3 and 1 mg/kg, p.o.)and ticlopidine (100 and 300 mg/kg, p.o.) 1 hr after the injection of sodium laurate and successively once a day over a period of 14 days dosedependently inhibited the development of ischemic lesion in the posterior limb and decrease the skin temperature of the ipsilateral thigh. In contrast, acetylsalicylic acid given at 10 and 30 mg/kg (p.o.) significantly exacerbated the development of ischemic lesion in the ipsilateral limb on day 3, and on days 3, 7 and 10, respectively, but not at 100 mg/kg (p.o.). On the other hand, cilostazol (10 and 30 mg/kg, p.o.) had little preventive effect on the progression of ischemic lesion and the decrease of skin temperature of the ipsilateral thigh. ǽThese observations suggest that pamicogrel can be clinically effective against chronic arterial occlusive diseases.