;PMID: 12515739 ;source_file_1862.mrg ;Release 0.9 of PennBioIE ;Funded by NSF ITR EIA-0205448 ;0)section:[e:0..36] = [t:0..36] ;1)section:[e:42..179] = [t:42..179] ;2)sentence:[e:183..293] = [t:183..293] ;3)section:[e:297..401] = [t:297..401] ;4)section:[e:405..493] = [t:405..493] ;5)sentence:[e:497..691] = [t:497..691] ;6)sentence:[e:692..822] = [t:692..822] ;7)sentence:[e:823..1155] = [t:823..1155] ;8)sentence:[e:1156..1271] = [t:1156..1271] ;9)sentence:[e:1272..1462] = [t:1272..1462] ;10)sentence:[e:1463..1774] = [t:1463..1774] ;11)sentence:[e:1775..1817] = [t:1775..1817] ;12)sentence:[e:1819..1898] = [t:1819..1898] ;13)sentence:[e:1900..2041] = [t:1900..2041] ;14)section:[e:2045..2116] = [t:2045..2116] ;15)section:[e:2120..2165] = [t:2120..2165] ;section 0 Span:0..36 ;Circulation. 2003 Jan 7;107(1):32-7. (SEC (FRAG (NN:[0..11] Circulation) (.:[11..12] .) (CD:[13..17] 2003) (CC:[18..21] Jan) (CD:[22..27] 7;107) (-LRB-:[27..28] -LRB-) (CD:[28..29] 1) (-RRB-:[29..30] -RRB-) (::[30..31] :) (CD:[31..33] 32) (CD:[33..36] -7.))) ;section 1 Span:42..179 ;Comment in: Circulation. 2003 Jun 10;107(22):e210; author reply e210. ; Circulation. 2003 Jun 24;107(24):e223; author reply e223. (SEC (FRAG (NNP:[42..49] Comment) (IN:[50..52] in) (NNP:[52..53] :) (NNP:[59..70] Circulation) (.:[70..71] .) (CD:[72..76] 2003) (NNP:[77..80] Jun) (CD:[81..83] 10) (CD:[83..87] ;107) (-LRB-:[87..88] -LRB-) (CD:[88..90] 22) (-RRB-:[90..91] -RRB-) (CD:[91..96] :e210) (::[96..97] ;) (NN:[98..104] author) (VBZ:[105..110] reply) (NN:[111..115] e210) (.:[115..116] .) (NN:[122..133] Circulation) (.:[133..134] .) (CD:[135..139] 2003) (NNP:[140..143] Jun) (CD:[144..150] 24;107) (-LRB-:[150..151] -LRB-) (CD:[151..153] 24) (-RRB-:[153..154] -RRB-) (CD:[154..159] :e223) (::[159..160] ;) (NN:[161..167] author) (RB:[168..173] reply) (CD:[174..178] e223) (.:[178..179] .))) ;sentence 2 Span:183..293 ;Atorvastatin reduces the ability of clopidogrel to inhibit platelet ;aggregation: a new drug-drug interaction. ;[183..195]:substance:"Atorvastatin" ;[219..230]:substance:"clopidogrel" ;[271..275]:substance:"drug" ;[276..280]:substance:"drug" (SENT (FRAG-HLN (S (NP-SBJ (NN:[183..195] Atorvastatin)) (VP (VBZ:[196..203] reduces) (NP (NP (DT:[204..207] the) (NN:[208..215] ability) (S-1 (-NONE-:[215..215] *ICH*))) (PP (IN:[216..218] of) (NP (NN:[219..230] clopidogrel))) (S-1 (NP-SBJ (-NONE-:[230..230] *)) (VP (TO:[231..233] to) (VP (VB:[234..241] inhibit) (NP (NN:[242..250] platelet) (NN:[251..262] aggregation)))))))) (::[262..263] :) (NP (DT:[265..266] a) (JJ:[267..270] new) (NML (NN:[271..275] drug) (HYPH:[275..276] -) (NN:[276..280] drug)) (NN:[281..292] interaction)) (.:[292..293] .))) ;section 3 Span:297..401 ;Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, Tait AR, ;Carville DG, Guyer KE, Bates ER. (SEC (FRAG (NNP:[297..300] Lau) (NNP:[301..303] WC) (,:[303..304] ,) (NNP:[305..312] Waskell) (NNP:[313..315] LA) (,:[315..316] ,) (NNP:[317..324] Watkins) (NN:[325..327] PB) (,:[327..328] ,) (NNP:[329..333] Neer) (NNP:[334..336] CJ) (,:[336..337] ,) (NNP:[338..346] Horowitz) (NNP:[347..349] K,) (NNP:[350..354] Hopp) (NNP:[355..357] AS) (,:[357..358] ,) (NNP:[359..363] Tait) (NNP:[364..366] AR) (,:[366..367] ,) (NNP:[368..376] Carville) (NNP:[378..380] DG) (,:[380..381] ,) (NNP:[382..387] Guyer) (NNP:[388..390] KE) (,:[390..391] ,) (NNP:[392..397] Bates) (NN:[398..400] ER) (.:[400..401] .))) ;section 4 Span:405..493 ;Department of Anesthesiology, University of Michigan, Ann Arbor, USA. ;weiclau@umich.edu (SEC (FRAG (NNP:[405..415] Department) (IN:[416..418] of) (NNP:[419..433] Anesthesiology) (,:[433..434] ,) (NNP:[435..445] University) (IN:[446..448] of) (NNP:[449..457] Michigan) (,:[457..458] ,) (NNP:[459..462] Ann) (NNP:[463..468] Arbor) (,:[468..469] ,) (NNP:[470..473] USA) (.:[473..474] .) ('':[476..489] weiclau@umich) (.:[489..493] .edu))) ;sentence 5 Span:497..691 ;BACKGROUND: We observed that the prodrug clopidogrel was less effective in ;inhibiting platelet aggregation with coadministration of atorvastatin during ;point-of-care platelet function testing. ;[530..537]:substance:"prodrug" ;[538..549]:substance:"clopidogrel" ;[630..642]:substance:"atorvastatin" (SENT (NP (NN:[497..507] BACKGROUND) (::[507..508] :)) (S (NP-SBJ (PRP:[509..511] We)) (VP (VBN:[512..520] observed) (SBAR (IN:[521..525] that) (S (NP-SBJ (NP (DT:[526..529] the) (NN:[530..537] prodrug)) (NP (NN:[538..549] clopidogrel))) (VP (VBD:[550..553] was) (ADJP-PRD (RBR:[554..558] less) (JJ:[559..568] effective)) (PP (IN:[569..571] in) (S-NOM (NP-SBJ (-NONE-:[571..571] *)) (VP (VBG:[573..583] inhibiting) (NP (NN:[584..592] platelet) (NN:[593..604] aggregation)) (PP (IN:[605..609] with) (NP (NP (NN:[610..626] coadministration)) (PP (IN:[627..629] of) (NP (NN:[630..642] atorvastatin))))) (PP-TMP (IN:[643..649] during) (NP (NML (NML (NN:[651..656] point)) (HYPH:[656..657] -) (PP (IN:[657..659] of) (HYPH:[659..660] -) (NP (NN:[660..664] care)))) (NN:[665..673] platelet) (NN:[674..682] function) (NN:[683..690] testing)))))))))) (.:[690..691] .))) ;ERROR_Sentence has multiple Children (Sentence Error)[497..691]::NP:S: ;sentence 6 Span:692..822 ;Because atorvastatin is metabolized by cytochrome P450 (CYP) 3A4, we ;hypothesized that clopidogrel might be activated by CYP3A4. ;[700..712]:substance:"atorvastatin" ;[732..757]:cyp450:"cytochrome P450 (CYP) 3A4" ;[780..791]:substance:"clopidogrel" ;[815..821]:cyp450:"CYP3A4" (SENT (S (SBAR-ADV (IN:[692..699] Because) (S (NP-SBJ-2 (NN:[700..712] atorvastatin)) (VP (VBZ:[713..715] is) (VP (VBN:[716..727] metabolized) (NP-2 (-NONE-:[727..727] *)) (PP (IN:[728..730] by) (NP-LGS (NML (NML (NN:[732..742] cytochrome) (NN:[743..747] P450)) (NML (-LRB-:[748..749] -LRB-) (NN:[749..752] CYP) (-RRB-:[752..753] -RRB-))) (NN:[754..757] 3A4))))))) (,:[757..758] ,) (NP-SBJ (PRP:[759..761] we)) (VP (VBD:[762..774] hypothesized) (SBAR (IN:[775..779] that) (S (NP-SBJ-1 (NN:[780..791] clopidogrel)) (VP (MD:[792..797] might) (VP (VB:[798..800] be) (VP (VBN:[801..810] activated) (NP-1 (-NONE-:[810..810] *)) (PP (IN:[812..814] by) (NP-LGS (NN:[815..821] CYP3A4))))))))) (.:[821..822] .))) ;sentence 7 Span:823..1155 ;METHODS AND RESULTS: Platelet aggregation was measured in 44 patients ;undergoing coronary artery stent implantation treated with clopidogrel or ;clopidogrel plus pravastatin or atorvastatin, and in 27 volunteers treated ;with clopidogrel and either erythromycin or troleandomycin, CYP3A4 ;inhibitors, or rifampin, a CYP3A4 inducer. ;[953..964]:substance:"clopidogrel" ;[969..980]:substance:"clopidogrel" ;[986..997]:substance:"pravastatin" ;[1001..1013]:substance:"atorvastatin" ;[1050..1061]:substance:"clopidogrel" ;[1073..1085]:substance:"erythromycin" ;[1089..1103]:substance:"troleandomycin" ;[1105..1111]:cyp450:"CYP3A4" ;[1112..1122]:substance:"inhibitors" ;[1128..1136]:substance:"rifampin" ;[1140..1146]:cyp450:"CYP3A4" ;[1147..1154]:substance:"inducer" (SENT (NP (NNS:[823..830] METHODS) (CC:[831..834] AND) (NNS:[835..842] RESULTS) (::[842..843] :)) (S (NP-SBJ-1 (NN:[844..852] Platelet) (NN:[853..864] aggregation)) (VP (VBD:[865..868] was) (VP (VBN:[869..877] measured) (NP-1 (-NONE-:[877..877] *)) (PP-LOC (PP (IN:[878..880] in) (NP (NP (NP (CD:[881..883] 44) (NNS:[884..892] patients)) (VP (VBG:[894..904] undergoing) (NP (NML (JJ:[905..913] coronary) (NN:[914..920] artery)) (NN:[921..926] stent) (NN:[927..939] implantation)))) (VP (VBN:[940..947] treated) (NP (-NONE-:[947..947] *)) (PP-CLR (IN:[948..952] with) (NP (NP (NN:[953..964] clopidogrel)) (CC:[965..967] or) (NP (NP (NN:[969..980] clopidogrel)) (CC:[981..985] plus) (NP (NN:[986..997] pravastatin) (CC:[998..1000] or) (NN:[1001..1013] atorvastatin)))))))) (,:[1013..1014] ,) (CC:[1015..1018] and) (PP-LOC (IN:[1019..1021] in) (NP (NP (CD:[1022..1024] 27) (NNS:[1025..1035] volunteers)) (VP (VBN:[1036..1043] treated) (NP (-NONE-:[1043..1043] *)) (PP-CLR (IN:[1044..1048] with) (NP (NP (NN:[1050..1061] clopidogrel)) (CC:[1062..1065] and) (NP (CC:[1066..1072] either) (NP (NP (NN:[1073..1085] erythromycin) (CC:[1086..1088] or) (NN:[1089..1103] troleandomycin)) (,:[1103..1104] ,) (NP (NN:[1105..1111] CYP3A4) (NNS:[1112..1122] inhibitors))) (,:[1122..1123] ,) (CC:[1124..1126] or) (NP (NP (NN:[1128..1136] rifampin)) (,:[1136..1137] ,) (NP (DT:[1138..1139] a) (NN:[1140..1146] CYP3A4) (NN:[1147..1154] inducer)))))))))))) (.:[1154..1155] .))) ;ERROR_Sentence has multiple Children (Sentence Error)[823..1155]::NP:S: ;sentence 8 Span:1156..1271 ;Atorvastatin, but not pravastatin, attenuated the antiplatelet activity of ;clopidogrel in a dose-dependent manner. ;[1156..1168]:substance:"Atorvastatin" ;[1178..1189]:substance:"pravastatin" ;[1232..1243]:substance:"clopidogrel" (SENT (S (NP-SBJ (NN:[1156..1168] Atorvastatin) (,:[1168..1169] ,) (CONJP (CC:[1170..1173] but) (RB:[1174..1177] not)) (NN:[1178..1189] pravastatin)) (,:[1189..1190] ,) (VP (VBD:[1191..1201] attenuated) (NP (NP (DT:[1202..1205] the) (NN:[1207..1219] antiplatelet) (NN:[1220..1228] activity)) (PP (IN:[1229..1231] of) (NP (NN:[1232..1243] clopidogrel)))) (PP (IN:[1244..1246] in) (NP (DT:[1247..1248] a) (ADJP (NN:[1249..1253] dose) (HYPH:[1253..1254] -) (JJ:[1254..1263] dependent)) (NN:[1264..1270] manner)))) (.:[1270..1271] .))) ;sentence 9 Span:1272..1462 ;Percent platelet aggregation was 34+/-23, 58+/-15 (P=0.027), 74+/-10 ;(P=0.002), and 89+/-7 (P=0.001) in the presence of clopidogrel and 0, 10, ;20, and 40 mg of atorvastatin, respectively. ;[1306..1313]:quantitative-value:"34+/-23" ;[1315..1322]:quantitative-value:"58+/-15" ;[1334..1341]:quantitative-value:"74+/-10" ;[1358..1364]:quantitative-value:"89+/-7" ;[1394..1405]:substance:"clopidogrel" ;[1410..1411]:quantitative-value:"0" ;[1413..1415]:quantitative-value:"10" ;[1417..1419]:quantitative-value:"20" ;[1425..1427]:quantitative-value:"40" ;[1428..1430]:quantitative-units:"mg" ;[1435..1447]:substance:"atorvastatin" (SENT (S (NP-SBJ (NN:[1272..1279] Percent) (NN:[1281..1289] platelet) (NN:[1290..1301] aggregation)) (VP (VBD:[1302..1305] was) (NP-PRD (NP (QP (CD:[1306..1308] 34) (SYM:[1308..1311] +/-) (CD:[1311..1313] 23))) (,:[1313..1314] ,) (NP (QP (CD:[1315..1317] 58) (SYM:[1317..1320] +/-) (CD:[1320..1322] 15)) (PRN (-LRB-:[1323..1324] -LRB-) (S (NP-SBJ (NN:[1324..1325] P)) (VP (SYM:[1325..1326] =) (NP (CD:[1326..1331] 0.027)))) (-RRB-:[1331..1332] -RRB-))) (,:[1332..1333] ,) (NP (QP (CD:[1334..1336] 74) (SYM:[1336..1339] +/-) (CD:[1339..1341] 10)) (PRN (-LRB-:[1342..1343] -LRB-) (S (NP-SBJ (NN:[1343..1344] P)) (VP (SYM:[1344..1345] =) (NP (CD:[1345..1350] 0.002)))) (-RRB-:[1350..1351] -RRB-))) (,:[1351..1352] ,) (CC:[1353..1356] and) (NP (NP (QP (CD:[1358..1360] 89) (SYM:[1360..1363] +/-) (CD:[1363..1364] 7))) (PRN (-LRB-:[1365..1366] -LRB-) (S (NP-SBJ (NN:[1366..1367] P)) (VP (SYM:[1367..1368] =) (NP (CD:[1368..1373] 0.001)))) (-RRB-:[1373..1374] -RRB-)))) (PP (IN:[1375..1377] in) (NP (NP (DT:[1378..1381] the) (NN:[1382..1390] presence)) (PP (IN:[1391..1393] of) (NP (NP (NN:[1394..1405] clopidogrel)) (CC:[1406..1409] and) (NP (NP (NP (CD:[1410..1411] 0) (NML-1 (-NONE-:[1411..1411] *P*))) (,:[1411..1412] ,) (NP (CD:[1413..1415] 10) (NML-1 (-NONE-:[1415..1415] *P*))) (,:[1415..1416] ,) (NP (CD:[1417..1419] 20) (NML-1 (-NONE-:[1419..1419] *P*))) (,:[1419..1420] ,) (CC:[1421..1424] and) (NP (CD:[1425..1427] 40) (NML-1 (NN:[1428..1430] mg)))) (PP (IN:[1431..1433] of) (NP (NN:[1435..1447] atorvastatin)))) (,:[1447..1448] ,) (ADVP (RB:[1449..1461] respectively))))))) (.:[1461..1462] .))) ;sentence 10 Span:1463..1774 ;Erythromycin attenuated platelet aggregation inhibition (55+/-12 versus ;42+/-12% platelet aggregation; P=0.002), as did troleandomycin (78+/-18 ;versus 45+/-18% platelet aggregation; P<0.0003), whereas rifampin enhanced ;platelet aggregation inhibition (33+/-18 versus 56+/-20% platelet ;aggregation, P=0.001). ;[1463..1475]:substance:"Erythromycin" ;[1521..1528]...[1543..1544]:quantitative-value:"55+/-12"..."%" ;[1536..1544]:quantitative-value:"42+/-12%" ;[1585..1599]:substance:"troleandomycin" ;[1601..1608]...[1623..1624]:quantitative-value:"78+/-18"..."%" ;[1616..1624]:quantitative-value:"45+/-18%" ;[1667..1675]:substance:"rifampin" ;[1718..1725]...[1740..1741]:quantitative-value:"33+/-18"..."%" ;[1733..1741]:quantitative-value:"56+/-20%" (SENT (S (NP-SBJ (NN:[1463..1475] Erythromycin)) (VP (VBD:[1476..1486] attenuated) (NP (NN:[1487..1495] platelet) (NN:[1496..1507] aggregation) (NN:[1509..1519] inhibition) (PRN (-LRB-:[1520..1521] -LRB-) (FRAG (NP (NP (QP (CD:[1521..1523] 55) (SYM:[1523..1526] +/-) (CD:[1526..1528] 12))) (PP (IN:[1529..1535] versus) (NP (NP (QP (CD:[1536..1538] 42) (SYM:[1538..1541] +/-) (CD:[1541..1543] 12)) (NN:[1543..1544] %)) (NP (NN:[1545..1553] platelet) (NN:[1554..1565] aggregation))))) (::[1565..1566] ;) (S (NP-SBJ (NN:[1567..1568] P)) (VP (SYM:[1568..1569] =) (NP (CD:[1569..1574] 0.002))))) (-RRB-:[1574..1575] -RRB-))) (,:[1575..1576] ,) (PP (IN:[1577..1579] as) (SINV-NOM (VP (VBD:[1580..1583] did)) (NP-SBJ (NN:[1585..1599] troleandomycin)) (PRN (-LRB-:[1600..1601] -LRB-) (FRAG (NP (NP (QP (CD:[1601..1603] 78) (SYM:[1603..1606] +/-) (CD:[1606..1608] 18))) (PP (IN:[1609..1615] versus) (NP (NP (QP (CD:[1616..1618] 45) (SYM:[1618..1621] +/-) (CD:[1621..1623] 18)) (NN:[1623..1624] %)) (NP (NN:[1625..1633] platelet) (NN:[1634..1645] aggregation))))) (::[1645..1646] ;) (S (NP-SBJ (NN:[1647..1648] P)) (VP (SYM:[1648..1649] <) (NP (CD:[1649..1655] 0.0003))))) (-RRB-:[1655..1656] -RRB-)))) (,:[1656..1657] ,) (SBAR-ADV (IN:[1658..1665] whereas) (S (NP-SBJ (NN:[1667..1675] rifampin)) (VP (VBD:[1676..1684] enhanced) (NP (NN:[1685..1693] platelet) (NN:[1694..1705] aggregation) (NN:[1706..1716] inhibition)) (PRN (-LRB-:[1717..1718] -LRB-) (FRAG (NP (NP (QP (CD:[1718..1720] 33) (SYM:[1720..1723] +/-) (CD:[1723..1725] 18))) (PP (IN:[1726..1732] versus) (NP (NP (QP (CD:[1733..1735] 56) (SYM:[1735..1738] +/-) (CD:[1738..1740] 20)) (NN:[1740..1741] %)) (NP (NN:[1743..1751] platelet) (NN:[1752..1763] aggregation))))) (,:[1763..1764] ,) (S (NP-SBJ (NN:[1765..1766] P)) (VP (SYM:[1766..1767] =) (NP (CD:[1767..1772] 0.001))))) (-RRB-:[1772..1773] -RRB-)))))) (.:[1773..1774] .))) ;sentence 11 Span:1775..1817 ;CONCLUSIONS: CYP3A4 activates clopidogrel. ;[1788..1794]:cyp450:"CYP3A4" ;[1805..1816]:substance:"clopidogrel" (SENT (NP (NNS:[1775..1786] CONCLUSIONS) (::[1786..1787] :)) (S (NP-SBJ (NN:[1788..1794] CYP3A4)) (VP (VBZ:[1795..1804] activates) (NP (NN:[1805..1816] clopidogrel))) (.:[1816..1817] .))) ;ERROR_Sentence has multiple Children (Sentence Error)[1775..1817]::NP:S: ;sentence 12 Span:1819..1898 ;Atorvastatin, another CYP3A4 substrate, competitively inhibits this ;activation. ;[1819..1831]:substance:"Atorvastatin" ;[1841..1847]:cyp450:"CYP3A4" ;[1848..1857]:substance:"substrate" (SENT (S (NP-SBJ (NP (NN:[1819..1831] Atorvastatin)) (,:[1831..1832] ,) (NP (DT:[1833..1840] another) (NN:[1841..1847] CYP3A4) (NN:[1848..1857] substrate))) (,:[1857..1858] ,) (ADVP (RB:[1859..1872] competitively)) (VP (VBZ:[1873..1881] inhibits) (NP (DT:[1882..1886] this) (NN:[1887..1897] activation))) (.:[1897..1898] .))) ;sentence 13 Span:1900..2041 ;Use of a statin not metabolized by CYP3A4 and point-of-care platelet function ; testing may be warranted in patients treated with clopidogrel. ;[1909..1915]:substance:"statin" ;[1935..1941]:cyp450:"CYP3A4" ;[2029..2040]:substance:"clopidogrel" (SENT (S (NP-SBJ (NP (NP (NN:[1900..1903] Use)) (PP (IN:[1904..1906] of) (NP (NP (DT:[1907..1908] a) (NN:[1909..1915] statin)) (VP (RB:[1916..1919] not) (VBN:[1920..1931] metabolized) (NP (-NONE-:[1931..1931] *)) (PP (IN:[1932..1934] by) (NP-LGS (NN:[1935..1941] CYP3A4))))))) (CC:[1942..1945] and) (NP (NML (NML (NN:[1946..1951] point)) (HYPH:[1951..1952] -) (PP (IN:[1952..1954] of) (HYPH:[1954..1955] -) (NP (NN:[1955..1959] care)))) (NN:[1960..1968] platelet) (NN:[1969..1977] function) (NN:[1979..1986] testing))) (VP (MD:[1987..1990] may) (VP (VB:[1991..1993] be) (ADJP-PRD (VBN:[1994..2003] warranted)) (PP-LOC (IN:[2004..2006] in) (NP (NP (NNS:[2007..2015] patients)) (VP (VBN:[2016..2023] treated) (NP (-NONE-:[2023..2023] *)) (PP-CLR (IN:[2024..2028] with) (NP (NN:[2029..2040] clopidogrel)))))))) (.:[2040..2041] .))) ;section 14 Span:2045..2116 ;Publication Types: Clinical Trial Randomized Controlled Trial (SEC (FRAG (NNP:[2045..2056] Publication) (NNP:[2057..2062] Types) (::[2062..2063] :) (NNP:[2069..2077] Clinical) (NNP:[2078..2083] Trial) (NNP:[2089..2099] Randomized) (NNP:[2100..2110] Controlled) (NNP:[2111..2116] Trial))) ;section 15 Span:2120..2165 ;PMID: 12515739 [PubMed - indexed for MEDLINE] (SEC (FRAG (NNP:[2120..2124] PMID) (::[2124..2125] :) (CD:[2126..2134] 12515739) (NN:[2135..2136] -LSB-) (NNP:[2136..2142] PubMed) (::[2143..2144] -) (NN:[2145..2152] indexed) (IN:[2153..2156] for) (NNP:[2157..2165] MEDLINE-RSB-)))