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TERATOLOGY 50:15-26 (194)
AR26-055%
Prevention of Fluvastatin-Induced Toxicity, Mortality, and Cardiac Myopathy in Pregnant Rats
by Mp evald onict Acid Supplementation `RReOgMulAatNoryV.ToHxiRcAolBo,gy,HDOrWuAg RSaDfetAy.DHepAaRrtTmeMnAt,N,SaandbosRRAesYeMarOchNDInsHi.tCeO,XS,anJdRo.z Pharmaceuticals Corporation. Ea Hanaver, Nei Jersey 41996
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TABLE 3. Percent body weight hangs and relaive food consumption compared o conirls
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amich
which did of were sacrificed moribund.
000035
MEVALONATE AND PREGNANT RAT FLUVASTATIN TOXICITY 25
):
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SemTAeeBncniLllE___ Fupvassaon
6.
T
iSmeSmaengdmeeinntcil1denlcleoowfsstre Fluvasatin
at
me
nt-reSlatS0eedgmm0eanttereUnlanlmemvoarltoaRnlaittyee'spnplemencaion vey TORE TURE Russo
HQ oEeRDEme1mg4he To3msM Tet m:L 0 sw a-wo . mesw 2 ooma
i 2i78f5
ofdi
yf:
To ciliate malianesus resentaotfigaoan, thecontrol groupals negaive) were omied
ia --
da Maicrsoshcopiacsisfaianledsil.nygTsihnceogncsaGirrsdotiueodpmVyofo1pa(altvuhavyraiswtiaaysciocfnhamar2ya4oc.-. fsa myocarditis and lesionsof myofibe hy.
mptlaoatdsietvirecamtleeeassiionunrsde.emgreTenhete.s,hIyntphteehrrepelaaabspsipeaenacrreaendogtfeosdbpeefcricfooimrcremqluiaaltnditoitn-o. with greater degrees of hyperplasia seen at the higher
i
evneinatghrsiewssieareten tcvmoancasuipsdrieearvreidodtuersgeesanvetdrmayetniitnonplr(aoTtagebuldaenat3n,rd a emome dying fusing or aher partion.
dd(a1o2ys)mecg/okfgo/fdlaumyv)a.spttoaTttahhienrrreiensdepiGodrnoadspueppessaerIteVoianbnGed rVIleos(s2uIe4lrlpmd1ge2s/gdkrgeV!e of hyperplasia/hyperkeratosis in the animals adminis-
:
cnommrepanertsunriitoannn,iymahacetaenlebdsayilionnlsgeswaieornaescnwdhoawrrieatdhciutncetareifdezbwemydidcahryyos. eT antuation of sated groups of myofibers ac.
tIe)redcmoemvpaalroendatteoanthde 12lomwg/dkogs/edaoyf fflluuvvaassttaattiinn(Garloounpe (GHriostsolVo)g.ical evidenceof{luvastatininduced myoar-
E Ee 4y % daysasanitgoh3rt.piaTmrhetaeesriJsteiisoitnoanosetdiyetpmeicaralwaeonrfdoachnheiammroaarlc.s. OE oy widespread yeoplasmic vacuolar changes in
idLiniakltehwfeiibsemer,evmianultohyneastauenr-dvlsiouvrpipnilgnefGmlearnmtmeoaVdtuiaGonrpnoduwVpaIss(fInlloultvaapnsrtdeasteIVin.nt at 12 and 24 mgkg/day) animals, myocardial lesions
) : Ctnlearmtyyofdiebfeirnse,d Lreo.untdheeomspctuyrrveanccueoloefsla(rFgge. a4ndansdma5l.l were not detected.
Occasionally these were accompanied by 4 sarcolem:
E Tmaealernenie speontsae mTay:anogdfuitiounweifraolnsapmarofmoltatithfoeperrrmyaeytscoieevcnleatlroidifninfairltlethprmeaajtrusearspty,oi.nvwtehaincrehe:.. which had been givenlower dose
poourTdthieeedsmhaaettreesriinnmaillhtaarxdiDdbcoIeseSeefnCfleeUcetvnSsecilSon,uIdnauOtnceNderdecbdonysiinfsltteuwdovoapfsrtmeaavtiteroiruen:snal mortality at delivery and durin the postpartum
(12Emgd/Tkhge/sdasya)lgeosdfiaofnylsuvFawrseotrvaaetsitncaoasnlisoingdere.orAeuldpl hraaenldiamtcaeadlrsdtidoaycitlnhege. Cause of death in these animals
imApeydnroeicoinadnrccdre(ieTaaoalsfbelleeeaisrnil6oi)sn.esir`lwiMlnaiicsourrtdoneesrctopoepucfiptecestadlewivmaniostdrhetoneabcloseiletlryoo,vfwesad-usugswpgoiesctsithtautine.ndog Lexie affect on the dams immediately prio to, or dur-
:
.
aTehe onlytr`eTaewtrimmcienhnatlsraesclaecabrtvieefddice(eleocavantsitnmaotaitlnes.d oMcocsutrroefdthien
3ivn1ag.s,ta9pt0air)ntuharanivtdieoinbn.eeTpnhreesgtanubdasinoetrdpaitnnidonnolnaapncrdteagdtiinsnapgnotsriarttaisto,sn(aTonfsdefeliutn-.
etSnouCrdToaTueessoeuIast(ooWff1aso1o1 r)udesesnvatafdo4c1me9Gad)rc.ohiuGntprhGoiVruc1okp(eunLIpiLVnIgo(.1u7(tmNaoeofvuae1lo2vtf).. _ cstnuarocsakenlassifcnfecglrupomvruuaelpssatsutaltit(ioeAnd.n wSicniahnswveertirahtypezieldrtol,iywssueulnelepsiv.uemblislnLiaiistnmheiedetdmewbdidratythpaol.lsaictoIelnrnetafoalefll,
D ent aloinoenuorvwsittshhteactmoeinvnce aeilanlod.nuacItenedfGdrrieodsutpnsoetmIalilcnhaftnlhduiencIVck,e.
stHuuosbwese.evqeFurle,unvttalhsyetaantteionmneawatasasulrdameobtreltceatlelidetviyenlosmbaisnteersrvunecadkllsiomnoingl,kpaustpoesdr parearition, aswell as during the lactation period, may
en4in7g8.copicalls. the forestomach thickening was be arefleocftadiveorsne effects reltaotdefiicvieent
E {chnaaralctgeE rriozuepdsbwyhheipecihthmeorlveicaaelliohvymepdeerfaplcluiavdsaissatua/pthpiylnpe,emrekinentrcaalttuiodosinin.sg mbayTtmhearetnerarelnslauallctttaoitxniidocinictaaytnetdhlaatclkouvfalsittatetricna-rienadsuciendflmuaetnecerd;
No evidence of ulceration accompanied these hyper- nal and neonatal mortality cobeu coml pletd ely blocked
i
000036
a --
| Rv.HRBETAL
) Frying whew erPe
ol
nEhnonieyxaieostt,SeTniEtrpeweRiithohisSamenvna3l4owainic aamicyidcesuoepepplmleimneeientedneydifle3audmvae2ys.n4 a1hnT2aona8mnidemcsTeyehSvleeennvodtisinpcaomsceecnsruutuurimprnCpilgnogerfnmienbluneltaaacHptrtelliggsoaeennssedtap,trVnieolvoneeanaabntntsddxnpmaotopcdpaaarorletey.
S Be T omg o A aSAeTr aI HtEmeantayl mruoaesseuesswvhrcahyalwlohwas Steegveeneoif'n hhee
hiap conrtate saupplpleemmeenptiaotnionrepreenveendtemd omarr ok
nMoltarnedduIcVe (tfhleudviarsetcattienffaetcto1f2 falnudv2a4stmga/tkoignn/dtahye),gaisttdriidc Aloe AW. {1989EDRixoAweTrs.UiRochEemisCtIesTaEnDd bilo of ovasa-
r ny oe Ee s Foe ri forestomach squamous epithelium, although the de-' Brown.M.S. snd JL. Gadseets 1980) Multivalent
Keratosia is the result of directorcontactieitation by KEabrom. RG. DB Weston, FG. Kuchavais. T. Slr, 13.
scree Bains ner a, flu`Tvhaestfaltuivnaostnattihen-siqnduuacmeoduesarfloyrecsatrodmiaacchleepsiiotnhselcihuamr.-
| CC ian, tint eT LaitseremofmiHeMsOci.sCsoonresdtursohatnse. Emigebon:IverroomtiinbeisaSkym(s1988
Hp on
rion) rition) se emble thos nr ebny peer foe, resembled those induced by isoproterenol (preg. ' "SFET SE RE Kithawala. FG. T. Scllen. RG. reATA Engstrom. DB. Sr Weinstein, H.
cumalton posi lad toslrsion ofcer tis) appeared to be the resultof sarcoplasmic fluid ac.
cumulation possibly related to alteration of cellular
EREon inraationa Sympesion on Adbmarosmi Rome Goer Sa3,
Hus ne,
,
e cbleeatrw.eeLnt ikpree-wiaisnidte1,spa onsottpakrntouwmnalaetsihWonhtsa,tipfoainnty,inisthneoitf _FiTempSeRtriuEn.gF5hm.1Ta5o.,t TMaecDronmay lod,f WC0y5p7e.f ripPorpir,oi0iDo n3em.niBaD.uecMm aed,.BRReYJs..
amse a mle ait FHS Several factors existed which probably contributed to
the develoofpmymocearndit al damage and/or death of
EMG CommymeA
BEA, 55%.
Grreduciase Ts. oe
nbibior,
Ktos.
ovat to rab.
ns pr
J
Sma ee pte ee tay nA Th Sy SE tion, the exaggerated pharmacologic actiofvliuvtasy. Jinsker. DH. JS. MacDonald. RT. Rebasso, and DL. Bokelman
btaitoisny,ntih.ees.isi.nhwiabsitiaonsiogfnifmiecvaanltonfaacttoer.anHdMGc-hoCloesAterroel- a n-Sie sger nieofa Smepvet aline sodsoPhIb R otaflSs hSyodrpe3py.
nd Eien :30 Aare. ;Sebo 0, for the synthesis of steroid hormones, cell membranes,
cell growth, and normal cellular metabolism (Brown
ices ia inhibitor. Fund. Appl. Toxicol. imanuscript:
B RBSLESOL D SET e PnSL te ara y abr g%
re
0060037