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2

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2. 04HrIEI IYMnAHPnIHI TOY ENTYnOY

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3

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A. lTOIXEIA TAYTOTHTAI TOYTEXNOBAAITOY

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Eioo<; TExvof3AoOTOU (EnE ~ A.E.): A.E.

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5

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H ETO I psio JJ no pel va ou IJ IJETEXEI OE a noi 0 ori nOTE EnlXEi p 11011 no PEjJ<PEPOU C; oxonou, uno onorovonnors ETOIPIKO Tuna KOI va auvEpy6~ETOI IJE onorocnnore CPUOIKO ri VOjJIKO npcoomo, IJE onorocnnore rpono, xcrornv onooooeoc Tile;

6

LUVEAEUOEWe;, AOIJ~oVOIJEvlle; IJE EVIOXUIJEVIl nAEI04JIlq>io TWV TPIWV TETOPTWV (3/4) TOU ETOIPIKOU KEc.poAoiou.

LE neplrrnocn nou I"') npOTOOI"') npoEPXETOI ana oAoMIlPWIJEVO EPYO nou uAOnOl~SI1KE aTO nxckno TOU nPA=E - ¢>OOI1 A', nopoxcxoupe va Emauvocp9Ei n UXETIKri Aninpoon oAoKAripwanc TOU tpyou oro OIKOIOAoYI1TIKO TOU cpoKEAou.

Ap91J. npOOTOKOAAou rrET Anoq»ool1C; oAoKA~p6)ol1C; tpyou : .

B. OIKONOMIKA ITOIXEIA TEXNOBJ\AITOY

APXIKa I"') sroipdo (ELFAR EnE) EiXE IJETOXIKO KEc.paAoIO 21.000 € KOI 700 ETOIPIKO IJEpiolO o~ioe; TPIOVTO EUPW (30 €) TO Ko8EVO IJE TI1V napOKClTW ouv8Earr

* npO~AE4J11 ylO aU~1l011 TOU IJETOXIKOU KEcpoAaiou EVTOe; TOU 2006 OE 1.000.000 € IJEOW TWV aKoAou8wv aTooiwv.

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METOXOI / ETAIPOI lli.IOTHTA ETaIPIKO MEpil5lQ
EAloapET MOTOOUKO EPEYN HTHl: - ET AI POl: 4.340
MivblC;;- TllJo9EOC;; MOTOOUKOC; EPEYNHTH1: - ETAIP01: 1.178
lUH.II;TpIOr; BAoXOKOC:; EPEYNHTH1:- ETAIPOi: 1.767
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AIOXEiplor'lC:; Tr'lC; nEplOUoioC; TOU
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7

KuKAoe; Epyamwv (av unaPXouv):Ktpol"} npo c.papwv( av unapxouv):-

Iuv8£an PETOK/KOU K£([)oAoiou T£Kvo{3Aoarou:

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H apXIK~ ouvsson TI"}e; ELFAR EnE ~TOV:

METOXOI/ ETAIPOI Il\IOTHTA nOl:OITO
~MMETOXHL
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Mivroc; MOTOOUKOC; EPEYN HTHL -ET AIPOL 25% METa rnv npWTI"} OU~I"}Ol"} TOU IJETOXIKOU KEqmAaiou En~A8E rpononolnon TOU xorooronxou IJE TI"}V ncpccrno IJETOXIK~ OUV8E0I1:

METOXOI / ETAIPOI If.IOTHTA nm:OITO
LYMMETOXHL
EAIOOI3ET MOToouKa EPEYNHTHl:-ETAIPOl: 35%
Miv6)c::-TI~o9EOC:: MOTOOUKOC:: EPEYNHTHl:- ETAIPor 9,5%
ArllJllTplO~ BAaxoKo~ EPEYNHTHl:- ETAIPOl: 1425%
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XapoAalJno~ ral3po~ EPEYNHTHl:- ETAIPOI 13%
K6)VOTaVTivo~ AAE~6nouAoc:: EPEYNHTHl:- ETAIPOl: 15%
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ETolpEia A~lonoil')o'1e; & ETAIPOr 2,5%
AIOXEipIOI')C; Tile; nEplOUoioe; TOU
nov/lJiou naTpoov 8

METO rnv npooB~KIl TIl~ VIANEX KG! Ttl OEUTEPIl G!J~1l01l TOU ~ETOXIKOU KEcpaAaiou OE 1.000.000 € 80 EnEA8EI rpononolnon TOU KOTaOToTIKoU ~E rnv ncpmcrrto ~ETOXIK~ ouv8E°tl:

METOXOI / ETAIPOI ffiIOTHTA n02:0ITO
rVMMETOXH2:
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EAIUO(3£T MOTUOUKO EPEYNHTHl: -ETAIPOI 15%
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L LUVTO~1l nEplvpacp~ TWV opaOTl1pIOT~TWV TWV IOIWTWV EnEVOUTWV /

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9

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H BIANE= A.E EivOi 11 npwTIl CPOPIJaKEUTIK~ Biopnyovlc OTrjV EMooo, EXoVTOC; Eva IJEpiolO neplnou 10% enl TWV nwA~OEwV.

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'EXEI TtAOC; Or'lIJJOupy~aEI TIJ~IJO nou nopoKoAou8Ei KAIVIK£e; IJEAErEC; nou yivOVTOI, OE ouvepvoolo IJE ETOIPEiEC; nou sxnpootonsl, OTa IJEyoAuTEpa naVEnlOTr]lJtOKO VOaOKOIJEio Kal EPEUVr]TIKO KEVTPO Tr]C; Xwpoe;, EAtYXOVTae; Tr]V OPOOTIKOTr'lTO KOI rnv oocpaAEIO V£WV KOI npeororuruov CPOPIJOKEUTIKWV ououov,

2. 100}..0YIOlJoi - onoTEAtOIJOTO Xp~or]C; ~ EKKa8opiOTIKO Or'llJEIWIJaTO TWV TPIWV

TEAEUTOiwv ETWV TWV IOIWT~)v EnEVouTwv / XPr]IJOTOnrOTWTIKwV CPOPEWV

(En louvimTOVTO I ) ..

3. nopouoioor] OIKOVOIJIKWV OTOIXEiwv nou va onooEIKvUOUV Tr]V oUVOTOTIlTO KoAulj.Jr]e; Tr]C; loioe; aUjJIJETOx~e; TWV CPUOIKWV npooionov, ouuqxovo IJE TO eruouvorrrouevo EYYPOCPO (ernouverrrovrm).

LuvonTIKOe; niVOKOe; OIKOVOIJIKWV OTOIXEiwv TWV IOIWTWV EnEVOUTWV / XPr]IJOTOnIOTWTIKWV oopaov (EKTOe; TWV CPUOIKWV npootonrov).

OIKONOMlKA ITOIXEIA TOY EnENLWTH BlANE::

2003 2004 2005
2uvoAo EVEpYr]TIKOU 160.850.816 177.499.641 136.090.836
Bpoxu n p08Ea1JEC; U nOXPEwoEI C; 135.002.100 . 153.031.115 111.105.835
Ku KAoC; EPYOOlWV 211.374.832 234.230.426 249.704.406
AnOTEAEOIJOTO xononc 39.677.770 40.285.219 56.603,860 10

r. ITOIXEIA EnEN.6Yl:HI

nEpiAIl4Jfl Tile; EnEVO UOTIe; (2 oEA.):

AUT~ Tq unYIJ~ 11 ETOIPEio tXEI ovomu~EI ouoie; OE npOKAIVIKEC; OOKlptc;, eMil ulo ~piaKETOI OE areolo oVQmu~llC; I-IE noMe UnOOXOI-IEVO OnOTeAtOI-lOTO, EVW unapxouv KOI TOUA(JXIUTOV 2 VEO' EVoEXopEva npovpcuuoro. 01 OUOiEC; nou ~piaKoVTol OE npoKAlvIKE:C; OOKIIJEC; ooopouv rrrnv Ynsproon KOI TIC:; KOPOIOYYEIOKEC; Aa8EvEIEC; EVW eMil nou ~piaKETOI OE araolo Ovanruq,C; oeopo TOV Kcpxivo. To EVOEXOIJEVO vEo npoYPopJJOTO orpopouv 0) ornv YnEpTOOfj KOI ~) crrjv YnoyoVllJOTIlTO KOI orov OPlJaVaE~OpTWIJEVO Kopxlvo .. l:UYKEVTPWTIKC, <:po iVOVTO I orov KaTw81 niVOKO:

ONOMA

OVIIA

eSPAnEYTIKO nsA:fo

1. npOI1YIJEVQ npOIOVTO - MIIJI1TEC; nEnTli5iwv aE npm(AIVIKEC; .40KIJjEC;

ELSARTAN AVTO'YWVIUT~C; YnoooXEO KopOlaYYEIOKEC; Aa8tvEIEC;,

AYYElon:vaivllC; II Yneproon, A8llpaaKA~pwall

•• •• •

, . . .

KapOIOYYEIOKEC; AaStvElEr"

YnEpToaQ, A:9I1PoaMriPOOOTl AI!J~E:DUIKri yonqn

•

•

. ,

ELAMINOSARTAN AVTavwVlUT~C;

AYYEIOTEVaivqc; II

YnOOOXEO . KapOIOYYEIOKE.C; Acr8EvE1ESr

Yne:pTo.oll, A8Ilpooo~PtJ)0Tl

2. npO'IOVT1I O'E A.lat5ncoala A.viIRTU~I1C; - YnoaxOiJEVQ AnOttAEoHOTa

ELTRAP AVTaywvIOT~C; YnaoaXEo KapKivoc;, AYYEloYEvEaq epolJ~ivqC;

3. npoonT1Kt.c; - EvliEXOIJEVQ NED npoypUPIJQTO

ELGUARTAN MIIJIlTEC; KAwvloivlle; KOI KOPOIOYYEIOKE.e; Aa8EvEIEC;,

AYYEIOTEvoivqC; II Yneproon

ELGON~D

Ava 'A oyo AnEAEu8tpwollC;

0PIJOVIle; rovrlJonC1iqtJ~, rOVJIJI)rI1TOJ

Tile; OPIJOvoE~opnil)JEVOC; KOPldvoC;

To nporovro aura Tile; ELDRUG EXOUV npaKuljJEI ana Til ouvepvooio pilOC; oVE~opTIlTqe; OIJOOOC; LXEOIOalJmJ <1>0PIJOKEUTIKWV np0'iovTwv 11 onolo cnorrxslro: ono TOV Ko8qyqT~ IWOWIl MOTaouKo, TI-I~lJo XIlIJEioc;., navEnI.or~Plo nOTpWV KOI roue OUVEPYOTEC; TOU ornv EMcoo KOI TO' E~WTEpIKO. To npoiovro KoAumoVTol ana rplo EMIlVIKO LlmAwlJOTO EUPEoITExviac.; KOillIE8vEic; PCT AIT~OE'C; EUPEOITEXViOC; (IOE nOpapTIlPo).

Ovopcoio npoY6VToC;

EL5ARTAN

11

To npolov ELSARTAN (AvaaroAEoc; Tile; AYYEIOTEvoivqC; IT) VIO TIlV YnEpTOUIl KOI TIC; KapOlaYYEIOKEC; Ao8tvEIEe; ExEI; OUVTE9Ei oro Flovarncrruno nOTpWV oro T~~~o Xq~EloC; KD.I ova rrruocerc I ce ouvepvoolo JJE EPEUVIlTEe; Tau QVOOE.IOU Kop610XElpaUPVIKOU KEVTPOU (KPEjJOOTIVOc;, KuplaKioqc;, BAaXOKOC;) Kal TOU navEnIOTq~iau Tqe; Boarwvqc; (rof3pae;).

Ovopooic npotovroc

ELUROSARTAN

To npoTovELUROSARTAN OE ui5poq)fAq KO.I uopoqmf3q !Jopc:p~ EXEI O}(Ei5100TEi KOI OUVTE8Ei ornv nClTpa arc Tp~jJo XrWEioc;, nOVEnIOT~PIO nOTpWV «n a~loAoYEiTOI OE ouvspvcolc JJE TOUe; EPEUVqTEC; K08rWqTE<; .!J.. BAoXaKO, 8. KpEpoarlvD, l1. KOKKIVOOTO Qvooso Kop510XEI.pOUPYIKO KMPO KOI oro ATTIKO navEllIoTlljJlOKO Nooosouelo Ko8wC; KOI ,lJE TOV Ka8twqT~ X. roi3pa oro navEnlar~plo Tfl<; BoarwvflC;. H u5poc:poi3q jJopc:p~ 80 XPflOl,IJOnolq8EI y,lo 51.00EPj.JIK~ xpi]crq.

ovouoolo npolovroc

ELAMINOSARTAN

nepl.ypa.qn; npO'iOVT1H;

To npolov ELAMINOSARTAN tXEI OXEOI0 orsi KOI OUVTE8EiOTflV nClTpa oro Tplipo XIlj.JEiac;, naVEnIOTIi(.HO nOTpWV KOt O~OAoYEiTat OE ouvspvcoio IJE TOUe; EpEuvqTEe; Ka8IlYIlTEC; l1. BAaxo.Ko, /J.. KPEl-JOOTIVO, !J.. KOKKIVO oro QVaOEIO Kop51.0XE1POUPYIKO KMPO KOt oro ATTIKO navEnlarrJlJlOKO NOOOKOIJEio Ka8wc; Kat jJE TOV Ka8l1vqT~ X. raf3po OTO nOvEntOTIiPIO rqc; BOOTwvqC;.. To 'ELAMINOSARTAN KD.I nopaywya TaU 80 XPflOl.j,.lOnolrj8ouv oov npolovro olnAIic; Kal TptnAIic; OpaOIlC; (RAS/55, RAS/AvnnflKTIKn, RAS/ A VTJOYYEIOYEWET1Ki].,

12

Ovouooio ELTRAP

npoiovror; nEPIYPCUpq npOi'oVTOC;

To npolov EL TRAp· (AvoaroMac; T~<; epop~lv~C;) Via TOV Kcpxlvo Kal Via TIC; KapOloaYYEIOKE<; aaHEvE:IEI:; EXEI ouvresel OTO nave:nlar~IJIO nOTpWV Tp~pa X~pEiac; Kal ovonruooeroi OE ouvepvooio PE TOV KaH~Y~T~Mlx6A~MapaYKouo6KI1 KGI TOUe;

OUVEpyaTE<; TOU ana TO

EpyaOT~plo <l>aplJoKoAovlae; TaU

TP~POTOC; IOTpIK~C;, naVEnlOT~pIOU naTpwv Kal TO QVaOEIO KOPOIOXElPOUPYIKO Ktvrpo.

AEnTOPEpEOTEpa arolXEio KOI XOpaKT~pIOTIK6 TWV uno aVamU~1l npoiovnov T~e; ELDRUG:

n Eplypac.pr; TOU n poe; eunop: Kr; EKPETOMEUO'l EPEUV'lTI KOU onOTEAEOIJOTOC; (1 OEA.):

ELSA RTA N

(AvrOyevVIOTrjC; TaU unoooxio AT1 Ylo TTJ e£ponEio KOPOIOryEIOKWV oae£v£l.wv)

To ELSARTAN slvoi EVOC; IJ~ nEnTI6IKOC; PIP~T~C:; T~C; OYYEIOTEvoiv~C; II (All) a onoioe; EKAEKTIKO pnAoKapEI TOUe; unoooXEie; Tile; All. AV~KEI OE pia vee kornvoplo Kop610YYEI.aKwv <pappa.Kwv nou ovouozovro: ovrOYWVIOTEe; Tile; AIl KOI EivOi nopouoio pE TO Losartan, EVO <papPoKo TO onoio npoo<paToElo~XHIlKE ornv OVapa ana Til Merck pE TqV EpnoplK~ ovoucclc Kozaar, H OVapa TaU Losartan (Kozaar) sivm $2 ?i1:C; ETqoiwC;.

01 OvrOVWVIOTEC; T~e; All EXOUV nopopoio ?ipaoll pE TOUe; ovooroxdc TaU METOTPEnTIKOU Ev~upou T~C; AYYEIOTEVoiv~e; II (MEA), 01 onoloi xp~m!JonolouvrOi EUpEWe; KOTa T~C; uneproonc KOI Tqe; KaPDIOK~e; OVmapKEIOe;. 'O!Jwc;, 01 ovrovovrorec Tile; All DEY npoxoxouv ~qpo ~~XO KOI OYYEIOOlO~!JOTO, !JIO nopEvEPYEIO nou aUXVa axETi~ETOI !JE TOUe; OVOOToAEiC; TaU MEA.

H anoTEAEQlJ.GnKOTqTO TOOO TaU ELSARTAN 000 Kat TaU losartan, E~apT(JTa.l an6 Til EY~UI-lIK~ uerorponn TOUe; in vivo OE Evav EYEPYO I-lETo~oAiTIl. 'OTOV aUTO TO Buo <paPPOKO xoprWOUVTOI aov !JIO onA~ 50011 ana TO OTapO OE aVOlo8~TanalllPEvo UnEPTOUlKa KouvEAIO KOI apaupoiouc;.. qOVTIunspruorxrj DpaO~ TaU ELSARTAN zivcn ncpouom ~ KOI KaAuTEPIl ana OUT~ Tau Lasartan. EnlnAEov, TO ELSARTAN unopel va OUVTE8Ei OE Aiya Kal ul.jJrjAwv onoocoeov ara15la, nape:xoVTae; Eva xaprjAou koorouc <paPPOKO. AUTO CiVEI EVa OUYKPITIKO nAEOVEKTql-l0.

ELSARTAN

13

To OVO~EVO~EVO nAEOVEKT~~OTa TaU ELSARTAN slvoi:

o. "liEUTEPIlC; VEVIOC;" CPOPJ,lOKEUTIKO np0i"ov J,lE noAu UqJIlAi) 6POUTIKOTI1TO OTOV

XOPIlVEiTOI ana TO OTOJ,la .

p. TOXlJTEPIl anoppO<PIlTIKOTIlTO ana TO EVTEPO

y. ~EVOAIl Ol(jPKEIO OPOOIl<; KOI better peak trough ratio E~OITlo<; TIlC, oPV~c, uerorponqc TOU ELSARTAN orov opoonso ~ETaJ3oAiTIl TOU

6. VP~VOPIl KOI XOjJllAOU xocrouc ouv8EOIl.

To KUPIO nA£OVEKT~~OTO TOU ELSARTAN OUVKP1VO~EVO ~E aMouC; OVTOVWVIOTEC; TOU AT! unoooXEo slvor:

I. H (xapllAou KOurOUt;) oVV8E01J

H ouv8EOll Tau Eisartan dvoi XO~IlAOU xoorouc H OUV8EOr'l TOU 1,5 olunoKaTEOTIl~EvOU Ev610jJEOOU~KAEI6i, EnITUVXOVETOI OE rpio 1l0A1C; OTa61o nou nEPIAo~J3avouv arEpEOEKAEKTIKEC" Ka8opEC; KOI ~E UljJllA£C; onooooEIC; (>85%) oVTI6pooEIC;. EnmMov, 11 OUV8EOll TaU n:AIKou 1,2,5 TplunoKoTEOTIl~EVOU npoiovror; EnlTUVXOVETOI OE EVa anAD aro610 ~E u6POSUjJE8uAiwOll OHI SEOIl 2.

IUVKEKpl~Eva, uio OEIPO TPIWV OVTI(')p6oEWV (TpITuAiwOIl-OAKuAiwOIl-U(')poAuOIl) onOiTEiTOI Via ~Ia OTEPEOEKAEKT1K~, uljJr'lA~C; ano6oollc, ouv8EOll TaU 1,5 onmoxorscrquevou IjJl(,)o~oAiou oov Ev611JIJEOO KAEIOi. KOTaMIlAIl noooroolo TaU TETpO~OAiou ~E Trt, CI-Trt, Benzyl KOI nopovovo OUTWV ~E mOKOAOu81l u6PO~UjJEBuAiwOIl, nopEXEI EvwuEIC;-npmpopjJoKO ~E ulIlllM (')POOTIKOT'1TO KOI olapKElo 6pOOIlC;.

II. H 61lipKEIO 6ptiullt;

H napouuio TaU npOOTOTEUIJEVOU IJE CI-Trt TETpO~OAiou KOi '1 apv~ ononpoorcolo TaU orov opvoviouo npoo6i6EI oro c.pOP~OKO ~EvoMTEPIl 610pKEIa 6paUIlC;.

Yncpxouv nopooeivuoro q:>aplloKwv ITT '1 V ovopc nou nEptEXOUV npoorcolo IJE Trt. To ELSARTAN nEplExEI plo 0IJa60 TETpa~oAiou npaITTOTEU~EVO IJE CI-Trt '1 onoio iawc, eivoi OIWOVTIK~ Via IJEyOAlJTEPr'l 6t6pKEIO 6paullC;. napa6EIVIJo c.pOPI.J(JKOU OT'1V ovopo nou nEplEXEI rnv 1010 npoororeunxn a~aoo elvoi TO clotrimazole. AUTO TO <pOPjJOKO EivOI Eva EUPEWC; q>oOlJaTOC; OVTIIJIKP0J3tOK6 nou XPIlOllJOnOIEiTOI ornv Oeponelo OEPIJOTIKWV IJOAUVOEWV nou npokoxouvroi an6 oloc.popa EIOIl naSoy6vwv IJIKpOopvovlapwv. 'AAAEC; noootpcrec jJEAETE<; E~<pavi~ouv TO clotrimazole cov Eva unOox6IJEVO c.pop~aKo Via Til BEponEla TaU ~EAOVWIJOTOC;.

14

BIOAoYIKq A~loAoy"ul1 in vivo TOOV UUVTlBEIJEVIDV EvcilaEOOV Yla avaOToAq TOU aUOTqIJOTOC; pEvivl1c;-aVVEIOTEVuivl1C; (RAS) KOI BEpanEia TI1C; YnEpTOUTJC; IJEUOO Ala~EPIJIKric; xopqYrJ a.,C;.

LTDX0C; Tile; £VDH1TOe; aUT~e; eivoi va OUYKPl8Ei Il opaOTIKDTr]Ta I.lIl-nEnTIOIKtiw 1Jll.Illni)V HIe; ovvaoroolvn; II OE EVa 1J0VTEAo aValo8llTonollllJ£vwv KoviKAwv IJE uncproon E~Opn;)I.IEVI"[ cno TI"[V OYYEIOT£Voivl"[ II, Via va EUPE8Ei TO nMov OPOOTIKO IJOPIO.

ME8oooAoyio:

riO TI"[V o~IOAeYI"[OI"[ TI"[e; in vivo OPOOTIKOTI"[TOe; TWV OUVTE8EIIJEVWV uopkov oav OVOOTOAEWV TWV unoooXEwV TI"[e; OYYEIOTOoivlle; II eo XPll011J0nOl1l8ouv EV~AIKEe; OPPEVEC; New Zealand White K6vlKAOI IJE ~apoe; 2.5-3 kg. 'DAa TO ~WO Bo ovorcsnroncmaouv I.IE 30 mg/kg nEVTo~op~ITOVI"[~ Ba OloowAI"[vw8ouv «en 80 TE80uv OE IJI"lxaVIK~ ovonvoq IJE XOP~VIlOI"[ 100% o~uyovou (respirator for small animals, MD Industries, Mobile, AL, USA). ria T'lV OUVEX~ KOTaypa<p~ TI"[e; nle:OEWC; 80 TOnOe£T1"[8Ei K08ET~POC; one nOAUOUPE8avI"[ OTIW KOPWTioo, nou 80 CYUVO£ETOI jJ£ow transducer IJE OUOKEU~ KaToypQ{p~C; (multicchannel recorder, Nihon-Kohden, Model 6000, Japan). ria TI"[V O'llJloupyio unEpTOOEWe; E~apnilIJEVI"[e; ana TI"[V OVYEIOTOOivl"[ II, 8a XOPrwEiToI OT'lV O<POViTIOO IJtow EVOe; OEUTtpou Ko8ET~PO nOAuoupE8ov'le; 6IaAUI-I0 5 1J9/ml ovvaorooivnc II (Hypertensin, CIBA) OE Dextrose 5% . LE nporWOUI.IEVO m:lp0I.lOTO OEiX81lKE DTI £YXUOIl TOU EV Myw 610AuI-JOTOe; IJE pu8IJo 0.2 rnl/min (1 IJg/min) I.IEOW ovrxioc OUVExOUe; EYXUOEWC; (Harvard Apparatus, Natick, MA, USA) OlllJlOUPYEi oo~ap~ uneproon, nou 610TI1PEiTOI OT08EP~ Ko8' ov Xpovo OIOPKEi Il tYXUOil. nEvrE Amn) IJETa T'lV orcseponolnon Tile; nlEOEWC; OE unEpTOOIKa EninE60 80 xoprwouVTor 01 OVTOYWVIOTEe; Tile; ovvaoroolvqc II, nou eo ExoUV OUVTE8Ei an6 rnv OIJOoa TaU K. MaTOOUKO, oov bolus OE <PA£~O TaU WTOC; TaU KoviKAou KOI OE 600£1(:; 0.1, 0.5, 1 KOI 2 mg. H rrrtoon Tqe; nle:OEWe; TWV nElpOIJOTO~WV ana TIlV KelBE 66011 nElpOIJOTIKOU tp0PI.IOKOU 80 ouvxpiverm !.IE H]V rmoon Tile; n IEOEWe; UTO i 010 1.1 OVT EAo , a no bol us XOP~Yll on AO~O pTOVIle; OE 66011 0.0 5 ~ 0.1 mg. H ovrnmeproorxq 6POOTlKOTr)TO TWV ovrovovrottbv Tr)e; ovvaorocivnc II 80 !.I EAETelTO I KOI !JETO TrJV per os XOP~Yllo~ TOUe; IJE gavage UTa i610 nElpOIJOT1KO 1J0VTEAo.

AVOUEV6uEVO onoTEAEoUOTO:

H ~10AoY1K~ o~IOAOYilOIl TWV OUVTE8EIIJ£VWV uopuov Ba OIEUKOAUVEI TOV OXE61001J0 KOI TIlV napaywv~ VEWV neprooorepo 0POOTIKWV aVTIOnEpTOolKWV uopkov.

nEploplauoi KOI npoOnoB£oElc

Av KOI EXOUIJE 6Ei~EI nwe; 11 YEVIK~ oVOI081l0io nopEp~oivEI OpvllTIKO UTa nElpOIJOTO TOU KopOlaYYEIOKOlJ OUOT~lJaTOC; (Vlahakos et al, Brain Research, 347:372-375, 1985), 11 IJEyelAr) nporWOUIJEVr) zunupio ucc IJE TO IJOVTEAO TWV ovolo8r)TonOIIlIJEVWV KoviKAWV IJOe; E6EI~E, nwe; VIO

IS

TOV oxono Tile; ~IOAOYIK~e; O~IOAOYllalle; noMwv popkov, TO npOTEIV0I-IEVO 1-I0VTEAo onOTEAEi KOA~ KOI YP~YOPIl I-1E80150 1-1£ o~loniaria «en movo'\1l4.l1J,JOTIlTO (Vlahakos et al. Letters in Peptide Science, 3: 191-194, 1996, Matsoukas et a I. Bioorg Med Chern. 8( 1): 1-10, 2000, Polevaya et al. Bioorg Med Chern, 9(6):1639-47, 2001, Roumelioti et al Bioorg Med Chern Lett 12(18):262- 7,2002).

BIOAoYIKte;/KAIVIKte; IJEAETEe; TOOV OUVTIStlJEVOOV EV6>OEOOV YIO KOTOaToAit TOOV OUaTl1lJ(lTOOV pEvivl1e;-OYYEloTEVaivl1e; KO I au IJ na911TI KOU 1 1J£000 Ala~EPIJ I Kite; xoPitVI1011C;.

01 1-1£Af:rEe; OUTEe; nEpl'\OJ,J~OVouv KaT' opXoe; in vivo ~!O'\OYIKEe; 15oKII-IEe; O£ novrhoo YIO KOToaroM TWV ouornpcnov pevlvnc-ovvaorevolvqc KOI oU!Jna8IlTIKoU.

cDumo'\0YIKO novrhoo KOI unEpTomKo novrioo (SHR) 80 J,J£AETT'j8ouv OE OI-lOOEe; 3-5 nOVTIKlwV, !J£ Ton08E:T1l01l q>AEf3IKwv KOI 0PTIlPIOKWV Ka8ET~pwv YIO XOP~YIlOIl <papl-loKwv/A~4.l1l olucroc KOI ouvEX~ KaTOYpo<p~ apTIlPloK~C; nleoqr; ovriororro. H 15E~IO AOYOVIO OPTIlPio KOI '1 otppovinfo <PAE:~O 80 Ko8ETIlPIOarOuv IJE ovoroflnoio TIlV npOflYOUIJEVrj uepo Tile; o~Eioe; IJ£AETIlc;,. KOI 01 nOVTIKoi So 010TflP'180uv OE nAoarlKo KAOUf310 Til IJEPO Tile; IJEAf:rIle;. To <pUOIO'\0YIKO novrixro 80 Mf30uv EVEOIJ.la 1000mg/kg E~WYEVOUe; AYYEIOTEvoivllC; II, I-IE OUVEX~ KOTOypQ(p~ opTIlPlaK~C; nieonc, 'Orov f'l OPTilPtOK~ nlaon EnovtA8EI OE <PUOIOAOYIKO EninE150 So Aof3ouv IJE olrqon IJE Ko8ET~pa IJIO OOOf'l Tile; ouoiae; KOTW ana Til I-lEAETIl KOI f'l xop~Yf'latl Tile; AYYEIOTEVoivIle; II 80 EnoVOAtl<P8Ei. AvoAoya I-IE TO f3081J0 I-IEiwa'1e; Tf'lC; apTIlPloK~e; nlsonc, 01 EnOIJEVE<; 156aEI<; unopel va EivOI IJEyaAIJTEpEC; ~ I-lIKpOTEPEc;,. 6nwc; 80 onorrdrm. H ED50 KOI E090 TtlC; ouoioc So Ko80ptarEi OE 5 nOVTiKJo. EDSO EivOI rj is 6 Oil Tile; ouaiac; Il onola ovaarEMEI KOTO 50% TIlV aU~1l01l Tile; niEaT1C; on6 rnv AYYEIOTEvoivll II. 'EvoC; OUVOAIK6e; opI8!Joe; 25-30 novrino So XPEtaoSouv YIO npwToKoMo oveupeonc Tile; npwTIle; OOOIlC;· 01 iOIEe; I-IETP~OEl<; nou naprvpooovroi 80 EnOVaAIl<P80uv OE 5 uneprootso novrhco )JE rnv ED 50 150011 Kat OE 6Mo 5 I-IE 'rnv ED90 150011 KOTW ana OUVEX~ )Jf:rPIlOIl rnc opTIlPlaK~C; nieonc.

H IJEAETIl KaToOToA~e; TOU OUlJnaSf'lTIKOU oUOT~)JaTOC; So npaYI-l0TOn011l8Ei OE <PUOIOAOYIKO novrhoo, An6 nEVTE c.pUOIOAOYIKO novrixm 80 AIl<P80uv 0.3 ml clue Ylo 'rnv I-IETP'10'1 Tile; VOPEntVE<ppiVIle;. LTIlV OUVEXEIO 80 '\a(3ouv TIlV ED50 ooooxovio Tile; ouoloc ana TO OTOIJO Kal 80 '\'1<P80uv 0.3 ml aiIJOTOC; !JETa 1,2,4,6,10,12,18 KOI 24 WPEC; Yla I-ltrPIlOil Tile; voperuveeolvnc, To iiSlo npwToKoMo 80 EnovaAf'l<P8Ei OE 5 aMa <pUOIO'\OYIKa novrino IJE rnv ED90 00011 Tile; ouoiac;. Eov 11 ED90 iS6ull vro TIlV AYYEloTEvoivll II EivOI OVEnapK~C; ylO Til IJEiwOIl TOU'\aXIUTOV KaTo 50% TWV EnlnEiSwv Tile; voperuveoplvnc nAaUIJOTOC; UTa IJEYIOTO Tf'l<; is paoqc:;, np608ETEe; OOO£[(:; So XPEIOUSEi va IJ£AETIl80uv.

16

In vitro IJEAhll TCI)V cpaplJaKoAoYIKWV 1~IOT~T(IlV TCI)V GUVTIOEIJEVCI)V EVWGEroV Yla avaGToA~ TroV GUOTI'WiJTCI)v pEvivllc;-aYYEloTEVoivllC; Kal GUlJnaOI1TIKOU, IJE06) l1lOi5EPIJ I K~C; xop~Yl1al1C;.

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AVTOYWYIOTEe TOU unoi5oxEo ATl Tne Angn

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17

¢JapUOKO UE IJIKTD EVEPYEIO: AVTOY6lVIOTES TOU unoliOXEO ATlmc Angn KOIOYCIlVIOTEC; TlIlV o2~olipEVEDYIKrlJV unoliOXElIlV

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18

tpAEJ3£c; KOI TWV ouo XEPIWV KOI IJIO nEplXElpil)o OUTOIJOTIle; niEOTIe; KoBE nME AmTO (Dinamapp, Tampa, FL, USA) ronoerrnuevn yupw ana TO ~POXIOVIO. 01 jJEAErEe; So OUlJnEplM~ouv OPXIKO jJlO OEIPo bolus EVEOEWV Tile; AYYEIOTEVoivIle; II YIO va q:lTIa~ouv IJIO KOlJnuAil ov6Aoyo IJE TIlV onovrnon ornv niaon, H i5aoll Tile; AYYEloTEvoivlle; II nou ~pE8IlKE va npoxoxei IJIO OU~IlOil ornv niEoil 30 J,JE 40 mmHg GTIlV OPXIK~ <pO all 80 XPIlOIIJOno.IIl8Ei YIO TqV l)oKllJooio. Go l)oKlpoarouv IJOVEe; ana TaU OTOIJOTOe; i500EIe; TaU ouvl)UOOIJOU, ~EKIVWVTae; J,JE pia l)001l unoAoYloJ,JEvil ana TO n€.lpOjJOTO OE ~wa. H EnlAE:YjJEvil l)oOil Tile; AYYEloTEvoivIle; II 80 yiVEI EVEOil oov bolus OE TOKTO l)loOT~IJOTa jJETO ana rnv XOP~YIlOil TaU <pOPJ,JOKOU one TO orouo (KoBE cope, Ko8E 2 WpEe;, JJETO Ko8E 4 WPEc;" K.An.) EWe; TIlV EniOTpOCP~ Tile; unuvrqoru; OTIlv nison OTIlV OPXIK~ Tlp~. Ko8E 50011 TaU OUVOUOOIJOU 80 50KlPOOTEi OE 3-7 ESEAoVTEe;. Onolol)~noTE oMo OTOjJO unopel va AO~EI ana ulo EWe; rpac i560EIe; PE E~l)ojJol)laiEe;oloKonEe; j.lETO~U Tile; l)oooAoyioc;. rTO 5EllTEpo npwToKoMo 80 ripovporonomaouv napouoro KaTOOToA~e; TaU OUlJn081lTIKOU, onoKAEI0I-I0U Tile; AVVEloTEvoivIle; IT KOI oncvmcnc Tqe; niEOlle; OE ov8pwnoue;. 01 ED50 & ED90 500EIe; TaU ouvl)UOOjJOU 80 iSOKljJOOTOUV orrjv ouvEXEm OTOl)IOKO IJE EAE:VXOj.lEVEC; J.lEAErEC; plOe; l)oor)C; placebo OE nAllPWpEVOue; unEpToOIKOUe; OVl)pEC:;, j.lE EAEYXO niEOlle; KOI PErPIlOIl Tile; BUN, serum iKPETIVivllC;, PRA, plasma aldosterone KOI znlneoo vopsruvepplvnc npiv KOI IJETO rn 5000Aoyio. Mm 56or) TOU placebo KOI pia i560q TaU I-lEAETOjJEVOU tpapl-I0KOU 80 i5iVETOI a' EvO crossover design OTO iOlo CrrOIJO IJETO ana pia E~i50IJOoo. Emo aaSEVEic;80 A6~ouv K68Eooarl. 0 XPOVIKOe; Ko8op10I-IOe; TWV i5EIYI-I0TWV cluoroc 80 E~OPTIl8Ei ana Til i510PKEIO TaU onoTEAEOjJOTOC; TOU <pOPIJOKOU onox; Ko8opiOTIlKE OTIC; I..lEAErEC; Tr)e; oocoxovloc OE opoAoue; E8EAoVTEc;" onwe; oro npdrro npwToKoMo. AKOIJO ruo EKTETOj.lEVEC; IJETOYEVEOTEPEC; i50KIIJOoiEC; Tile; OOtpOAEIOe; KOI Tile; onoTEAmpOTIKOTrITOC; TOU ouvcuoouou 80 onorrncouv mmpo08ETo KAIVIKO <P0PIlOKoAoVIKo napoporo pE noMlte; i56aEIc;" pE TIlV ~0~8ElO Tile; cpa PjJO KO~ 101.1 Ilxovioc:;.

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19

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x. fo13pac;, Ka811Y'lT~~ IaTpIK~C;, np6£6poc; AVTI-unEpToOlK~C; 'Evwof")C; HnA. Boston University, USA,

A. nOTpIVOc;, EnJKEc.poM~ EnJTpon~~ XopToypa<plof")C; DNA, U.s.A.

M. MapaYKouilQKIC;, OIJOTIIJO~ Ko8IlyrjT~C; IaTpIK~C;, naVEnIOT~IJIO naTpwv, T. llposopor; EOCb.

4. Kp£poaTlvoc;, Ka8'lyr]T~~ IaTpIK~C;, l\.jVT~C, 8' Kop610AoYIK~C; KAIVIK~<;' QVaOEIO

Kap61oXEIPOUPYIKO KEVTPOjATTIKO Noooxopdo,

4. KOKKIVOC;, Ko8r]Y'1T~C; IOTpIK~C;, D.jVT~C; A' Kop6IoAoYII<Jic; KAIVIK~C;/ QVaOEIO Kap610XEIPOUPYIKO KEVTPO, A8~vo.

K. ItK£pl)C;, OjJaTIIJO~ Ka8r]Yr]T~C; IaTpIK~~ Kano61OTpiOKO naVEnIOT~IJIO A8llvwv.

Z. KUPIOKiill)C;, D./VT~C; AYYElonAaOTIK~~, QV(JOEIO Kap610XEIPOUPYIKO KEVTPOj Epu8pac; ~TOUpOC;.

4. BAoXOKOC;, Ka8'1Y'1T~C; IOTpIK~c,t N£(ppoAOyo<;, ~ulJ~ouAoC; Yneproonc, Qvao£lo

Kop610XEIPOUPYIKO KEVTpO/ ATTIKO NOOOKOjJEio.

X. cDAoopiltAI)c;, Ko8'1YIlT~C; IOTpIK~C;, nOVEnlOT~IJIO Florpeov.

E. HAIOlipolJiTr}C;, Kap610AoyoC;, QVClOEIO Kap61oXEIPOUPYIKO KEvrpO.

B. AnoOToAonouAou, D./VTpIO TOjJEa Avocoxovloc, Austin Research Institute, Australia.

X. nAoTaouKoc;, Ko8rjyr]T~~ BIOXIlIJEia~ KO! Avoooxovtoc KOOjJ~TWP IaTpIK~C; KOI ~xoA~C; 0ETIKWV EnJOTIlIJWV, TEMPLE University, Pensylvannia, USA.

A~ J\uKoupyuinl)C;, Ko8rjY'lT~C, XlljJEiac;, npoE6poc, EMIlVIKOIJ AvolKTOlJ navEnlOTr]lJiou KOI T. tlpurovqc TOU nOVEnIOTlljJiou nOTpWV.

22

nopOKoAOUI-lE OUl-lnAr'lPWOTE TOV nOpOKOTW nivoko (IJOVO OTI1V nepirrrtetm nou 0 TEXO(JAoOTOC; 6EV elvm IJIKpolJEaoio EnlXEip11(J1l onOOC; oUTIl opil;rrol OTO nOpOpTlllJO TOU o611YoU EqJOPIJOY';C;) YIO TIC:; TuX6v XpnI-lOTOOOT~OEIC:; nou tXEI Aaj3EI 0 TExvoj3AoOTOC; Tr}V TEAEUTOio rprsrlo ( ouuqxovo I-IE TnV EmOUVOnT6I-lEvr] YnEu8uvr] ~~Awor] TOU N1599/86).

npOYP0I-II-l0- MtTpo/Opaan an6 TO Apl8l-loc; KOl qucpopnvlo EXOOOr"JC; Y4JOC; Or] 1-1601 OC;
onoio XPflI-lOTOOOT~8r]KE r] Tr]C; O)(ETIK~C; YnoupYIK~C; XP'lI-lOTOO6TfloflC:;
EnlXEipqofl An6qmoflC; (OE EUpW) A. npOVnOAOrIIMOE EnENA Yl:HE - .4IAP0POEH TON .4AnANON TOY EPrOY LuvoAo Ilpounoxovrouou Tr]C; EntvouO'lC; : 1.440.800 €

AITOUI-lEV'l Enlxop~yr]or] : 720.400

loio OUI-lI-lETOX~ : 720.400

TpanE~IK6c; ~OVEIOI-l6C; (Or]I-lEIWOTE KOI TO ovouo Tr]C; TpanE~OC;):

KaTOVOI-l~ TOU npounoxoviopou avo «rrqvoplo OOnaV'lC; (XIA. €.):

napOUOIOaTE TIlV t!lop8pwoq TWV oonovov TOU EPYOU, cuvoxixo, KOI VIO TO rpio Ern AEITouPviac; TOU, onwc; avaAUTIKO nEpIYP0<PETOI aTO eruouvcrrropevo EnIXEIPr"JIJOTIKO OXEOIO KQI IOlaiTEpa aTO axi:OIO Tr"J<; EnEVouaqc; .

23

24

EI60I MnANHL (OE XIAla~EC; EYPQ) npOOnOAOY10I-lOC; !AITOUI-lEVIl nOOOOTO Tnt; OanavllC
~a.navllt; En Ixop~Yllall ~ni TOU OUVOAII<OU n/y
"oj, • 500/0
APXIKE2: EnENllYIEII 720.400 360.200
E<50q>IKEC; EKTO~i 0 0 -
2
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r M ' ,~I;f1.¥Jj~c 655.400 327.700 45,5%
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METOCPOPIKcl J,J£OG 20.000 10.000 1,4%
'Enm~o 35.000 17.500 2/4%
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10,000 5.000
rn,.
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. _"r-
nAPOXH E=EIAIKEYMENON 64.000 32.000 4,40/0
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rENIKEI MflANEI EKKINHIHI THI 656.400 328.200 45,60/0
EnENAYIHI
AI-lOIj3EC; npootorukou 429.200 214.600 29,8%
Al.lolj3tC; Kal E~o<5a TpiTW\J 90.000 45.000 6,2%
~16<popo E~ooa 87.200 43.600 6/1%
nOpOXEC; rplrtov 50.000 25.000 3,5%

rENIKO IVNOAO 1.440.800 720.400 100% EeonAIO'uoc Iuv8Eanc Ka. TauTonoinanc IapTavciJv

'Opyava YymAOc TExvoAoyioc CIuvoAo 390.000 €)

1) UPLC-MS: 210.000 € ,\

cG \.

U'Y_S \-'~

--=======-

-- t.. C.Qou G

):0 \L V t'\ .I-

IuaKEuEc EpyoO'Tnpiou (IuvoAo 253.400 €)

2) Analytical HPLC: 50.000 €

3) Preparative HPLC: 130.000 €

J

AVO'\UTIKOC; voe, (O,OOOlg oVOVvWOIIJOn)To): 3.000 €

<POPjJO. KEU IKOC, ~uvoc, (0,01g OVOYVWOIjJOTrITO~: 700 € ,

C])M.KP04'UyOKEVTPOC;: 3.500 € --",Qe?\-\.<) . 1\ /.J'1 ~)

3)LUOKEutC; nEpIOTpoc.pIK~C, E~Cm:lIOIlC; «Rotavapor 2X 3.500=7.000. €. 'Il, wv- \

7' . ~, 'c>.l t'S~1"""l~ )

~OKEU~ Auoc.pI'\onoi'lOIlc, (Freezer Dryer): 21.000 €- . \ J:\ \ ~ \2._(!)O)

4 [uaKEu~ YnEpKo8opou NEPOU: 12.000 € J r\ ~ ~ \ '"'\

\~\~ c \ ,~)

. @IO Ol~ellall uvprov: 4.300 €...J ~ _~- .,---_--:=:

w '( (" 11.2:-0 s-

~\f£

8) ria OlljJloupyio KEVOU: 3.000 €

@¢loiJpvOC;: 2.000 € \> ~.\. aV .. n ... -<rJ \. () ~A '" ~ ~ '1 f~

25

,A\_,,~:.:__8) ruaAlvo OKEuIl Via npovuoronolncn XrUJIKWV OVTlOpaOEWV: 21.400 €

€ 1. ~ . -

1. \..,v...JZ 9) Software KOI HjY (Silicon Graphics) Via Molecular Modeling (Anopolrnro Via oWOT6

OXEOlOOjJ6 CPOPjJOKEUTIKWV npoiovnov): 40.000 €

'\ If\~O)4JUVEiO-KOTmIJUKTIlC; Via OUVT~PllOll OUVTEeEVTWV rrporovrev: 2.000 €

~ 1 )HilEKTPOV'KOi YnoiloYIDTEC; X 2: 3.s00 € ~ '\!: .. n ",,!.,'., ") .. ~ ( ~ 1-< J

. 12)Dewar A~(JJTr 3.000 € I

_____ " ~?-T L t\ y ..... JV) r-

13)AVTIOpOOT~POC; 63 L: 70.000 € ) I

(\/p "(7'rrr- t.., /.

14)LuaKEu~ oVTiopOOIlC; jJ£ jJIKPOKUjJOTO: 32.000 € cc- \ IJ

15)Rotavapor 20 L: 18.000 € - 16)AuT6KAEIOTO niEollC; KOI 8EPI-lOKpOaioc; 7.000 €

- ------

26

1.

Avopa KOToypmplKoU ruscaov KOI KopoloypaCPIlI-l0 = 12.000 €

E~onAlouoc BIOAoVIKWY AOKIUWY IapTDYWY OE nElpaUDToi:roo

IYNOJ\O: 12.000€

Avopa UETO(J)OPIKOU UEOOU Via Tny EEunnptrnan Troy OyaVKWY Tnc ETalpEiae 1 EnOYYEAI-l0TIK6 OUTOKiv'1To= 20.000 € j

IYNOJ\O: 20.000€

Ayopa EninAroy- Ef,onAlouou ypmpEiou

~YNOAO: 3S.000€

AooouaTEC aKrynTOnO I rioEIe;

80naVEC; V'O OIKOIWI-l0TO EUPEOITExvioC;, EKI-lETOMEU6I-lEVEC; OOEIEC; rexvovvecloc KOI 1-l'1

npOOTOTEU61-lEVil TEXvoyvwolo axETI~6I-lEV'1I-lE T'1I-lETmpOpa TExvoAoyioC;.

~YNOI\.O: 10.000€

napOY'; EEEllilKEUUEYroV ouuBouAEUTIKWY unnpEOIOOY EEolPETIKriC anuaaioc

l. nopOX~ V0I-lIKWV aUI-l~ouAwv OE 8tl-lOTO nVEUI-l0TIKWV OIKOIWI-lOTWV KOI KOTOXUPWOIlC;

EU PEOITEXvlWV I

2. 8'1l-llouPVio O~I-lOTOC; KOI ETOIPIK~C; TOUTOTIlToC; TOU TEXVO~AoOTOU,

27

IYNOAO: 64.0000

AlJo.ptc; npo(J6JmKou: l:uvoAo : 429.200 €

1. 3 Ka8rJYflTEC; (1.000 X 10) = 30.000 €

2. 1 XrJ~IK6C; (1.000 X 10) = 10.000 €

3. 1 BIOAOVOC; (1.500 X 24) = 36.000 €

4. 2 xrunxol (300 X 10) = 6.000 €

5. 2 Xr]~IKoi (400 X 20) = 16.000 €

6. 1 Xr]~IK6C; (1.750 X 24) = 42.000 €

7. 1 XrJ~'KOC;- BIOXIl~IK6C; (400 X 10) = 4.000 €

8. 5 Xfl~IKOi (400 X 10) = 20.000 €

9. 3 XrJj.JIKoi (1.750 X 24) = 126.000 €

10.1 Xr'J~IKOC;- BIOAOYOC;- BIDXrJIJIK6C; (1.300 X 24 !J~VEC;) = 31.200 €

11. 1 Xr}lJIKOC;- BIOXr]J.lIKOC; (1.300 X 24 IJ~VEC;) = 31.200€

12. 1 rpa~~aTEac; (1.300 X 24 !J~VEC;) = 31.200 € 13.1 BOfl86C; Ipouporeo (400 X 20 I.l~VEC;) = 8.000 € 14. 1 AOYIOT~C; (600 X 24 ~~VEC;) :;:: 14.400 €

15.1 BOf'l80C; AOVIOT~ (300 X 24 I.l~VEC;) = 7..200 €

16. 2 LlIOIKf'lTIK~ YnoOT~p'~r] (400 X201-l~VEC;) = 16.000 €

40nOVEC; OIJOIProv KO. t~oi5o TpiT6JV- nopoXi:C; TpiT6JV

1. EKn6vrJuf'l ~EAETWV KOI EPEUVWV cvopoc Via TO npo'(OVTO nou 80 nOpaVEI n ETOIPEio

2. EKnOVf'lUn IJEAETWV KOI EnIOTrJ!JovIKWV EPEUVWV Via TO npoiovro

3. napox~ unqpsonov unoanipl~rJC; KOI OIOXEipIOf'lC; TOU tpvou

4. 'E~oi5a unol3oA~C; KOI npooroolcc AIT~OEWV EUPEOITEXViOC;

5. Lu~l3ouAEuTIK~ unoOT~pl~r'J OE EPEUVEC; ovopov

28

6.2:UjJ~O'\OIOYPOCPIKn KOI VOjJlKn KO'\UljJll

(luvoAo: 140.000 €)

iuinpopo 'E~o~o- A£ITOUPYIKC 'E~oZ;o (2 srn) (luvoAo 87.200 €)

EvolKioaq xwpou 50 T.jJ OTO EmOTlljJovlKO n6pKO (2 trll): 525€/ jJnva == 12,600€ TljJO'\OYlo LlEH, LlEYAn, TaxuopojJlKO, K.T.A. (Zern): 450€ / unvo == 10.800 € 2:uVTnpqoll npoiovrtov KOI IJOVOOOe; (cp.IO'\Ee; nepkov, ljJUKTEe; KOI ljJUKTIKO UAIKO): 4.500 € OOOInOPIKO vro 2trq EawTEplKOU KOI £~WTEPIKOU: 53.300 €

flroronolnon epvcornplou ISO: 6.000 €

KOTOVOPrl TOU npolinoAoYlopou KOT' ETO~:

2006 2.007 2008
luvoAIKO~ nv 450.000 € 790.BOO€ 200.000 €
IZ;io OUIJP£TOXI1 225.000 € 395 .. 400 € 100.000 €
.4llpOOIO .4onovll 225.000 € 395.400 € 100.000 €
Tpon£~IKoc; - - -
AOVEIOP°C; 2:ulJnAIlPWOTE TOUe; napoKoTw nivOKEe; Aap~ovoVTae; Un04J1l TOV oorwo apaplJoYIie; KOI TO EnlXEIPlljJOTIKO OOe; OXfOIO:

1. Xp IlIJOTO pon LlIlIJOOlOe; Llonavqe;

nOao n pO~AEnOIJ EVil IlIJEpOIJ nvl a
A'oOOIl 360.200 € 11/2006
B'0601l 216.120 € 11/2007
Ano nAil PWIJ Ii 144.080 € 11/2008 2. np6~AE4J1l OU~nOEWV M£TOXIKOU KEcpaAaiou

Au~liaEIe; IJETOXIKOU KEcpaAo'iou Ilooo n po ~'\En6IJEvll H IJEpOIJ nvlo
1 n aU~1l01l M.K. 62.000 19/07/2006 211 ou~rlOll M.K. 1.000.000 10/2006
311 OU~Ilall M .K.
8EV unorrsirtn E. nAPOYI:IAIH EnIXEIPHMATIKOY I:XEAIOY

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29

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30

u\Eu8Epa. IE YEVIKEC; YPOIJIJEC; OIJWC; 80 pnopouce va XOPOKT'lPIOTEi u4J'lM, OVO<POPIKO IJ£ TO KOTO nooo O~lonOIEiTOI OT'lV nopoywy~ TO unopyov £pYOUTamOKO 5UVOIJIKO. l:UYKEKPIIJEVO, UTIC; apXEC; TOU 2003 un~pxov OV051KOi pu81J0i o~lonoillOnC; TOU napaywYIKOIJ 5UVOIJIKOU OT'l q>aPlJaKO~IOI-''lXovio, nou TOV MaPTIO Eq>TOOOV OE nocoorc 91,1%. IT'l aUVEXEIO TO nooooro aUTO IJEIWVrrOI KOI croaeponorelroi UTa 80% TOV IouAlo.

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napai5oxt.:; nwA~O'Ewv

1. H nWf.rWIl TWV 51KOIWIJOrWV TWV ELSARTAN, ELUROSARTAN, ELAMINOSARTAN 80 yiVEI UTO 30 zroc TOU EnlXEIPIlIJOTIKOU l:XE5iou (El:)

2. 01 TIIJEe; nwA'lU'lC; TWV 51KOIWIJOTWV TWV noponovc OUUlWV EivOI 5.000.000 € / ouoio.

3. To Eao5a ana TO 51KOIWIJOTO OITriOEWV EupEaIT£XVioc; TWV uno OvanTU~'l npoToVTWV ELTRAP, ELGONAD, ELGOUARTAN, So npOKU4JOUV oro 50 troe; TOU E.I. ( unoAoyisoVTOI OE sOO.OOO€ / ouaia)

4. To soooo ana TO OIO<pOPO nEnTiolO vro OIOYVWOTIKOUC; & EPEuvIlTIKOUC; oxonouc EKTIIJOUVTOI OE 122.000 € neplnou OT'lV srrio (20.000 € TOV 10 Xpovo KOI OlJ~l1alllO% ETlloiwC;)

5. To e:ooi':io ana Tr]V nopox~ unnpeouov npoc; TpiTOUC; EKTIIJWVTOI OE 150.000 € nspinou UTIlV SErio (20.000 € TOV 10 Xp6vo KOI OIJ~r]OIl 20% ernokoc)

6. {J,.EV unoAoyi~oVTal ta050 nepov Tile; SETiae; (nwAfJOEIe; i':iIKalwlJOrwv vEWV OUOIWV, nrrrrioro, nopoxri Un'lPEOIWV)

~a tuoi5a

1. AVO<POPIKO IJETI<; XP'llJaTooOTrioEIC; an6 EPEuvllTIKO npoYPOlJlJOTO, eo avEA80uv aE 1.000.000 € UTrlV saia (250.000 € / eroc - EKTOC; TOU lou).

2. {J,.EV unoAoyi~oVTal Eaooa an6 xprllJaTOOOT~aEIC; EPEUVIlTIKWV npovocpportov ntpov Tile; SETiae;.

KOOTOC; nwAquEwv

1. ITO auvoAIKO KOOTOC; TWV nwArioEwv nEpIAOIJ~OVOVTOI TO «ocroc TOU npootoruxou KOI 01 unEpyoAo~iEe; (OIJOI~tC; TpiTWV) oAwv TWV OXEoiwv opaolle;·

2. To npootoruco 80 onooxoA'l8Ei I-'E 5ETEie; aU1J136oEIC; (ara8Epou Tll..lriIJOTOe; / ETOC;).

AOln6 KO(JT11

31

1. Qe; E~OOO OIOiKI101le; KOI OU:J8EOIle;, unoAoyi~ovral TO ovoAwolJ.Jo KOI TO AOlna AEITOUpYIKa E~ooa oAwv TWV O)(Eoiwv 5paolle;

2. To nocooro TWV nVEUIJOTIKWV 5IKOIW!JClTWV TOU nOVEnIOTrwiOu florpcov (5%)

ouvunoAoyi~£Tol KOI Eni TWV 51KOIWI..IOTWV QlT~OEWV EUpEom:xvioe; TWV ELTRAP, ELGONAD KOI ELGOUARTAN

XPIlIlOTOpOEe;

1. H ononAqpw!J~ TWV noyiwv 80 yiVEI IJE 35% uerpnrok TO 10 troe; KOI TO unoAOIno E~0c.pAI101l TO 20 eroc TaU E.L.

2. 'OAE<; 01 UnOAOInE<; nArlPWj.lE<; 80 yiVOVTOI !JEoo aTO trot:; nou oeopouv.

3. Avriorono oAo TO Eo050 80 Elonpax80uv !JEOO aTO eroc ovocopcc nou OVTlaTOIXOUV.

Ao.nEe; nopoiSoxte;

1. Anoof3EoEIC;: 12% (!JEOOe; OUVTEAEaT~C;) enl TaU ouvoxou TWV noyiwv

2. eopoc oUVTEAE~t:; 35%

3. ~IOVO!J~ !JEplo!JaTwv OE !JETOXOUe;: METa TO 30 troe; nou E!Jc.povi~oVTal KEp511 ana TTl 5POOTT1PICTIlTO, 11 ETOIPElo 80 510VEi!JEI O)(EOCV cAo TO KEp51l moue; tJET6xouC;.

4. TponE~IKoc; OOVEIO!JOC;: ~EV 90 XPllOltJonOl1l90uv ~poXUXpCVIO ~ lJoKpoXp6vI0 TponEQKo

OOVEIO

H ETOIPEio slvoi VEooumOTI1, OEV unOPXEI nponvouusvo ovrloroiync EnIXElpl1!JOTIK~C; c.pOPIJOKEUTIK~C; 5POOT'lPIOTIlTOC:; OTIlV EMooo. b.EOOIJEVOU OTI 01 EPYOOTIlPIOKEt:; ouv8EOEIC; EivOI npoiovro uljJI1A~C; n:xvoAoyioC; KOI OVTIOT081JIOTIK~C; a~iac; 01 npo~AtljJEIC; EivOi IOIOiTEPO EUoiwVEC;.

LUlJnArlPWOTE TOV nopOKOTW niVOKO

2006 2007 2008
StOEIC; spvooioc 8 10 12
KEPOrJ - - -
KuKAoC; epvoouov - - -
KUKAoC; EPYOOlWV KUPIOC; ElJnOpIK~C; - - -
OpoOTIl pI6TrJTOC; 2:ulJnAIlPWOTE TOU nopoxcrto nivOKEC; IJE TIC; npo~At4JEIC; V'O TOUC; opI8\.JoOEiKTEC; anOOOTIK6TflTOC; KOI pEUOT6TIlTOC;

Ap I e I-IO~Ei KTEC; a nO~OTI KOTIlTOC;

2006

2007

2008

32

M I KTOU K£POOU~ - - -
Ka8opou K£POOU~ - - -
An6ooall~ loiwv KECPOAOiwv3 - - - ApIOIJoZiEiKTEC; PEUOTOTI1TOC; 2006 2007 2008
KUKAOc.pOPIOK~~ pEuOT6TIlTa~4 - - -
TOIJEIOK~~ pEuOT6TIlTO~ - - -
EI5IK~~ PEUOT6TI1TO~6 - - - r LUj..mAIlPWOTE TOV nopoxcno nlvoxo jJE rnv EKTijJllall ovovsnlou KEc.pOAOiou KiVIlOIl~

2006 2007 2008
nWA~aEI~ - - -
KUKAO<POpouv EVEPYIlTIK6 - - -
Bpoxunp68EalJE~ UnOxp£(DaEI~ - - -
KE<pOAOIO «lvnonr; - - - r LUjJnAIlPwOTE TOV napOK(JTW nlvoxo VIO TOV E~onAla!J6 nou eo OnOKTIl8Ei

A/A nEpIVpO<p~ E~OnAlaIJOU noa6TIlTo A~io
1 UPLC-MS Anopolrnro YIO TIlV rouronoinon KOI 1 210.000 €
Ef..EYXO Tile; c.pOPI..lOKOKIVnTIKnc; TWV nooiovrov
2 Analytical HPLC onopolrnro YIO TOV EAf..YXo TWV 1 50.000 €
OVTIC3p6oEWV auv8EallC; TWV npotovrtov
3 Preparative HPLC onopoirrrro YIO TOV KoBoPIOjJO 1 130.000 €
TWV OUV8EOEWV
4 EniallC; 80 ovoporrrouv opvovo KGI OKEUIl 20 253.400 €
onopolrqro YIO TIlV cnpooxorrrn Af:ITOUpyio EVOC;
EPYOOTTlPiou onux; nEplyp6c.pOVTOI avwTEpw ornv 1 APIH~l odK't1lS Mucrou Ktroom; = (Mtxre Kcpi'i'l EK~IE:1CiAAE1J01l9' Ka()npEs IlwAl10f:1I;) x 100

2 ArIH~IOodK1T)o; Krx8arou Kcpoom:; = (Kul1apa Ktpo'l EK~lcTlUA.E1J0119 KaOcIre.:; llWAi]crE:IS) x 100

1 ArnH~lol5ciKTl1S Arrol'iorlKonrraS IcSiwv Kl:cpaAaiwv = (KIlOnp6: Ki:r8'l EK~II::T6..IJu.:u01l9' :EtivoAO [oirov KEq>a),(llwV) x 100

,I ArLH~lol'klKTI]S KUKAO<POPIUKtiS Pf:DCHOT1lLUS = KUKAorporouv EVEP'YTJT1K6! Bpnxurrroeccr~II:S Ynoxp£liJaE1S

5 Apleflo6ct"'TI1S Ta~U;IaKiJc; (TIrnYflCLnKJis) PEUCJT(lTTjtllS = 6tatlCO"lf1o EVEPYTl'nK6! AT]c,mp6fh;CJfl£S Ynoxw:moEl':; b ArlH~I08dKTTjS El6lKl\'; (A~IE011S) PF.UCJTOTIl1:W; - (6taet01~LO Ew:rYllTIK6+ Anmnicru ) I BrnxurrpMh:aws

y 1[OXflf.(Om:IS

33

KOTrly_o_Qio GUGKEUEC; EPYOOiT1Piou
5 Ayopa KOToypOq>'KOU nlEGEWV KOI KOp<310ypaq>'ll-'o 1 12.000 € Z. ETO ENTYnO ynOBOAHE npOTAEHI THE lPAIHE B; EnIEYNAflTONTAI TA AKOA0 Y6A:

EmouvonTopEVO 'Eyypocpo nOOOTIlTO
EOIOUVO nTOIJ EVrov
Eyypacpwv
KOToaroTIKo iopuan~ TOU TEXVO~AOOTOU 4
'Eyypacp'l ouvolveon TOU LlrllJOOlOU Opvoviouou nopaywy~c; 1
rVWO'lc; OTnV EKJJETOAAEUan TOU OUYK£KPIJJEVOU £PEUVIlTIKOU
a nOTEAEaJJoTOe; .; anocpaan TOU ArwoOiou Opvoviouou
nopoywy~c; rVWO'lc; vro aUJJjJETox~ am MK TOU TExvo~AaOTou .;
ouuqxovlo nopaxwp'lall~ olKalwJJClTWV EKJJEToAAEuanc;
EnlXEIPIlJJOTIKO OXEOIO TOU TEXVO~AaOTOu 5
LTOIXEia n iorono i Ila'lc; TOU XPOVOU au OTa 0'1 e; Ko9E cpO peo 2
EnEVQUOIle;
'EYKPIOil TponE~ae; vto rn XOP~Y'lo'l oavEiou XP'lIJOTOOOTIlO'le; Tile; -
£nEVCua'lC; ('Eva npo~AEnETal OTO EnlX£IPilIJOTIKO OXE01O)
LTOIX£io TEKJJ n pkocnr; Tile; OUVOTOTIlTOe; K6AUljJn~ Tile; loiae; 3
aUIJIJETOX~~ OTnV £nEvouoq Ka9w~ KOI TOU K£cpaAoiou KivnallC;
OUT~e;
Yn£u9uvq Ll~AWOn TOU 6p9pou 8 TOU N. 1599/86 TOU <popEa rnc 1
EnEvOUOnC;
LUjJf3aa£lC; IJETocpop6c; TExvoAoyioC; 3
BloypacplKo alljJEIWIJOTO 21
Anoc.poon OAOKAr;pWOf]C; EPYOU nPA=E - eoon A' (E6v npoEPXETOI -
one TrW ocon A') 34

ynEY8YN H f1H/\illH

o avoooxo~ 0IlAWVEI unEu8uva OTI oAo TO OVuJTEPW K08w~ KOI TO ouvnupsvo 0' OUT~ TIlV nporoorj, eivm aKpl~~. Av nprv ana rqv Enlxop~Yllall ~ KOTa Til OIOPKEID Tile; EKTtAEa'l~ TOU tpyou npOKUljJEI KonOlD IJETD~OA~, 0 DVOOOXOe; 80 EloonOlr)OE:J OIJEOWe; Tfl rrET uvoospovroc TrW OITio Tile; aMoy~e;.

n6Tpo[ 25/09/2006

o NOlJllJoC; EKnpoownoc; TOU TE)(Vo~AoOTou

(Mlvwc; MOTaouKm;, XrWIKOe;,

unovooon, otppovlon)

35