Impactul farmacocinetic si clinic al factorilor neuroendocrini in terapia
Impactul farmacocinetic si clinic al factorilor neuroendocrini in terapia
Impactul farmacocinetic si clinic al factorilor neuroendocrini in terapia
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Nr.proiect:<br />
42-163/2008<br />
Titlu proiect:<br />
<strong>Impactul</strong> <strong>farmacoc<strong>in</strong>etic</strong> <strong>si</strong> <strong>cl<strong>in</strong>ic</strong> <strong>al</strong> <strong>factorilor</strong><br />
<strong>neuroendocr<strong>in</strong>i</strong> <strong>in</strong> <strong>terapia</strong> cu antip<strong>si</strong>hotice atipice<br />
Coordonator/director de proiect:<br />
Univer<strong>si</strong>tatea de Medic<strong>in</strong>a <strong>si</strong> Farmacie<br />
”Carol Davila” Bucuresti<br />
Acad.Prof.Dr.Victor A. Voicu<br />
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Date <strong>in</strong>iti<strong>al</strong>e<br />
Parteneri <strong>in</strong> consortiu:<br />
Buget/cof<strong>in</strong>antare:<br />
Partener 1 - Biopharmacy & Pharmacol Res SA<br />
Partener 2 - R&D Irist Labmed SRL<br />
V<strong>al</strong>oarea proiectului (<strong>in</strong>clude şi <strong>al</strong>te surse atrase): 2533333 lei.<br />
V<strong>al</strong>oarea contractului (sursa numai buget de stat): 2000000 lei.<br />
Durata contractului: 36 luni.<br />
Adresa web a proiectului:<br />
www.csm.ro/hormoantip<strong>si</strong><br />
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Date <strong>in</strong>iti<strong>al</strong>e<br />
Obiectivul / rezultatul f<strong>in</strong><strong>al</strong> <strong>al</strong> proiectului<br />
-Noi metode rapide de monitorizare <strong>farmacoc<strong>in</strong>etic</strong>a a expunerii la agenti antip<strong>si</strong>hotici atipici<br />
-Noi criterii de sc<strong>al</strong>are <strong>si</strong> ev<strong>al</strong>uare a expunerii la antip<strong>si</strong>hotice atipice de tip risperidona, p<strong>al</strong>iperidona <strong>si</strong><br />
clozap<strong>in</strong>a<br />
-Corelatii <strong>in</strong>tre concentratiile de hormoni steroizi <strong>si</strong> parametrii c<strong>al</strong>itativi <strong>si</strong> cantitativi ai proceselor de<br />
biotransformare hepatica pentru antip<strong>si</strong>hotice<br />
-Identificarea unor noi metaboliti cu activitate farmacologica sau rol de pro-drug<br />
-Evidentierea <strong>si</strong> po<strong>si</strong>bila utilizare a rolului pozitiv <strong>al</strong> hormonilor steroizi <strong>in</strong> cresterea eficacitatii<br />
tratamentului antip<strong>si</strong>hotic<br />
Elemente de noutate <strong>al</strong>e proiectului; orig<strong>in</strong><strong>al</strong>itate<br />
-Noi criterii de sc<strong>al</strong>are <strong>si</strong> ev<strong>al</strong>uare a expunerii la antip<strong>si</strong>hotice atipice de tip risperidona, p<strong>al</strong>iperidona <strong>si</strong><br />
clozap<strong>in</strong>a (non-<strong>si</strong>milaritatea metabolizorilor extremi)<br />
-Identificarea unor noi metaboliti cu activitate farmacologica sau rol de pro-drug (structuri N-oxid)<br />
-evidentierea non-echiv<strong>al</strong>entei farmacocientice <strong>si</strong> farmacod<strong>in</strong>amice a risperidonei<br />
sau activ 9-hidroxi-risperidona<br />
Beneficiarii rezultatelor; potenti<strong>al</strong>ul de aplicare <strong>in</strong> economie<br />
-Sectiile de p<strong>si</strong>hiatrie <strong>al</strong>e:<br />
Spit<strong>al</strong>ului Alexandru Obregia,<br />
Spit<strong>al</strong>ului Cl<strong>in</strong>ic de Urgenta Militar Centr<strong>al</strong> “Carol Davila” Bucuresti<br />
<strong>si</strong> a metabolitului<br />
Spit<strong>al</strong>ului de P<strong>si</strong>hiatrie <strong>si</strong> pentru Masuri de Siguranta Sapoca<br />
-Sectia de Farmacologie Cl<strong>in</strong>ica, Toxicologie <strong>si</strong> P<strong>si</strong>hofarmacologie a Spit<strong>al</strong>ului Cl<strong>in</strong>ic de Urgenta Floreasca<br />
-Risperidona N-oxid – pro-drug.<br />
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Stadiul de re<strong>al</strong>izare <strong>al</strong> proiectului<br />
Etapa 1 (28.02.2009)<br />
Ev<strong>al</strong>uarea <strong>si</strong> v<strong>al</strong>idarea procedurilor bioan<strong>al</strong>itice <strong>si</strong> biochimice de monitorizare a terapiei antip<strong>si</strong>hotice<br />
(clozap<strong>in</strong>a <strong>si</strong> risperidona)<br />
Buget de stat: 130000<br />
Cof<strong>in</strong>antare: 65635<br />
Activitati efectuate:<br />
Dezvoltarea <strong>si</strong> v<strong>al</strong>idarea metodelor bioan<strong>al</strong>itice de monitorizare a concentratiilor plasmatice <strong>si</strong> ur<strong>in</strong>are<br />
pentru medicamentele <strong>si</strong> metabolitii selectati <strong>in</strong> vederea determ<strong>in</strong>arii fenotipului <strong>farmacoc<strong>in</strong>etic</strong><br />
Selectarea metodelor de monitorizare a parametrilor biochimici <strong>in</strong> vederea determ<strong>in</strong>arii fenotipului<br />
neuroendocr<strong>in</strong><br />
Ev<strong>al</strong>uarea metodelor de monitorizare a parametrilor biochimici <strong>in</strong> vederea determ<strong>in</strong>arii fenotipului<br />
neuroendocr<strong>in</strong><br />
Achizitii re<strong>al</strong>izate: Partener P2<br />
Etuva de Laborator ED 53 70.83%/4193.0729.17%/4193.07<br />
An<strong>al</strong>izor Pentra 1.42%/28560 98.58%/28560<br />
Sistem Apa Ultrapura Direct Q Smart 66.67%/17077.233.33%/17077.2<br />
Freezer 66.67%/27900 33.33%/27900<br />
Spectrofotometru Uv/Vis cu Detector DAD 66.67%/99960 33.33%/99960<br />
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Stadiul de re<strong>al</strong>izare <strong>al</strong> proiectului<br />
Etapa 2 (15.12.2009)<br />
Proiectarea ev<strong>al</strong>uarii corelate fenotip <strong>farmacoc<strong>in</strong>etic</strong>-neuroendocr<strong>in</strong><br />
Buget de stat: 65000 (creditare)<br />
Cof<strong>in</strong>antare: 0<br />
Activitati efectuate:<br />
• Elaborarea protoco<strong>al</strong>elor de studii <strong>cl<strong>in</strong>ic</strong>e pe subiecti-pacienti. Disem<strong>in</strong>are<br />
• Obt<strong>in</strong>erea acordului favorabil <strong>al</strong> Comi<strong>si</strong>ei Institution<strong>al</strong>e de Etica<br />
• Elaborarea protoco<strong>al</strong>elor de screen<strong>in</strong>g pentru studii <strong>cl<strong>in</strong>ic</strong>e pe subiecti-pacienti.<br />
Achizitii re<strong>al</strong>izate: 0<br />
Etapa 3 (10.12.2010)<br />
Ev<strong>al</strong>uarea corelata fenotip <strong>farmacoc<strong>in</strong>etic</strong>-neuroendocr<strong>in</strong> <strong>si</strong> a <strong>al</strong>terarilor de fenotip pe termen lung <strong>si</strong><br />
implementarea modularii terapeutice a disfunctiilor neuroendocr<strong>in</strong>e asociate<br />
Buget de stat: 262245<br />
Cof<strong>in</strong>antare: 0<br />
Activitati efectuate:<br />
Implementarea protoco<strong>al</strong>elor aprobate<br />
Raportarea prelim<strong>in</strong>ara a rezultatelor monitorizarii <strong>cl<strong>in</strong>ic</strong>e<br />
Monitorizarea parametrilor biochimici<br />
Achizitii re<strong>al</strong>izate:<br />
Materi<strong>al</strong>e, materii prime (CO)<br />
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Modul de implicare <strong>al</strong> t<strong>in</strong>erilor cercetatori<br />
Stagii de formare: 2<br />
Participare la se<strong>si</strong>uni COST B25:3<br />
Mirona Botescu, Miron D<strong>al</strong>ia, Flavian Radulescu<br />
"Strengths and Ch<strong>al</strong>lenges with Phy<strong>si</strong>ologic<strong>al</strong>ly based Prediction of Pharmacok<strong>in</strong>etics <strong>in</strong> Children", COST B25 Expert Meet<strong>in</strong>g Work<strong>in</strong>g Group 1, 26<br />
March 2009, at COST Office, Brussels.<br />
Tra<strong>in</strong><strong>in</strong>g PANSS rater - 4<br />
Participari la congrese <strong>in</strong>ternation<strong>al</strong>e pentru t<strong>in</strong>erii cercetatori<br />
2009 - XXIV CINP Congress Collegium Internation<strong>al</strong>e Neuro-Psychopharmacologicum, Paris.<br />
Participanti: Gabriela Maria Puiu, Mirona Alexandra Botescu<br />
Teme de cercetare doctor<strong>al</strong>a: 6<br />
Titlu: An<strong>al</strong>iza polimorfismului citocromului P450 2D6 ca sursă majoră de variabilitate <strong>farmacoc<strong>in</strong>etic</strong>ă şi a relaţiilor doză – concentraţie pentru<br />
tramadol<br />
Doctorand: Mirona Alexandra Botescu.<br />
Coordonator sti<strong>in</strong>tific: Acad.Prof.Dr. Victor Voicu<br />
Titlu: <strong>Impactul</strong> <strong>factorilor</strong> <strong>neuroendocr<strong>in</strong>i</strong> asupra parametrilor <strong>farmacoc<strong>in</strong>etic</strong>i <strong>si</strong> a raspunsului terapeutic <strong>in</strong> <strong>terapia</strong> cu compu<strong>si</strong> antip<strong>si</strong>hotici atipici<br />
Doctorand: Gabriela Maria Puiu.<br />
Coordonator sti<strong>in</strong>tific: Acad.Prof.Dr. Victor Voicu<br />
Titlu: Monitorizarea biochimica <strong>in</strong> tratamentul cu antip<strong>si</strong>hotice atipice<br />
Doctorand: Gabriela Piriu.<br />
Coordonator sti<strong>in</strong>tific: Prof.Dr.V<strong>al</strong>eriu Atana<strong>si</strong>u<br />
Titlu: Ev<strong>al</strong>uarea impactului <strong>farmacoc<strong>in</strong>etic</strong> <strong>al</strong> profilului hormon<strong>al</strong> steroid ca sursa de variabilitate în procesele de biotransformare hepatică a<br />
xenobioticelor<br />
Doctorand: Elena Gosav.<br />
Coordonator sti<strong>in</strong>tific: Prof.Dr. Constant<strong>in</strong> Mircioiu<br />
Teze de doctorat re<strong>al</strong>izate parti<strong>al</strong> <strong>in</strong> cadrul proiectului: 2<br />
Doctoranzi: Nicoleta Raducanu, Ionut Oprea (an<strong>al</strong>iza corelata genotip-fenotip)<br />
Teme de cercetare postdoctor<strong>al</strong>a: 1<br />
Titlu: Transferul xenobioticelor la <strong>in</strong>terfete membranare. Relatii <strong>si</strong> corelatii <strong>in</strong> vitro-<strong>in</strong> vivo (Flavian Radulescu)<br />
Coordonator sti<strong>in</strong>tific: Acad.Prof.Dr. Victor Voicu<br />
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Indicatori de rezultat re<strong>al</strong>izati <strong>in</strong> cadrul proiectului<br />
-1 model experiment<strong>al</strong> <strong>in</strong>tegrat pentru <strong>in</strong>vestigarea profilului <strong>farmacoc<strong>in</strong>etic</strong> <strong>al</strong> agentilor antip<strong>si</strong>hotici atipici, a<br />
performantelor c<strong>al</strong>itative <strong>si</strong> cantitative <strong>al</strong>e <strong>si</strong>stemelor enzimatice de biotransformare <strong>si</strong> a evolutiei / rolului<br />
<strong>factorilor</strong> <strong>neuroendocr<strong>in</strong>i</strong><br />
- 1 metoda de extractie lichid – lichid d<strong>in</strong> matrici biologice pentru clozap<strong>in</strong>a, risperidona <strong>si</strong> metaboliti<br />
- 1 metoda de an<strong>al</strong>iza cromatografica pentru clozap<strong>in</strong>a, risperidona <strong>si</strong> metaboliti<br />
Număr de cereri de brevete depuse în proiectelor d<strong>in</strong> care - nation<strong>al</strong>e: 1.<br />
Voicu VA., Radulescu FS., Miron DS., Draghici C., Utilizarea N-oxidului risperidonei ca pro-medicament <strong>in</strong> tratamentul<br />
or<strong>al</strong>, <strong>in</strong>trarect<strong>al</strong>, parenter<strong>al</strong> sau transdermic cu risperidona (A-01304/09.12.2010).<br />
Disem<strong>in</strong>ari<br />
Număr de articole publicate în urma proiectelor, d<strong>in</strong> care:<br />
în reviste <strong>in</strong>dexate ISI : 3<br />
Voicu VA., Medvedovici A., Miron DS., Radulescu FS., A novel approach on pharmacok<strong>in</strong>etic / pharmacodynamic correlations of risperidone: understand<strong>in</strong>g its safety<br />
and efficacy profiles, Acta Endocr<strong>in</strong>ologica (Buc) 2010, 6(2), 265-285.<br />
Radulescu M., Voicu VA., Medvedovici A., David V., Retention study of some cation-type compounds u<strong>si</strong>ng bile acid sodium s<strong>al</strong>ts as ion pair<strong>in</strong>g agents <strong>in</strong> liquid<br />
chromatography, DOI: 10.1002/bmc.1531, Biomedic<strong>al</strong> Chromatography, 2010.<br />
Voicu VA., Medvedovici A., Radulescu M., Iorgulescu EE., David V.Unusu<strong>al</strong> Retention Behavior of Some Cationic-Type Aldoximes Used as AChE Reactivators Under<br />
Ion-Pair<strong>in</strong>g Liquid Chromatographic Mechanism , An<strong>al</strong>ytic<strong>al</strong> Letters, 2010, 43(7), 1267-1276.<br />
Număr de articole acceptate spre publicare în urma proiectelor, d<strong>in</strong> care:<br />
-în reviste <strong>in</strong>dexate în <strong>al</strong>te baze de date <strong>in</strong>ternaţion<strong>al</strong>e recunoscute: 2<br />
1.Radulescu FS., Voicu VA., Miron DS., Puiu GM., Gosav E., Liquid chromatographic methods for <strong>si</strong>multaneous therapeutic monitor<strong>in</strong>g of some atypic<strong>al</strong> antipsychotic<br />
drugs, Therapeutics, Pharmacology and Cl<strong>in</strong>ic<strong>al</strong> Toxicology, 2011.<br />
2.Radulescu FS., Voicu VA., Drăghici C., Miron DS., Botescu MA., The potenti<strong>al</strong> role of N-oxide metabolites as prodrugs for neuropsychotropic agents, Therapeutics,<br />
Pharmacology and Cl<strong>in</strong>ic<strong>al</strong> Toxicology, 2011.<br />
-<strong>in</strong> curs de ev<strong>al</strong>uare în reviste <strong>in</strong>dexate ISI: 2<br />
Voicu VA., de Leon J., Medvedovici A., Radulescu FS., Miron DS., Correlation of molecular descriptors differences and pharmacok<strong>in</strong>etic / pharmacodynamic<br />
consequences for CNS-act<strong>in</strong>g drugs and their active metabolites, Ba<strong>si</strong>c and Cl<strong>in</strong>ic<strong>al</strong> Pharmacology and Toxicology, Noiembrie 2010.<br />
Arsene AL., Voicu VA., Miron DS., Radulescu FS., Puiu GM., Experiment<strong>al</strong> and theoretic<strong>al</strong> ev<strong>al</strong>uation of the impact of metabolic process on the lipophilicity of CNS<br />
act<strong>in</strong>g drugs, Revista Farmacia, Noiembrie 2010.<br />
Participare la retele de cercetare<br />
COST Doma<strong>in</strong> Biomedic<strong>in</strong>e and Molecular Biosciences Propos<strong>al</strong> Reference oc-2010-2-8455 Title: The blood-bra<strong>in</strong><br />
barrier: A target for improv<strong>in</strong>g drug therapy of CNS disorders and prevent<strong>in</strong>g neurotoxicity (BBBNet)<br />
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Activitati, obiective,<br />
estimarea necesarului de f<strong>in</strong>antare pentru anul 2011<br />
Buget <strong>in</strong>iti<strong>al</strong> (conform contractului) 907292 = 720.000 (f<strong>in</strong>antare) + 187.292 (cof<strong>in</strong>antare)<br />
Activitati prevazute a se re<strong>al</strong>iza <strong>in</strong> anul 2011<br />
Ev<strong>al</strong>uari 6-9 luni<br />
Determ<strong>in</strong>area bioan<strong>al</strong>itica a profilului <strong>farmacoc<strong>in</strong>etic</strong> <strong>al</strong> entitatilor generate <strong>in</strong> vivo pr<strong>in</strong> actiunea<br />
enzimelor polimorfice<br />
Concluzii asupra <strong>al</strong>tererarii fenotipului <strong>farmacoc<strong>in</strong>etic</strong> <strong>in</strong> conditiile <strong>al</strong>terarilor function<strong>al</strong>e specifice<br />
patologiei <strong>si</strong> <strong>al</strong> compliantei<br />
Ev<strong>al</strong>uarea <strong>farmacoc<strong>in</strong>etic</strong>a <strong>si</strong> statistica a profilelor plasmatice <strong>si</strong> ur<strong>in</strong>are<br />
Concluzii asupra <strong>al</strong>tererarii fenotipului neuroendocr<strong>in</strong> <strong>in</strong> conditiile <strong>al</strong>terarilor function<strong>al</strong>e specifice<br />
patologiei <strong>si</strong> <strong>al</strong> compliantei<br />
Obiective ce vor fi at<strong>in</strong>se <strong>in</strong> cadrul etapei<br />
-Noi criterii de sc<strong>al</strong>are <strong>si</strong> ev<strong>al</strong>uare a expunerii la antip<strong>si</strong>hotice atipice de tip risperidona, p<strong>al</strong>iperidona <strong>si</strong><br />
clozap<strong>in</strong>a<br />
-Corelatii <strong>in</strong>tre concentratiile de hormoni steroizi <strong>si</strong> parametrii c<strong>al</strong>itativi <strong>si</strong> cantitativi ai proceselor de<br />
biotransformare hepatica pentru antip<strong>si</strong>hotice<br />
Estimarea necesarului de f<strong>in</strong>antare pentru ultimul an de implementare: 360.000<br />
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