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Thursday, June 22, 2006: Poster Session Pharnwtcologieal control of lipids and lipoprotehts

Conclusions: Sugar cane-derived policosanol (usual and high-dose) has no lipoprotain-lowaring affacts in Caucasian patiants with hyparcholastarolamia or combinad hyparlipidamia. Funding: Madaus, Cologna, Garmany

Th-P16:329

THE EFFECT OF LEPTIN VERSUS FOOD R E S T R I C T I O N O N LIPID M E T A B O L I S M A N D A T H E R O S C L E R O S I S IN A P O E - / - A P O B 1 0 0 / 1 0 0 O B - / AND LDLR-/-APOB100/100 OB-/- MICE

J. McCormick, S. Kaufman, J. Witkosky, S. Stanislaus, J. Lofing, R. Lindbarg, M. Vaniant. Amgen bw., Thousand Octks, USA Objective: Tha affacts of laptin raplacamant at physiological concantrations or food rastriction were studiad in ApoE-/-ApoblOO/lOOob-/- (APOE) and Ldlr-/-ApoblOO/lOOob-/- (LDLR) mica. Glucosa, lipid matabolism, and atharosclarosis were avaluatad in naw tripla knock out lines of mica craatad to have all tha aspacts of tha Matabolic Syndroma. M e t h o d s : Groups were traatad daily with salina alona, salina with foodrastriction, or laptin for 86 days. Laptin doses were adjustad throughout tha axparimant in order to maintain a constant body waight. Tha food-rastrictad groups were fad to match tha body waights of laptin-traatad mica. Plasma cholastarol, triglycaridas, blood glucosa and insulin lavals were maasurad at 0, 48 and 75 days into traatmant. A glucosa tolaranca test was also parformad at tha and of tha traatmant pariod. Atharosclarotic lasions were quantifiad by image analysis in pinnad-out aorta. Results: In both linas, insulin lavals were dacraasad in food-rastrictad and laptin-traatad mica. Glucosa lavals were significantly dacraasad only in APOE food rastrictad mica. Triglycarida lavals dacraasad only in LDLR, laptin traatad and food rastrictad mica. Cholastarol lavals were dacraasad in both lines of laptin-traatad or food-rastrictad mica, with a graatar affact in tha laptin-traatad mica. Glucosa tolaranca was improvad in L D L R mica traatad with laptin. Mica traatad with laptin had significantly less lasion than food rastrictad mica. Conclusion: Laptin raplacamant has diffaring affacts on glucosa and lipid matabolism in both lines of mica. Howavar, laptin raducad atharosclarotic lasions in APOE and L D L R mica. ] Th-P16:330 I AN ORALLY ACTIVE CONSTRUCT BASED ON 1 SERUM AMYLOID A PROMOTES CHOLESTEROL E X P O R T IN V I V O

R. Kisilavsky L2"3, R. Tan 3, J.B. Ancsin L2"3, EM. Kim L3 , S.E Tam L2'3 . 1Queen's Uuiversi~, Kingston, Cat~Ma: "-Kingston General Hospital, Kingston, Canada; 3Atherochent, Ottawa, Canada Objective: To axamina if an agent based on tha nautral cholastarol astarasaanhancing (CEH)domaJn of sarum amyloid A (SAA) promotas macrophaga (Mph) cholastarol axport in vivo. M e t h o d s : J774 mouse Mph were cholastarol-loadad with tad blood cell mambrana fragmants that had been aquilibratad with 3 H-cholastarol. Tha Mph were then injactad into normal CD-1 mica via tha tail-vain and allowad to astablish thamsalvas in tha animal for 24 h. During this pariod two, 25 uL, blood samplas (6 and 24 h) were taken from tha tail tip to astablish a basalina, following which tha agent to ba tastad was aithar injactad IV or given by gavaga. Blood samplas, 25 uL, were taken from tha tail tip at multipla intarvals tharaaftar over 24-48 h. Tha samplas were collactad in hapaxinized capillary tubes, cantrifu~ad to separate cells from plasma and 3H-cholesterol/uL plasma datarminad Results: An agent basad on tha previously identified structura of tha CEH-anhancing domain of SAA when given IV caused prompt export of Mph cholesterol in a dose-dependent manner. When given by gavaga this agent also promoted cholesterol export, but with altarad kinatics, and fasting tha mica ovarnoght improved tha efficacy of tha agent. Similarly, equal quantities of tha agent in concentrated and dilute preparations ravaalad that tha concentrated samples were more effective in promoting cholesterol export. Conclusions: An agent based on tha structure of tha CEH-anhancing domain pf SAA promotes Mph cholesterol in vivo when given IV or orally. Funding: Grants MOP-3153, PPP-62602, PP2-67645 from CIHR and AtharoCham Inc

I Th-P16:331

I

I I

ASSESSMENT OF LIPOPROTEIN PROFILES (ALPS STUDY) A N D A N T I O X I D A N T A C T I V I T Y IN HEALTHY SUBJECTS TREATED WITH AGI-1067

M.H. Davidson ]'2, J. Smith 3 , R. Scott 3 , R. Small 3 , J. Choi 3 , J.E Kana 4 .

1Section of Preventive Medicine, Department of Cardiology, Rush Uuiversi~ College of Medicine, Chicago, IL, USA." "-RcNiant Research, bzc., Chicago, IL, USA." 3Atherogenics, Inc., Alpharetta, GA, USA." 4Cardiovascular Research btstitute, Universi~ of CalifotTda, San Francisco, CA, USA B a c k g r o u n d : AGI-1067 is a phanolic antioxidant with potant antiatharosclarotic and anti-inflammatory affacts. Objective: To assass tha affacts of AGI-1067 on LDL-C and HDL-C, CETR paraoxonasa and other paramatars. M e t h o d s : Haalthy subjacts (18-65 yr) were randomizad 1:1 to racaiva 300 mg AGI-1067 (n=127) or matching placabo (n=127) daily for 12 waaks. Eligibility includad LDL-C _<190 mg/dl; tha analysas includad a stratification of basalina LDL-C at _< and > 130 mg/dL. Results: Small changas in LDL-C occurrad in tha AGI-1067 and placabo groups (3.0-t-1.6 vs. -1.3-t-1.6 mg/dL, raspactivaly; p=0.057). Tha LDLC changas corralatad (p<0.0001) with CETP mass. CETP incraasad with AGI-1067 and dacraasad with placabo (0.26-t-0.03 vs. -0.04-t-0.03 mg/dL; p < 0.001). There were small but significantly graatar dacraasas in HDL-C with AGI-1067 (-4.0-t-0.6 mg/dL) than with placabo (-0.5-t-0.6 mg/dL; p<0.001). Paxaoxonasa activity incraasad with AGI-1067 comparad to littla changa with placabo (1.8-t-0.7 vs. 0.2-t-0.6 U/L; p=0.077); tha incraasa was graatast for basalina LDL-C _<130 mg/dL (p=0.003). A p t B did not changa in aithar LDL-C strata with AGI-1067, and apoA1 dacraasad only for LDL-C > 130 mg/dL. AGI-1067 was well tolaratad with no clinically significant changas in laboratory or ECG parameters. Conclusions: Ovarall, tha changes in LDL-C and HDL-C with AGI-1067 treatment were modest and unlikely to ba clinically significant. These changes may have involved modifications of CETP and scavenger receptor B type I. AGI-1067 had favorable increases on tha potantially CHD-protactiva effects of paraoxonasa activity. AGI-1067 was well tolerated.

I Th-P16:332 I EVEROLIMUS AFFECTS CHOLESTEROL H O M E O S T A S I S IN M A C R O P H A G E S S. B a l l o s t a l L. A r n a b o l d i l M. C a n a v a s i l E Pfistar 2, A. Granata 1 , • .1 . 1Department of Pharmacological Sciences, R. Dorant-, A. Corsml

Uuiversi~ of Milan, Milan, Italy: 2Novartis Pharma AG, Basel, Switzerland Savaral studias hava documantad a dosa-ralatad alavation of sarum lipid lavals in transplantad patiants traatad with avarolimus. Ganarally, incraasas in both total cholastarol or triglycaridas ara apparant altar 2-3 months of tharapy with this drug. Tha prasant study addrassas tha potantial machanism of avarolimus-inducad hyparlipidamia by maasuring its affact on callular lipid homaostasis in macrophagas. Mousa paritonaal macrophagas (MPM) wara incubatad with incraasing concantrations of avarolimus (from 0.0001 to 1 uM) for 24 hours, than cholastarol accumulation, astarification or afflux, and triglycarida synthasis wara avaluatad using standard tachniquas. Evarolimus causad a concantration-dapandant incraasa (up to 50%, p<0.01) of astarifiad cholastarol biosynthasis inducad by acatylatad LDL, and this affact was consaquant to a stimulation of tha astarifying anzyma ACAT activity (up to 40%, p < 0.05). Cholastarol afflux inducad by HDL was incraasad up to 50% laading to a 18% raduction of total callular cholastarol contant. Moraovar, avarolimus raducad up to 50% triglycaridas biosynthasis. Tha prasant findings show that avarolimus, at concantrations similar to its tharapautic ranga (0.01 uM), aYfacts cellular lipid homaostasis incraasing cholastarol astarification and afflux, and raducing triglycarida synthasis. Altogathar tha prasant findings highlight tha ability of avarolimus to intarfara with callular cholastarol homaostasis and provida avidanca for combining avarolimus with hypolipidamic drugs, such as fluvastatin. Funding: Tha study was supportad by Novartis AG.

ITh-P16:3331 SLAI PLITD -INL ODWI AE RBIENTGI C EDFIFSELCI PTI DOEFMSIYAN T H E T I C

BILE

S. Kojic-Damjanov 1, M. Djaric 1, M. Mikov " , 1 Chmcal . . ~. Centet=Novt Sad, Novi SaN, Serbia - Montenegro: "-Medical Faculty Novi Sad, Uuiversi~ of Novi SaN, Novi Sad, Serbia - Montenegro Objective: Synthatic bile acids axa, nowadays, very intarasting as potantially naw hypolipidamic drug, dua to their significant role in cholastarol catabolism.

XIV bztetT~ttioual Symposium on Atherosclerosis, Rome, Italy, June 18-22, 2006