762 5-aminolevulinic acid-derived protoporphyrin ix mediated fluorescence diagnosis and photodynamic therapy of macrophages within the atherosclerotic plaque

Atherosclerosis Supplements 12, no. 1 (2011) 13–184 762 5-AMINOLEVULINIC ACID-DERIVED PROTOPORPHYRIN IX
heart disease event were constructed. A Cox Proportional Hazard model was MEDIATED FLUORESCENCE DIAGNOSIS AND PHOTODYNAMIC
applied to the data with stratification for gender and smoking status.
THERAPY OF MACROPHAGES WITHIN THE ATHEROSCLEROTIC
Results: Seventy-four events were recorded, with roughly half the number of
events recorded for female smokers (10 events) than the other three groups Y. Tian1, C. Peng1, X. Sun1, J. Cheng1, L. Yang2, J. Wu2, Z. Zhang3, (21−22 events per group), the majority of these events occurring between the W. Cao4. 1Department of Cardiology, The Second Affiliated Hospital, Harbin ages of 30 and 55. The estimated hazard ratio for men vs. women was 1.72 Medical University, 2 Department of Pathophysiology, Bio-pharmaceutical Key (95% CI 1.07–2.76) and for smoking vs. non-smoking was 1.40 (95% CI 0.87– Laboratory of Heilongjiang Province, Harbin Medical University, 3 Department of Physics, Harbin Institute of Technology, Harbin, China, 4Materials Research Discussion/conclusion: In FH patients the risk of having a coronary disease
Institute, The Pennsylvania State University, University Park, PA, USA event is high, even in 2006 when statin treatment had been available for morethan 15 years. Moreover, even with a relatively small number of events recorded, Introduction: 5-aminolevulinic acid-derived protoporphyrin IX (ALA-PpIX) has
there is clear support for the expectation that being male and smoking increases shown great potential in detection and treatment of cancer.
Objective: To detect the accumulation of ALA-PpIX in the plaque macrophages
and evaluate the effects of PDT on macrophages.
765 NITRIC OXIDE-DONATING STATINS EXERT BENEFICIAL
Methods: The fluorescence of PpIX was detected by fluorescence microscope
EFFECTS ON ACUTE VASCULAR INFLAMMATION IN
in THP-1 macrophages and plaque fresh-frozen sections of rabbit carotid artery.
NORMOCHOLESTEROLEMIC RABBITS
Immunofluorescent staining of plaque macrophages and SMCs was performed R. Baetta1, A. Granata1, L. Arnaboldi1, N. Ferri1, S. Bellosta1, A. Bonomo1, to locate ALA-PpIX. Plaque burden was evaluated by Hematoxylin and eosin D. Miglietta2, P. Pfister3, A. Corsini1. 1Department of Pharmacological (H&E) staining. Plaque macrophages and SMCs content was determined by Sciences, University of Milan, Milan, 2 NicOx Research Institute, Bresso, Italy , 3 NicOx SA, Sophia Antipolis, France Results: PpIX was found accumulated in the cytoplasm of THP-1 macrophages.
In the plaque fresh-frozen sections, the fluorescence of ALA-PpIX was detected
Introduction: Evidence has emerged suggesting that polymorphonuclear
where macrophages immunofluorescence staining was positive. Compared with leukocytes (PMN) can make important contributions to vascular inflammatory the control group, the plaque area was reduced by 59% (P < 0.01) at 4 week processes underlying atherogenesis, thus representing new possible targets for after PDT, the plaque macrophages content decreased by 56% (P < 0.001) at atheroprotection. Nitric oxide (NO)-donating statins are a new class of drugs 1 week and 64% (P < 0.001) at 4 week respectively.
aimed to combine the effects of statins with the atheroprotective properties of Conclusion: ALA-PpIX is preferentially accumulated in the macrophages of
NO (PNAS 2004;101: 8497–8502).
plaque and ALA-PpIX mediated PDT significantly decreases macrophages Aim: We investigated the effects of a short-term treatment with two NO-donating
content, indicating a promising strategy of atherosclerotic plaque macrophages derivatives of atorvastatin, NCX 6560 (successfully investigated in early clinical development; Circulation. 2010;122:A14267) and NCX 616, as compared toatorvastatin, on PMN infiltration in rabbit carotids subjected to perivascular collar 763 EFFECT OF MIPOMERSEN ON LP(A) IN PATIENTS WITH
placement, a model of acute arterial inflammation related to atherogenesis.
HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA; RESULTS
Methods: Chow-fed rabbits (n = 10/group) received a daily oral dose of vehicle
FROM TWO PHASE 3 STUDIES
or experimental compounds (equivalent to 5 mg/kg/day atorvastatin) for 6 days.
Collars were implanted after the last dose of treatment. Twenty-four hours E. Steinhagen-Thiessen1, J.L. Witztum2, S. Tsimikas2, J.M. Donovan3, later arteries were removed, immunostained for PMN, and measured by image W. Cromwell4. 1Lipid Ambulatory Clinic, Charite − Universit ¨ Berlin, Berlin, Germany , 2 Department of Medicine, University, San Diego, Results: Collared carotids from the control group had a high content of PMN.
CA, 3 Clinical Research, Genzyme Corporation, Cambridge, MA, 4Division Unlike atorvastatin, which did not influence the average value of PMN-positive- of Atherosclerosis and Lipoprotein Disorders, Presbyterian Cardiovascular area compared to control, both the NO-donating statins NCX 616 and NCX 6560, which retain the inhibitory activity of atorvastatin on HMG-CoA reductase Background and Aim: Lp(a) is considered an independent risk factor for
and release bioactive NO, reduced PMN infiltration of about 40% (p < 0.05) and coronary artery disease (CAD). The EAS consensus panel has recommended screening and treatment of elevated Lp(a). We evaluated effects of mipomersen Conclusions: NO-donating derivatives of atorvastatin exert, in addition to the
(MIPO), an antisense apo B synthesis inhibitor, on Lp(a) in two Phase 3 studies effect of statin, additional beneficial effects on vascular inflammation, thus in which patients with HeFH with CAD or severe HeFH (LDL-C >5.1 mmol/L with supporting a pharmacological rationale for their clinical development.
CAD/equivalent or >7.8 mmol) (n = 124 and 58, respectively) were randomized(1:2) to placebo (PBO) or MIPO 200 mg/week subcutaneous in addition to 766 LONG TERM COURSE IN PATIENTS WITH HOMOZYGOUS FAMILIAL
ongoing maximally tolerated statin and other hypolipidemic therapies for 26 HYPERCHOLESTEROLEMIA UNDERGOING LIPID-APHERESIS
weeks. The primary endpoint was % change in LDL-C from baseline to week A. Vogt1, C. Keller1, N. Weiss2. 1Metabolic Center, Medizinische Poliklinik, 28 or 2 weeks following the last dose. Significant (p < 0.001) reductions in LDL-C Ludwig-Maximilians-University, Munich, 2 University Center for Vascular were seen with MIPO (−28% and −36%) vs PBO (+5.2% and +13%), reported Medicine and Department of Medicine III, Technische Universit ¨ Results for Lp(a): Most patients had elevated Lp(a) levels (>20 mg/dL) at
Introduction: Homozygous familial hypercholesterolemia (FH) leads to several
baseline (71% and 62%). Median % reductions in Lp(a) were 21% and 39% fold elevated LDL-cholesterol and early cardiovascular disease (CVD). As lipid- for MIPO vs 0% and 5% for PBO (p < 0.001). 21.5% of MIPO-treated patients lowering medication is not sufficiently effective patients need lipid apheresis (LA) to reduce LDL-cholesterol and slow the course of CVD.
reactions (MIPO: 93% and 90% vs PBO: 42% and 32%) and flu-like symptoms Method: In 16 homozygous FH patients (9 males, 14 females) clinical
(MIPO: 49% and 46% vs PBO: 32% and 21%). Persistent ALT elevations manifestations of CVD were documented before and since initiation of LA. Data 3×ULN on consecutive measure at least 7 days apart were observed in MIPO patients (6% and 15%) without clinically significant elevations in bilirubin.
Results: 9 of the patients had CVD (9 aortic valve disease, 5 coronary artery
These results suggest that mipomersen as a potential add-on therapy for disease) before initiation of LA. The first event occurred at a mean age of 12.5 reducing elevated Lp(a) and LDL-C in patients with HeFH.
years (range 5−28). LA was initiated at a mean age of 14 years (range: 5−39).
Among 7 FH patients without CVD 2 developed CVD during LA (one in the 764 OCCURRENCE OF CORONARY HEART DISEASE IN A COHORT OF
first and one after 7 years of LA), whereas the other 5 remained disease free HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIC PATIENTS
until now (mean duration of treatment 15.4 years (9−21)). Among the 9 patients IN NORWAY
with prior CVD 5 developed further disease manifestation 5.6 years (0−14) after G. Langslet1, T. Dadd2, A. Jarman2, K. Retterstøl3, L. Ose3. 1Lipid Clinic, Oslo initiation of LA, whereas the remaining 4 patients did not progress (mean follow- University Hospital, Oslo, Norway , 2 Unilever Discover Colworth, Bedford, UK, up 16.75 years (10−23)). 5 patients died from CVD after a mean duration of LA 3 Oslo University Hospital, Oslo, Norway of 3.6 years (0−11). The patients still alive are now treated for a mean durationof 17.3 years (9−27).
Introduction: Heterozygous familial hypercholesterolemia (HeFH) is an
Conclusion: Long-term lipid-apheresis in patients with homozygous familial
inherited autosomal dominant disorder in the LDL-receptor (LDL-R) gene, hypercholesterolemia. slows atherosclerotic disease progression or can prevent causing non-functioning LDL-receptors on the cell surface, resulting in reduced the development of CVD, especially if initiated early and optimally before the LDL-cholesterol uptake in cells, increased serum LDL-cholesterol levels and increased risk of developing coronary heart disease (CHD).
Material and Methods: In 2006, we provided data on 545 HeFH patients with a
genetically confirmed diagnosis, without diabetes mellitus before a CHD event.
“Event tables” with regard to occurrence of first clinically manifested coronary

Source: http://www.math.psu.edu/cao/Papers_PDF/TianYe6-2011.pdf