Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients

Bloedon, LeAnne T.; Dunbar, Richard L.; Duffy, Danielle; Pinell-Salles, Paula; Norris, Robert B.; DeGroot, Bruce; Movva, Rajesh; Navab, Mohamad; Fogelman, Alan M.; Rader, Daniel J.

doi:10.1194/jlr.p800003-jlr200

Cited by 280 publications

(257 citation statements)

References 31 publications

(46 reference statements)

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“…16,17 Widespread clinical application, however, has been deterred because of the formidable cost and lack of availability for mass-production capability; therefore, synthetic apoA-I mimetic peptides, such as 4F (18 amino acids), have been developed that have been demonstrated to attenuate atherosclerosis in experimental animal models and to improve HDL function in humans. 18,19 The amphipathic peptide 4F is characterized by 4 phenylalanine residues on a hydrophobic face and demonstrates approximately a million-fold ability to bind to some oxidized lipids, compared with native apoA-I. The observed salutary effects of 4F relate to a preferential removal of oxidation products from lipoproteins and cellular membranes, thereby resulting in a Figure 1.…”

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confidence: 99%

Proinflammatory High‐Density Lipoprotein Results from Oxidized Lipid Mediators in the Pathogenesis of Both Idiopathic and Associated Types of Pulmonary Arterial Hypertension

et al. 2015

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Pulmonary arterial hypertension (PAH) is characterized by abnormal elaboration of vasoactive peptides, endothelial cell dysfunction, vascular remodeling, and inflammation, which collectively contribute to its pathogenesis. We investigated the potential for highdensity lipoprotein (HDL) dysfunction (i.e., proinflammatory effects) and abnormal plasma eicosanoid levels to contribute to the pathobiology of PAH and assessed ex vivo the effect of treatment with apolipoprotein A-I mimetic peptide 4F on the observed HDL dysfunction. We determined the "inflammatory indices" HII and LII for HDL and low-density lipoprotein (LDL), respectively, in subjects with idiopathic PAH (IPAH) and associated PAH (APAH) by an in vitro monocyte chemotaxis assay. The 4F was added ex vivo, and repeat LII and HII values were obtained versus a sham treatment. We further determined eicosanoid levels in plasma and HDL fractions from patients with IPAH and APAH relative to controls. The LIIs were significantly higher for IPAH and APAH patients than for controls. Incubation of plasma with 4F before isolation of LDL and HDL significantly reduced the LII values, compared with sham-treated LDL, for IPAH and APAH. The increased LII values reflected increased states of LDL oxidation and thereby increased proinflammatory effects in both cohorts. The HIIs for both PAH cohorts reflected a "dysfunctional HDL phenotype," that is, proinflammatory HDL effects. In contrast to "normal HDL function," the determined HIIs were significantly increased for the IPAH and APAH cohorts. Ex vivo 4F treatment significantly improved the HDL function versus the sham treatment. Although there was a significant "salutary effect" of 4F treatment, this did not entirely normalize the HII. Significantly increased levels for both IPAH and APAH versus controls were evident for the eicosanoids 9-HODE, 13-HODE, 5-HETE, 12-HETE, and 15-HETE, while no statistical differences were evident for comparisons of IPAH and APAH for the determined plasma eicosanoid levels in the HDL fractions. Our study has further implicated the putative role of "oxidant stress" and inflammation in the pathobiology of PAH. Our data suggest the influences on the "dysfunctional HDL phenotype" of increased oxidized fatty acids, which are paradoxically proinflammatory. We speculate that therapies that target either the "inflammatory milieu" or the "dysfunctional HDL phenotype," such as apoA-I mimetic peptides, may be valuable avenues of further research in pulmonary vascular diseases.Keywords: pulmonary arterial hypertension, low-density lipoprotein, high-density lipoprotein, inflammatory index, hydroxyeicosatetraenoic acids, hydroxyoctadecadienoic acids, pulmonary arterial endothelial cells, pulmonary arterial smooth muscle cells.

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confidence: 99%

Proinflammatory High‐Density Lipoprotein Results from Oxidized Lipid Mediators in the Pathogenesis of Both Idiopathic and Associated Types of Pulmonary Arterial Hypertension

et al. 2015

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“…Results show that unformulated D-4F has a low bioavailability but is safe and welltolerated. Perhaps, the most important finding of this study was the observation that D-4F treatment reduced the HDL inflammatory index in high risk subjects [96]. The next step in the clinical evaluation of 4F will be to test whether multiple oral doses of D-4F improve HDL function in CAD patients.…”

Section: Discussionmentioning

confidence: 99%

Vasculoprotective Effects of Apolipoprotein Mimetic Peptides: An Evolving Paradigm in HDL Therapy

White¹,

Datta²,

Mochon³

et al. 2009

VDP

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Anti-atherogenic effects of high density lipoprotein (HDL) and its major protein component apolipoprotein A-I (apoA-I) are principally thought to be due to their ability to mediate reverse cholesterol transport. These agents also possess anti-oxidant properties that prevent the oxidative modification of low density lipoprotein (LDL) and anti-inflammatory properties that include inhibition of endothelial cell adhesion molecule expression. Results of the Framingham study revealed that a reduction in HDL levels is an independent risk factor for coronary artery disease (CAD). Accordingly, there has been considerable interest in developing new therapies that specifically elevate HDL cholesterol. However, recent evidence suggests that increasing circulating HDL cholesterol levels alone is not sufficient as a mode of HDL therapy. Rather, therapeutic approaches that increase the functional properties of HDL may be superior to simply raising the levels of HDL per se. Our laboratory has pioneered the development of synthetic, apolipoprotein mimetic peptides which are structurally and functionally similar to apoA-I but possess unique structural homology to the lipid-associating domains of apoA-I. The apoA-I mimetic peptide 4F inhibits atherogenic lesion formation in murine models of atherosclerosis. This effect is related to the ability of 4F to induce the formation of pre-β HDL particles that are enriched in apoA-I and paraoxonase. 4F also possesses anti-inflammatory and anti-oxidant properties that are independent of its effect on HDL quality per se. Recent studies suggest that 4F stimulates the expression of the antioxidant enzymes heme oxygenase and superoxide dismutase and inhibits superoxide anion formation in blood vessels of diabetic, hypercholesterolemic and sickle cell disease mice. The goal of this review is to discuss HDL-dependent and -independent mechanisms by which apoA-I mimetic peptides reduce vascular injury in experimental animal models.

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“…Infusion of CSL-112, human apo A-1 reconstituted with phosphatidylcholine to resemble HDL, and a successor to the prior molecule CSL-111 [Bloedon et al 2008], robustly promotes cholesterol efflux from macrophages when added to serum of volunteers. CSL-112 leads to raised levels of pre-β1-HDL, with efflux mediated by ATP-binding cassette (ABC) ABCA1, and is in phase II development in ACS patients .…”

Section: Emerging Drug Therapiesmentioning

confidence: 99%

“…Additional approaches to HDL treatments include use of apo A-1 upregulators (such as RVX-208), delipidated pre-β-HDL [Waksman et al 2010], reconstituted apo A-1/HDL [Tardif et al 2007], and apo A-1 mimetic peptides [Bloedon et al 2008]. Infusion of CSL-112, human apo A-1 reconstituted with phosphatidylcholine to resemble HDL, and a successor to the prior molecule CSL-111 [Bloedon et al 2008], robustly promotes cholesterol efflux from macrophages when added to serum of volunteers.…”

Section: Emerging Drug Therapiesmentioning

confidence: 99%

Reducing residual risk: modern pharmacochemistry meets old-fashioned lifestyle and adherence improvement

Kones¹

2013

Therapeutic Advances in Cardiovascular Disease

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Despite remarkable advances in identifying and managing coronary heart disease, the global burden of cardiovascular (CV) risk and levels of undetected, subclinical heart disease remain enormous. Substantial numbers of patients do not reach their therapeutic goals, others are unable to tolerate the treatments, half may fail to adhere to their programs, and in those who do attain their targets, major cardiovascular events may continue. Wellknown risk factors, such as obesity and diabetes, have now gained the upper hand, with no evidence-based remedy capable of reversing this trend. All told, less than 1% of American adults and adolescents qualify for ideal CV health; world-wide, the growing prevalence of CV risk factors in children is imposing. A number of novel emerging drug therapies are in development, some recently approved for use in patients with familial hypercholesterolemia.Hopefully, they will contribute significantly to the current therapeutic armamentarium. However, for meaningful improvement in total and residual CV risk, an optimal mix of all available modalities will likely be necessary, including earlier and more effective prevention, aggressive medical care, revascularization and device implantation, judicious use of novel agents, and reengineering of the environment.

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Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients

Cited by 280 publications

References 31 publications

Proinflammatory High‐Density Lipoprotein Results from Oxidized Lipid Mediators in the Pathogenesis of Both Idiopathic and Associated Types of Pulmonary Arterial Hypertension

Proinflammatory High‐Density Lipoprotein Results from Oxidized Lipid Mediators in the Pathogenesis of Both Idiopathic and Associated Types of Pulmonary Arterial Hypertension

Vasculoprotective Effects of Apolipoprotein Mimetic Peptides: An Evolving Paradigm in HDL Therapy

Reducing residual risk: modern pharmacochemistry meets old-fashioned lifestyle and adherence improvement

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