Abstract 1696: Compound RVX-208 Modulates HDL-C Levels and Function in Non-human Primates and in Early (phase I) Human Trials

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Larbi Krimbou ◽  
Ravi Jahagirdar ◽  
Dana Bailey ◽  
Anouar Hafiane ◽  
Isabelle Ruel ◽  
...  
Keyword(s):  
Oral Administration ◽  
Healthy Volunteers ◽  
Size Distribution ◽  
Cholesterol Efflux ◽  
Oral Absorption ◽  
Therapeutic Potential ◽  
Human Study ◽  
Treated Group ◽  
Atherosclerotic Cardiovascular Disease ◽  
Hdl Function

The novel compound RVX-208 is a small molecule that upregulates the gene expression of apoA-I and raises HDL-C in non-human primates. Here, we examined the effects of oral administration of RVX-208 on serum apoA-I and HDL-C levels , HDL size distribution, and HDL function. African green monkeys received RVX-208 (7.5, 15 and 30 mg/kg; twice daily and 60 mg/kg; once daily) or vehicle control for 28, 42, and 63 days. We report that RVX-208 chronic treatment resulted in a highly significant increase in the average of serum apoA-I and HDL-C levels (57% and 92%, respectively). Interestingly, RVX-208 treatment modified the distribution of HDL particle size causing a significant increase in preβ1-LpA-I and larger α1-LpA-I species. The ability of serum to promote cholesterol efflux via ABCA1, ABCG1 or SR-BI-dependent pathways in a cell culture model was significantly increased by RVX-208. The phase Ia safety and pharmacokinetic human study comprised of a total of 80 subjects. In the multiple ascending dose arm, 24 participants were randomly assigned to 3 cohorts of 8 healthy volunteers (6 active and 2 placebo), and received oral administration of RVX-208 at 2, 3 and 8 mg/kg per day or placebo for 7 days. The compound was well tolerated and had good oral absorption meeting the objectives of safety and pharmacokinetics. ApoA-I, HDL-C, HDL size distribution and ABCA1-dependent cholesterol efflux were assessed at days 1 (predose) and 7. The percent change from baseline to day 7 for apoA-I was 11% higher (P = 0.03) in the RVX-208 treated participants compared to placebo. Interestingly, preβ1-LpA-I change was 30% (P = 0.02) higher in the actively treated group and was found to strongly correlate with increased apoA-I levels (R2 = 0.72). Furthermore, ABCA1-dependent cholesterol efflux change was 10% higher (P = 0.03) and was found to correlate with increased preβ1-LpA-I . Taken together, these pharmacodynamic data from human healthy volunteers show consistent trends in apoA-I production and HDL functionality, supporting the findings in the African green monkey. Further investigation of the effect of RVX-208 on the HDL metabolic pathway is ongoing in humans and animals to establish the mechanisms of action and therapeutic potential in treating atherosclerotic cardiovascular disease.

Abstract 576: Salicylamine, A γ-ketoaldehyde Scavenger, Improves HDL Function and Reduces Atherosclerosis in Apoe Deficient Mice

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Jiansheng Huang ◽  
Patricia Yancey ◽  
Lei Ding ◽  
Youmin Zhang ◽  
John Oates ◽  
...  
Keyword(s):  
Western Blot ◽  
Cholesterol Efflux ◽  
Adduct Formation ◽  
Molar Ratio ◽  
Atherosclerotic Cardiovascular Disease ◽  
Dependent Manner ◽  
Cholesterol Accumulation ◽  
Cholesterol Efflux Capacity ◽  
Hdl Function ◽  
The Impact

Background: Lipid peroxidation products impair the cholesterol efflux capacity of high-density lipoprotein (HDL) and promote the development of atherosclerosis. The impact of inhibition of malondialdehyde (MDA)-HDL adduct formation by scavengers on HDL function and whether small molecule aldehyde scavengers protect against the development of atherosclerosis was examined. Methods and Results: Western blot analysis of ApoAI revealed that the amount of ApoAI crosslinking increased with MDA concentration. In the presence of LPS, MDA-HDL (HDL modified by 1mM MDA) versus control HDL stimulated 2- and 1.8-fold more expression of TNF-α and IL-1β in Apoe-/- macrophages demonstrating that MDA-HDL has reduced anti-inflammatory function. HDL-mediated macrophage cholesterol efflux was decreased by ~ 42%, 55%, 70%, and 80%, respectively, for HDL modified with 0.125 mM, 0.25 mM, 0.5 mM, and 1mM MDA, demonstrating that MDA modification of HDL affects its cholesterol efflux capacity in a dose dependent manner. Analysis by Western blot demonstrated that 5mM of salicylamine (SAM) and 5mM of pentylpyridoxamine (PPM), γ-ketoaldehyde scavengers, attenuated MDA mediated crosslinking of apoA-I in HDL (molar ratio of MDA and HDL is 1:5) by 60% and 80 % (P<0.05), respectively. Both SAM and PPM maintained the cholesterol efflux capacity of MDA treated HDL in Apoe-/- macrophages. In addition, pretreatment of LDL with SAM prevented MDA-ApoB adduct formation, and compared to incubation with LDL containing MDA-ApoB adducts, SAM treatment resulted in 57% less cholesterol accumulation in J774 macrophages. Importantly, administration of the ketoaldehyde scavenger, SAM, versus the nonreactive analogue, 4-SAM, to Apoe-/- mice consuming a Western diet for 16 weeks reduced the extent of proximal aortic atherosclerosis by 28% (P<0.05). Conclusions: Treatment with salicylamine, a γ-ketoaldehyde scavenger: 1) inhibits MDA-ApoA1 adduct formation thereby preserving HDL cholesterol efflux capacity; 2) prevents MDA-apoB100 formation resulting in less macrophage cholesterol accumulation; 3) reduces atherosclerosis in Apoe -/- mice. These results support the therapeutic potential of salicylamine in the treatment of atherosclerotic cardiovascular disease.

Molecular Patterns of Extreme and Persistent Cholesterol Efflux Capacity

2021 ◽  
Vol 41 (10) ◽  
pp. 2588-2597
Author(s):  
Ayea El-Ghazali ◽  
Sneha Deodhar ◽  
Suzanne Saldanha ◽  
Brooke Smyth ◽  
Mark Izbrand ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Size Distribution ◽  
Cholesterol Efflux ◽  
Total Phospholipid ◽  
Density Lipoprotein ◽  
Population Based ◽  
Size Exclusion ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cholesterol Efflux Capacity ◽  
Cardiovascular Biomarker

Objective: Cholesterol efflux capacity (CEC), the ability of extracellular acceptors to pick-up cholesterol from macrophages, is a clinically relevant cardiovascular biomarker. CEC is inversely associated with incident atherosclerotic cardiovascular disease events. However, CEC is only modestly associated with HDL-C (high-density lipoprotein cholesterol) levels, which may explain the failure of HDL-C raising therapies to improve atherosclerotic cardiovascular disease outcomes. Determinants of variation in CEC are not well understood. Thus, we sought to establish whether extreme high and low CEC is a robust persistent phenotype and to characterize associations with cholesterol, protein, and phospholipids across the particle size distribution. Approach and Results: CEC was previously measured in 2924 participants enrolled in the Dallas Heart Study, a multi-ethnic population-based study from 2000 to 2002. We prospectively recruited those who were below the 10th and above 90th percentile of CEC. Our study revealed that extreme low and high CEC are persistent, robust phenotypes after 15 years of follow-up. Using size exclusion chromatography, CEC to fractionated plasma depleted of apolipoprotein B (fraction-specific CEC) demonstrated significant differences in CEC patterns between persistent high and low efflux groups. Fraction-specific CEC was correlated with fraction-specific total phospholipid but not apolipoprotein A-I, cholesterol, or total protein. These correlations varied across the size distribution and differed among persistent high versus low efflux groups. Conclusions: Extreme high and low CEC are persistent and robust phenotypes. CEC patterns in fractionated plasma reveal marked variation across the size distribution. Future studies are warranted to determine specific molecular species linked to CEC in a size-specific manner.

scholarly journals Scavenging dicarbonyls with 5’-O-pentyl-pyridoxamine improves insulin sensitivity and reduces atherosclerosis through modulating inflammatory Ly6Chi monocytosis and macrophage polarization

2019 ◽  
Author(s):  
Jiansheng Huang ◽  
Patricia G. Yancey ◽  
Linda S. May-Zhang ◽  
Huan Tao ◽  
Youmin Zhang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Cholesterol Efflux ◽  
Macrophage Polarization ◽  
Atherosclerotic Cardiovascular Disease ◽  
Aortic Lesion ◽  
Cholesterol Efflux Capacity ◽  
Atherosclerotic Lesions ◽  
Hdl Function

BackgroundLipid peroxidation products impair HDL function and contribute to the development of atherosclerosis. Ours and other studies have shown that reactive dicarbonyls such as Isolevuglandins (IsoLG) and malondialdehyde (MDA), crosslink apoAI and impair the ability of HDL to promote cholesterol efflux. We examined whether scavenging of reactive dicarbonyls protects against the development of insulin resistance and atherosclerosis.Methods and ResultsHere, we found that 5’-O-pentyl-pyridoxamine (PPM), a potent scavenger of reactive dicarbonyls, abolished MDA-mediated crosslinking of apoAI in HDL by 80 % (P<0.05). In addition, PPM prevented the reduction in cholesterol efflux capacity of MDA treated HDL and preserved the cholesterol efflux capacity of MPO-modified HDL in Apoe−/− macrophages. Furthermore, PPM significantly improved the cholesterol efflux capacity and PON1 activity of HDL in Ldlr−/− mice (P<0.05), indicating that PPM protects HDL from modifications by reactive dicarbonyls and maintains HDL function in vivo. Importantly, PPM improved hyperglycemia and insulin sensitivity in male Ldlr−/− mice. Administration of 1 mg/mL of PPM, versus 1 mg/mL of the nonreactive analogue PPO, to Ldlr−/− mice consuming a western diet (WD) for 16 weeks reduced the extent of proximal aortic atherosclerosis by 48% and by 46% (P<0.05) in female and male Ldlr−/− mice. PPM also reduced the extent of en face aortic lesion by 52% in male Ldlr−/− mice. In addition, PPM reduced pro-inflammatory enzyme MPO expression by 57.5% and the number of TUNEL positive cells by 52% (P<0.01) in atherosclerotic lesions of Ldlr−/− mice. Immunohistochemistry studies revealed that PPM reduced the lesion macrophage content by 55% (P<0.05). Importantly, PPM increased M2 marker Arg1+ in macrophages of lesions and reduced the number of blood pro-inflammatory Ly6Chi monocytes and the ratio between Ly6Chi and Ly6Clow, but not the numbers of Ly6Clow, neutrophils in Ldlr−/− mice. Similarly, treatment of Apoe−/− mice on a WD for 16 weeks with PPM significantly reduced the extent of atherosclerotic lesions and also enhanced plaque stability as evidenced by a 47% increase in fibrous cap thickness and a 64.7% reduction in necrotic core area.ConclusionsReactive dicarbonyl scavenging with PPM in vivo preserves HDL function which improves insulin sensitivity and decreases atherosclerosis development. These results support the therapeutic potential of reactive dicarbonyl scavenging in the treatment of insulin resistance and atherosclerotic cardiovascular disease.

Clinical Pharmacokinetics and Pharmacodynamics of Pwt-143, an Oral, Potent and Selective Inhibitor of Phosphatidylinositol 3-Kinase P110delta, Following Single Oral Administration to Healthy Volunteers

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4858-4858
Author(s):  
Ofir M Moreno ◽  
Vanessa Zann ◽  
Pui Leung
Keyword(s):  
Oral Administration ◽  
Healthy Volunteers ◽  
Human Study ◽  
Selective Inhibitor ◽  
Basophil Activation ◽  
Functional Assay ◽  
Pharmacokinetic Data ◽  
Blood Samples ◽  
Dose Levels ◽  
Phosphatidylinositol 3

Abstract Background: The Phosphatidylinositol 3-Kinases p110δ isoform (P110δ PI3K) is hyperactive in B cell malignancies and is central to multiple signaling pathways that drive proliferation, survival, homing and retention of malignant cells in lymphoid tissue and bone marrow. PI3Kd inhibitors have demonstrated important clinical activity in various lymphoid malignancies, albeit with certain toxicities and PK limitations. PWT-143, comprised of a novel molecular scaffold that is distinctive from other known PI3Kd-selective inhibitors, is a potent and selective inhibitor of P110δ PI3K enzymatic activity. PWT-143 exhibits low nanomolar potency in cellular assays, as well as in a pre-clinical whole blood functional assay of basophil activity (poster presented at 54th ASH Annual Meeting, 2012). PWT-143 also demonstrated highly favorable pharmacokinetics from oral administration in preclinical experiments. Preclinical toxicology and safety pharmacology data supported initial clinical assessment of oral PWT-143 in healthy volunteers, consistent with its target selectivity profile. Here we report the initial PK and PD results of a single dose of oral PWT-143 in healthy volunteers. Methods: A flexible, adaptive first-in-human study was conducted using a Translational Pharmaceutics® platform which enables rapid real-time PK/PD analysis and GMP manufacture of drug products between dosing periods. Based on the NOAEL in rats and dogs, with a standard safety margin for a first-in-human study, the starting dose level was 10 mg, with higher doses and/or formulation adjustments to be selected, based on review of emerging safety, tolerability and pharmacokinetic data. Blood samples were collected at regular time intervals, and plasma concentrations of PWT-143 were measured using a validated liquid chromatography tandem mass spectrometry method. Blood samples were also collected for testing with a PD assay; specifically, basophil activation assessed via CD63 expression by flow cytometry following ex-vivo stimulation with an anti-FCeR1 monoclonal antibody. Results: To date, subjects (n=3/cohort) have been orally administered 10 mg and 30 mg of PWT-143, and escalation is continuing (n=6/cohort). The 10 mg and 30 mg doses resulted in up to 55 % and 80 % inhibition of basophil activation, respectively, within 4 hours of dosing. Both doses resulted in no reported Adverse Events nor clinically significant changes in vital signs, ECGs or safety laboratory assessments. The geometric mean Cmax and half-life were 3.9 ng/ml (range; 2.0-6.6 ng/ml) and 29 hours (range; 20-42 hours), respectively, following oral administration of 30 mg. Conclusions: Measurable plasma levels of PWT-143, as well as significant inhibition of basophil activation have been observed at the lowest planned dose levels. These findings suggest that PWT-143 is orally bioavailable and exhibits potent on-target activity in humans. PK results suggest daily dosing is achievable. Results from the completed study with all dose levels will be presented. Disclosures No relevant conflicts of interest to declare.

Abstract 111: A Novel Assay that Incorporates Measurement of Ex Vivo LCAT Activity with Measurement of Cholesterol Efflux Capacity - Assessment of Two Biomarkers of Serum HDL Function

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Heidi L Collins ◽  
Anthony C Sulpizio ◽  
Seanna M Unruh ◽  
Steven J Adelman
Keyword(s):  
Cholesterol Efflux ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Inverse Correlation ◽  
Hdl Cholesterol ◽  
Cholesterol Esterification ◽  
High Density Lipoproteins ◽  
Cholesterol Efflux Capacity ◽  
Hdl Function ◽  
Artery Disease

Atheroprotective properties of high-density lipoproteins (HDL) may be due to the ability to remove lipids from peripheral cells to the liver for excretion during reverse cholesterol transport (RCT). Assays that measure functionality of serum HDL are needed to evaluate the therapeutic potential of treatments targeting HDL metabolism. Recent work shows an inverse correlation between cholesterol efflux capacity of serum HDL and coronary artery disease, demonstrating the value of measuring HDL functionality. Another function of HDL that promotes RCT is the capacity for esterification of cholesterol by lecithin:cholesterol acyltransferase (LCAT). A novel assay was developed that in addition to measurement of serum HDL efflux capacity incorporates measuring the capacity for esterification of HDL-cholesterol by LCAT. Assay methodology includes measurement of global cholesterol efflux via all known pathways (ABCA1, SR-BI, ABCG1 and passive diffusion) from J774 macrophage cells to serum HDL, and measurement of the proportion of cholesterol transferred to serum HDL that is esterified by LCAT over 4h. Assay validation included assessment of intra-assay repeatability, inter-assay precision, linearity, LOQ and specificity. Results showed the intra-assay variability (%CV) from six independent preparations of serum HDL is ≤10% for both the % efflux and the % esterification of cholesterol. Inter-assay variability between four separate assays is ≤13% for both the % efflux and the % esterification of cholesterol. Cholesterol efflux is linear up to concentrations of 2.8% serum HDL and cholesterol esterification is linear up to concentrations of 4% serum. The LOQ for the assay is 0.15% cholesterol efflux and 0.40% cholesterol esterification. Global cholesterol efflux was determined to be specific for known cholesterol acceptors such as serum HDL (p≤0.0001 versus media blank). The cholesterol esterification measured was determined to be specific for the action of LCAT because the presence of LCAT inhibitor decreased the % ester by 86-97% (p≤0.0009). This novel assay allows the measurement of two functional aspects of an individual subject’s serum HDL, the capacities for both cholesterol efflux and for esterification of cholesterol by LCAT.

Eudragit L-100 Capsules Aromatize and Quaternerize Chitosan for Insulin Nanoparticle Oral Delivery During Toxic Oxidative Stress in Rat Liver and Kidney

2020 ◽  
Vol 8 (3) ◽  
pp. 239-254 ◽  
Author(s):  
Reza Mahjub ◽  
Farzane K. Najafabadi ◽  
Narges Dehkhodaei ◽  
Nejat Kheiripour ◽  
Amir N. Ahmadabadi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oral Administration ◽  
Oral Delivery ◽  
Biochemical Parameters ◽  
Kidney Injury ◽  
Regular Insulin ◽  
Treated Group ◽  
Histopathological Change ◽  
Diabetic Rats ◽  
Liver And Kidney

Background: Insulin, like most peptides, is classified as a hydrophilic and macromolecular drug that is considered as a low permeable and unstable compound in the gastrointestinal (GI) tract. The acidic condition of the stomach can degrade insulin molecules. Moreover, the presence of proteolytic activities of some enzymes such as trypsin and chymotrypsin can hydrolyze amide-bonds between various amino-acids in the structures of peptides and proteins. However, due to its simplicity and high patient compliance, oral administration is the most preferred route of systemic drug delivery, and for the development of an oral delivery system, some obstacles in oral administration of peptides and proteins including low permeability and low stability of the proteins in GI should be overcome. Objective: In this study, the effects of orally insulin nanoparticles (INPs) prepared from quaternerized N-aryl derivatives of chitosan on the biochemical factors of the liver in diabetic rats were studied. Methods: INPs composed of methylated (amino benzyl) chitosan were prepared by the PEC method. Lyophilized INPs were filled in pre-clinical capsules, and the capsules were enteric-coated with Eudragit L100. Twenty Male Wistar rats were randomly divided into four groups: group1: normal control rats, group 2: diabetic rats, group 3: diabetic rats received capsules INPs(30 U/kg/day, orally), group 4: the diabetic rats received regular insulin (5 U/kg/day, subcutaneously). At the end of the treatment, serum, liver and kidney tissues were collected. Biochemical parameters in serum were measured using spectrophotometric methods. Also, oxidative stress was measured in plasma, liver and kidney. Histological studies were performed using H and E staining . Results: Biochemical parameters, and liver and kidney injury markers in serum of the diabetic rats that received INPs improved significantly compared with the diabetic group. INPs reduced oxidative toxic stress biomarkers in serum, liver and kidney of the diabetic treated group. Furthermore, a histopathological change was developed in the treated groups. Conclusion: Capsulated INPs can prevent diabetic liver and oxidative kidney damages (similar regular insulin). Therefore oral administration of INPs appears to be safe. Lay Summary: Although oral route is the most preferred route of administration, but oral delivery of peptides and proteins is still a challenging issue. Diabetes Mellitus may lead to severe complications, which most of them are life-threatening. In this study, we are testing the toxicity of oral insulin nanoparticles in kidney and liver of rats. For this investigation, we will prepare insulin nanoparticles composed of a quaternized derivative of chitosan. The nanoparticles will be administered orally to rats and the level of oxidative stress in their liver and kidney will be determined. The data will be compared to the subcutaneous injection of insulin.

scholarly journals Cholesterol Efflux Capacity Associates with the Ankle-Brachial Index but Not All-Cause Mortality in Patients with Peripheral Artery Disease

Diagnostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1407
Author(s):  
Robert K. Clemens ◽  
Monika Hunjadi ◽  
Andreas Ritsch ◽  
Lucia Rohrer ◽  
Thomas O. Meier ◽  
...  
Keyword(s):  
Peripheral Artery Disease ◽  
Cholesterol Efflux ◽  
Ankle Brachial Index ◽  
Mortality Rates ◽  
High Density Lipoproteins ◽  
Peripheral Artery ◽  
Cholesterol Efflux Capacity ◽  
Hdl Function ◽  
All Cause Mortality ◽  
Artery Disease

Background: Cholesterol efflux is an important mechanism by which high-density lipoproteins (HDLs) protect against cardiovascular disease. As peripheral artery disease (PAD) is associated with high mortality rates, mainly due to cardiovascular causes, we investigated whether cholesterol efflux capacity (CEC) of apolipoprotein B (apoB)-depleted plasma, a widely used surrogate of HDL function, may serve as a predictive marker for mortality in this patient population. Methods: In this prospective single-center study (median follow-up time: 9.3 years), apoB-containing lipoproteins were precipitated from plasma of 95 patients with PAD and incubated with J744-macrophages, which were loaded with radiolabeled cholesterol. CEC was defined as the fractional radiolabel released during 4 h of incubation. Results: Baseline CEC was lower in PAD patients that currently smoked (p = 0.015) and had a history of myocardial infarction (p = 0.011). Moreover, CEC showed a significant correlation with HDL-cholesterol (p = 0.003) and apolipoprotein A-I levels (p = 0.001) as well as the ankle-brachial index (ABI, p = 0.018). However, CEC did not differ between survivors and non-survivors. Neither revealed Kaplan–Meier and Cox regression analyses any significant association of CEC with all-cause mortality rates. Conclusion: Taken together, CEC is associated with ABI but does not predict all-cause mortality in patients with PAD.

The Length of Disulfide Bond-Containing Linkages Impacts the Oral Absorption and Antitumor Activity of Paclitaxel Prodrugs-Loaded Nanoemulsions

Nanoscale ◽  
2021 ◽  
Author(s):  
Yanlin Gao ◽  
Shiyi Zuo ◽  
Lingxiao Li ◽  
Tian Liu ◽  
Fudan Dong ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Oral Administration ◽  
Disulfide Bond ◽  
Rational Design ◽  
Oral Absorption ◽  
Oral Paclitaxel

Rational design of oral paclitaxel (PTX) preparations is still a challenge. Many studies focus on developing PTX-loaded nanoemulsions (NEs) for oral administration. Unfortunately, PTX has poor affinity with the commonly...

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