HDL therapies — past, present and future

For a number of years, high-density lipoprotein (HDL) has been recognized to have an athero-protective role by promoting reverse lipid transport, a process facilitating the cholesterol efflux from atherosclerotic plaques in the artery wall and its elimination by the liver via biliary excretion. On the contrary, low-density lipoprotein (LDL) particles carry cholesterol to the organs and tissues where it can be used to produce hormones or maintain cell metabolism. When an imbalance develops, as a result of either an excess level of cholesterol associated with LDL (LDL-C) or a less effective cholesterol elimination by HDL (HDL-C), this causes an excess of cholesterol to be transported to the tissues and promotes the deposition of cholesterol. This often occurs in the artery walls, particularly in the coronary arteries. There is no approved medical treatment for directly suppressing or treating the atherosclerotic plaque once it is formed. Epidemiological studies have shown that the risk of developing cardio-vascular disease (CVD) is higher in patients with low levels of HDL-C regardless of LDL-C levels, even in patients optimally treated with LDL-C-lowering therapies. These data highlight that low HDL-C and low HDL particle number is an important target of therapies aiming to reduce the residual risk of CVD

On the motivations for Merleau-Ponty’s ontological research

This paper attempts to clarify Merleau-Ponty’s later work by tracing a hitherto overlooked set of concerns that were of key consequence for the formulation of his ontological research. I argue that his ontology can be understood as a response to a set of problems originating in reflections on the intersubjective use of language in dialogue, undertaken in the early 1950s. His study of dialogue disclosed a structure of meaning-formation and pointed towards a theory of truth (both recurring ontological topics) that post-Phenomenology premises could not account for. A study of dialogue shows that speakers’ positions are interchangeable, that speaking subjects are active and passive in varying degrees, and that the intentional roles of subjects and objects are liable to shift or ‘transgress’ themselves. These observations anticipate the concepts of ‘reversibility’ and ‘narcissism’, his later view of activity and passivity, and his later view of intentionality, and sharpened the need to adopt an intersubjective focus in ontological research

IDENTIFICATION D'UN DOMAINE DE LIAISON DE L'APOLIPOPROTEINE AI AUX CELLULES D'HEPATOME HUMAIN HEPG 2

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Clinical tolerability and safety profile of CER-001, a novel bio-engineered pre-\u3b2 HDL-mimetic, across the clinical development programme

Background: The main protective effect of HDL against atherosclerosis is its ability to mobilise cholesterol from lipid-rich atherosclerotic plaques. Cerenis Therapeutics has developed CER-001, an engineered discoidal particle comprising recombinant human ApoA-I and phospholipids mimicking the natural nascent, discoidal pre-\uf062 HDL particle. In preclinical studies, CER-001 promotes cholesterol efflux from macrophages and from atherosclerotic plaques. In clinical trials in patients with familial hypercholesterolaemia or hypoalphalipoproteinaemia, CER-001 reduced carotid wall thickness and enhanced ex vivo cholesterol efflux capacity, thus affecting atherosclerotic burden. Several clinical development programs are underway. Purpose: To report the clinical tolerability and safety findings observed with CER-001 across the clinical development programs performed to date. Methods: Adverse event (AE), serious AE (SAE) and other safety-related data were collated to evaluate the safety profile of CER-001 to determine whether any specific treatment-related AEs emerge as clinical experience with the product increases. Results: In the Phase I study, no treatment-related AEs were reported with single IV doses of CER-001 (0.25 to 45 mg/kg). There were no deaths, SAEs or AEs that led to withdrawal. There were no adverse findings associated with CER-001, relative to placebo, on vital signs, ECGs, clinical chemistry, haematology, immunogenicity and coagulation parameters. In multiple dose studies involving CER-001 (3 to 12 mg/kg), there have been no unusual or particularly concerning AEs reported to date. After six administrations, one each week, in post-ACS patients, no antibodies against ApoA-I were detected at 6 months. AE data from 530 subjects in Phase II studies, including type and incidence of AEs, SAEs and AEs causing withdrawal from study treatment, shows a safety profile comparable with placebo except for infusion reactions, which occurred more frequently with CER-001. Treatment-related infusion reactions occurred in 16 of 410 subjects (4%) treated with CER-001 in Phase II studies. These were reversible in all cases and either resolved spontaneously or after management with antihistamines, steroids and/or IV fluids. In studies evaluating liver enzymes (ALT, AST), no 3-times upper limit of normal elevations were seen during CER-001 therapy. Conclusions: To date, CER-001 appears to have a clinical safety profile similar to placebo in terms of type and incidence of AEs, SAEs and AEs causing withdrawal from study treatment. CER-001 was not associated with any adverse impact on hepatic safety. Not unusually, a slightly higher incidence of infusion reactions has been reported and clinical study sites should be aware of the possibility of infrequent infusion reactions and be prepared to provide supportive care if necessary. Safety support is continuing with CER-001 clinical development for short- and long-term treatment

Cell surface adenylate kinase activity regulates the F(1)-ATPase/P2Y (13)-mediated HDL endocytosis pathway on human hepatocytes.

International audienceWe have previously demonstrated on human hepatocytes that apolipoprotein A-I binding to an ecto-F(1)-ATPase stimulates the production of extracellular ADP that activates a P2Y(13)-mediated high-density lipoprotein (HDL) endocytosis pathway. Therefore, we investigated the mechanisms controlling the extracellular ATP/ADP level in hepatic cell lines and primary cultures to determine their impact on HDL endocytosis. Here we show that addition of ADP to the cell culture medium induced extracellular ATP production that was due to adenylate kinase [see text] and nucleoside diphosphokinase [see text] activities, but not to ATP synthase activity. We further observed that in vitro modulation of both ecto-NDPK and AK activities could regulate the ADP-dependent HDL endocytosis. But interestingly, only AK appeared to naturally participate in the pathway by consuming the ADP generated by the ecto-F(1)-ATPase. Thus controlling the extracellular ADP level is a potential target for reverse cholesterol transport regulation