1,721,027 research outputs found
Lomitapide-a microsomal triglyceride transfer protein inhibitor for homozygous familial hypercholesterolemia
Full text linkPurpose of Review: Homozygous familial hypercholesterolemia (HoFH) is a rare, genetic condition characterized by high levels of Low density lipoprotein cholesterol (LDL-C); overt, early-onset atherosclerotic cardiovascular disease (ASCVD); and premature cardiovascular events and mortality. Lomitapide is a first-in-class microsomal triglyceride transfer protein inhibitor for the treatment of HoFH. This review provides an update on data emerging from real-world studies of lomitapide following on from its pivotal phase 3 clinical trial in HoFH. Recent Findings: Recent registry data have confirmed that HoFH is characterized by delayed diagnosis, with many patients not receiving effective therapy until they are approaching the age when major adverse cardiovascular events may occur. Data from case series of varying sizes, and from a 163-patient registry of HoFH patients receiving lomitapide, have demonstrated that lomitapide doses are lower and adverse events less severe than in the phase 3 study. Lomitapide enables many patients to reach European Atherosclerosis Society LDL-C targets. Some patients are able to reduce frequency of lipoprotein apheresis or, in some cases, stop the procedure altogether—unless there is significant elevation of lipoprotein (a). Modelling analyses based on historical and clinical trial data indicate that lomitapide has the potential to improve cardiovascular outcomes and survival in HoFH. Summary: Real-world clinical experience with lomitapide has shown the drug to be effective with manageable, less marked adverse events than in formal clinical studies. Event modelling data suggest a survival benefit with lomitapide in HoFH
Lipoprotein apheresis in the management of familial hypercholesterolaemia: historical perspective and recent advances.
No full textAt present, lipoprotein apheresis, combined with high-dose statin and ezetimibe therapy, is the best available means of treating patients with homozygous and statin-refractory heterozygous familial hypercholesterolaemia (FH). However, the extent of cholesterol-lowering achieved is often insufficient to meet the targets set by current guidelines. The recent advent of three new classes of lipid-lowering agents provides new hope that the latter objective may now be achievable. These compounds act either by reducing low-density lipoprotein (LDL) production by inhibiting apolipoprotein B synthesis with an antisense oligonucleotide (mipomersen) or by inhibiting microsomal triglyceride transfer protein (lomitapide), or by enhancing LDL catabolism via monoclonal antibody-mediated inhibition of the activity of proprotein convertase subtilisin/kexin 9 (PCSK9) (evolocumab). Depending on the outcome of current trials, it seems likely that these compounds, used alone or combined with lipoprotein apheresis, will markedly improve the management of refractory FH
Italian Multicenter Study on Low-Density LipoproteinApheresis: Retrospective Analysis (2007)
No full textA retrospective study--the Italian Multicenter Study on Low-density Lipoprotein Apheresis (IMS-LDLa)--was carried out, which involved 19 centers for LDLa in Italy, distributed all over the country--in the north, center, south, and the major islands. The survey was conducted through two consecutive questionnaires, which can be downloaded online from a dedicated site. The total number of procedures performed until 2007 was 31 012, and the number of patients undergoing treatment until 2007 were 229. The treated patients still surviving consisted of 136 (74 males and 62 females); those surviving but not treated numbered 95, and those deceased numbered 14. The techniques utilized, listed by frequency of use, were the following: dextran sulfate cellulose adsorption, direct adsorption of lipids (DALI), heparin extracorporeal LDL precipitation, immunoadsorption, plasma-exchange, cascade filtration, and Lipocollect 200. The mean treated plasma and blood volumes per session were 3916.5 mL and 8735.1 mL, respectively. The most frequently utilized vascular access points were: venous 84.4% and arteriovenous fistula 15.5%. Hematoma by venipuncture (230 episodes), low outlet flow (125 episodes), and circuit coagulation (44 episodes) were reported as to be the most frequent side effects. In the second questionnaire (filled in by 19 centers) the centers were asked to report their data on: quality diagnosis of dyslipidemia and referents for genetic-molecular and clinical diagnosis, cholesterol-lowering drugs and dosages, typology of cardiovascular check-ups at the beginning of treatment and in follow-up, non-cholesterol-lowering drugs with priority for cardiologic drugs, including oral anti-coagulants, and, lastly, information related to the appropriateness of curing patients still under treatment with LDLa and, where possible, news on patients no longer under treatment
Effects of selective H.E.L.P. LDL-apheresis on plasma inflammatory markers concentration in severe dyslipidemia: Implication for anti-inflammatory response.
No full textTherapeutic plasmapheresis is a recognized medical procedure in which various techniques are used to separate and remove undesirable or excessively elevated plasma elements from blood. The main purpose of the procedure is to remove the substances responsible for the disease (autoantibodies, circulating immune complexes, lipoproteins and other molecules) from the patient’s blood. Low-Density-Lipoproteins- apheresis (LDL_a) is the selective removal of all apolipoprotein-B100-containing lipoproteins: LDL, very low-density lipoprotein, and lipoprotein (a). They are lowered acutely by 65–75%. There is little effect on other plasma lipidic and non-lipidic components. LDL_a was reported to increase resistance of LDL to oxidation, counteract procoagulatory state and relief disturbances of hemorheology associated with atherosclerosis. These effects are likely to be regarded as to be pleiotropic effects. In the sense that they are not necessarily related to the apolipoprotein-B100-containing lipoproteins level in plasma. There is robust evidence that LDL_a can induce the stabilization of atherosclerotic plaques through its lipidlowering action. However, other effects unrelated to the apolipoprotein-B100-containing lipoproteins extracorporeal removal, such as the decrease of cytokines and adhesion molecules induced by LDL_a were also reported. Altogether these actions are thought to favorably influence regression of florid, nonfibrous atherosclerotic lesions through a blockade of lipid deposition in the vessel wall, plaque stabilization, and ultimately, coronary and extracoronary artery disease progression. This brief review provides some indication on existing evidence of Heparin-induced Extracorporeal Low-density-lipoprotein Precipitation LDL_a effects on plasma mediators of inflammation
Lipoprotein apheresis and pcsk9-inhibitors. Impact on atherogenic lipoproteins and anti-inflammatory mediators in familial hypercholesterolaemia
No full textBackground: A combination therapy with PCSK9-inhibitors (PCSK9-I) and lipoprotein-apheresis (LA) may have synergistic effects on circulating lipid and lipoprotein levels, in particular in Homozygous Familial Hypercholesterolaemic (HoFH) subjects. The relationships between the above mentioned novel therapeutic approaches as highly effective treatment option for Dyslipidemia in Heterozygous Familial Hypercholesterolaemic (HeFH) patients deserve further investigation in larger datasets. Objective: This review aims to present the role of lipoprotein apheresis in the management of familial hypercholesterolaemia and discuss the potential advantages and disadvantages of its combination with PCSK9 inhibitors. Methods: A comprehensive literature search regarding lipoprotein apheresis in patients with familial hypercholesterolaemia and its combination with PCSK9 inhibitors has been performed. Results: LA is also a potent therapeutic player having impact on inflammation and related mediators. A large body of evidence on this is available. On the contrary, only few observations are available on PCSK9-I effects on inflammation. Conclusions: It is quite clear that further investigation on possible direct and/or indirect pleiotropic effects of PCSK9-I on inflammatory molecules is necessary and to be expected. Evidence on both arguments with regard to HoFH and HeFH, are reported in short
Effect of selective H.E.L.P. LDL-apheresis on plasma inflammatory markers concentration in severe dyslipidemia: implication for anti-inflammatory response.
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Looking at Lp(a) and Related Cardiovascular Risk: from Scientific Evidence and Clinical Practice
No full textPurpose of Review: A considerable body of data from genetic and epidemiological studies strongly support a causal relationship between high lipoprotein(a) [Lp(a)] levels, and the development of atherosclerosis and cardiovascular disease. This relationship is continuous, unrelated to Lp(a) threshold, and independent of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels. Unfortunately, the mechanism(s) through which Lp(a) promotes atherosclerosis are not clarified yet. Suggested hypotheses include: an increased Lp(a)-associated cholesterol entrapment in the arterial intima followed by inflammatory cell recruitment, abnormal upload of proinflammatory oxidized phospholipids, impaired fibrinolysis by inhibition of plasminogen activation, and enhanced coagulation, through inhibition of the tissue factor pathway inhibitor. This review is aimed at summarizing the available evidence on the topic. Recent Findings: There are two clinical forms, isolated hyperlipidemia(a) [HyperLp(a)] with acceptable LDL-C levels (< 70 mg/dL), and combined elevation of Lp(a) and LDL-C in plasma. To date, no drugs that selectively decrease Lp(a) are available. Some novel lipid-lowering drugs can lower Lp(a) levels, but to a limited extent, as their main effect is aimed at decreasing LDL-C levels. Significant Lp(a) lowering effects were obtained with nicotinic acid at high doses. However, adverse effects apart, nicotinic acid is no longer prescribed and available in Europe for clinical use, after European Agency of Medicines (EMA) ban. Summary: The only effective therapeutic option for now is Lipoprotein Apheresis (LA), albeit with some limitations. Lastly, it is to be acknowledged that the body of evidence confirming that reducing plasma isolated elevation of Lp(a) brings cardiovascular benefit is still insufficient. However, the growing bulk of clinical, genetic, mechanistic, and epidemiological available evidence strongly suggests that Lp(a) is likely to be the smoking gun
Homozygous familial hypercholesterolaemia in childhood – The first case report in Southeast Europe
No full textHomozygous familial hypercholesterolaemia (HoFH) is the rare, severe, but treatable disease characterised by exceedingly high levels of low-density lipoprotein cholesterol (LDL-C) and subsequent premature coronary heart disease. Of note, HoFH detection rate and patient access to healthcare and treatment modalities still differ considerably across EU countries. To our current knowledge, there are still no published reports describing HoFH in the paediatric population of Southeastern Europe. In this case report, a few important topics on obstacles in getting adequate health care service and management of HoFH children from Southeastern Europe are tackled
VARIABLES INVOLVED IN THE TREATMENT OF SEVERE HYPERLIPOPROTEINEMIAS BY COMBINED DRUG AND LDL-APHERESIS TREATMENT
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