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New clinical perspectives of hypolipidemic drug therapy in severe hypercholesterolemia
No full textPatients with homozygous familial hypercholesterolemia (HoFH) represent the most severe patients within the spectrum of dyslipidemias. Untreated LDL-Cholesterol (LDL-C) levels in these patients are usually in the range 500 to 1200 mg/dL. Moreover, these patients exhibit a scarce responsiveness or even nonresponsiveness to oral lipid lowering agents. Patients with heterozygous familial hypercholesterolemia (HetFH) tend to have untreated LDL-C levels of 250-500 mg/dL. Many of these patients are responsive to HMGCoA-reductase inhibitors (statins) and/or other specific drugs. Unfortunately, a significant subset of these patients (5-10%) have a severe and/or refractory form of HetFH and after current maximal oral therapy, they remain significantly far from treatment goals (NCEP ATPIII guidelines). This would be defined as LDL-C levels of ≥ 190 mg/dL (prior CAD or CAD equivalent) or ≥ 250 mg/dL (no prior CAD or CAD risk-equivalent). The only current therapy option for these patients is Low Density Lipoproteins-apheresis (LDL_a). While LDL_a is very effective in reducing LDL-C, many patients do not receive this extracorporeal therapy because of costs and limited availability of LDL_a centers. Recently, new potent lipid-lowering drugs have been developed and are currently under investigation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role controlling the levels of LDL-C. Studies have demonstrated that PCSK9 acts mainly by enhancing degradation of the LDL receptor (LDLR) protein in the liver. Inactivation of PCSK9 in mice reduces plasma cholesterol levels. Since the loss of a functional PCSK9 in human is not associated with apparent deleterious effects, this protease is becoming an attractive target for lowering plasma LDL-C levels either alone or in combination with statins. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL-C showed to be an effective therapy to reduce LDL-C concentrations in patients with HozFH who are already receiving lipid-lowering drugs, including high-dose statins. Lomitapide is a potent inhibitor of microsomal triglyceride transfer protein and is highly efficacious in reducing LDL-C and triglycerides. Lomitapide is currently being developed for patients with HozFH at doses up to 60 mg/d. These new powerful lipid-lowering drugs might be possibly superior than available hypolipidemic agents. Their mechanisms of action, effectiveness, safety, and indication in severe, genetically determined dyslipidemias, are reviewed
LDL aferesi: stato dell’arte
No full textNella rassegna si riportano elementi inerenti la Lipidoaferesi e la LDL aferesi (LA, LDL_a). Sono descrittein breve le tecniche, nella loro evoluzione nelle ultime tre decadi, del resto già ampiamente elucidatein letteratura. Le indicazioni consolidate, il trattamento e le nuove possibili indicazioni emergenti,sono illustrate più ampiamente. In particolare, si riportano le evidenze di letteratura sull’uso della LAe della LDL_a nella Ipercolesterolemia Familiare (IF), nella Restenosi, nella Glomerulosclerosi Focale,nell’Arteriosclerosi Obliterante, nella Sudden Hearing Loss, nella Maculopatia Degenerativa Senile,nella Sepsi, nel post Trapianto Cardiaco e nello Stroke. Si descrivono in sintesi il progetto ed i risultatidello Studio Multicentrico Italiano per la LDL_a, che ha condotto nel 2009 alla II Consensus ConferenceItaliana sulla LDL_a. Uno spazio più ampio è dedicato agli effetti delle tecniche di LA ed LDL_a sugliendpoints cardiovascolari e sulla progressione e regressione dell’arteriosclerosi. La LDL_a pediatricaviene illustrata nelle sue più recenti evidenze. Infine, si conferisce una trattazione ampia e dettagliatasugli effetti lipid-unrelated della LDL_a, cioè quelli cd. pleiotropici e pleiotropici-equivalenti, con particolareriguardo per gli effetti sulla protezione vascolare e sui peptidi mediatori dell’infiammazione.Su questi ultimi sono riportate le evidenze più recenti della letteratura. Infine, vengono brevementeesposti i farmaci ipolipemizzanti di più recente introduzione, con un particolare interesse verso future,promettenti nuove molecole ancora in fase di sperimentazione
H.E.L.P. LDL-apheresis clinical experience in Italy
No full textH.E.L.P. LDL-apheresis clinical experience in ItalyStefanutti Claudia, Shafii Mahnaz, Di Giacomo Serafina, Morozzi Claudia, Mazzilli Sara and the Italian Multicenter Study on Low-Density-Lipoprotein -Apheresis Working GroupExtracorporeal Therapeutic Techniques Unit - Immunohematology and Transfusion MedicineDepartment of Molecular Medicine - University of Rome ‘La Sapienza’, ‘Umberto I’ Hospital 155, V.le del Policlinico Rome I-00161 EU The clinical benefits of LDL-apheresis (LDL_a) have been demonstrated in numerous studies: the H.E.L.P. LDL-Apheresis Multicenter Study, the LDL-Apheresis Atherosclerosis Regression Study (LAARS), the German Multicenter LDL-Apheresis Trial, and the Familial Hypercholesterolemia (FH) Regression Study. The use, efficacy and safety of the heparin-induced extra-corporeal LDL-precipitation (H.E.L.P.®)- LDL –apheresis (H.E.L.P.-LDL_a) for the long-term management of patients with severe dyslipidemia has been studied in a single center (Rome, “La Sapienza” University) open retrospective survey. The data from 22 patients were evaluated accounting for 1437 H.E.L.P. LDL_a procedures. The PlasmatTM Futura System is the device for H.E.L.P.-LDL_a. used selectively to remove apolipoprotein B100-containing-lipoproteins in patients with severe dyslipidemia in our center. Regular H.E.L.P. LDL_a treatment was administered weekly or biweekly in Homozygous and Heterozygous FH patients. H.E.L.P. LDL_a treatment was beneficial and safe in patients with refractory hypercholesterolemia genetically determined, and coronary artery disease. The increasing use of H.E.L.P. LDL_a in Italy was recently reported also by the coordination (Rome) of the Italian Multicenter Study on LDL-apheresis Working Group (unpublished data). Among 101 patients submitted to LDL_a in 18 Italian centers, 41 have been treated with H.E.L.P. LDL_a
Timing clinical events in the treatment of pancreatitis and hypertriglyceridemia with therapeutic plasmapheresis
No full textBackground: Hyperlipidemic pancreatitis (HP) is caused by severe hypertriglyceridemia (SHTG). Evidence of SHTG refractoriness to standard medical treatment but not to therapeutic apheresis has increased in the last years. Methods: Described is the timing of clinical events and the sequence of therapeutic plasma-exchange (TPE) procedures to treat pancreatitis due to SHTG in a male patient, Caucasian, aged 49. years, referred to emergency for severe epigastric pain. There was no history of alcohol consumption, a pre-existing mild hyperlipidemia was treated with diet alone, and biliary imaging was normal. Physical examination revealed epigastric tenderness. Laboratory investigation revealed marked hypertriglyceridemia (11,355. mg/dL; range: 30-150), and hypercholesterolemia (941. mg/dL; range: 80-200). Serum amylase (Amy) and lipase (Lip) were increased: 160. UI/L (range: 20-100) and 175. UI/L (range: 13-60), respectively. A computerized tomography (CT) scan of the abdomen revealed a picture compatible with acute pancreatic phlogosis. It was diagnosed as " acute secondary pancreatitis (AP) and SHTG" Results: The patient was successfully submitted to three sessions of TPE in emergency. He was released from hospital after 13. days of hospitalization. The levels of lipids and lipoproteins in his plasma were as follows: triglycerides (TG) 185. mg/dL; total cholesterol (TC) 179. mg/dL; HDL-cholesterol (HDLC) 22. mg/dL; LDL-cholesterol (LDLC) 120. mg/dL. Conclusions: The decision to submit the patient with clinical evidence of HP caused by SHTG to apheresis was correct. The improvement in the clinical picture was fast and the recovery was complete. © 2011 Elsevier Ltd
Management of homozygous familial hypercholesterolemia in real-world clinical practice: A report of 7 Italian patients treated in Rome with lomitapide and lipoprotein apheresis
No full textHomozygous familial hypercholesterolemia (HoFH) is a rare, genetically determined condition of highly elevated low-density lipoprotein cholesterol (LDLC) levels. If untreated, patients do not typically survive beyond the second decade of life. Traditional lipid-lowering therapies (statins and ezetimibe) are largely ineffective in HoFH patients, and extracorporeal lipoprotein apheresis (LA) forms the mainstay of treatment. Lomitapide is a microsomal triglyceride transfer protein inhibitor approved for the treatment of HoFH as an adjunct to LA. We undertook to examine the efficacy and safety of lomitapide in 7 HoFH patients treated with LA in the Lipid Clinic and Therapeutic Apheresis Unit in Rome, Italy outside a clinical trial setting
A complicated pregnancy in homozygous familial hypercholesterolaemia treated with lipoprotein apheresis: A case report
No full textBACKGROUND AND AIMS: During pregnancy total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels increase significantly and lipoprotein apheresis (LA) is considered the most effective therapy in homozygous familial hypercholesterolaemia (HoFH) for modulating lipid and lipoprotein levels and reducing maternal and foetal complications. CLINICAL CASE: A primigravida 28 years old Caucasian female patient, previously diagnosed as to be HoFH, was admitted at our outpatient service at the beginning of pregnancy. METHODS: The patient was continuously submitted to LA every two weeks without foetal complication. During pregnancy two methods have been utilised: selective apheresis, and later plasma exchange. At 33 weeks gestational age the patient developed progressively hypertension, associated to LDL-C levels increase. Weekly LA was favoured. RESULTS: At 34 weeks +5 days patient suddenly experienced acute chest pain and abnormal electrocardiogram heart tracing and cardiac enzymes increase. An emergency caesarean section was performed without complications and the foetus was healthy. The patient was immediately transferred to Coronary Intensive Care Unit, where she was diagnosed non-ST elevation myocardial infarction (NSTEMI). Notwithstanding the patient improved in few days and was quickly discharged in fair clinical condition. CONCLUSIONS: LA is a safe and effective tool in HoFH subjects even in pregnancy. Evidence based guidelines for the management of these patients during pregnancy are still lacking.
Italian Multicenter Study on Low-Density Lipoprotein Apheresis Working Group 2009 Survey
No full textWe present results of the second survey of the Italian Multicenter Study on Low-Density Lipoprotein Apheresis (IMSLDLa-WG/2). The study involved 18 centers in 2009, treating 66 males and 35 females, mean age 47 +/- 18 years. Mean age for initiation of drug treatment before low-density lipoprotein apheresis (LDLa) was 31 +/- 18 years, mean age to the first LDLa was 37 +/- 20 years and average duration of treatment was 9 +/- 6 years. The techniques used included direct adsorption of lipids, dextran sulfate cellulose adsorption, heparin-mediated low-density lipoprotein (LDL) precipitation, cascade filtration, and plasma exchange. The mean treated plasma/blood volumes/session were 3127 +/- 518mL and 8666 +/- 1384mL, respectively. The average plasma volume substituted was 3500 +/- 300mL. Lipid therapy before LDLa included ezetimibe, statins, -3 fatty acids and fenofibrate. Baseline mean LDL cholesterol (LDLC) levels were 386 +/- 223mg/dL. The mean before/after apheresis LDLC level decreased by 67% from 250 +/- 108mg/dL (P=0.05 vs. baseline) to 83 +/- 37mg/dL (P=0.001 vs. before). Baseline mean Lipoprotein(a) [Lp(a)] level was 179 +/- 136mg/dL. Mean before/after apheresis Lp(a) level decreased by 71% from 133 +/- 120mg/dL (P=0.05 vs. baseline) to 39 +/- 44mg/dL (P=0.001 vs. before). Major and minor side effects occurred in 27 and 62 patients, respectively. Among patients with coronary artery disease (CAD), 62.3% had coronary angiography and 50.4% coronary revascularization before LDLa. Single vessel, double vessel and triple vessel CAD occurred in 19 (30.1%), 15 (23.8%) and 29 (46%) patients, respectively. Both CAD and extra-CAD occurred in 41.5%, 39% had hypertension, 9.9% were smokers, 9.9% consumed alcohol and 42% were physically active. Ischemic cardiovascular events were not observed in any patient over 9 +/- 6 years of treatment. Two centers have also treated 34 patients (females: 17/males 17; no. sessions: 36; average plasma volume treated: 3000mL) for sudden hearing loss (SHL). Relief of symptoms was obtained, independently of the system used (HELP; cascade-filtration)
The lipid- and lipoprotein- [LDL-Lp(a)] apheresis techniques. Updating.
Full text linkTherapeutic plasmapheresis allows the extracorporeal removal of plasmatic lipoproteins (Lipid-apheresis) (LA). It can be non selective (non specific), semi - selective or selective low density lipoprotein-lipoprotein(a) (specific [LDL- Lp(a)] apheresis) (Lipoprotein apheresis, LDLa). The LDL removal rate is a perfect parameter to assess the system efficiency. Plasma-Exchange (PEX) cannot be considered either specific nor, selective. In PEX the whole blood is separated into plasma and its corpuscular components usually through centrifugation or rather filtration. The corpuscular components mixed with albumin solution plus saline (NaCl 0.9%) solution at 20%-25%, are then reinfused to the patient, to substitute the plasma formerly removed. PEX eliminates atherogenic lipoproteins, but also other essential plasma proteins, such as albumin, immunoglobulins, and hemocoagulatory mediators. Cascade filtration (CF) is a method based on plasma separation and removal of plasma proteins through double filtration. During the CF two hollow-fiber filters with pores of different diameter are used to eliminate the plasma components of different weight and molecular diameter. A CF system uses a first polypropylene filter with 0.55 μm diameter pores and a second one of diacetate of cellulose with 0.02 μm pores. The first filter separates the whole blood, and the plasma is then perfused through a second filter which allows the recovery of molecules with a diameter lower than 0.02 μm, and the removal of molecules larger in diameter as apoB100-containing lipoproteins. Since both albumin and immunoglobulins are not removed, or to a negligible extent, plasma-expanders, substitution fluids, and in particular albumin, as occurs in PEX are not needed. CF however, is characterized by lower selectivity since removes also high density lipoprotein (HDL) particles which have an antiatherogenic activity. In the 80's, a variation of Lipid-apheresis has been developed which allows the LDL-cholesterol (LDLC) (-61%) and Lp(a) (-60%) removal from plasma through processing 3 liters of filtered plasma by means of lipid-specific thermofiltration, LDL immunoadsorption, heparin-induced LDL precipitation, LDL adsorption through dextran sulphate. More recently (90's) the DALI®, and the Liposorber D® hemoperfusion systems, effective for apoB100- containing lipoproteins removal have been developed. All the above mentioned systems are established LDL-apheresis techniques referable to the generic definition of LDLa. However, this last definition cannot describe in an appropriate manner the removal of another highly atherogenic lipoprotein particle: the Lp(a). Thus it would be better to refer the above mentioned techniques to the wider scientific and technical concept of lipoprotein apheresis
Combined treatment with Dif1stat and diet reduce plasma lipid indicators of moderate hypercholesterolemia more effectively than diet alone: a randomized trial in parallel groups.
No full textAn open-labeled randomized trial with parallel groups was carried out to study the effects of Dif1stat (Monascus purpureus-Linear aliphatic alcohols-Niacin) in the treatment of primary moderate hypercholesterolemia. The trial lasted 8 months. The patients, males and females, were assigned to two groups: A (#130), treated with diet, and B (#110) submitted to diet + Dif1stat. After 4 months, group A did not show significant changes in Total cholesterol (TC), LDL-cholesterol (LDLC), HDL-cholesterol (HDLC) or non-HDL-cholesterol (non-HDLC). The same group, showed a reduction in TC (-22%), LDLC (-30%) and non-HDLC (-27%) after 8 months (P < or = 0.001). After 4 months, TC (-21.3%), LDLC (-29%), and non-HDLC (-26%) were significantly lowered in group B (P < or = 0.001). In group B, TC, LDLC and non-HDLC showed a further reduction after 8 months: -29.4, -38 and -37%, respectively (P < or = 0.001). Even triglycerides (TG) decreased significantly (-33%) (P < or = 0.001). After 8 months, group B showed a significant reduction of TG (-33%) (P < or = 0.001), when compared to group A. Some safety parameters were significantly reduced in both groups: AST and gamma-GT in group A after 4 and 8 months, as well as ALT, AST and gamma-GT in group B after 8 months (P < or = 0.001). Dif1stat, given with a suitable diet, was well tolerated in the long-term and induced an anti-atherogenic plasma lipid and lipoprotein profile, in patients with moderate hypercholesterolemia
Cytokines profile in serum of homozygous familial hypercholesterolemia is changed by LDL-apheresis
No full textObjective: The effects of LDL-apheresis (LDLa) with dextran sulphate on plasma cytokines in 6 homozygous familial hypercholesterolemic (HozFH) patients, were evaluated. Methods: Plasma IL-1 alpha; IL-1ra; IL-4; IL-6; IL-10; IL-12(p40); IL-12(p70); TNF-alpha, sTNF-R, VEGF, VEGF-R1, E-Selectin (ESEL), and P-Selectin (PSEL) concentrations were measured before and after LDLa on three consecutive sessions for each patient. Results: TNIF-alpha was significantly reduced (-60%; P = 0.01), while TNF-R was only slightly increased (+15%), although not significantly. Plasma VEGF was significantly reduced (-57%; P = 1.87301E-05), while VEGF-R1 was significantly increased (+56%; P = 0.05). ESEL and PSEL were reduced but not to a statistically significant extent (-19%, -15%, respectively). IL-1 alpha level was dramatically reduced (-87%; P = 0.0001). IL-1ra concentration was only slightly increased in plasma, but not significantly. IL-4 and IL-10 levels were significantly reduced in plasma after apheresis (-50%; P = 0.03, and -55%; P = 0.004, respectively). On the contrary, IL-6 concentration showed a slight decrease (-8%). Plasma IL-12p40 was significantly increased (+47%; P = 0.0004). On the other hand, IL-12p70 was reduced, but the difference (-31%) was not statistically significant. Conclusions: Plasma cytokines imbalance is associated with inflammation and atherogenesis. In this study LDLa changed several circulating cytokines inducing anti-inflammatory and anti-atherogenic changes in cytokines plasma profile in HozFH patients with/without pre-existing angiographically demonstrated coronary heart disease (CHD) and aortic valvular disease (AVD). (C) 2011 Elsevier Ltd. All rights reserved
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