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chylomicronemia syndrome

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https://www.readbyqxmd.com/read/27855567/pradigastat-disposition-in-humans-in-vivo-and-in-vitro-investigations
#1
Alana Upthagrove, Jin Chen, Charles D Meyers, Kenneth Kulmatycki, Angela Bretz, Lai Wang, Lana Peng, Safet Palamar, Melissa Lin, Tapan Majumdar, Phi Tran, Heidi J Einolf
1. Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effective in lowering postprandial triglycerides in healthy human subjects and fasting triglycerides in familial chylomicronemia syndrome (FCS) patients. 2. Here we present the results of human oral absorption, metabolism and excretion (AME), intravenous pharmacokinetic (PK), and in vitro studies which together provide an overall understanding of the disposition of pradigastat in humans. 3. In human in vitro systems, pradigastat is metabolized slowly to a stable acyl glucuronide (M18...
November 18, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27771961/building-a-better-understanding-of-the-burden-of-disease-in-familial-chylomicronemia-syndrome
#2
Zahid Ahmad, Rob Halter, Michael Stevenson
No abstract text is available yet for this article.
October 24, 2016: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/27676196/new-oral-agents-for-treating-dyslipidemia
#3
Steven E Gryn, Robert A Hegele
PURPOSE OF REVIEW: We provide an overview of orally administered lipid-lowering therapies under development. RECENT FINDINGS: Recent data support statins for intermediate risk primary prevention, and ezetimibe for high-risk secondary prevention. Novel agents in development include bempedoic acid and gemcabene, and work continues on one remaining cholesteryl ester transfer protein inhibitor, anacetrapib, to determine whether this class can reduce cardiovascular risk...
September 26, 2016: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/27274009/effect-of-pradigastat-a-diacylglycerol-acyltransferase-1-inhibitor-on-the-qtcf-interval-in-humans
#4
Charles D Meyers, Adele Noe, Atish Salunke, Aishwarya Movva, Kenneth Kulmatycki, Srikanth Neelakantham, Anne Crissey, Tapan Majumdar, Jin Chen
Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chylomicronemia syndrome. To evaluate the effects of supratherapeutic concentrations of pradigastat on the QTc interval, 2 studies were conducted. The first study assessed the safety, tolerability, and pharmacokinetics of single escalating intravenous doses of pradigastat (10, 30, 100, and 115 mg over 60 minutes) in healthy adults. Single intravenous doses were safe, well tolerated, and at the higher doses resulted in supratherapeutic pradigastat exposure...
November 2016: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/27206931/editorial-commentary-dietary-management-of-familial-chylomicronemia-syndrome
#5
EDITORIAL
Lauren Williams, Don P Wilson
No abstract text is available yet for this article.
May 2016: Journal of Clinical Lipidology
https://www.readbyqxmd.com/read/27200950/long-term-costs-and-consequences-of-patients-with-familial-chylomicronemia-syndrome-a-simulation-model-approach
#6
F Lin, S Thomas, F Calado, J Clegg
No abstract text is available yet for this article.
November 2014: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
https://www.readbyqxmd.com/read/27153815/clinical-biochemical-and-molecular-analysis-of-two-infants-with-familial-chylomicronemia-syndrome
#7
Yonghong Zhang, Jing Zhou, Wenxin Zheng, Zhangzhang Lan, Zhiwei Huang, Qingnan Yang, Chengbo Liu, Rui Gao, Yongjun Zhang
Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disease due mainly to inherited deficiencies in the proteins or enzymes involved in the clearance of triglycerides from circulation. It usually happens in late childhood and adolescence, which can have serious consequences if misdiagnosed or untreated. In the present study, we investigated two Chinese male babies (A and B), 30d and 48d in age, respectively, who have milky plasma. Clinical, biochemical, and radiological assessments were performed, while samples from the patients were referred for molecular diagnosis, including genetic testing and subsequent analysis of related genes...
2016: Lipids in Health and Disease
https://www.readbyqxmd.com/read/26848137/reduction-in-lipoprotein-associated-apoc-iii-levels-following-volanesorsen-therapy-phase-2-randomized-trial-results
#8
Xiaohong Yang, Sang-Rok Lee, Yun-Seok Choi, Veronica J Alexander, Andres Digenio, Qingqing Yang, Yury I Miller, Joseph L Witztum, Sotirios Tsimikas
Elevated apoC-III levels predict increased cardiovascular risk when present on LDL and HDL particles. We developed novel high-throughput chemiluminescent ELISAs that capture apoB, lipoprotein (a) [Lp(a)], and apoA-I in plasma and then detect apoC-III on these individual lipoproteins as apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoAI complexes, respectively. We assessed the effects on these complexes of placebo or 100-300 mg volanesorsen, a generation 2.0+ antisense drug that targets apoC3 mRNA in patients with hypertriglyceridemia, including familial chylomicronemia syndrome (n = 3), volanesorsen monotherapy (n = 51), and as add-on to fibrate (n = 26), treated for 85 days and followed for 176 days...
April 2016: Journal of Lipid Research
https://www.readbyqxmd.com/read/26780002/novel-therapeutics-in-hypertriglyceridemia
#9
REVIEW
Steven E Gryn, Robert A Hegele
PURPOSE OF REVIEW: We provide an overview of recent advances in the therapy of hypertriglyceridemia, focusing on several new therapies with potential for treating of familial chylomicronemia, other forms of hypertriglyceridemia, and for triglyceride-lowering in patients with other lipid disorders. RECENT FINDINGS: Newer triglyceride-lowering modalities under evaluation include gene therapy for lipoprotein lipase deficiency (alipogene tiparvovec), and antisense oligonucleotides against mRNA for apolipoproteins B (mipomersen) and C3 (volanesorsen, ISIS 304801)...
December 2015: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/26536493/albumin-versus-solvent-detergent-treated-pooled-plasma-as-replacement-fluid-for-long-term-plasma-exchange-therapy-in-a-patient-with-primary-hypertriglyceridemia-and-recurrent-hyperlipidemic-pancreatitis
#10
Danilo Di Bona, Angelo B Cefalù, Elisabetta Scirè, Giacomo M Lima, Claudia Maria Rizzo, Antonina Giammanco, Carlo M Barbagallo, Maurizio R Averna, Sergio Rizzo, Calogero Caruso
BACKGROUND: Chylomicronemia syndrome is a metabolic condition characterized by severe fasting hypertrigliceridemia (≥ 1000 mg/dL) and other clinical features including chronic abdominal pain and recurrent acute pancreatitis. In patients with acute or recurrent pancreatitis, plasma exchange (PEx) is indicated for the treatment of acute disease and prevention of recurrence. The use of plasma instead of albumin as replacement fluid has been suggested for its putative ability to replace the deficient enzyme possibly leading to better clinical improvement...
March 2016: Transfusion
https://www.readbyqxmd.com/read/26337181/severe-hypertriglyceridemia-due-to-a-novel-p-q240h-mutation-in-the-lipoprotein-lipase-gene
#11
Angela Ganan Soto, Adam McIntyre, Sungeeta Agrawal, Shara R Bialo, Robert A Hegele, Charlotte M Boney
BACKGROUND: Lipoprotein Lipase (LPL) deficiency is a rare autosomal recessive disorder with a heterogeneous clinical presentation. Several mutations in the LPL gene have been identified to cause decreased activity of the enzyme. FINDINGS: An 11-week-old, exclusively breastfed male presented with coffee-ground emesis, melena, xanthomas, lipemia retinalis and chylomicronemia. Genomic DNA analysis identified lipoprotein lipase deficiency due to compound heterozygosity including a novel p...
2015: Lipids in Health and Disease
https://www.readbyqxmd.com/read/25963481/evaluation-of-food-effect-on-the-oral-bioavailability-of-pradigastat-a-diacylglycerol-acyltransferase-1-inhibitor
#12
RANDOMIZED CONTROLLED TRIAL
Surya P Ayalasomayajula, Charles D Meyers, Jing Yu, Mark Kagan, Ralph Matott, Parasar Pal, Tapan Majumdar, Zhenzhong Su, Anne Crissey, Sam Rebello, Gangadhar Sunkara, Jin Chen
Pradigastat, a diacylglycerol acyltransferase 1 inhibitor, is being developed for the treatment of familial chylomicronemia syndrome. The results of two studies that evaluated the effect of food on the oral bioavailability of pradigastat using randomized, open-label, parallel group designs in healthy subjects (n=24/treatment/study) are presented. In study 1, a single dose of 20 mg pradigastat was administered under the fasted condition or with a high-fat meal. In study 2, a single dose of 40 mg pradigastat was administered under the fasted condition or with a low- or high-fat meal...
October 2015: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/25936326/practical-recommendations-for-the-management-of-hyperlipidemia
#13
REVIEW
S Fischer, U Schatz, U Julius
Hyperlipidemia is a risk factor for atherosclerosis. Raised low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) levels are severe risk factors for atherosclerosis. The role of high-density lipoprotein cholesterol (HDL-C) is controversial. Total cholesterol, LDL-C, HDL-C, triglycerides and lipoprotein(a) levels should be determined in a fasting state. The basis of treating hyperlipidemia remains diet, physical exercise and weight reduction. Olive oil and nuts have been shown to be beneficial. Statins remain first line drug treatment...
May 2015: Atherosclerosis. Supplements
https://www.readbyqxmd.com/read/25889044/effect-of-the-dgat1-inhibitor-pradigastat-on-triglyceride-and-apob48-levels-in-patients-with-familial-chylomicronemia-syndrome
#14
Charles Daniel Meyers, Karine Tremblay, Ahmed Amer, Jin Chen, Liewen Jiang, Daniel Gaudet
BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare lipid disease caused by complete lipoprotein lipase (LPL) deficiency resulting in fasting chylomicronemia and severe hypertriglyceridemia. Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which mediates chylomicron triglyceride (TG) synthesis, is an attractive strategy to reduce TG levels in FCS. In this study we assessed the safety, tolerability and TG-lowering efficacy of the DGAT1 inhibitor pradigastat in patients with FCS...
2015: Lipids in Health and Disease
https://www.readbyqxmd.com/read/25686595/indications-for-apheresis-as-an-ultima-ratio-treatment-of-refractory-hyperlipidemias
#15
P Grützmacher, C Kleinert, C Dorbath, B Öhm
Lipid apheresis is at present well established in routine treatment of diverse hyperlipoproteinemias refractory to conventional dietary and medical regimens, especially in countries with high medical and socioeconomic standards. Severe familial hypercholesterolemia with atherosclerotic vessel disease involving the coronary arteries is the most frequent indication for lipid apheresis as well as homozygous familial hypercholesterolemia before the development of cardiovascular complications.In hyperlipoproteinemia (a) with progressive vessel disease, lipid apheresis is regularly accepted in Germany...
April 2015: Clinical Research in Cardiology Supplements
https://www.readbyqxmd.com/read/25633714/effect-of-hepatic-impairment-on-the-pharmacokinetics-of-pradigastat-a-diacylglycerol-acyltransferase-1-dgat1-inhibitor
#16
Masaru Hirano, Dan Meyers, GangaRaju Golla, Parasar Pal, Pascale Pinot, TsuHan Lin, Tapan Majumdar, Sam Rebello, Gangadhar Sunkara, Jin Chen
BACKGROUND AND OBJECTIVE: Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, is under development to treat familial chylomicronemia syndrome. The potential impact of hepatic impairment on the pharmacokinetics of pradigastat was evaluated in this study. METHODS: In this study, a single oral dose of 20 mg pradigastat was administered first to patients with mild and moderate hepatic impairment (n = 10/group) and subsequently to patients with severe hepatic impairment (n = 6)...
July 2015: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/25627776/effect-of-renal-impairment-on-the-pharmacokinetics-of-pradigastat-a-novel-diacylglycerol-acyltransferase1-dgat1-inhibitor
#17
Sachiko Mita, Dan Meyers, Parasar Pal, TsuHan Lin, Tapan Majumdar, Sam Rebello, Gangadhar Sunkara, Jin Chen
BACKGROUND AND OBJECTIVE: Pradigastat, a diacylglycerol acyltransferase1 inhibitor, is being developed for the treatment of familial chylomicronemia syndrome. The primary objective of this clinical study was to evaluate the effect of renal impairment on the pharmacokinetics of pradigastat. METHODS: In an open-label, parallel-group study, the single-dose (40 mg) pharmacokinetics of pradigastat were evaluated in patients with mild (n = 9), moderate (n = 10) and severe renal impairment (n = 9) compared with matched healthy subjects (n = 28)...
July 2015: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/25506434/hypertriglyceridemia-induced-pancreatitis-chylomicronemia-syndrome-treated-with-supportive-care
#18
Emin Uysal, Yahya Ayhan Acar, Emel Gökmen, Ahmet Kutur, Hatice Doğan
Hypertriglyceridemia is a rare cause of pancreatitis. In treatment pancreatic rest, lifestyle changes, medications (fibrates, n-3 polyunsaturated fatty acids, and nicotinic acid) are essential. Many experimental treatment modalities have been reported as insulin and heparin infusion and plasmapheresis. In this study we present the hypertriglyceridemia-induced pancreatitis treated with supportive care.
2014: Case Reports in Critical Care
https://www.readbyqxmd.com/read/25499947/familial-chylomicronemia-syndrome-and-response-to-medium-chain-triglyceride-therapy-in-an-infant-with-novel-mutations-in-gpihbp1
#19
Zahid Ahmad, Don P Wilson
BACKGROUND: Severe hypertriglyceridemia predisposes to attacks of acute pancreatitis, a serious condition complicated by multiorgan failure, pancreatic necrosis, and mortality rates up to 20% in adults and 6.5% in children. OVERVIEW: We describe an infant who suffered from an episode of acute pancreatitis from severe hypertriglyceridemia. Two major challenges complicate the case: identifying the etiology of severe hypertriglyceridemia and finding an efficacious treatment...
November 2014: Journal of Clinical Lipidology
https://www.readbyqxmd.com/read/25470695/targeting-apoc3-in-the-familial-chylomicronemia-syndrome
#20
Daniel Gaudet, Diane Brisson, Karine Tremblay, Veronica J Alexander, Walter Singleton, Steven G Hughes, Richard S Geary, Brenda F Baker, Mark J Graham, Rosanne M Crooke, Joseph L Witztum
The familial chylomicronemia syndrome is a genetic disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis due to a deficiency in lipoprotein lipase (LPL). Currently, there are no effective therapies except for extreme restriction in the consumption of dietary fat. Apolipoprotein C-III (APOC3) is known to inhibit LPL, although there is also evidence that APOC3 increases the level of plasma triglycerides through an LPL-independent mechanism. We administered an inhibitor of APOC3 messenger RNA (mRNA), called ISIS 304801, to treat three patients with the familial chylomicronemia syndrome and triglyceride levels ranging from 1406 to 2083 mg per deciliter (15...
December 4, 2014: New England Journal of Medicine
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