scholarly journals N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels

2019 ◽  
Vol 40 (33) ◽  
pp. 2785-2796 ◽  
Author(s):  
Veronica J Alexander ◽  
Shuting Xia ◽  
Eunju Hurh ◽  
Steven G Hughes ◽  
Louis O’Dea ◽  
...  
Keyword(s):  
Single Dose ◽  
Multiple Dose ◽  
Phase 1 ◽  
Low Density Lipoprotein ◽  
Injection Site Reaction ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Tolerability Profile ◽  
Double Blind ◽  
Favourable Safety

Abstract Aims Elevated apolipoprotein C-III (apoC-III) levels are associated with hypertriglyceridaemia and coronary heart disease. AKCEA-APOCIII-LRx is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits apoC-III protein synthesis. Methods and results The safety, tolerability, and efficacy of AKCEA-APOCIII-LRx was assessed in a double-blind, placebo-controlled, dose-escalation Phase 1/2a study in healthy volunteers (ages 18–65) with triglyceride levels ≥90 or ≥200 mg/dL. Single-dose cohorts were treated with 10, 30, 60, 90, and 120 mg subcutaneously (sc) and multiple-dose cohorts were treated with 15 and 30 mg weekly sc for 6 weeks or 60 mg every 4 weeks sc for 3 months. In the single-dose cohorts treated with 10, 30, 60, 90, or 120 mg of AKCEA-APOCIII-LRx, median reductions of 0, −42%, −73%, −81%, and −92% in apoC-III, and −12%, −7%, −42%, −73%, and −77% in triglycerides were observed 14 days after dosing. In multiple-dose cohorts of 15 and 30 mg weekly and 60 mg every 4 weeks, median reductions of −66%, −84%, and −89% in apoC-III, and −59%, −73%, and −66% in triglycerides were observed 1 week after the last dose. Significant reductions in total cholesterol, apolipoprotein B, non-high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol, and increases in HDL-C were also observed. AKCEA-APOCIII-LRx was well tolerated with one injection site reaction of mild erythema, and no flu-like reactions, platelet count reductions, liver, or renal safety signals. Conclusion Treatment of hypertriglyceridaemic subjects with AKCEA-APOCIII-LRx results in a broad improvement in the atherogenic lipid profile with a favourable safety and tolerability profile. ClinicalTrials.gov Identifier: NCT02900027.

scholarly journals Alirocumab therapy in individuals with type 2 diabetes mellitus and atherosclerotic cardiovascular disease: analysis of the ODYSSEY DM-DYSLIPIDEMIA and DM-INSULIN studies

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Kausik K. Ray ◽  
Stefano Del Prato ◽  
Dirk Müller-Wieland ◽  
Bertrand Cariou ◽  
Helen M. Colhoun ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Atherosclerotic Cardiovascular Disease ◽  
Open Label ◽  
Double Blind ◽  
Mixed Dyslipidemia

Abstract Background Individuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778). Methods In DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C ≥ 100 mg/dL; n = 413) were randomized to open-label alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C ≥ 70 mg/dL; n = 441) were randomized in a double-blind fashion to alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin < 9% (DM-DYSLIPIDEMIA) or < 10% (DM-INSULIN). Alirocumab dose was increased to 150 mg Q2W at week 12 if week 8 LDL-C was ≥ 70 mg/dL (DM-INSULIN) or non-HDL-C was ≥ 100 mg/dL (DM-DYSLIPIDEMIA). Lipid reductions and safety were assessed in patients with ASCVD from these studies. Results This analysis included 142 DM-DYSLIPIDEMIA and 177 DM-INSULIN participants with ASCVD, including 95.1% and 86.4% with coronary heart disease, and 32.4% and 49.7% with microvascular diabetes complications, respectively. At week 24, alirocumab significantly reduced LDL-C, non-HDL-C, ApoB, and LDL-PN from baseline versus control. This translated into a greater proportion of individuals achieving non-HDL-C < 100 mg/dL (64.6% alirocumab/23.8% UC [DM-DYSLIPIDEMIA]; 65.4% alirocumab/14.9% placebo [DM-INSULIN]) and ApoB < 80 mg/dL (75.1% alirocumab/35.4% UC and 76.8% alirocumab/24.8% placebo, respectively) versus control at week 24 (all P < 0.0001). In pooling these studies, 66.4% (alirocumab) and 67.0% (control) of individuals reported treatment-emergent adverse events. The adverse event pattern was similar with alirocumab versus controls. Conclusions Among individuals with T2DM and ASCVD who had high non-HDL-C/LDL-C levels despite maximally tolerated statin, alirocumab significantly reduced atherogenic cholesterol and LDL-PN versus control. Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov. NCT02642159. Registered 30 December 2015 and Clinicaltrials.gov. NCT02585778. Registered 23 October 2015

scholarly journals Daily Oral Administration of the Novel Androgen 11β-MNTDC Markedly Suppresses Serum Gonadotropins in Healthy Men

2020 ◽  
Vol 105 (3) ◽  
pp. e835-e847 ◽  
Author(s):  
Fiona Yuen ◽  
Arthi Thirumalai ◽  
Cindy Pham ◽  
Ronald S Swerdloff ◽  
Bradley D Anawalt ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Double Blind Study ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Healthy Men ◽  
Drug Concentrations ◽  
Serum Gonadotropin

Abstract Background 11β-methyl-19-nortestosterone (11β-MNT) is a modified testosterone (T) with androgenic and progestational activity. A single oral dose of the prodrug, 11β-MNT dodecylcarbonate (11β-MNTDC), was well tolerated in healthy men. Methods We conducted a randomized, double-blind study at 2 academic medical centers. 42 healthy men (18–50 years) were randomized to receive oral placebo or 11β-MNTDC, 200 or 400 mg daily, for 28 consecutive days. Primary outcome (safety and tolerability) measures were assessed twice per week. Subjects underwent serial blood sampling over 24 hours on days 1 and 28 to assess secondary outcomes: pharmacokinetics (serum drug concentrations); pharmacodynamics of 11β-MNTDC (serum sex steroids and gonadotropins); and mood and sexual function (via validated questionnaires). Results There were no serious adverse events. No participants discontinued because of an adverse event or laboratory test abnormality. 11β-MNTDC resulted in a dose-related increase in serum 11β-MNTDC and 11β-MNT concentrations sustained over 24 hours. Administration of 11β-MNTDC resulted in a marked suppression of serum gonadotropins, T, calculated free T, estradiol, and SHBG over the treatment period (P &lt; 0.01). Adverse effects that may be related to 11β-MNTDC included weight gain, acne, headaches, fatigue, and mild mood changes, with 5 men reporting decreased libido and 3 decreased erectile/ejaculatory function. Serum low-density lipoprotein cholesterol, weight (~2 kg), hematocrit, and hemoglobin increased and serum high-density lipoprotein cholesterol decreased in both 11β-MNTDC groups. Conclusion Daily oral 11β-MNTDC for 28 days in healthy men markedly suppressed serum gonadotropin and T concentrations without serious adverse effects. These results warrant further evaluation of 11β-MNTDC as a potential male oral contraceptive.

scholarly journals Efficacy and safety of Monascus purpureus Went rice in subjects with hyperlipidemia

2005 ◽  
Vol 153 (5) ◽  
pp. 679-686 ◽  
Author(s):  
Cheng-Chieh Lin ◽  
Tsai-Chung Li ◽  
Ming-May Lai
Keyword(s):  
Total Cholesterol ◽  
Apolipoprotein B ◽  
Clinical Laboratory ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Monascus Purpureus ◽  
Lipid Lowering ◽  
Controlled Study ◽  
Double Blind

Objective: The purpose of this study was to assess the lipid-lowering effect of Monascus purpureus Went rice on serum lipids in patients with hyperlipidemia, and to assess its safety by reporting adverse events and clinical laboratory measurements. Design and methods: This was a randomized, double-blind, placebo-controlled study. In all, 79 patients (aged 23–65 years) with a mean baseline low-density lipoprotein cholesterol (LDL-C) level of 5.28 mmol/l (203.9 mg/dl) received a twice daily dose of placebo or Monascus purpureus Went rice (600 mg) for 8 weeks. Results: At week 8, Monascus purpureus Went rice therapy reduced LDL-C by 27.7%, total cholesterol by 21.5%, triglycerides by 15.8% and apolipoprotein B by 26.0%. High-density lipoprotein cholesterol and apolipoprotein A-I levels were increased by 0.9 and 3.4% respectively (not significant). No patient in the Monascus purpureus Went rice treatment group had an alanine aminotransferase (ALT), aspartate aminotransferase (AST) or creatine phosphokinase (CPK) measurement that was ≥ 3 times the upper limit of normal at week 4 and week 8. Conclusion: Monascus purpureus Went rice significantly reduced LDL-C, total cholesterol, triglycerides and apolipoprotein B levels, and was well tolerated in patients with hyperlipidemia. However, this study only provides data from an 8-week trial and long-term safety and efficacy data are needed.

scholarly journals Metabolic and Clinical responses to Bunium Persicum (Black Caraway) supplementation in overweight and obese patients with type 2 diabetes: a double-blind randomized placebo-controlled clinical trial

2020 ◽  
Author(s):  
Saber Jafari-Maskouni ◽  
Mansour Shahraki ◽  
Milad Daneshi-Maskooni ◽  
Alireza Dashipour ◽  
Ali Shamsi-Goushki ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Serum Glucose ◽  
Lipoprotein Cholesterol ◽  
Controlled Clinical Trial ◽  
Model Assessment ◽  
Eligibility Criteria ◽  
Double Blind ◽  
Bunium Persicum ◽  
Clinical Responses

Abstract Background: Diabetes mellitus is the most common metabolic disorder worldwide. We aimed to determine the effects of Bunium Persicum (BP) on serum glucose indices, lipid profile, and nesfatin-1 levels in overweight or obese T2DM patients.Methods: Participant recruitment took place in the diabetic clinic of Bu-Ali hospital in Zahedan. Based on the eligibility criteria, 60 participants were randomly divided into two groups, namely BP (n=30) and placebo (n=30). The supplementation was one 1000 mg capsule 2 times /day BP with meals (lunch and dinner) for 8 weeks. Bodyweight, waist circumference, serum nesfatin-1, fasting blood sugar (FBS) and insulin (FBI), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured. Quantitative insulin sensitivity checks index (QUICKI), homeostasis model assessment-insulin resistance (HOMA-IR), and Body Mass Index (BMI) were also calculated.Results: In comparison with placebo, BP significantly decreased FBS, HOMA-IR, and BMI (P<0.05). The differences in the FBI, QUICKI, TG, TC, LDL, HDL, WC, and Nesfatin-1 were not significant (P>0.05).Conclusion: BP supplement improved serum glucose indices and decreased BMI among overweight or obese T2DM patients; though, further trials are suggested to confirm results.Trial Registration: Iranian Registry of Clinical Trials (IRCT), IRCT20181207041876N1, Registered 18/01/2019, https://irct.ir/trial/35752

Efficacy and Safety of Cerivastatin 0.8 mg in Patients with Hypercholesterolaemia: The Pivotal Placebo-Controlled Clinical Trial

2000 ◽  
Vol 28 (2) ◽  
pp. 47-68 ◽  
Author(s):  
W Insull ◽  
J Isaacsohn ◽  
P Kwiterovich ◽  
P Ma ◽  
R Brazg ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Heart Association ◽  
Pharmacological Therapy ◽  
Apolipoprotein A1 ◽  
Lipoprotein Cholesterol ◽  
Controlled Clinical Trial ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Primary Hypercholesterolaemia

This pivotal, multicentre, double-blind, parallel-group study evaluated the efficacy and safety of cerivastatin 0.8 mg. Patients with primary hypercholesterolaemia were randomized, after 10 weeks' dietary stabilization on an American Heart Association (AHA) Step I diet, to treatment with cerivastatin 0.8 mg ( n = 776), cerivastatin 0.4 mg ( n = 195) or placebo ( n = 199) once daily for 8 weeks. Cerivastatin 0.8 mg reduced mean low density lipoprotein-cholesterol (LDL-C) by 41.8% compared with cerivastatin 0.4 mg (–35.6%, P < 0.0001) or placebo. In 90% of patients receiving cerivastatin 0.8 mg LDL-C was reduced by 23.9–58.4% (6th–95th percentile). Overall attainment of the National Cholesterol Education Program (NCEP) goal was achieved by 84% of patients receiving cerivastatin 0.8 mg and by 59% of those with coronary heart disease (CHD). In the sub-population meeting the NCEP criteria for pharmacological therapy for LDL-C reduction, 74.6% of patients, including the 59% with CHD, reached the goal with cerivastatin 0.8 mg. Cerivastatin 0.8 mg also reduced mean total cholesterol by 29.9%, apolipoprotein B by 33.2% and median triglycerides by 22.9% (all P < 0.0001). Mean high density lipoprotein-cholesterol (HDL-C) and apolipoprotein A1 were elevated 8.7% ( P < 0.0001) and 4.5% ( P < 0.0001), respectively, by cerivastatin 0.8 mg. Reductions of triglyceride and elevation in HDL-C were dependent upon triglyceride baseline levels; in patients having baseline triglyceride levels 250–400 mg/dl, cerivastatin 0.8 mg reduced median triglycerides by 29.5% and elevated HDL-C by 13.2%. Cerivastatin 0.8 mg was well tolerated. The most commonly reported adverse events included headache, pharyngitis and rhinitis (4–6%). Symptomatic creatine kinase elevations > 10 times upper limit of normal occurred in 0%, 1% and 0.9% of patients receiving placebo, cerivastatin 0.4 mg or cerivastatin 0.8 mg, respectively. Cerivastatin 0.8 mg is an effective and safe treatment for patients with primary hypercholesterolaemia who need aggressive LDL-C lowering in order to achieve NCEP-recommended levels.

scholarly journals Metabolic and Clinical responses to Bunium Persicum (Black Caraway) supplementation in overweight and obese patients with type 2 diabetes: a double-blind randomized placebo-controlled clinical trial

2020 ◽  
Author(s):  
Saber Jafari-Maskouni ◽  
Mansour Shahraki ◽  
Milad Daneshi-Maskooni ◽  
Alireza Dashipour ◽  
Ali Shamsi-Goushki ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Serum Glucose ◽  
Lipoprotein Cholesterol ◽  
Controlled Clinical Trial ◽  
Model Assessment ◽  
Eligibility Criteria ◽  
Double Blind ◽  
Bunium Persicum ◽  
Clinical Responses

Abstract Background : Diabetes mellitus is the most common metabolic disorder worldwide. We aimed to determine the effects of Bunium Persicum (BP) on serum glucose indices, lipid profile, and nesfatin-1 levels in overweight or obese T2DM patients. Methods : Participant recruitment took place in the diabetic clinic of Bu-Ali hospital in Zahedan. Based on the eligibility criteria, 60 participants were randomly divided into two groups, namely BP (n=30) and placebo (n=30). The supplementation was one 1000 mg capsule 2 times /day BP with meals (lunch and dinner) for 8 weeks. Bodyweight, waist circumference, serum nesfatin-1, fasting blood sugar (FBS) and insulin (FBI), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured. Quantitative insulin sensitivity checks index (QUICKI), homeostasis model assessment-insulin resistance (HOMA-IR) and Body Mass Index (BMI) were also calculated. Results : In comparison with placebo, BP significantly decreased FBS, HOMA-IR, and BMI (P<0.05). The differences in the FBI, QUICKI, TG, TC, LDL, HDL,WC and Nesfatin-1 were not significant (P>0.05). Conclusion : BP supplement improved serum glucose indices and decreased BMI among overweight or obese T2DM patients; though, further trials are suggested to confirm results. Trial Registration : Iranian Registry of Clinical Trials (IRCT), IRCT20181207041876N1, Registered 18/01/2019, https://irct.ir/trial/35752

scholarly journals Effects of sodium selenite and selenium-enriched yeast on cardiometabolic indices of patients with atherosclerosis: A double-blind randomized clinical trial study

2021 ◽  
Vol 13 (4) ◽  
pp. 314-319
Author(s):  
Mahdiyeh Khabbaz Koche Ghazi ◽  
Samad Ghaffari ◽  
Mohammad Naemi ◽  
Rezvaniyeh Salehi ◽  
Mohammadreza Taban Sadeghi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Randomized Clinical Trial ◽  
Sodium Selenite ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Serum Levels ◽  
Lipoprotein Cholesterol ◽  
Model Assessment ◽  
Double Blind ◽  
Additional Clinical Trial

Introduction: Atherosclerosis and related cardiovascular diseases (CVDs) are the major causes of mortality worldwide. The available reports regarding the effects of selenium (Se) supplementation in the realm of atherosclerosis have been equivocal. The present investigation is aimed to assess the effects of sodium selenite and Se-enriched yeast supplementation on metabolic parameters among atherosclerotic patients. Methods: In this double-blind placebo-controlled randomized clinical trial, 60 patients diagnosed with atherosclerosis were randomly allocated into either 200 μg/day selenite, yeast, or placebo groups for eight consecutive weeks. Serum levels of lipid profile and glycemic indices were measured at the baseline and end of the intervention. Results: There were no significant within-or between-group changes in levels of total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-c), fasting blood sugar, insulin, and homeostatic model assessment for IR throughout the study (P≥0.05). Only the low density lipoprotein cholesterol (LDL-c) levels were significantly lower in the yeast group in comparison with the placebo group (P= 0.015). Conclusion: The administration of Se-enriched yeast is significantly effective in decreasing LDL-c levels in patients with atherosclerosis. Additional clinical trial studies investigating the effect of Se administration on glucose homeostasis parameters and lipid profiles in atherosclerotic patients are suggested for a more definitive conclusion.

Effects on Health of Dietary Supplementation with 100 mg d-α-Tocopheryl Acetate, Daily for 6 Years

1995 ◽  
Vol 23 (5) ◽  
pp. 342-357 ◽  
Author(s):  
S Takamatsu ◽  
M Takamatsu ◽  
K Satoh ◽  
T Imaizumi ◽  
H Yoshida ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Myocardial Damage ◽  
Lipoprotein Cholesterol ◽  
Tocopheryl Acetate ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Lipid Parameter ◽  
Double Blind ◽  
Double Blind Design

To evaluate the clinical antioxidant effects of vitamin E, 161 healthy volunteers aged 39 to 56 years, were given 100 or 3 mg of d-α-tocopheryl acetate orally daily for 6 years using a randomized, double-blind design. Among the 147 volunteers who qualified for the analysis, seven of the 73 volunteers receiving 3 mg d-α-tocopheryl acetate daily and none of the 74 volunteers receiving 100 mg had coronary disorders including myocardial damage ( P < 0.02). ST or T wave abnormalities on electrocardiograms were considered to indicate coronary disorders (four volunteers). The mean serum total tocopherol (TOC) concentration in the 100-mg group was significantly higher than that in the 3-mg group 6 months after the start of the study, and this raised value was maintained throughout the study; the level in the 3-mg group did not change significantly from the baseline value. The low-density lipoprotein cholesterol/total TOC ratio, a parameter of the inhibition of peroxidation of low-density lipoprotein cholesterol, was the only serum lipid parameter that was significantly different, at baseline, in the volunteers with coronary disorders compared with the others. These findings indicate that long-term supplementation with 100 mg tocopheryl acetate daily may prevent the early stages of coronary atherosclerosis by decreasing peroxidation of low-density lipoprotein cholesterol.

Sign in / Sign up

Export Citation Format

Share Document