Pharmacokinetics and pharmacodynamics of HTD1801 (berberine ursodeoxycholate, BUDCA) in patients with hyperlipidemia

Background Reduction in elevated serum cholesterol concentrations is important in the management of individuals at risk of atherosclerotic cardiovascular disease (ASCVD), such as myocardial infarction and thrombotic stroke. Although HMGCoA reductase inhibitors (“statins”) are frequently used for this purpose, a significant proportion of patients remain at increased residual risk of ASCVD as they do not adequately address some of the associated co-morbidities such as diabetes and fatty liver disease. Methods A double-blind, randomized, placebo-controlled, dose ranging study was carried out that compared three doses of berberine ursodeoxycholate (BUDCA) to placebo in a cohort of subjects with a history of hypercholesterolemia and serum LDL cholesterol levels above 2.59 mmol/L (> 99.9 mg/dL). BUDCA was administered in two divided doses each day for 28 days. The primary endpoints of the study were safety and tolerability of this new compound, as well as its effect in lowering serum lipid and lipoprotein concentrations. Results A total of 50 subjects were enrolled into three dose cohorts in this study. BUDCA was generally well tolerated, even at doses of 2000 mg per day (the highest dose group); there were no significant adverse effects reported and this highest dose was associated with significant reductions in LDL cholesterol. By day 28 and with the highest dose of BUDCA, there were significant reductions in the serum concentrations of total cholesterol by 8.2% (P = 0.0004) and LDL cholesterol by 10.4% (P = 0.0006), but no significant changes in triglyceride and HDL cholesterol concentrations. Conclusions BUDCA is a new single molecular entity that has a significant but modest effect in safely lowering serum LDL-cholesterol concentrations in individuals with a history of hypercholesterolemia. It has a potential use for treating hypercholesterolemia in individuals who cannot take statins, and possibly as adjunctive to other agents, such as ezetimibe or bempedoic acid. Trial registration The study was registered on Clinicaltrials.gov (NCT03381287).

Antidiabetic Activity of the Methanolic Extracts of Thuja occidentalis Twings in Alloxan-induced Rats

Objective and Background: In hyperglycemic and alloxan-induced diabetic rats, the effect of Thuja occidentalis methanolic residue extract on blood glucose levels and some biochemical parameters were investigated. Methods: Significantly decreased blood glucose level by 22.85% and 27.66%, in hyperglycemic rats, respectively after 3 h, were seen in a single oral administration of the extract at a dose of 200 and 400 mg/kg. Blood glucose level was decreased by 50% in alloxan-induced diabetic rats within three weeks of daily treatment of Thuja occidentalis methanolic residue extract (200 and 400 mg/kg p.o). Alloxan-induced diabetic rats showed significant hypercholesterolemia in comparison with the control in alloxan induced rats. Results: In both normal and diabetic rats, there was also a significant decrease of elevated serum cholesterol and triglycerides. Hypertriglyceridemia was also shown to be prevented by treatment with plant extract (200 and 400mg/kg p.o) (p<0. 05). As compared with the control animals, diabetic control rats did not show any change in a level of creatinine and urea. Conclusion: Thuja occidentalis treatment may improve glucose homeostasis in alloxaninduced diabetes and alleviate kidney and liver function. Thuja occidentalis twigs could be a potential source of the new oral antidiabetic drug.

Osteocardiology: Defining the Go/No-Go Time Point for Therapy

Recent epidemiological studies have revealed that the risk factors associated with coronary artery calcification (CAC), including male gender, smoking, hypertension, and elevated serum cholesterol, are similar to the risk factors associated with the development of calcific aortic valve disease (CAVD). The results of the experimental and clinical studies demonstrate that traditional risk factors initiate early atherosclerosis which over time differentiates to form bone in the heart causing clinical CAC and CAVD. Understanding the cellular mechanisms of cardiovascular calcification, the end-stage process of the atherosclerosis will help define the specific time point to modify this cellular process of bone formation in the heart termed osteocardiology. This time point between subclinical atherosclerosis and clinical calcification is the go/no-go time point, or the point of no return with severe clinical calcification in the heart. This review will summarize the development of bone formation in the heart termed osteocardiology, to define the go/no-go time point for therapy initiation to slow the progression of cardiovascular calcification.

Hypercholesterolemia and ApoE deficiency result in severe infection with Lyme disease and relapsing-feverBorrelia

The Lyme disease (Borrelia burgdorferi) and relapsing-fever (Borrelia hispanica) agents have distinct infection courses, but both require cholesterol for growth. They acquire cholesterol from the environment and process it to form cholesterol glycolipids that are incorporated onto their membranes. To determine whether higher levels of serum cholesterol could enhance the organ burdens ofB. burgdorferiand the spirochetemia ofB. hispanicain laboratory mice, apolipoprotein E (apoE)-deficient and low-density lipoprotein receptor (LDLR)-deficient mice that produce large amounts of serum cholesterol were infected with both spirochetes. Both apoE- and LDLR-deficient mice infected withB. burgdorferihad an increased number of spirochetes in the joints and inflamed ankles compared with the infected wild-type (WT) mice, suggesting that mutations in cholesterol transport that result in high serum cholesterol levels can affect the pathogenicity ofB. burgdorferi. In contrast, elevated serum cholesterol did not lead to an increase in the spirochetemia ofB. hispanica.In the LDLR-deficient mice, the course of infection was indistinguishable from the WT mice. However, infection of apoE-deficient mice withB. hispanicaresulted in a longer spirochetemia and increased mortality. Together, these results argue for the apoE deficiency, and not hypercholesterolemia, as the cause for the increased severity withB. hispanica.Serum hyperlipidemias are common human diseases that could be a risk factor for increased severity in Lyme disease.

Supplementation with the Extract of Schisandrae Fructus Pulp, Seed, or Their Combination Influences the Metabolism of Lipids and Glucose in Mice Fed with Normal and Hypercholesterolemic Diet

Schisandrae Fructus (SF), which possesses five tastes: sweet (fruit skin), sour (pulp), bitter/pungent (seed core), and saltiness (all parts), can produce a wide spectrum of biological activities in the body. Here, we investigated the effects of the ethanolic extract of SF pulp, seed, or their combination (namely, EtSF-P, EtSF-S, or EtSF-P/S, resp.; collectively called EtSF) on the metabolism of lipids and glucose in normal diet- (ND-) and hypercholesterolemic diet- (HCLD-) fed mice. Supplementation with EtSF significantly reduced hepatic triglyceride and cholesterol levels by 18–47% in both ND- and HCLD-fed mice. EtSF supplementation reduced serum triglyceride levels (approximately 29%), whereas EtSF-P and EtSF-S/P elevated serum cholesterol (up to 26 and 44%, resp.) in HCLD-fed mice. Treatment with EtSF decreased hepatic glucose levels (by 9–44%) in both ND- and HCLD-fed mice. Supplementation with EtSF-S or EtSF-S/P (at 1 and 3%) increased biliary or fecal TC contents in HCLD-fed mice. However, supplementation with EtSF-S/P at 9% reduced biliary TC levels in HCLD-fed mice. EtSF-P or EtSF-S/P supplementation reduced serum alanine aminotransferase activity in HCLD-fed mice. The findings suggested that supplementation with EtSF lowered lipid and glucose accumulation in the liver and increased fecal cholesterol contents in mice. Dietary supplementation with EtSF-P or EtSF-S/P attenuated liver damage in HCLD-fed mice.

Immune Response to Lipoproteins in Atherosclerosis

Atherosclerosis, the underlying cause of cardiovascular disease, is characterized by chronic inflammation and altered immune response. Cholesterol is a well-known risk factor associated with the development of cardiovascular diseases. Elevated serum cholesterol is unique because it can lead to development of atherosclerosis in animals and humans even in the absence of other risk factors. Modifications of low-density lipoproteins mediated by oxidation, enzymatic degradation, and aggregation result in changes in their function and activate both innate and adaptive immune system. Oxidized low-density lipoprotein (LDL) has been identified as one of the most important autoantigens in atherosclerosis. This escape from self-tolerance is dependent on the formation of oxidized phospholipids. The emerging understanding of the importance of immune responses against oxidized LDL in atherosclerosis has focused attention on the possibility of development of novel therapy for atherosclerosis. This review provides an overview of immune response to lipoproteins and the fascinating possibility of developing an immunomodulatory therapy for atherosclerosis.