Therapy of Canine Hyperlipidemia with Bezafibrate.

BackgroundBezafibrate (BZF) is effective in the treatment of hypertriglyceridemia in human patients, but there are no data on its use in dogs.ObjectiveTo assess the safety of BZF in hyperlipidemic dogs and its efficacy in decreasing serum triglyceride (TG) and cholesterol (CHO) concentrations.AnimalsForty-six dogs, 26 females and 20 males, mean (±SD) age of 9 (±3) years, with TG ≥150 mg/dL (33 dogs also were hypercholesterolemic [>300 mg/dL]).MethodsProspective, uncontrolled clinical trial. Dogs were treated with bezafibrate once daily, using 200 mg tablets at a dosage of 4-10 mg/kg (depending on body weight). Serum TG and CHO concentrations and alanine aminotransferase (ALT) and creatine kinase (CK) activity before and after 30 days of treatment were compared.ResultsSixteen dogs (34.8%) had primary hyperlipidemia, and 30 dogs (65.2%) had secondary hyperlipidemia (including spontaneous hyperadrenocorticism [41.3%, n = 19/46], chronic treatment with glucocorticoids [10.8%, n = 5/46], and hypothyroidism [15.2%, n = 7/46]). After 30 days, serum TG concentration normalized (<150 mg/dL) in 42 dogs (91.3%) and CHO concentration normalized (<270 mg/dL) in 22 of 33 dogs (66.7%). There was no difference in baseline TG concentration between the primary and secondary hyperlipidemia subgroups, but the decrease in TG concentration after treatment was greater in the primary hyperlipidemia subgroup. No adverse effects were observed, but ALT activity decreased significantly after 30 days of treatment.Conclusions and clinical importanceOver 30 days, BZF was safe and effective in treatment of primary and secondary hyperlipidemia in dogs

Regulation of hepatic cholesterol metabolism in CETP+/-/LDLR+/- mice by cholesterol feeding and by drugs (cholestyramine and lovastatin) that lower plasma cholesterol

1. The hepatic mechanisms involved in the simultaneous regulation of plasma cholesterol concentration and cholesteryl ester transfer protein (CETP) activity were investigated by sharply modifying the hepatic rates of cholesterol synthesis. This was accomplished by cholestyramine, lovastatin and cholesterol feeding in human CETP transgenic mice cross-bred with low-density lipoprotein receptor (LDLr)-knockout mice, generating CETP+/-/LDLr+/- mice, which present a plasma lipoprotein profile resembling that of humans. 2. Analyses of pooled data showed that the plasma CETP activity correlated positively with plasma total cholesterol concentration, hepatic CETP mRNA and the liver microsomal cholesterol content; a negative correlation was found between plasma CETP activity and the liver 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and LDLr mRNA levels. These coordinated events represent an efficient control system that stabilizes the cell cholesterol content. 3. Nonetheless, not all cholesterol metabolism regulatory systems seem to fit into a coherent pattern of responses, suggesting that other unknown cellular mechanisms play roles depending on the type of pharmacological intervention. 4. For example, microsomal cholesterol content was not affected by cholestyramine, but was increased on cholesterol feeding (as predicted), and, surprisingly, on lovastatin treatment. Furthermore, although both plasma cholesterol-lowering drugs increased CYP7A1 mRNA and had no effect on CYP27 mRNA, other metabolic components were differentially modified. Cholestyramine and lovastatin, respectively, did not modify and increased both HMG-CoA and sterol responsive element binding protein 1c mRNA, did not modify and lowered liver X receptor alpha mRNA, lowered and increased ATP binding cassette A1 mRNA and lowered and did not modify scavenger receptor B1 mRNA. 5. That is, different to unabsorbed cholestyramine, lovastatin, as an absorbed plasma cholesterol-lowering drug, may have modified the activity of other unknown genes that play roles in the interaction of CETP with the metabolism of hepatic cholesterol.33121209121

Therapy of Canine Hyperlipidemia with Bezafibrate.

BackgroundBezafibrate (BZF) is effective in the treatment of hypertriglyceridemia in human patients, but there are no data on its use in dogs.ObjectiveTo assess the safety of BZF in hyperlipidemic dogs and its efficacy in decreasing serum triglyceride (TG) and cholesterol (CHO) concentrations.AnimalsForty-six dogs, 26 females and 20 males, mean (±SD) age of 9 (±3) years, with TG ≥150 mg/dL (33 dogs also were hypercholesterolemic [>300 mg/dL]).MethodsProspective, uncontrolled clinical trial. Dogs were treated with bezafibrate once daily, using 200 mg tablets at a dosage of 4-10 mg/kg (depending on body weight). Serum TG and CHO concentrations and alanine aminotransferase (ALT) and creatine kinase (CK) activity before and after 30 days of treatment were compared.ResultsSixteen dogs (34.8%) had primary hyperlipidemia, and 30 dogs (65.2%) had secondary hyperlipidemia (including spontaneous hyperadrenocorticism [41.3%, n = 19/46], chronic treatment with glucocorticoids [10.8%, n = 5/46], and hypothyroidism [15.2%, n = 7/46]). After 30 days, serum TG concentration normalized (<150 mg/dL) in 42 dogs (91.3%) and CHO concentration normalized (<270 mg/dL) in 22 of 33 dogs (66.7%). There was no difference in baseline TG concentration between the primary and secondary hyperlipidemia subgroups, but the decrease in TG concentration after treatment was greater in the primary hyperlipidemia subgroup. No adverse effects were observed, but ALT activity decreased significantly after 30 days of treatment.Conclusions and clinical importanceOver 30 days, BZF was safe and effective in treatment of primary and secondary hyperlipidemia in dogs

Acute in vivo chylomicron metabolism and postalimentary lipoprotein alterations in normolipidemic male smokers

Increased postprandial lipemia has been stated as one of the mechanisms responsible for atherogenesis in smokers. We measured the postalimentary lipid response and the in vivo intravascular delipidation index of an artificial chylomicron emulsion in healthy adult smokers and controls. The blood was collected in the fasting state immediately after the smokers smoked one cigarette. The lipemia was measured 2, 4, 6 and 8 h postalimentarily in smokers (S, n=8) and in non-smoking controls (C, n=8) and the chylomicron metabolism rate was measured 2, 4, 6, 8, 12, 16, 20, 24 and 30 min after the injection of an artificial emulsion to S (n= 10) and to C (n=10). The lipoproteins were isolated in the fasting period and 4 h after the fatty meal and their chemical composition in cholesterol, triglycerides, phospholipids and protein was determined. Smokers showed an increased lipolysis percentage value (mean +/-S.E.M) of the artificial chylomicron (39.1 +/-3.1) compared to controls (26.5 +/-3.3) and higher levels of HDL2-PL: 28.4 +/-4.3 (S) versus 16.2 +/-2.0 (C) mg/dl (mean +/-S.E.M.). In conclusion, the oral fat tolerance was not altered in smokers but an upregulation of the rate of metabolism of the TG-rich lipoproteins was elicited immediately after smoking one cigarette. (C) 2001 Elsevier Science B.V. All rights reserved.305416719910

Plasma 27-hydroxycholesterol/cholesterol ratio is increased in low high density lipoprotein-cholesterol healthy subjects

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Sterol 27-hydroxylase converts cholesterol to 27-hydroxycholesterol (27-OHC) which is widely distributed among tissues and is expressed at high levels in the vascular endothelium and macrophages. There is a continuous flow of this oxysterol from the tissues into the liver; where it is converted to bile acids. Objective: Measure plasma concentrations of 27-OHC in subjects that differ according to their plasma HDL-C concentration. Methods: Healthy men presenting low HDL-C (1.55 mmol/L), n 18, BMI <30 kg/m(2) were recruited after excluding secondary causes that might interfere with their plasma lipid concentrations such as smoking, heavy drinking and diabetes. Blood samples were drawn after a 12 h fasting period for the measurement of 27-OHC by the combined GC/MS analysis utilizing deuterium-label internal standards. Results: The plasma ratio 27-OHC/total cholesterol (median and range nmoL/mmoL) was 50.41 (27.47-116.00) in the High HDL-C subjects and 6334 (36.46-91.18) in the Low HDL-C subjects (p = 0.0258). Conclusion: Our data indicate that the production of 27-0HC by extrahepatic tissues and its transport to the liver may represent an alternative pathway for a deficient reverse cholesterol transport system when plasma HDL-C is low. (C) 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.461516191621Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)LIMHC/FMUSP (Medical Investigation Laboratories, Hospital das Clinicas/Faculty of Medical Sciences of University of Sao Paulo)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [2010/52654-6