The pleiotropic effect of statins in haemodialysis patients is not the consequence of an inhibition of LDL oxidation by myeloperoxidase.
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Animals↗
Biomedical subjects
J Ducobu
Publications and source records attributed to J Ducobu.
Antigens and granularity of blood monocytes in relation to inflammatory markers and lipids in postmenopausal women.
OBJECTIVES: The menopause is associated with an increase of inflammatory markers (C-reactive protein, fibrinogen), cytokines (INFgamma, TNF, etc.) and blood lipoproteins. In vitro, CRP, LDL and fibrinogen can modulate or potentiate interleukines production by monocytes. The aim of this work was to study, the relationships in vivo between hs-CRP, fibrinogen, lipoproteins and the phenotype of circulating monocytes. METHODS: The monocytes phenotype, in postmenopausal women (n=26) without history of cardiovascular disease, was determined, by flow cytometry, measuring granularity and CD14, HLA-DR and CD62-L antigens expression. Blood monocytes were divided in CD14+dim monocytes (low CD14 expression) and CD14+bright monocytes (high CD14 expression). RESULTS: HLA-DR was negatively correlated with hs-CRP and fibrinogen. The relationships between ApoB, LDL/ApoB ratio and CD14 expression was restricted to the CD14+bright monocytes. Blood lipids, i.e. total cholesterol, LDL-c and ApoB were correlated with the granularity of both subsets. CD14+dim monocytes were characterized by a low granularity and CD62-L expression. CONCLUSIONS: Our data show that fibrinogen and hs-CRP are correlated with a reduced antigen-presenting capacity. Expression of CD14 on CD14+bright monocytes is negatively associated to atherogenic LDL. Blood monocytes granularity was positively correlated with serum lipids indicating that monocytes could uptake modified LDL in circulation and not restricted to subendothelial space.
Aged↗
Beneficial effects of atorvastatin on sd LDL and LDL phenotype B in statin-naive patients and patients previously treated with simvastatin or pravastatin.
BACKGROUND: The presence of increased levels of small dense (sd) LDL (phenotype B) is associated with a substantial increase of cardiovascular disease risk. Since lowering of plasma low-density lipoprotein-cholesterol (LDL-C) by statins involves an up-regulation of the LDL receptor, we questioned whether LDL lowering by atorvastatin affects different LDL subfractions equally. METHODS: Fifty-four hypercholesterolemic patients, requiring treatment for prevention of coronary heart disease received atorvastatin (10, 20 or 40 mg/day), either as initial therapy (n=33), or as replacement therapy (n=21) for pravastatin or simvastatin (both at 40 mg/day). In addition to plasma lipid measurements, cholesterol LDL subfractions were separated and analysed before and after 3 months of treatment. RESULTS: In addition to the expected LDL-C decrease (-34%; p<0.0001), a major reduction in sd LDL occurred after atorvastatin therapy (-38.2%; p<0.0001). Interestingly, sd LDL decreased as much in patients previously treated with other statins (-36%; p<0.002). A close correlation (r=0.89, p<0.001) was found between reduction of sd LDL and that of LDL-C, in patients with phenotype B. Although high-density lipoprotein-cholesterol (HDL-C) was not affected by atorvastatin treatment, plasma triglycerides decreased by 27.4% (p<0.0001). Only a weak correlation (r=0.35, p<0.01) was found between the reduction of plasma triglycerides and the decrease of sd LDL after atorvastatin treatment. CONCLUSION: These results show that the reduction of LDL-C by atorvastatin largely reflects a lowering of sd LDL. Our data also suggest that triglyceride lowering plays only a partial role in sd LDL reduction.
Adolescent↗
[Multifactorial approach of the cardiovascular risks in case of diabetes].
All patients with type 2 diabetes are at increased risk of cardiovascular diseases. Diabetics have a greater burden of atherogenic risk factors than non diabetics including mainly arterial hypertension and dyslipidemia. If strict glycemic control is recommended because of proved benefit in terms of microvascular disease the protection against macrovascular disease is less established. Vigorous risk factors reduction (diminution of blood pressure, reduction of lipids, smoking cessation) should be a priority in a multifactorial approach of diabetes treatment, involving the patients and the doctors. In addition to lifestyle and behaviour counselling, polypharmacologic treatment is often needed.
Behavior Therapy↗
[Innovative therapies in metabolic diseases: ezetimibe (Ezétrol), nicotinic acid (Niaspan), acids omega-3 (Omacor), rimonabant (Acomplia)].
In the field of dyslipidemia and metabolic syndrome, four innovative therapies are reviewed: Ezetimibe (Ezétrol) is a selective cholesterol absorption inhibitor. Co-administration of ezetimibe with low dose of statins shows LDL lowering comparable to that of the highest dose of the respective statin alone. Combination therapy helps more patients in achieving target LDL-cholesterol. Nicotinic acid (Niacin) favourably modifies all lipoprotein level (including Lp(a)). Extended release niacin (Niaspanâ) is a new galenic form, with less side effects (flushing and hepatotoxicity) than the native nicotinic acid. This new preparation represents an effective option in the management of dyslipidemia. The polyunsatured fatty acids (PUFA) omega-3 (Omacor) decreases cardiovascular deaths and mainly fatal arrhythmias after myocardial infarction. Their favourable effects are linked mainly to their anti-inflammatory and antiarrhythmic properties. The PUFA omega-3 could be added to the secondary prevention after myocardial infarction. The blockade of the endocannabinoid system by a specific inhibitor of CB1 receptor (rimonabant or Acomplia) decreases food intake and weight and increases adiponectin and insulin sensitivity. Clinical studies on obesity and tobacco dependence are very encouraging.
Anticholesteremic Agents↗
[The endocannabinoid system and the regulation of the metabolism].
The endocannabinoid system modulates many physiological functions by acting on receptors CB1 and CB2. The endocannabinoids are produced only when and where they are needed. They act locally and are immediately metabolised after their action. Overactivation of the endocannabinoid system is observed in obesity, with stimulation of the appetite in the hypothalamus and fat accumulation in the adipocytes with increase of insulin resistance and decrease of adiponectin. Nicotine use overactivates also the endocannabinoid system. CB1 blockade by a specific inhibitor (rimonabant) decreases food intake and weight in animal studies and increases adiponectin and insulin sensitivity. Moreover, rimonabant decreases tobacco dependence. Clinical studies with rimonabant are encouraging.
Animals↗
[Rimonabant (Acomplia), specific inhibitor of the endocannabinoid system].
The endocannabinoid system plays a major role in the regulation of body energy by stimulation of the appetite in the hypothalamus and increase of fat accumulation in adipocytes. The blockade of the cannabinoid system (CB1) by the specific inhibitor (rimonabant) decreases food intake and adiposity in animals and in humans. Moreover rimonabant lowers tobacco addiction. Clinical studies (RIO-LIPIDS and RIO-EUROPE) have recently confirmed that rimonabant combined with a hypocaloric diet over 1 year, promoted significant decrease of body weight, waist circumference and improvement of dyslipidemia. Rimonabant was well tolerated with mild and transient side effects. The future place of rimonabant in the strategy of obesity is still to be clarified.
Anti-Obesity Agents↗
Oxidation of low density lipoproteins by myeloperoxidase at the surface of endothelial cells: an additional mechanism to subendothelium oxidation.
The present paradigm of atherogenesis proposes that low density lipoproteins (LDL) are trapped in subendothelial space of the vascular wall where they are oxidized. Myeloperoxidase (MPO) plays a key role in oxidative damage. We propose that LDL oxidation by myeloperoxidase (Mox-LDL) could occur at the surface of the endothelial cells and not restricted to the subendothelial space. The triad constituted by endothelial cells, circulating LDL and MPO in close interaction, constitutes a synergic mechanism for the genesis of Mox-LDL.
Cell Membrane↗
Monoclonal antibodies against LDL progressively oxidized by myeloperoxidase react with ApoB-100 protein moiety and human atherosclerotic lesions.
Oxidized-LDL are involved in atherosclerosis pathogenesis, while the production of anti-ox-LDL monoclonal antibodies is critical for the development of diagnostic tools. This work reports the production of four monoclonal antibodies raised against human LDL, oxidized at different levels by the myeloperoxidase system. Characterization of these monoclonal antibodies showed that they do not cross-react with neither native LDL, VLDL nor hydrogen peroxide or Cu(2+)-oxidized LDL. Three of these antibodies recognize an epitope restricted to the protein moiety of mildly oxidized LDL, whereas the fourth antibody was partly dependent on the lipid presence of strongly oxidized LDL. All the antibodies were shown to react with human atherosclerotic lesions.
Antibodies, Monoclonal↗
Lipid and apoprotein changes during atorvastatin up-titration in hemodialysis patients with hypercholesterolemia: a placebo-controlled study.
BACKGROUND: Patients with end-stage renal disease commonly present with an atherogenic lipid profile characterized by the accumulation of triglyceride-rich, apoprotein B-containing "remnant" lipoproteins, small dense low-density lipoprotein, and low levels of high-density lipoprotein. They are at increased cardiovascular risk and may benefit from drastic lipid-lowering treatment with atorvastatin, a potent, broadacting lipid regulator. This study aims to assess the effects of atorvastatin on the lipid profile in hemodialysis patients, to determine wether atorvastatin is also effective at lowering lipid levels in this particular high-risk subgroup. METHODS: In this randomized, placebo-controlled, double-blind study in hemodialysis patients with hypercholesterolemia (n = 42, mean total cholesterol 243 +/- 33 mg/dl (6.3 +/- 0.8 mmol/l)), the efficacy of 4-weekly increasing doses of atorvastatin (10 - 40 mg daily) was investigated. Lipids and apoproteins were measured in plasma and isolated lipoprotein fractions. RESULTS: Mean total cholesterol and low-density lipoprotein cholesterol progressively decreased with increasing doses of atorvastatin (total cholesterol -33%, low-density lipoprotein cholesterol -43% after 12 weeks), while high-density lipoprotein cholesterol remained unchanged. Plasma levels of apoprotein B and apoprotein E were also significantly reduced by atorvastatin 10 mg, while up-titration to 20 and 40 mg daily provided additional benefits by lowering triglycerides and apoprotein C-III. At week 12, the fraction of small dense low-density lipoprotein was significantly reduced from 23% - 18%, and apoprotein B-containing intermediate-density lipoproteins were no longer detectable. CONCLUSION: In conclusion, atorvastatin not only treated hypercholesterolemia but also favorably affected the uremic lipid profile in patients on hemodialysis. Atorvastatin 4-weekly dose escalation up to 40 mg daily was well-tolerated. Further prospective studies are needed to evaluate the impact of this improved lipid profile on morbidity and mortality.
Aged↗
[Ezetimibe (Ezetrol): the statins' partner].
Ezetimibe is a new cholesterol absorption inhibitor that selectively inhibits dietary and biliary cholesterol absorption from the intestine. This drug inhibits cholesterol absorption without affecting the absorption of triglycerides, biliary salts and fat-soluble vitamins. Inhibition of cholesterol absorption using ezetimibe 10 mg/day alone resulted in substantial reductions of plasma LDL-C concentrations (approximately 18%). Coadministration of ezetimibe 10 mg/day with statins 10 mg/day showed LDL lowering comparable to or greater than that of the highest dose of the respective statin alone. Combination therapy of ezetimibe with statins helped more patients in achieving their target LDL-C goal. Ezetimibe in coadministration with statins or alone had also favourable effects on triglycerides and HDL. In clinical studies, ezetimibe alone or coadministered with a statin was shown to have a safety profile (asymptomatic mild increases in aminotransferase levels, without evidence of rhabdomyolysis) similar to placebo or to the statin alone. Large clinical studies on clinical endpoints are in progress.
Animals↗
[Recent progress in the "fibrinogen hypothesis"].
Several clinical and epidemiological studies have demonstrated that a high level of plasma fibrinogen is an independent risk factor for coronary, cerebral and peripheral artery disease. The role of fibrinogen in cardiovascular diseases is mainly due to thrombotic complications in advanced stages of the atherothrombotic disease. However, fibrinogen also plays an active role in the initiation and development of atheromatous plaques. The relations between fibrinogen and ischemic cardiopathies, other vasculopathies and diabetes mellitus are discussed. The controversial effects of statins on fibrinogen are also described.
Biomarkers↗
[Oral antidiabetic drugs in 2003].
Treatment of patients with type 2 diabetes includes in the first place diet, weight reduction, exercise, and the control of cardiovascular risk factors. Because the compliance with these interventions is not sustained, drug therapy is required for most patients. There are five therapeutic options in type 2 diabetes: increase insulin release with sulfonylureas or glinides; increase insulin action with biguanides or glitazones; modify intestinal absorption of carbohydrate with a glucosidase inhibitor or absorption of fat with a lipase inhibitor; associate these drugs or use new therapeutic agents; administer exogenous insulin. Many patients with type 2 diabetes will overtime need combination of different drugs and insulin, but the best strategy is not known and more trials are needed to give better evidence for the therapeutic choices.
Administration, Oral↗
[Metabolic modifications related to immunosuppressive drugs].
After transplantation, immunosuppressive drugs induce frequently lipid changes and glucose intolerance which result in worsening of the patient's prognosis. The mechanisms of the metabolic changes of corticosteroid hormones, cyclosporine, tacrolimus, sirolimus and mycophelonate are shortly reviewed but are not fully understood. Controlling serum lipids is critical in the management of the patients after transplantation. Statins seem to be the best choice but it remains some concerns about drug interactions and risk of rhabdomyolysis. Fibrates except gemfibrozil are not recommended because potential renal side effects.
Anticholesteremic Agents↗
[Chronic fatigue: introduction].
Chronic fatigue is frequent in primary care practice. After exclusion of medical causes, psychosocial factors and chronic fatigue syndrome (CFS) must be searched. The differential diagnosis is long and difficult, but it depends more of good clinical evaluation than of extensive laboratory investigation.
Diagnosis, Differential↗
[Lipids and AIDS].
HIV infection induces an early decrease of cholesterol and a late increase of triglycerides (TG) with a reduction of HDL. These changes are proportional with the lowering of CD4, which reflects the infection's severity. Both the increase of TG synthesis and the decrease of TG catabolism, in relation with a reduction of lipoprotein lipase activity, are responsible of these changes. Moreover, LDL catabolism is enhanced by macrophage scavenger receptors, due to a high proportion of small, dense LDL which are more easily oxidized. Many cytokines (interferon alpha, interleukins, TNF) play probably a pathogenic role in the dyslipidemia. Some HIV patients who received antiproteases may develop lipodystrophy with central obesity, insulino-resistance, glucose intolerance and sometimes diabetes (like in syndrome X). Other patients present a cushingoid, buffalo hump. This complication may be observed also with antiretroviral treatment other than antiproteases. The physiopathology of these findings could be in relation with structural homologies between antiproteases and some important proteins, involved in lipid and adipocyte metabolism. Cardiovascular risk linked to these perturbations is evident. The treatment is not different from the treatment for seronegative, hyperlipidemic patients: struggle against risk factors, diet advices, fibrates or statins. The antiproteases bring huge contribution to the prognosis of AIDS patients but the risk of cardiovascular complications could impair this therapeutic progress. So, it is essential to understand the pathogeny of these complications in order to discover new antiproteases, without these adverse side effects.
Acquired Immunodeficiency Syndrome↗
[Recommendations of the Belgian Lipid Club for the diagnosis and treatment of hyperlipidemias: summary for the practitioner].
The present paper summarizes the last recommendations of the Belgian Lipid Club for the diagnosis and treatment of hyperlipidaemias which were published in 1999. These guidelines are in agreement with the "Recommendations of the second Task Force of European and other societies on Coronary Protection", published in 1998. We will briefly describe the evidence supporting the treatment of dyslipidaemias, especially hypercholesterolaemia, to improve coronary prognosis of at high risk subjects as well as the general strategies, lipid objectives and therapeutic means, in a practical way for the clinician.
Anticholesteremic Agents↗