Properties Of Fibrations Research Articles

Exploring the Symmetry of Curvilinear Regression Models for Enhancing the Analysis of Fibrates Drug Activity through Molecular Descriptors

Quantitative structure-property relationship (QSPR) modeling is crucial in cheminformatics and computational drug discovery for predicting the activity of compounds. Topological indices are a popular molecular descriptor in QSPR modeling due to their ability to concisely capture the structural and electronic properties of molecules. Here, we investigate the use of curvilinear regression models to analyze fibrates drug activity through topological indices, which modulate lipid metabolism and improve the lipid profile. Our QSPR approach predicts the physicochemical properties of fibrates based on degrees and distances from topological indices. Our results demonstrate that topological indices can enhance the accuracy of predicting physicochemical properties and biological activities of molecules, including drugs. We also conducted density functional theory (DFT) calculations on the investigated derivatives to gain insights into their optimized geometries and electronic properties, including symmetry. The use of topological indices in QSPR modeling, which considers the symmetry of molecules, shows significant potential in improving our understanding of the structural and electronic properties of compounds.

Pretreatment by low-dose fibrates protects against acute free fatty acid-induced renal tubule toxicity by counteracting PPARα deterioration

Development of a preventive strategy against tubular damage associated with proteinuria is of great importance. Recently, free fatty acid (FFA) toxicities accompanying proteinuria were found to be a main cause of tubular damage, which was aggravated by insufficiency of peroxisome proliferator-activated receptor alpha (PPARα), suggesting the benefit of PPARα activation. However, an earlier study using a murine acute tubular injury model, FFA-overload nephropathy, demonstrated that high-dose treatment of PPARα agonist (0.5% clofibrate diet) aggravated the tubular damage as a consequence of excess serum accumulation of clofibrate metabolites due to decreased kidney elimination. To induce the renoprotective effects of PPARα agonists without drug accumulation, we tried a pretreatment study using low-dose clofibrate (0.1% clofibrate diet) using the same murine model. Low-dose clofibrate pretreatment prevented acute tubular injuries without accumulation of its metabolites. The tubular protective effects appeared to be associated with the counteraction of PPARα deterioration, resulting in the decrease of FFAs influx to the kidney, maintenance of fatty acid oxidation, diminution of intracellular accumulation of undigested FFAs, and attenuation of disease developmental factors including oxidative stress, apoptosis, and NFκB activation. These effects are common to other fibrates and dependent on PPARα function. Interestingly, however, clofibrate pretreatment also exerted PPARα-independent tubular toxicities in PPARα-null mice with FFA-overload nephropathy. The favorable properties of fibrates are evident when PPARα-dependent tubular protective effects outweigh their PPARα-independent tubular toxicities. This delicate balance seems to be easily affected by the drug dose. It will be important to establish the appropriate dosage of fibrates for treatment against kidney disease and to develop a novel PPARα activator that has a steady serum concentration regardless of kidney dysfunction.

Fibric acid derivatives in cardiovascular disease prevention: results from the large clinical trials

Results from five large placebo-controlled trials with second-generation fibrates have shown varying success in reducing cardiovascular events. This review focuses on a number of extended analyses from these trials that may relate to the success or failure of fibrate therapy and indicate who might likely benefit from this therapy. Results have been far from uniform and several trials have been adversely impacted by high off-trial statin use. Collective evidence suggests, however, that fibrates have optimum cardiovascular benefit in diabetes or other manifestations of insulin resistance. Much of this evidence comes from posttrial analysis in subgroups with more sharply defined clinical characteristics than in the overall trial population. Analyses also suggest that different fibrates have a different range of favorable clinical properties, that the cardiovascular benefit of fibrates may not be readily measured or mostly predicted by changes in traditional lipid measurements, and that other nonlipid properties of fibrates as peroxisome proliferator-activated receptor agents might explain some of the benefit of these drugs. Results of major clinical endpoint trials with fibrates, although not uniformly positive, provide substantial evidence for a selective therapeutic role of these drugs in cardiovascular event reduction in diabetes or insulin resistance.

Cardioprotective Properties of Fibrates

Several large intervention trials have investigated the potential of fibrates to reduce cardiovascular events. The results have varied widely: positive, with gemfibrozil in the primary prevention Helsinki Heart Study (HHS)1 and the secondary prevention Veterans Administration High Density Lipoprotein Intervention Trial (VA-HIT)2; positive, with reservations related to an increase in noncardiovascular mortality in the primary prevention World Health Organization trial (clofibrate)3; and mixed, with bezafibrate in the secondary prevention Bezafibrate Infarction Prevention (BIP) study4 and with fenofibrate in the combined primary and secondary prevention FIELD study,5 in which positive outcomes were observed only in certain subgroups. Reasons for the differences between the outcomes of these studies are not immediately apparent. Article p 1556 It emerged in post hoc subgroup analyses of the HHS,6 VA-HIT,7 and BIP8 data that fibrate-induced reductions in cardiovascular events were especially great (of the order of 30% to 50%) in subjects with evidence of insulin resistance or other features of the metabolic syndrome, such as dyslipidemia and increased body weight. However, this finding was not replicated with fenofibrate in the FIELD study.5 In another post hoc analysis of VA-HIT, it was found that diabetics with preexisting cardiovascular disease derived a major reduction in future events when treated with gemfibrozil,7 but again, this was not confirmed with fenofibrate in FIELD.5 The observation that the cardioprotective effects of gemfibrozil in the HHS and VA-HIT studies were substantially greater than those found with other fibrates in the World Health Organization, BIP, and FIELD studies may reflect no more than the play of chance. It may also reflect differences in the populations studied in the trials. However, it is possible that gemfibrozil has protective properties that are lacking in other fibrates or that other fibrates have adverse …

Anti-atherogenic properties of fibrates may be largely due to their anti-inflammatory effects

Current understanding of the pathophysiology of atherosclerosis has undergone a remarkable evolution. Compelling evidence has evolved at both the basic science and clinical level for the importance of inflammation in the pathogenesis of atherosclerosis and its complications. Recent research has shown that both systemic and local inflammation plays a central role in all phases of the atherosclerotic process. Inflammatory cells dominate early atherosclerotic lesions, inflammatory cytokines accelerate progression of the lesions, and activation of inflammation can elicit acute coronary syndromes. Robust clinical studies have affirmed that fibrates are anti-atherogenic and can improve the cardiovascular risk profile. Fibrates not only modulate the serum concentrations of triglyceride and cholesterol, but also inhibit systemic inflammatory statue and inflammatory response in vascular cells. Fibrates act anti-inflammatory effects in monocyte/macrophage, T lymphocyte, endothelial cells, vascular smooth muscle cells and adipocytes. Since atherosclerosis is now regarded as an inflammatory disease and those inflammatory cells play critical important roles in the initiation and development of atherosclerosis, we hypothesize that anti-atherogenic properties of fibrates may be largely due to their anti-inflammatory effects.

Antiatherogenic Properties of Fibrates

In an era dominated by the use of statins as agents to reduce cardiovascular risk, fibrates have been largely forgotten. This is despite a remarkably robust evidence base certifying to the cardioprotective effects of these agents. In the Helsinki Heart Study (HHS), a 5-year, double-blind, placebo-controlled trial of the effects of gemfibrozil in 4081 men aged 40 to 55 years who were free of clinically manifest CHD at entry to the study, there was a statistically significant 34% reduction in the incidence of total coronary events from 41.4 per 1000 in the placebo group to 27.3 per 1000 in the gemfibrozil group.1 In the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), a 5-year, double-blind, placebo-controlled trial with gemfibrozil in 2531 men with clinical CHD and low levels of both high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, the primary end point (nonfatal myocardial infarction or death attributable to CHD) was reduced significantly by 22% from 21.7% in the placebo group to 17.3% in the gemfibrozil group.2 Positive results have also been obtained in angiographic studies with gemfibrozil in the Lopid Coronary Angiography Trial,3 with bezafibrate in the Bezafibrate Coronary Atherosclerosis Intervention Trial4 and with fenofibrate in the Diabetes Atherosclerosis Intervention Study.5 See page 1193 The cardiovascular benefits of treatment with fibrates appear to be greatest in people with insulin resistance and other features of the metabolic syndrome. In the HHS, a baseline level of serum triglyceride >200 mg/dL or a HDL cholesterol <40 mg/dL or a …

Haemostatic system and arterial disease: future perspectives

The thrombotic component in ischaemic heart disease (IHD) is now generally accepted. Two main questions to be answered are, first, how far it is necessary to further improve our understanding of the biological processes involved and, secondly, the implications of what we have already learned for prevention, both secondary and primary. As far as life-style modification is concerned, distinguishing between the lipid and haemostatic contribution is of limited practical significance since the recommendations to be made are the same from either viewpoint. Implications for pharmacological prevention are more complex. The strong and independent relation of fibrinogen not only with IHD but also with stroke and lower extremity arterial disease raises the question of whether lowering fibrinogen levels may be beneficial. In trials now in progress it may be possible to approtion any clinical benefits between the lipid-modifying and fibrinogen-lowering properties of fibrates. Selective fibrinogen-lowering agents and the enhancement of fibrinolytic activity should be developed but uncertainties about the long-term safety of all new medicines indicates the need to make the best use of those already available. The re-evaluation of oral anticoagulants in lower than conventional doses and in combination with platelet-active agents are two such possibilities. Finally, the potential value of agents that simultaneously influence lipids and the haemostatic system should be assessed. Besides fibrates, other lipid-modifying regimens including the statins, recently show to be clinically effective, have these combined properties.

�ber einige formale Eigenschaften von Faserungen und h-Faserungen

The aim of this paper is to study some formal properties of fibrations (=continuous maps which have the covering homotopy property), cofibrations (=maps which have the homotopy extension property), h-fibrations ([2],6.4) and h-cofibrations([2],2.2). We introduce the notion of a generalized homotopy system in a category (2). This notion will be selfdual. To show that fibrations and cofibrations, h-fibrations and h-cofibrations are dual notions, no use will be made of adjoint functors. Our approach admits the transition from a categoryC to other categories, e.g. to the categoryCB of objects over a given object B ofC.