In the medical and dental field, the importance and need for the study of materials and drugs for use as bone grafts or regeneration in injured areas due to the presence of fractures, infections or tumors that cause e...In the medical and dental field, the importance and need for the study of materials and drugs for use as bone grafts or regeneration in injured areas due to the presence of fractures, infections or tumors that cause extensive loss of bone tissue is observed. Bone is a specialized, vascularized and dynamic connective tissue that changes throughout the life of the organism. When injured, it has a unique ability to regenerate and repair without the presence of scars, but in some situations, due to the size of the defect, the bone tissue does not regenerate completely. Thus, due to its importance, there is a great development in therapeutic approaches for the treatment of bone defects through studies that include autografts, allografts and artificial materials used alone or in association with bone grafts. Pharmaceuticals composed of biomaterials and osteogenic active substances have been extensively studied because they provide potential for tissue regeneration and new strategies for the treatment of bone defects. Statins work as specific inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoAreductase). They represent efficient drugs in lowering cholesterol, as they reduce platelet aggregation and thrombus deposition;in addition, they promote angiogenesis, reduce the β-amyloid peptide related to Alzheimer’s disease and suppress the activation of T lymphocytes. Furthermore, these substances have been used in the treatment of hypercholesterolemia and coronary artery disease. By inhibiting HMG-CoAreductase, statins not only inhibit cholesterol synthesis, but also exhibit several other beneficial pleiotropic effects. Therefore, there has been increasing interest in researching the effects of statins, including Simvastatin, on bone and osteometabolic diseases. However, statins in high doses cause inflammation in bone defects and inhibit osteoblastic differentiation, negatively contributing to bone repair. Thus, different types of studies with different concentrations of statins have been studied to positively or negatively correlate this drug with bone regeneration. In this review we will address the positive, negative or neutral effects of statins in relation to bone defects providing a comprehensive understanding of their application. Finally, we will discuss a variety of statin-based drugs and the ideal dose through a theoretical basis with preclinical, clinical and laboratory work in order to promote the repair of bone defects.展开更多
The use of fibrates in the treatment of dyslipidaemia has changed significantly over recent years.Their role appeared clear at the start of this century.The Helsinki Heart Study and Veterans Affairs High-Density Chole...The use of fibrates in the treatment of dyslipidaemia has changed significantly over recent years.Their role appeared clear at the start of this century.The Helsinki Heart Study and Veterans Affairs High-Density Cholesterol Intervention Trial suggested significant benefit,especially in patients with atherogenic dyslipidaemia.However,this clarity disintegrated following the negative outcomes reported by the Bezafibrate Infarction Prevention,Fenofibrate Intervention and Event Lowering in Diabetes and Action to Control Cardiovascular Risk in Diabetes randomised controlled trials.In this review we discuss these and other relevant trials and consider patient subgroups such as those with the metabolic syndrome and those needing treatment to prevent the microvascular complications associated with diabetes in whom fibrates may be useful.We also discuss observations from our group that may provide some explanation for the varying outcomes reported in large trials.The actions of fibrates in patients who are also on statins are interesting and appear to differ from those in patients not on statins.Understanding this is key as statins are the primary lipid lowering agents and likely to occupy that position for the foreseeable future.We also present other features of fibrate treatment we have observed in our clinical practice;changes in creatinine,liver function tests and the paradoxical high density lipoprotein reduction.Our purpose is to provide enough data for the reader to make objective decisions in their own clinical practice regarding fibrate use.展开更多
AIM： To evaluate the effcacy, effect of preventing cardio-vascular diseases and safety of statins-fbrates combination therapy in diabetic dyslipidemia patients.METHODS： We searched the databases of MEDLINE, EM-BASE,...AIM： To evaluate the effcacy, effect of preventing cardio-vascular diseases and safety of statins-fbrates combination therapy in diabetic dyslipidemia patients.METHODS： We searched the databases of MEDLINE, EM-BASE, web of knowledge and Cochrane central register of Controlled Trials for literatures about the coadministration of statins and fibrates as the treatment of patients with dyslipidemia and type 2 diabetes mellitus. We included re-lated randomized controlled trials, controlled clinical trials and cross-sectional studies and excluded animal trials and clinical observations. The primary endpoints outcomes were the concentration of plasma total cholesterol （TC）, triglyc-eride （TG）, high density lipoprotein cholesterol （HDL-C） and low density lipoprotein cholesterol （LDL-C）. The secondary outcomes were cardiovascular diseases （CVD） and adverseevents.RESULTS： Ten studies were included in this meta-analysis. For lipid modifying efficacy, the combination of statins and fibrates therapy had more significant effecton reducing TC [ P = 0.004, weighted mean difference （WMD） = -8.19, 95%CI： -13.82--2.56] and TG concentra-tion （P 〈 0.001, WMD = -47.29, 95%CI： -68.66--25.92） and increasing HDL-C concentration （P 〈 0.00001, WMD = 3.79, 95%CI： 2.25-5.33） when compared with statins monotherapy, while the effect of reducing LDL-C concen-tration （ P = 0.50, WMD = -2.52, 95%CI： -9.76-4.72） was insignificant. To fibrates monotherapy, the combination therapy was more effective on reducing TC （ P 〈 0.00001, WMD = -48.51, 95%CI： -57.14--39.89）, TG （ P 〈 0.00001, WMD = -26.07, 95%CI： -30.96--21.18）, LDL-C concentra-tion （ P 〈 0.00001, WMD = -45.74, 95%CI： -53.35--38.13） and increasing HDL-C concentration （ P = 0.04, WMD = 1.38, 95%CI： 0.04-2.73）. For cardiovascular diseases, the coad-ministration therapy had no signifcant effect on reducing the incidence of these events when compared with mono-therapy （For primary clinical endpoints, P = 0.12, OR = 0.61, 95%CI： 0.33-1.14）; for secondary clinical endpoints, P =0.13, OR = 0.66, 95%CI： 0.38-1.14）. For adverse events happened during the follow-up, both the incidence of hepatic-related （alanine aminotransferase and/or aspartate aminotransferase of patients were ≥ 3 times of upper limit of normal） （ P = 0.38, OR = 0.55, 95%CI： 0.15-2.06） and muscular-related （myopathy and/or creatine phosphokinase ≥ 3 times of upper limit of normal） adverse events （P = 0.10, OR = 1.62, 95%CI： 0.91-2.86） had no signifcant dif-ference between these two therapies.CONCLUSION： The results showed statins-fbrates com-bination therapy was more effective on lipid modification and well tolerated but there was no significant effect on preventing cardiovascular diseases.展开更多
Primary biliary cholangitis(PBC)is a chronic autoimmune cholestatic liver disease characterized by progressive bile duct destruction,leading to fibrosis,cirrhosis,and eventual liver failure.Over the past two decades,s...Primary biliary cholangitis(PBC)is a chronic autoimmune cholestatic liver disease characterized by progressive bile duct destruction,leading to fibrosis,cirrhosis,and eventual liver failure.Over the past two decades,significant advancements have paved the way for novel therapeutic strategies.Ursodeoxycholic acid(UDCA)has been the cornerstone of PBC management,improving survival and delaying disease progression in most patients.However,up to 40%of patients demonstrate an inadequate response to UDCA,necessitating additional treatment options.Obeticholic acid(OCA),a farnesoid X receptor agonist,has emerged as a second-line therapy,showing efficacy in reducing alkaline phosphatase levels and improving liver biochemistry.Beyond UDCA and OCA,a new wave of therapeutic agents are reshaping the PBC landscape.These include fibrates,peroxisome proliferator-activated receptor agonists and novel immunomodulatory drugs aimed at reducing autoimmune-mediated liver injury.Bile acid transport inhibitors,anti-fibrotic agents,and gut microbiome-targeted therapies are also under investigation,offering hope for personalized treatment approaches.This review highlights the evolution of PBC therapy,emphasizing the unmet needs of patients with refractory disease and the potential of emerging therapies to improve outcomes.As the therapeutic landscape continues to expand,optimizing treatment strategies through precision medicine holds the promise of transforming the management of PBC.展开更多
We present a proof of the Strominger-Yau-Zaslow (SYZ) conjecture by demonstrating that mirror symmetry fundamentally represents an equivalence of computational structures between Calabi-Yau manifolds. Through developm...We present a proof of the Strominger-Yau-Zaslow (SYZ) conjecture by demonstrating that mirror symmetry fundamentally represents an equivalence of computational structures between Calabi-Yau manifolds. Through development of a rigorous quantum complexity operator formalism, we show that mirror pairs must have equivalent complexity spectra and that the SYZ fibration naturally preserves these computational invariants while implementing the required geometric transformations. Our proof proceeds by first establishing a precise mathematical framework connecting quantum complexity with geometric structures, then demonstrating that the special Lagrangian torus fibration preserves computational complexity at both local and global levels, and finally proving that this preservation necessarily implies the geometric correspondences required by the SYZ conjecture. This approach not only resolves the conjecture but reveals deeper insights about the relationship between computation and geometry in string theory. We introduce new complexity-based invariants for studying mirror symmetry and demonstrate how our framework extends naturally to related geometric structures.展开更多
A discrete Hopf fibration of S15 over S8 with S7 (unit octonions) as fibers leads to a 16D Polytope P16 with 4320 vertices obtained from the convex hull of the 16D Barnes-Wall lattice Λ16. It is argued (conjectured) ...A discrete Hopf fibration of S15 over S8 with S7 (unit octonions) as fibers leads to a 16D Polytope P16 with 4320 vertices obtained from the convex hull of the 16D Barnes-Wall lattice Λ16. It is argued (conjectured) how a subsequent 2-1 mapping (projection) of P16 onto a 8D-hyperplane might furnish the 2160 vertices of the uniform 241 polytope in 8-dimensions, and such that one can capture the chain sequence of polytopes 241,231,221,211in D=8,7,6,5dimensions, leading, respectively, to the sequence of Coxeter groups E8,E7,E6,SO(10)which are putative GUT group candidates. An embedding of the E8⊕E8and E8⊕E8⊕E8lattice into the Barnes-Wall Λ16 and Leech Λ24 lattices, respectively, is explicitly shown. From the 16D lattice E8⊕E8one can generate two separate families of Elser-Sloane 4D quasicrystals (QC’s) with H4 (icosahedral) symmetry via the “cut-and-project” method from 8D to 4D in each separate E8 lattice. Therefore, one obtains in this fashion the Cartesian product of two Elser-Sloane QC’s Q×Qspanning an 8D space. Similarly, from the 24D lattice E8⊕E8⊕E8one can generate the Cartesian product of three Elser-Sloane 4D quasicrystals (QC’s) Q×Q×Qwith H4 symmetry and spanning a 12D space.展开更多
The cardioprotective effects of lipid-lowering drugs have been primarily attributed to their effects on blood lipid metabolism.However,emerging evidence indicates that lipid-lowering drugs also modulate the synthesis ...The cardioprotective effects of lipid-lowering drugs have been primarily attributed to their effects on blood lipid metabolism.However,emerging evidence indicates that lipid-lowering drugs also modulate the synthesis and secretion of adipose tissue-secreted proteins referred to as adipokines.Adipokines influence energy homeostasis and metabolism and have also been shown to modulate the vascular inflammatory cascade.The purpose of this review will be to examine the reported effects of commonly used lipid-lowering drugs(statins,fibrates,niacin and omega-3-fatty acids) on the circulating concentrations of leptin,adiponectin,tumor necrosisfactor-α(TNF-α),Retinol binding protein 4(RBP4) and resistin.Overall,the lipid-lowering drugs reviewed have minimal effects on leptin and resistin concentrations.Conversely,circulating adiponectin concentrations are consistently increased by each lipid-lowering drug reviewed with the greatest effects produced by niacin.Studies that have examined the effects of statins,niacin and omega-3-fatty acids on TNF-α demonstrate that these agents have little effect on circulating TNF-α concentrations.Niacin and fibrates appear to lower RBP4 but not resistin concentrations.The results of the available studies suggest that a strong relationship exists between pharmacological reductions in blood lipids and adiponectin that is not obvious for other adipokines reviewed.展开更多
Nonalcoholic fatty liver disease(NAFLD) is the most common chronic liver disease in developed countries and is associated not only with increased risk for liver disease-related complications but also with higher cardi...Nonalcoholic fatty liver disease(NAFLD) is the most common chronic liver disease in developed countries and is associated not only with increased risk for liver disease-related complications but also with higher cardiovascular morbidity. Accordingly, lipid-lowering agents are frequently considered in these patients to reduce cardiovascular risk. However, there have been concerns regarding the safety of these agents in patients with chronic liver diseases. In the present review, we discuss the safety of lipid-lowering agents in patients with NAFLD as well as their effects on both cardiovascular and liver disease in this population. Accumulating data suggest that statins are safe in patients with NAFLD and that they reduce the increased cardiovascular morbidity of this population. However, it is still unclear whether statins are also useful as a treatment for NAFLD per se, since there are very limited and conflicting data on their effects on liver histology. There is also very scarce evidence regarding the safety and efficacy of other lipid-lowering agents in patients with NAFLD. Randomized controlled studies are needed to evaluate the role of lipid-lowering agents and particularly statins for the prevention of both cardiovascular and liver disease-related complications in this high-risk population.展开更多
Diabetic retinopathy affects a substantial proportion of patients with diabetes mellitus(DM) and is the leading cause of blindness in working-aged adults. Even though the incidence of diabetic retinopathy has declined...Diabetic retinopathy affects a substantial proportion of patients with diabetes mellitus(DM) and is the leading cause of blindness in working-aged adults. Even though the incidence of diabetic retinopathy has declined in the last decades, its prevalence increased and is expected to rise further as a result of the increasing incidence of type 2 DM(T2DM) and the longer life expectancy of patients with DM. The pathogenesis of diabetic retinopathy is multifactorial. Some observational studies suggested an association between dyslipidemia and the development and progression of retinopathy in patients with DM but others did not confirm this association. Regarding lipid-lowering agents, studies that evaluated the role of statins in the management of these patients are mostly small and yielded discrepant results. Large randomized studies with statins in patients with T2DM showed no benefit of these agents on diabetic retinopathy but were not designed to address this effect. In contrast, both preclinical data and two large randomized controlled studies, the FIELD and the ACCORD trial, showed that fenofibrate delays the progression of diabetic retinopathy. Even though the mechanisms underpinning this favorable effect are not entirely clear, these findings suggest that fenofibrate might represent a useful tool for the management of diabetic retinopathy.展开更多
BACKGROUND Drug toxicity is a common and even serious problem in the gastrointestinal tract that is thought to be caused by a broad spectrum of agents.Although withdrawal of the causative agent would cure the disease ...BACKGROUND Drug toxicity is a common and even serious problem in the gastrointestinal tract that is thought to be caused by a broad spectrum of agents.Although withdrawal of the causative agent would cure the disease knowledge is scarce and mostly derives from case reports and series.AIM To investigate potential triggers of drug-induced colitis(DiC).METHODS We conducted a retrospective,observational case control study.Patients were assigned to DiC or one of two age-and gender-matched control groups(noninflammatory controls and inflammatory colitis of another cause)based on histopathological findings.Histopathology was reassessed in a subset of patients(28 DiC with atherosclerosis,DiC without atherosclerosis and ischaemic colitis each)for validation purposes.Medical history was collected from the electronic database and patient records.Statistical analysis included chi-squared test,t-test,logistic and multivariate regression models.RESULTS Drug-induced colitis was detected in 211 endoscopically sampled biopsy specimens of the colon mucosa(7%of all screened colonoscopic biopsy samples);a total of 633 patients were included equally matched throughout the three groups(291 males,mean age:62.1±16.1 years).In the univariate analysis,DiC was associated with diuretics,dihydropyridines,glycosides,ASS,platelet aggregation inhibitors,nonsteroidal anti-inflammatory drugs(NSAIDs),statins and fibrates,and with atherosclerosis,particularly coronary heart disease,and hyperlipoproteinaemia.Echocardiographic parameters did not show substantial differences.In the multivariate analysis only fibrates[odds ratio(OR)=9.1],NSAIDs(OR=6.7)and atherosclerosis(OR=2.1)proved to be associated with DiC.Both DiC reassessment groups presented milder inflammation than ischaemic colitis.The DiC patients with atherosclerosis exhibited histological features from both DiC without atherosclerosis and ischaemic colitis.CONCLUSION Several drugs indicated for the treatment of cardiovascular and related diseases are associated with DiC.Atherosclerosis and microcirculatory disturbances seem to play an important pathogenetic role.展开更多
Atherogenic dyslipidemia is characterized by increased triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol concentrations.It is highly prevalent in non-alcoholic fatty liver disease(NAFLD)and c...Atherogenic dyslipidemia is characterized by increased triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol concentrations.It is highly prevalent in non-alcoholic fatty liver disease(NAFLD)and contributes to the increased cardiovascular risk associated with this condition.Alongside insulin resistance it plays an important pathogenetic role in NAFLD/non-alcoholic steatohepatitis(NASH)development and progression.It has been shown that cholesterol-lowering reduces cardiovascular risk more in NAFLD vs non-NAFLD high-risk individuals.This evidence highlights the importance of effective lipid modulation in NAFLD.In this narrative review the effects of the most commonly used lipid-lowering therapies on liver outcomes alongside their therapeutic implications in NAFLD/NASH are critically discussed.Preclinical and clinical evidence suggests that statins reduce hepatic steatosis,inflammation and fibrosis in patients with NAFLD/NASH.Most data are derived from observational and small prospective clinical studies using changes in liver enzyme activities,steatosis/fibrosis scores,and imaging evidence of steatosis as surrogates.Also,relevant histologic benefits were noted in small biopsy studies.Atorvastatin and rosuvastatin showed greater benefits,whereas data for other statins are scarce and sometimes conflicting.Similar studies to those of statins showed efficacy of ezetimibe against hepatic steatosis.However,no significant anti-inflammatory and anti-fibrotic actions of ezetimibe have been shown.Preclinical studies showed that fibrates through peroxisome proliferator-activated receptor(PPAR)αactivation may have a role in NAFLD prevention and management.Nevertheless,no relevant benefits have been noted in human studies.Species-related differences in PPARαexpression and its activation responsiveness may help explain this discrepancy.Omega-3 fatty acids reduced hepatic steatosis in numerous heterogeneous studies,but their benefits on hepatic inflammation and fibrosis have not been established.Promising preliminary data for the highly purified eicosapentaenoic acid require further confirmation.Observational studies suggest that proprotein convertase subtilisin/kexin9 inhibitors may also have a role in the management of NAFLD,though this needs to be established by future prospective studies.展开更多
For human immunodeficiency virus(HIV)-infected patients, the 1990s were marked by the introduction of highly active antiretroviral therapy(HAART) representing a new perspective of life for these patients. The use of H...For human immunodeficiency virus(HIV)-infected patients, the 1990s were marked by the introduction of highly active antiretroviral therapy(HAART) representing a new perspective of life for these patients. The use of HAART was shown to effectively suppress the replication of HIV-1 and dramatically reduce mortality and morbidity, which led to a better and longer quality of life for HIV-1-infected patients. Apart from the substantial benefits that result from the use of various HAART regimens, laboratory and clinical experience has shown that HAART can induce severe and considerable adverse effects related to metabolic complications of lipid metabolism, characterized by signs of lipodystrophy, insulin resistance, central adiposity, dyslipidemia, increased risk of cardiovascular disease and even an increased risk of atherosclerosis. New drugs are being studied, new therapeutic strategies are being implemented, and the use of statins, fibrates, and inhibitors of intestinal cholesterol absorption have been effective alternatives. Changes in diet and lifestyle have also shown satisfactory results.展开更多
Gemfibrozil is a widely used lipid modifying drug with well-established hypolipidemic and anti-atherosclerotic benefits; however, the presence of a carboxylic acid moiety in its structure is responsible for side effec...Gemfibrozil is a widely used lipid modifying drug with well-established hypolipidemic and anti-atherosclerotic benefits; however, the presence of a carboxylic acid moiety in its structure is responsible for side effects in the gastrointestinal tract. The principle of bioisosterism was applied to design derivatives replacing the carboxylic acid group. The carboxylic acid group was replaced with bioisoteric groups, such as 1,2,4-triazole-3-thiol and hydroxamic acid. The derivatives were then synthesized, characterized, and evaluated in rats for reduced gastrointestinal irritation and hypolipidemic effects. Gemfibrozil was used as standard for comparison. The derivatives demonstrated less gastric irritation and retained hypolipidemic effects, however the hypolipidemic affects were significantly less than that of Gemfibrozil. The results of this study offers a direction for further research on the application of bioisosterism for the design of new derivatives of Gemfibrozil and other fibric acid derivatives.展开更多
Objective: This study compared the effects of combination statin and fibrate therapy with either statin or fibrate monotherapy on lipid profiles in patients with impaired glucose tolerance (IGT) and a high risk for ca...Objective: This study compared the effects of combination statin and fibrate therapy with either statin or fibrate monotherapy on lipid profiles in patients with impaired glucose tolerance (IGT) and a high risk for cardiovascular disease. Methods & Patients: Forty-five patients with IGT and dyslipidemia (men 25, women 20, mean age 61.7 ± 2.4 yrs) were assigned randomly to the 3 treatment groups for a 6-month period. Results: After 6 months of treatment, low density lipoprotein levels decreased in every group, especially the statin and statin + fibrate groups. Triglyceride levels also decreased in all three groups, especially the fibrate and statin + fibrate groups. High density lipoprotein cholesterol and fasting blood glucose levels did not change in any group. The levels of remnant like cholesterol particles decreased in the fibrate and statin + fibrate groups. There was no change during the study in the levels of creatine phosphokinase, lactate dehydrogenase, or creatinine. Conclusion: Combination statin and fibrate therapy results in greater improvement in lipid profiles than monotherapy with either drug. No marked adverse effects were observed with combination therapy during the study.展开更多
Although the “triglyceride paradox” states that hypertriglyceridemia is less frequent in Blacks and the risk of pancreatitis increases with severe hypertriglyceridemia, we herein report on a case of moderate hypertr...Although the “triglyceride paradox” states that hypertriglyceridemia is less frequent in Blacks and the risk of pancreatitis increases with severe hypertriglyceridemia, we herein report on a case of moderate hypertriglyceridemia revealed by an acute chest syndrome and a milky appearance serum in a 47-year-old type 2 diabetes black patient with prior history of recurrent acute pancreatitis. In addition to insulin therapy and coronary angioplasty, the combination of a statin and a fibrate resulted two months later in a substantial improvement in triglyceride levels and a normal serum appearance.展开更多
文摘In the medical and dental field, the importance and need for the study of materials and drugs for use as bone grafts or regeneration in injured areas due to the presence of fractures, infections or tumors that cause extensive loss of bone tissue is observed. Bone is a specialized, vascularized and dynamic connective tissue that changes throughout the life of the organism. When injured, it has a unique ability to regenerate and repair without the presence of scars, but in some situations, due to the size of the defect, the bone tissue does not regenerate completely. Thus, due to its importance, there is a great development in therapeutic approaches for the treatment of bone defects through studies that include autografts, allografts and artificial materials used alone or in association with bone grafts. Pharmaceuticals composed of biomaterials and osteogenic active substances have been extensively studied because they provide potential for tissue regeneration and new strategies for the treatment of bone defects. Statins work as specific inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoAreductase). They represent efficient drugs in lowering cholesterol, as they reduce platelet aggregation and thrombus deposition;in addition, they promote angiogenesis, reduce the β-amyloid peptide related to Alzheimer’s disease and suppress the activation of T lymphocytes. Furthermore, these substances have been used in the treatment of hypercholesterolemia and coronary artery disease. By inhibiting HMG-CoAreductase, statins not only inhibit cholesterol synthesis, but also exhibit several other beneficial pleiotropic effects. Therefore, there has been increasing interest in researching the effects of statins, including Simvastatin, on bone and osteometabolic diseases. However, statins in high doses cause inflammation in bone defects and inhibit osteoblastic differentiation, negatively contributing to bone repair. Thus, different types of studies with different concentrations of statins have been studied to positively or negatively correlate this drug with bone regeneration. In this review we will address the positive, negative or neutral effects of statins in relation to bone defects providing a comprehensive understanding of their application. Finally, we will discuss a variety of statin-based drugs and the ideal dose through a theoretical basis with preclinical, clinical and laboratory work in order to promote the repair of bone defects.
文摘The use of fibrates in the treatment of dyslipidaemia has changed significantly over recent years.Their role appeared clear at the start of this century.The Helsinki Heart Study and Veterans Affairs High-Density Cholesterol Intervention Trial suggested significant benefit,especially in patients with atherogenic dyslipidaemia.However,this clarity disintegrated following the negative outcomes reported by the Bezafibrate Infarction Prevention,Fenofibrate Intervention and Event Lowering in Diabetes and Action to Control Cardiovascular Risk in Diabetes randomised controlled trials.In this review we discuss these and other relevant trials and consider patient subgroups such as those with the metabolic syndrome and those needing treatment to prevent the microvascular complications associated with diabetes in whom fibrates may be useful.We also discuss observations from our group that may provide some explanation for the varying outcomes reported in large trials.The actions of fibrates in patients who are also on statins are interesting and appear to differ from those in patients not on statins.Understanding this is key as statins are the primary lipid lowering agents and likely to occupy that position for the foreseeable future.We also present other features of fibrate treatment we have observed in our clinical practice;changes in creatinine,liver function tests and the paradoxical high density lipoprotein reduction.Our purpose is to provide enough data for the reader to make objective decisions in their own clinical practice regarding fibrate use.
基金Supported by The National Scientific Foundation of China,No.81270946,No.81170758,No.30670988
文摘AIM： To evaluate the effcacy, effect of preventing cardio-vascular diseases and safety of statins-fbrates combination therapy in diabetic dyslipidemia patients.METHODS： We searched the databases of MEDLINE, EM-BASE, web of knowledge and Cochrane central register of Controlled Trials for literatures about the coadministration of statins and fibrates as the treatment of patients with dyslipidemia and type 2 diabetes mellitus. We included re-lated randomized controlled trials, controlled clinical trials and cross-sectional studies and excluded animal trials and clinical observations. The primary endpoints outcomes were the concentration of plasma total cholesterol （TC）, triglyc-eride （TG）, high density lipoprotein cholesterol （HDL-C） and low density lipoprotein cholesterol （LDL-C）. The secondary outcomes were cardiovascular diseases （CVD） and adverseevents.RESULTS： Ten studies were included in this meta-analysis. For lipid modifying efficacy, the combination of statins and fibrates therapy had more significant effecton reducing TC [ P = 0.004, weighted mean difference （WMD） = -8.19, 95%CI： -13.82--2.56] and TG concentra-tion （P 〈 0.001, WMD = -47.29, 95%CI： -68.66--25.92） and increasing HDL-C concentration （P 〈 0.00001, WMD = 3.79, 95%CI： 2.25-5.33） when compared with statins monotherapy, while the effect of reducing LDL-C concen-tration （ P = 0.50, WMD = -2.52, 95%CI： -9.76-4.72） was insignificant. To fibrates monotherapy, the combination therapy was more effective on reducing TC （ P 〈 0.00001, WMD = -48.51, 95%CI： -57.14--39.89）, TG （ P 〈 0.00001, WMD = -26.07, 95%CI： -30.96--21.18）, LDL-C concentra-tion （ P 〈 0.00001, WMD = -45.74, 95%CI： -53.35--38.13） and increasing HDL-C concentration （ P = 0.04, WMD = 1.38, 95%CI： 0.04-2.73）. For cardiovascular diseases, the coad-ministration therapy had no signifcant effect on reducing the incidence of these events when compared with mono-therapy （For primary clinical endpoints, P = 0.12, OR = 0.61, 95%CI： 0.33-1.14）; for secondary clinical endpoints, P =0.13, OR = 0.66, 95%CI： 0.38-1.14）. For adverse events happened during the follow-up, both the incidence of hepatic-related （alanine aminotransferase and/or aspartate aminotransferase of patients were ≥ 3 times of upper limit of normal） （ P = 0.38, OR = 0.55, 95%CI： 0.15-2.06） and muscular-related （myopathy and/or creatine phosphokinase ≥ 3 times of upper limit of normal） adverse events （P = 0.10, OR = 1.62, 95%CI： 0.91-2.86） had no signifcant dif-ference between these two therapies.CONCLUSION： The results showed statins-fbrates com-bination therapy was more effective on lipid modification and well tolerated but there was no significant effect on preventing cardiovascular diseases.
文摘Primary biliary cholangitis(PBC)is a chronic autoimmune cholestatic liver disease characterized by progressive bile duct destruction,leading to fibrosis,cirrhosis,and eventual liver failure.Over the past two decades,significant advancements have paved the way for novel therapeutic strategies.Ursodeoxycholic acid(UDCA)has been the cornerstone of PBC management,improving survival and delaying disease progression in most patients.However,up to 40%of patients demonstrate an inadequate response to UDCA,necessitating additional treatment options.Obeticholic acid(OCA),a farnesoid X receptor agonist,has emerged as a second-line therapy,showing efficacy in reducing alkaline phosphatase levels and improving liver biochemistry.Beyond UDCA and OCA,a new wave of therapeutic agents are reshaping the PBC landscape.These include fibrates,peroxisome proliferator-activated receptor agonists and novel immunomodulatory drugs aimed at reducing autoimmune-mediated liver injury.Bile acid transport inhibitors,anti-fibrotic agents,and gut microbiome-targeted therapies are also under investigation,offering hope for personalized treatment approaches.This review highlights the evolution of PBC therapy,emphasizing the unmet needs of patients with refractory disease and the potential of emerging therapies to improve outcomes.As the therapeutic landscape continues to expand,optimizing treatment strategies through precision medicine holds the promise of transforming the management of PBC.
文摘We present a proof of the Strominger-Yau-Zaslow (SYZ) conjecture by demonstrating that mirror symmetry fundamentally represents an equivalence of computational structures between Calabi-Yau manifolds. Through development of a rigorous quantum complexity operator formalism, we show that mirror pairs must have equivalent complexity spectra and that the SYZ fibration naturally preserves these computational invariants while implementing the required geometric transformations. Our proof proceeds by first establishing a precise mathematical framework connecting quantum complexity with geometric structures, then demonstrating that the special Lagrangian torus fibration preserves computational complexity at both local and global levels, and finally proving that this preservation necessarily implies the geometric correspondences required by the SYZ conjecture. This approach not only resolves the conjecture but reveals deeper insights about the relationship between computation and geometry in string theory. We introduce new complexity-based invariants for studying mirror symmetry and demonstrate how our framework extends naturally to related geometric structures.
文摘A discrete Hopf fibration of S15 over S8 with S7 (unit octonions) as fibers leads to a 16D Polytope P16 with 4320 vertices obtained from the convex hull of the 16D Barnes-Wall lattice Λ16. It is argued (conjectured) how a subsequent 2-1 mapping (projection) of P16 onto a 8D-hyperplane might furnish the 2160 vertices of the uniform 241 polytope in 8-dimensions, and such that one can capture the chain sequence of polytopes 241,231,221,211in D=8,7,6,5dimensions, leading, respectively, to the sequence of Coxeter groups E8,E7,E6,SO(10)which are putative GUT group candidates. An embedding of the E8⊕E8and E8⊕E8⊕E8lattice into the Barnes-Wall Λ16 and Leech Λ24 lattices, respectively, is explicitly shown. From the 16D lattice E8⊕E8one can generate two separate families of Elser-Sloane 4D quasicrystals (QC’s) with H4 (icosahedral) symmetry via the “cut-and-project” method from 8D to 4D in each separate E8 lattice. Therefore, one obtains in this fashion the Cartesian product of two Elser-Sloane QC’s Q×Qspanning an 8D space. Similarly, from the 24D lattice E8⊕E8⊕E8one can generate the Cartesian product of three Elser-Sloane 4D quasicrystals (QC’s) Q×Q×Qwith H4 symmetry and spanning a 12D space.
基金Supported by Boshell Diabetes and Metabolic Diseases Research Program
文摘The cardioprotective effects of lipid-lowering drugs have been primarily attributed to their effects on blood lipid metabolism.However,emerging evidence indicates that lipid-lowering drugs also modulate the synthesis and secretion of adipose tissue-secreted proteins referred to as adipokines.Adipokines influence energy homeostasis and metabolism and have also been shown to modulate the vascular inflammatory cascade.The purpose of this review will be to examine the reported effects of commonly used lipid-lowering drugs(statins,fibrates,niacin and omega-3-fatty acids) on the circulating concentrations of leptin,adiponectin,tumor necrosisfactor-α(TNF-α),Retinol binding protein 4(RBP4) and resistin.Overall,the lipid-lowering drugs reviewed have minimal effects on leptin and resistin concentrations.Conversely,circulating adiponectin concentrations are consistently increased by each lipid-lowering drug reviewed with the greatest effects produced by niacin.Studies that have examined the effects of statins,niacin and omega-3-fatty acids on TNF-α demonstrate that these agents have little effect on circulating TNF-α concentrations.Niacin and fibrates appear to lower RBP4 but not resistin concentrations.The results of the available studies suggest that a strong relationship exists between pharmacological reductions in blood lipids and adiponectin that is not obvious for other adipokines reviewed.
文摘Nonalcoholic fatty liver disease(NAFLD) is the most common chronic liver disease in developed countries and is associated not only with increased risk for liver disease-related complications but also with higher cardiovascular morbidity. Accordingly, lipid-lowering agents are frequently considered in these patients to reduce cardiovascular risk. However, there have been concerns regarding the safety of these agents in patients with chronic liver diseases. In the present review, we discuss the safety of lipid-lowering agents in patients with NAFLD as well as their effects on both cardiovascular and liver disease in this population. Accumulating data suggest that statins are safe in patients with NAFLD and that they reduce the increased cardiovascular morbidity of this population. However, it is still unclear whether statins are also useful as a treatment for NAFLD per se, since there are very limited and conflicting data on their effects on liver histology. There is also very scarce evidence regarding the safety and efficacy of other lipid-lowering agents in patients with NAFLD. Randomized controlled studies are needed to evaluate the role of lipid-lowering agents and particularly statins for the prevention of both cardiovascular and liver disease-related complications in this high-risk population.
文摘Diabetic retinopathy affects a substantial proportion of patients with diabetes mellitus(DM) and is the leading cause of blindness in working-aged adults. Even though the incidence of diabetic retinopathy has declined in the last decades, its prevalence increased and is expected to rise further as a result of the increasing incidence of type 2 DM(T2DM) and the longer life expectancy of patients with DM. The pathogenesis of diabetic retinopathy is multifactorial. Some observational studies suggested an association between dyslipidemia and the development and progression of retinopathy in patients with DM but others did not confirm this association. Regarding lipid-lowering agents, studies that evaluated the role of statins in the management of these patients are mostly small and yielded discrepant results. Large randomized studies with statins in patients with T2DM showed no benefit of these agents on diabetic retinopathy but were not designed to address this effect. In contrast, both preclinical data and two large randomized controlled studies, the FIELD and the ACCORD trial, showed that fenofibrate delays the progression of diabetic retinopathy. Even though the mechanisms underpinning this favorable effect are not entirely clear, these findings suggest that fenofibrate might represent a useful tool for the management of diabetic retinopathy.
文摘BACKGROUND Drug toxicity is a common and even serious problem in the gastrointestinal tract that is thought to be caused by a broad spectrum of agents.Although withdrawal of the causative agent would cure the disease knowledge is scarce and mostly derives from case reports and series.AIM To investigate potential triggers of drug-induced colitis(DiC).METHODS We conducted a retrospective,observational case control study.Patients were assigned to DiC or one of two age-and gender-matched control groups(noninflammatory controls and inflammatory colitis of another cause)based on histopathological findings.Histopathology was reassessed in a subset of patients(28 DiC with atherosclerosis,DiC without atherosclerosis and ischaemic colitis each)for validation purposes.Medical history was collected from the electronic database and patient records.Statistical analysis included chi-squared test,t-test,logistic and multivariate regression models.RESULTS Drug-induced colitis was detected in 211 endoscopically sampled biopsy specimens of the colon mucosa(7%of all screened colonoscopic biopsy samples);a total of 633 patients were included equally matched throughout the three groups(291 males,mean age:62.1±16.1 years).In the univariate analysis,DiC was associated with diuretics,dihydropyridines,glycosides,ASS,platelet aggregation inhibitors,nonsteroidal anti-inflammatory drugs(NSAIDs),statins and fibrates,and with atherosclerosis,particularly coronary heart disease,and hyperlipoproteinaemia.Echocardiographic parameters did not show substantial differences.In the multivariate analysis only fibrates[odds ratio(OR)=9.1],NSAIDs(OR=6.7)and atherosclerosis(OR=2.1)proved to be associated with DiC.Both DiC reassessment groups presented milder inflammation than ischaemic colitis.The DiC patients with atherosclerosis exhibited histological features from both DiC without atherosclerosis and ischaemic colitis.CONCLUSION Several drugs indicated for the treatment of cardiovascular and related diseases are associated with DiC.Atherosclerosis and microcirculatory disturbances seem to play an important pathogenetic role.
文摘Atherogenic dyslipidemia is characterized by increased triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol concentrations.It is highly prevalent in non-alcoholic fatty liver disease(NAFLD)and contributes to the increased cardiovascular risk associated with this condition.Alongside insulin resistance it plays an important pathogenetic role in NAFLD/non-alcoholic steatohepatitis(NASH)development and progression.It has been shown that cholesterol-lowering reduces cardiovascular risk more in NAFLD vs non-NAFLD high-risk individuals.This evidence highlights the importance of effective lipid modulation in NAFLD.In this narrative review the effects of the most commonly used lipid-lowering therapies on liver outcomes alongside their therapeutic implications in NAFLD/NASH are critically discussed.Preclinical and clinical evidence suggests that statins reduce hepatic steatosis,inflammation and fibrosis in patients with NAFLD/NASH.Most data are derived from observational and small prospective clinical studies using changes in liver enzyme activities,steatosis/fibrosis scores,and imaging evidence of steatosis as surrogates.Also,relevant histologic benefits were noted in small biopsy studies.Atorvastatin and rosuvastatin showed greater benefits,whereas data for other statins are scarce and sometimes conflicting.Similar studies to those of statins showed efficacy of ezetimibe against hepatic steatosis.However,no significant anti-inflammatory and anti-fibrotic actions of ezetimibe have been shown.Preclinical studies showed that fibrates through peroxisome proliferator-activated receptor(PPAR)αactivation may have a role in NAFLD prevention and management.Nevertheless,no relevant benefits have been noted in human studies.Species-related differences in PPARαexpression and its activation responsiveness may help explain this discrepancy.Omega-3 fatty acids reduced hepatic steatosis in numerous heterogeneous studies,but their benefits on hepatic inflammation and fibrosis have not been established.Promising preliminary data for the highly purified eicosapentaenoic acid require further confirmation.Observational studies suggest that proprotein convertase subtilisin/kexin9 inhibitors may also have a role in the management of NAFLD,though this needs to be established by future prospective studies.
基金financially supported in the our laboratory with resources from The National Council of Technological and Scientific Developmentthe State of Sao Paulo Research Foundationthe National Institute of Science and Technology of Complex Fluids.
文摘For human immunodeficiency virus(HIV)-infected patients, the 1990s were marked by the introduction of highly active antiretroviral therapy(HAART) representing a new perspective of life for these patients. The use of HAART was shown to effectively suppress the replication of HIV-1 and dramatically reduce mortality and morbidity, which led to a better and longer quality of life for HIV-1-infected patients. Apart from the substantial benefits that result from the use of various HAART regimens, laboratory and clinical experience has shown that HAART can induce severe and considerable adverse effects related to metabolic complications of lipid metabolism, characterized by signs of lipodystrophy, insulin resistance, central adiposity, dyslipidemia, increased risk of cardiovascular disease and even an increased risk of atherosclerosis. New drugs are being studied, new therapeutic strategies are being implemented, and the use of statins, fibrates, and inhibitors of intestinal cholesterol absorption have been effective alternatives. Changes in diet and lifestyle have also shown satisfactory results.
文摘Gemfibrozil is a widely used lipid modifying drug with well-established hypolipidemic and anti-atherosclerotic benefits; however, the presence of a carboxylic acid moiety in its structure is responsible for side effects in the gastrointestinal tract. The principle of bioisosterism was applied to design derivatives replacing the carboxylic acid group. The carboxylic acid group was replaced with bioisoteric groups, such as 1,2,4-triazole-3-thiol and hydroxamic acid. The derivatives were then synthesized, characterized, and evaluated in rats for reduced gastrointestinal irritation and hypolipidemic effects. Gemfibrozil was used as standard for comparison. The derivatives demonstrated less gastric irritation and retained hypolipidemic effects, however the hypolipidemic affects were significantly less than that of Gemfibrozil. The results of this study offers a direction for further research on the application of bioisosterism for the design of new derivatives of Gemfibrozil and other fibric acid derivatives.
文摘Objective: This study compared the effects of combination statin and fibrate therapy with either statin or fibrate monotherapy on lipid profiles in patients with impaired glucose tolerance (IGT) and a high risk for cardiovascular disease. Methods & Patients: Forty-five patients with IGT and dyslipidemia (men 25, women 20, mean age 61.7 ± 2.4 yrs) were assigned randomly to the 3 treatment groups for a 6-month period. Results: After 6 months of treatment, low density lipoprotein levels decreased in every group, especially the statin and statin + fibrate groups. Triglyceride levels also decreased in all three groups, especially the fibrate and statin + fibrate groups. High density lipoprotein cholesterol and fasting blood glucose levels did not change in any group. The levels of remnant like cholesterol particles decreased in the fibrate and statin + fibrate groups. There was no change during the study in the levels of creatine phosphokinase, lactate dehydrogenase, or creatinine. Conclusion: Combination statin and fibrate therapy results in greater improvement in lipid profiles than monotherapy with either drug. No marked adverse effects were observed with combination therapy during the study.
文摘Although the “triglyceride paradox” states that hypertriglyceridemia is less frequent in Blacks and the risk of pancreatitis increases with severe hypertriglyceridemia, we herein report on a case of moderate hypertriglyceridemia revealed by an acute chest syndrome and a milky appearance serum in a 47-year-old type 2 diabetes black patient with prior history of recurrent acute pancreatitis. In addition to insulin therapy and coronary angioplasty, the combination of a statin and a fibrate resulted two months later in a substantial improvement in triglyceride levels and a normal serum appearance.
