Influence of Statins and Fibrates Drugs on Bone Health and Regeneration

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.

Use of fibrates in the metabolic syndrome:A review

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.

Systematic review and meta-analysis of Statins-Fibrates therapy in diabetic dyslipidemia patients

AIM: To evaluate the efficacy,effect of preventing cardiovascular diseases and safety of statins-fibrates combination therapy in diabetic dyslipidemia patients.METHODS: We searched the databases of MEDLINE,EMBASE,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 related 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),triglyceride(TG),high density lipoprotein cholesterol(HDL-C) and low density lipoprotein cholesterol(LDL-C).The secondary outcomes were cardiovascular diseases(CVD) and adverse events.RESULTS: Ten studies were included in this metaanalysis.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 concentration(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 concentration(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 concentration(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 coadministration therapy had no significant effect on reducing the incidence of these events when compared with monotherapy(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 significant difference between these two therapies.CONCLUSION: The results showed statins-fibrates combination therapy was more effective on lipid modification and well tolerated but there was no significant effect on preventing cardiovascular diseases.

程序语言中共归纳数据类型的一种fibrations方法

范畴论与共代数是程序语言中共归纳数据类型研究的传统方法,这些方法在语义行为分析与共归纳规则描述等方面存在一定的不足。针对以上问题,提出了一种fibrations方法以对共归纳数据类型的语义行为与共归纳规则进行研究。该方法系统分析了fibration上共归纳数据类型的重索引函子、对偶重索引函子与真值函子等基本逻辑结构,应用等式函子与商函子等工具建立共归纳数据类型与其语义行为在程序逻辑上的对应关系,深入分析共归纳数据类型的语义行为;并以基范畴上自函子及其在全范畴上保持等式的提升为工具构造共递归操作,抽象描述共归纳数据类型具有普适意义的共归纳规则;最后通过实例分析简要介绍了fibrations方法的应用。

Pharmacological effects of lipid-lowering drugs on circulating adipokines

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.

Lipid-lowering agents in the management of nonalcoholic fatty liver disease

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.

Triggers of histologically suspected drug-induced colitis

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.

Role of lipid-lowering agents in the management of diabetic retinopathy

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.

类型系统的λω×_≤等式理论及其语义的合理性

类型系统在研究程序设计语言的理论基础方面起着十分重要的作用,特别地,带子类型的多态类型系统可刻画面向对象程序设计语言核心概念,如子类型、多态性等.为研究面向对象程序设计语言的形式理论基础,探讨了一个命名为类型系统λω×≤的带高阶子类型的多态类型系统,并利用插入子和fibration理论,引入λω×≤fibration作为该类型系统的语义模型.进一步,讨论了类型系统λω×≤的等式理论,特别是与受限全称量词有关的等式,并利用插入子的性质,证明了对于该等式理论,λω×≤fibration是合理的语义模型.

Is there a role of lipid-lowering therapies in the management of fatty liver disease?

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.

Impact of antiretroviral therapy on lipid metabolism of human immunodeficiency virus-infected patients: Old and new drugs

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.

Fibrations理论在索引归纳数据类型不确定语义中的应用

应用Fibrations理论对索引归纳数据类型的不确定语义计算进行了研究。论证了索引范畴的构造,提出了索引Fibration及其真值函子与内涵函子,建立了索引范畴上自函子的一种保持真值的提升,提出了部分F-代数的定义,并应用折叠函数等工具抽象描述了索引归纳数据类型不确定语义计算,辅以实例进行了简要分析,最后通过相关工作的论述指出了Fibrations理论研究方法的优势。

Fibrations理论在索引归纳数据类型语法构造中的应用

应用Fibrations理论对索引归纳数据类型的语法构造进行了研究。提出了索引fibration及其真值与内涵函子的定义,构造了索引与代数范畴,利用折叠函数与伴随函子等工具构造了索引范畴中一类相对复杂的索引归纳数据类型,辅以实例进行了简要分析,并通过相关工作的论述指出了Fibrations理论研究方法的优势。

Combination Lipid Therapy on Lipid Profiles in Patients with Impaired Glucose Tolerance

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.

Moderate Hypertriglyceridemia Revealed by Acute Chest Syndrome, a Milky Appearance Serum and Prior History of Recurrent Acute Pancreatitis in a Type 2 Diabetes Black Patient: A Case Report

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.

基于Fibrations理论的共享系统数据模型

传统共享系统数据模型的建模方法在语义性质分析和语义行为描述方面存在不足,针对以上问题提出了一种基于Fibrations理论的共享系统数据模型。主要工作体现在两个方面:首先,应用真值函子、保持真值的提升与内涵函子并结合代数方法精确分析了语义性质,应用等式函子、保持等式的提升及商函子并结合共代数方法形式化描述了语义行为;其次,在Fibrations理论框架内构造复杂归纳与共归纳数据结构上参数化的递归与共递归操作,抽象描述具有普适意义的归纳与共归纳规则,结合实例简要介绍了Fibrations理论的应用。相对于范畴论等传统方法,简洁描述与灵活扩展的Fibrations理论对共享系统数据模型的语义性质和语义行为进行了精确分析与形式化描述,抽象描述了复杂数据结构具有普适性的归纳与共归纳规则。

Synthesis and Chiral Separation of Fibratol, Isopropyl 2-(4-((4-chlorophenyl)(hydroxyl) methyl)-phenoxy)-2-methylpropanoate

Practical synthetic route for the formation of enantiomeric mixture of Isopropyl 2-(4-((4-chlorophenyl)(hydroxyl)methyl)phenoxy)-2-methylpropanoate (Fibratol 2a/b) from isopropyl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate (Fenofibrate 1) has been developed. Method has also been established for the chiral separation of enantiomers of Fibratol 2a/b that is synthesized using the route mentioned above. The optical activity determined for enantiomerically separated Fibratol (2a) and Fibratol (2b) are -5.2° and 8.0° which reflect their ability to rotate plane polarized light counterclockwise (levo) and clockwise (dextro), respectively.

Use of Cholesterol-Lowering Medications of Patients with Myocardial Infarction from 2007-2015 in Cardiology Clinic to “Mother Teresa” University Hospital in Albania

Background: Coronary Heart Disease (CHD) remains the leading cause of morbidity and mortality in Albania. According to Institute of Statistics of Albania (ISA), CHD remains in the 5 first places caused mortality and morbidity in our country. Currently, all the protocol treatments to Mother Teresa University Hospital (MTUH) are focused on low-density lipoprotein cholesterol (LDL-C) as the primary target for risk reduction therapy, followed by triglycerides (TG) and high-density lipoprotein cholesterol (HDL). Our clinicians recommend that the intensity and target goals of LDL-C-lowering therapy should be adjusted to individual treatment. The choice of a specific drug from anti hypercholesterolemia class depends on several factors which need to be evaluated better from our health providers. Methods and Findings: Data was collected between 2007 to 2015 at Mother Teresa University Hospital (MTUH), Intensive Care Unit in Cardiology Clinic. 700 patients were treated with statins as follows: Fluvastain 40 mg and 80 mg, Atorvastatin 10 mg and 20 mg, Simvastatin and Rosuvastatin 20 mg. Statins are increased significantly during the years compared with fibrates. Their use grew from 87% of all statin types to 95% in 2015, with different types from fluvastatin in 2007 to atorvastatin being the leading medication in 2015. Coronary Heart Disease, especially Myocardium Infarct, were studied as diseases when meanly the hypolipidic drugs were usually used in medical protocol treatment. Statins and fibrates were the therapy target to be studied when statin dominated the patients’ treatment and fibrates were used in limited quantity. Atorvastatin is now dominating the market, while fluvastatin was on the first statin therapy for several years in the past. Fibrate were used in the modest quantities in value from 2% to 1.5% in years 2007 to 2015. The use of statins in moderate-risk and high-risk patients showed continued growth subsequently, but stable with dosage of atorvastatin 20 mg. Lower statin dosage used was independently associated for all patients, young patients had used high dosage of statins and fluvastatin respectively 40 mg and 80 mg. The missing high dosage of atorvastatin was notable. The values of LDL were improved but not in the level of efficacy of treatment. Conclusion: Statin therapy becomes more selected compared with fibrate. Atorvastatin 20 mg remains the most important stain used in our clinic, but low dosage remains still a problem. The expected level of LDL-C is the target for the practitioners. More aggressive statins such as rosuvastatin start to be present in our clinic, but it is less used by the patients. Meanwhile the lifestyle, exercises, balance diet, smoking cessation are parts of the patients’ files. The side effects are minors and the medication process has continued.

EQUIVARIANT SELF EQUIVALENCES OF PRINCIPAL FIBRE BUNDLES

Let E be a compact Lie group, G a closed subgroup of E, and H a closed normal subgroup of G . For principal fibre bundle (E,p, E/G;G) and (E/H,p′,E/G;G/H), the relation between aut G(E) (resp. aut * G(E) ) and aut G/H (E/H) (resp.aut * G/H (E/H)) is investigated by using bundle map theory and transformation group theory. It will enable us to compute the group F G(E) (resp. E G(E)) while the group F G/H (E/H) is known.

2-local unstable homotopy groups of indecomposable A^(2)_(3)-complexes

In this paper,we calculate the 2-local unstable homotopy groups of indecomposable A^(2)_(3)-complexes.The main technique used is analysing the homotopy property of J(A,X),defined by Gray(1973) for a CW-pair(X,A),which is homotopy equivalent to the homotopy fibre of the pinch map X∪CA→∑A.