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.

Atorvastatin ameliorated myocardial fibrosis by inhibiting oxidative stress and modulating macrophage polarization in diabetic cardiomyopathy

In this editorial,we commented on the article published in the recent issue of the World Journal of Diabetes.Diabetic cardiomyopathy(DCM)is characterized by myocardial fibrosis,ventricular hypertrophy and diastolic dysfunction in diabetic patients,which can cause heart failure and threaten the life of patients.The pathogenesis of DCM has not been fully clarified,and it may involve oxidative stress,inflammatory stimulation,apoptosis,and autophagy.There is lack of effective therapies for DCM in the clinical practice.Statins have been widely used in the clinical practice for years mainly to reduce cholesterol and stabilize arterial plaques,and exhibit definite cardiovascular protective effects.Studies have shown that statins also have anti-inflammatory and antioxidant effects.We were particularly concerned about the recent findings that atorvastatin alleviated myocardial fibrosis in db/db mice by regulating the antioxidant stress and antiinflammatory effects of macrophage polarization on diabetic myocardium,and thereby improving DCM.

Statins redux:A re-assessment of how statins lower plasma cholesterol

Obesity associated dyslipidemia and its negative effects on the heart and blood vessels have emerged as a major healthcare challenge around the globe. The use of statins, potent inhibitors of hydroxyl-methyl glutaryl(HMG) Co-A reductase, a rate-limiting enzyme in cholesterol biosynthesis, has significantly reduced the rates of cardiovascular and general mortality in patients with coronary artery disease. How statins lower plasma cholesterol levels presents a mechanistic conundrum since persistent exposure to these drugs in vitro or in vivo is known to induce overexpression of the HMG Co-A reductase gene and protein. In an attempt to solve this mechanistic puzzle, Schonewille et al, studied detailed metabolic parameters of cholesterol synthesis, interorgan flux and excretion in mice treated with 3 common statins, rosuvastatin, atorvastatin or lovastatin, each with its unique pharmacokinetics. From the measurements of the rates of heavy water(D_2O) and [^(13)C]-acetate incorporation into lipids, the authors calculated the rates of whole body and organ-specific cholesterol synthesis in control and statin-treated mice. These analyses revealed dramatic enhancement in the rates of hepatic cholesterol biosynthesis in statin-treated mice that concomitantly elicited lower levels of cholesterol in their plasma. The authors have provided strong evidence to indicate that statin treatment in mice led to induction of compensatory metabolic pathways that apparently mitigated an excessive accumulation of cholesterol in the body. It was noted however that changes in cholesterol metabolism induced by 3 statins were not identical. While sustained delivery of all 3 statins led to enhanced rates of biliary excretion of cholesterol and its fecal elimination, only atorvastatin treated mice elicited enhanced trans-intestinal cholesterol excretion. Thus, blockade of HMGCR by statins in mice was associated with profound metabolic adaptations that reset their cholesterol homeostasis. The findings of Schonewille et al, deserve to be corroborated and extended in patients in order to more effectively utilize these important cholesterol-lowering drugs in the clinic.

Statine乃其类似物的合成

Statine及其类似物存在于一些具有抗肿瘤、抗病毒、抗炎症等生理活性的天然产物之中.本文简要介绍Statine及其类似物的存在及生理活性,并从不同的起始原料出发,介绍它们的立体选择性合成.

Statins and Sepsis Literature Review

Recent data suggest that, in addition to improving dyslipidemia, statin may reduce the risk of infections and infection-related complications. The aim of this study is to make a review of the literature about the effects of statins on clinically relevant outcomes of patients admitted to the hospital and having an infection and/or sepsis, principally in terms of intensive care unit admissions and related death.

Comment on: Statin use and risk of diabetes mellitus

In manuscript named "Statin use and risk of diabetes mellitus" by Chogtu et al, authors defined that pravastatin 40 mg/dL reduced the risk of diabetes by 30% in West of Scotland Coronary Prevention study. In fact, pravastatin 40 mg/d L reduced coronary heart disease risk approximately 30% in mentioned study.

固相合成法制备环肽Hymenistatin-1及其含statine的类似物

目的研究固相合成法制备Hymenistatin-1[HS-1,序列为cyclo-(-Pro-Pro-Tyr-Val-Pro-Leu-Ile-Ile-)]及其statine类似物的工艺步骤和影响因素。方法采用Fmoc或Boc保护α-氨基,以HBTU/NMM为缩合剂进行直链肽接肽反应、以BOP/HOBt/DIEA为缩合剂进行环化固相合成HS-1及其类似物。用色谱仪和质谱仪对合成的环肽及其杂聚肽类似物进行纯化鉴定。结果多肽合成收率可达65%,经反相高效液相色谱(RP-HPLC)柱对合成的多肽进行纯化后纯度均达到90%以上,通过基质辅助激光解吸附电离飞行质谱仪(MALDI-MS)检测所合成的环肽及环肽类似物的分子质量与理论分子质量相符。结论成功合成出了较高纯度的目标多肽化合物。

Statin加上抗癌药物可对抗脑癌细胞

据美国BIOCOMPARE科技新闻网（2007／1／24）报道，约翰霍普金斯Kimmel癌症研究中心的研究小组，利用与statin类药物和一种实验性抗癌药物阻断导致癌症生成的讯号，成功地杀死了脑癌细胞。

Impact of cardiologist intervention on guideline-directed use of statin therapy

BACKGROUND Statins have an important and well-established role in the prevention of atherosclerotic cardiovascular disease(ASCVD).However,several studies have reported widespread underuse of statins in various practice settings and populations.Review of relevant literature reveals opportunities for improvement in the implementation of guideline-directed statin therapy(GDST).AIM To examine the impact of cardiologist intervention on the use of GDST in the ambulatory setting.METHODS Patients with at least one encounter at the adult Internal Medicine Clinic(IMC)and/or Cardiology Clinic(CC),who had an available serum cholesterol test performed,were evaluated.The 2 comparison groups were defined as:(1)Patients only seen by IMC;and(2)Patients seen by both IMC and CC.Patients were excluded if variables needed for calculation of ASCVD risk scores were lacking,and if demographic information lacked guideline-directed treatment recommendations.Data were analyzed using student t-tests or χ^2,as appropriate.Analysis of Variance was used to compare rates of adherence to GDST.RESULTS A total of 268 patients met the inclusion criteria for this study;211 in the IMC group and 57 in the IMC-CC group.Overall,56%of patients were female,mean age 56 years(±10.65,SD),22%Black or African American,56%Hispanic/Latino,14%had clinical ASCVD,13%current smokers,66%diabetic and 63%hypertensive.Statin use was observed in 55%(n=147/268)of the entire patient cohort.In the IMC-CC group,73.6%(n=42/57)of patients were prescribed statin therapy compared to 50.7%(n=107/211)of patients in the IMC group(P=0.002).In terms of appropriate statin use based on guidelines,there was no statistical difference between groups[IMC-CC group 61.4%(n=35/57)vs IMC group,55.5%(n=117/211),P=0.421].Patients in the IMC-CC group were older,had more cardiac risk factors and had higher proportions of non-white patients compared to the IMC group(P<0.02,all).CONCLUSION Although overall use of GDST was suboptimal,there was no statistical difference in appropriate statin use based on guidelines between groups managed by general internists alone or co-managed with a cardiologist.These findings highlight the need to design and implement strategies to improve adherence rates to GDST across all specialties.

The Effect of Atorvastatin on Liver Function among Patients with Coronary Heart Disease in Gaza Strip

Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, are considered as one of the most important drugs and the drug of choice for reducing an abnormal cholesterol level. Statins are normally used to decrease the risk of coronary heart disease (CHD), but they tend to be associated with liver adverse effects. The objective of this prospective study was to investigate the effect of atorvastatin therapy on the liver function in patients with CHD. Study comprised of 66 newly diagnosed CHD patients who were selected from UNRWA clinics in the Gaza Strip. The patients were clinically examined and treated with atorvastatin (10 - 40 mg/day). A questionnaire was used to collect the data concerning patient’s characteristics. Total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), liver enzymes tests such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and total and direct blood bilirubin were measured before starting treatment and after 3 and 6 months of treatment. The results showed a significant increase in the mean values of ALT, AST, total bilirubin and direct bilirubin levels after 3 months then decreased after the next 3 months, but they were higher than the baseline with insignificant association.

Osteoprotegerin Secretion by Mevastatin via p38MAPK and NF-kB

Osteoprotegerin (OPG) is a protein produced by many cell types that has the remarkable property of inhibiting bone loss. It does this by binding to the key bone resorptive cytokine, receptor activator of NF-kB ligand (RANKL). This cytokine is produced mainly by osteoblastic cells and is instrumental in osteoclast differentiation. If the ratio of RANKL:OPG increases, bone resorption increases and results in bone loss in diseases such osteoporosis, rheumatoid arthritis and hypercalcaemia of malignancy. Hence, if drugs can be found that increase OPG, this will decrease the activity of osteoclasts and therefore bone resorption. Statins are cholesterol lowering drugs that have recently been shown to increase bone formation in rodents. It was hypothesised from this finding that this could be due to an increase in OPG production. If these commonly prescribed drugs could be used to prevent bone loss or to increase bone formation then this may prove a useful means of reducing fracture risk in patients. Treating Saos-2 osteoblast-like cells in vitro with mevastatin increased OPG production and secretion through the mevalonate pathway. A failure of geranylgeranylation of Rho and/or farnesylation of Ras proteins leads to an increase in PI-3K activation then AKT activation leading to several different signaling pathways such as MAPK’s and NF-kB. NF-kB and p38MAPK inhibitors prevented the statin stimulation of OPG but not the decrease in cell number, suggesting that statins regulate OPG secretion via PI-3K, p38MAPK and NF-kB.

氮端Fmoc保护的Statine类化合物的合成

采用DIC为羧基活化剂成功实现氮端Fmoc保护的亮氨酸与Meldrum’s acid反应,生成1,3-二氧杂环己烷-4,6-二酮衍生物,后者无需纯化直接在乙酸乙酯中加热回流,自动关环产生Tetramic acid化合物。Tetra-mic acid用NaBH4还原得到4-羟基-吡咯烷酮类衍生物,继之水解,即得氮端Fmoc保护的Statine(6a)。立体化学研究证明,6a具有3S,4S结构,且手性纯度很高。

新型含二茂铁Statine衍生物的合成

采用液相合成法,以DCC/HOBt作缩合试剂,合成了新型含二茂铁Statine化合物FcCO-NH-Val-Statine-Phe-Val-OMe,用IR、1HNMR、MALDI-TOF MS、元素分析进行了结构表征,分析了其波谱数据,抑菌实验表明其在浓度为5×10-4mol/L时,对米曲霉抑制率为29.4%。

Statin use and risk of diabetes mellitus

The 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors, statins, are widely used in the primary and secondary prevention of cardiovascular diseases to lower serum cholesterol levels. As type 2 diabetes mellitus is accompanied by dyslipidemia, statins have a major role in preventing the long term complications in diabetes and are recommended for diabetics with normal low density lipoprotein levels as well. In 2012, United States Food and Drug Administration released changes to statin safety label to include that statins have been found to increase glycosylated haemoglobin and fasting serum glucose levels. Many studies done on patients with cardiovascular risk factors have shown that statins have diabetogenic potential and the effect varies as per the dosage and type used. The various mechanisms for this effect have been proposed and one of them is downregulation of glucose transporters by the statins. The recommendations by the investigators are that though statins can have diabetogenic risk, they have more long term benefits which can outweigh the risk. In elderly patients and those with metabolic syndrome, as the risk of diabetes increase, the statins should be used cautiously. Other than a subset of population with risk for diabetes; statins still have long term survival benefits in most of the patients.

Lipid dysregulation in hepatitis C virus, and impact of statin therapy upon clinical outcomes

The hepatitis C virus(HCV) is one of the most common causes of chronic liver disease and the leading indication for liver transplantation worldwide. Every aspect of the HCV life cycle is closely tied to human lipid metabolism. The virus circulates as a lipid-rich particle, utilizing lipoprotein cell receptors to gain entry into the hepatocyte. It has also been shown to upregulate lipid biosynthesis and impair lipid degradation, resulting in significant intracellular lipid accumulation and circulating hypocholesterolemia. Patients with chronic hepatitis C(CHC) are at increased risk of hepatic steatosis, fibrosis, and cardiovascular disease including accelerated atherosclerosis. HMG Co A Reductase inhibitors, or statins, have been shown to play an important role in the modulation of hepatic steatosis and fibrosis, and recent attention has focused upon their potential therapeutic role in CHC. This article reviews the hepatitis C viral life cycle as it impacts host lipoproteins and lipid metabolism. It then describes the pathogenesis of HCV-related hepatic steatosis, hypocholesterolemia and atherosclerosis, and finally describes the promising anti-viral and anti-fibrotic effects of statins, for the treatment of CHC.

Prevention of hepatocellular carcinoma by correction of metabolic abnormalities: Role of statins and metformin

Hepatocellular carcinoma is the third leading cause of cancer-related deaths in the world. It is associated with an important mortality rate and the incidence is increasing. Patients showing metabolic syndrome seem to have higher incidence and mortality rates from hepatocellular carcinoma than healthy subjects, especially those with type 2 diabetes mellitus and obesity. Thus, metformin and statins, both to treat features of metabolic syndrome, have been proposed to decrease the risk of hepatocellular carcinoma. Otherwise, liver cancer is the result of a complex process which impairs several signaling cascades, such as RAS/RAF/mitogen-activated protein kinase kinase(MEK)/extracellularsignal-regulated kinase(ERK), phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K)/AKT/mammalian target of rapamycin(m TOR) and Wnt/β-catenin signaling. Metformin(through 5′-adenosine monophosphateactivated protein kinase pathway activation) and statins(through 3-hydroxy-3-methylglutaryl coenzyme A inhibition) show anti-tumoral properties modifying several steps of RAS/RAF/MEK/ERK, PI3K/AKT/m TOR and Wnt/β-catenin signaling cascades. On the other hand, metformin and statins have been found to reduce the risk of hepatocellular carcinoma up to 50% and 60%, respectively. Furthermore, both drugs have shown a dose-dependent protective effect. However, information about chemopreventive role of metformin and statins is mainly obtained of observational studies,which could not take into account some bias. In conclusion, given the rising of incidence of hepatocellular carcinoma and the important morbidity and mortality rates associated with this cancer, looking for chemopreventive strategies is an essential task. Randomized controlled trials are needed to determine the definite role of metformin and statins on the prevention of hepatocellular carcinoma.

Statin use and the risk of colorectal cancer: A population-based case-control study

AIM: To investigate whether the use of statins is associated with colorectal cancer risk. METHODS: We conducted a population-based case-control study in Taiwan. Data were retrospectively collected from the Taiwan National Health Insurance Research Database. Cases consisted of all patients who were aged 50 years and older and had a first-time diagnosis of colorectal cancer between the period 2005 and 2008. The controls were matched to cases by age, sex, and index date. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multiple logistic regression. RESULTS: We examined 1156 colorectal cancer cases and 4624 controls. The unadjusted ORs for any statin prescription was 1.10 (95% CI = 0.94-1.30) and the adjusted OR was 1.09 (95% CI = 0.91-1.30). When statin use was categorized by cumulative dose, the adjusted ORs were 0.99 (95% CI = 0.78-1.27) for the group with cumulative statin use below 105 defined daily doses (DDDs); 1.07 (95% CI = 0.78-1.49) for the group with cumulative statin use between 106 and 298.66 DDDs; and 1.30 (95% CI = 0.96-1.75) for the group with cumulative statin use of 298.66 DDDs or more compared with nonusers. CONCLUSION: This study does not provide support for a protective effect of statins against colorectal cancer.

Rhabdomyolysis after midazolam administration in a cirrhotic patient treated with atorvastatin

The administration of statins in patients with liver disease is not an absolute contraindication. Hepatotoxicity is a rare and often dose-related event and in the literature there are only a few described cases of fatal rhab-domyolysis in patients with chronic liver disease after statin administration. During treatment with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors,the factors responsible for myopathy may either be related to the patient,or due to interactions with other medications that are metabolic substrates of the same isozymes and therefore able to increase blood statin concentration. The most important side effects consist of increased transaminase levels,abdominal pain or muscle weakness,increased serum levels of creatine kinase and rhabdomyolysis. In this article we report a case of fatal rhabdomyolysis with acute renal failure after gastric endoscopy,where midazolam was used as a sedation agent in a patient with chronic liver disease treated with a high dose of atorvastatin. Therefore,we suggest paying particular attention to the potential risks of associating atorvastatin and midazolam in patients with chronic liver disease who need to undergo gastric endoscopy.

Pleiotropic effects of statins in the diseases of the liver

Statins are a class of molecules that inhibit HMG Co A reductase. They are usually prescribed as a lipid lowering medication. However, there is accumulating evidence that statins have multiple secondary effects both related and unrelated to their lipid-lowering effect. This narrative review of the literature aims to provide the reader with information from clinical studies related to the effect of statin and statins' potential use in patients with liver diseases. In patients with advanced liver disease due to any etiology, statins exhibit an antifibrotic effect possibly through the prevention of hepatic sinusoidal microthrombosis. Two randomized controlled trials confirmed that statins decrease hepatic vein pressure gradient in patients with portal hypertension and improve the survival of patients after variceal bleeding. Lower rates of infections were observed in patients with cirrhosis who received statin treatment. Statins decrease the risk of hepatocellular carcinoma(HCC) in patients with advanced liver disease in general but particularly in patients with chronic hepatitis B and C. Statins in patients with chronic hepatitis C likely increase the virological response to the treatment with pegylated interferon and ribavirin and have the potential to decrease the rate of fibrosis. Finally, data from randomized controlled trials also confirmed that the addition of statin prolongs the survival of patients with advanced HCC even more than sorafenib. Statins are a very promising group of drugs especially in patients with liver disease, where therapeutic options can often be limited. Some indications, such as the prevention of re-bleeding from esophageal varices and the palliative treatment of HCC have been proven through randomized controlled trials, while additional indications still need to be confirmed through prospective studies.

Neuroprotective effects of statins against amyloid β-induced neurotoxicity

A growing body of evidence suggests that disruption of the homeostasis of lipid metabolism affects the pathogenesis of Alzheimer＇s disease （AD）. In particular, dysregulation of cholesterol homeostasis in the brain has been reported to considerably increase the risk of developing AD. Thus, dysregulation of lipid homeostasis may increase the amyloid β （Aβ） levels by affecting amyloid precursor protein （APP） cleavage, which is the most important risk factor involved in the pathogenesis of AD. Previous research demonstrated that Aβ can trigger neuronal insulin resistance, which plays an important role in response to Aβ-induced neurotoxicity in AD. Epidemiological studies also suggested that statin use is associated with a decreased incidence of AD. Therefore, statins are believed to be a good candidate for conferring neuropro- tective effects against AD. Statins may play a beneficial role in reducing A^-induced neurotoxicity. Their effect involves a putative mechanism beyond its cholesterol-lowering effects in preventing A[3-induced neurotoxicity. However, the underlying molecular mechanisms of the protective effect of statins have not been clearly determined in Aβ-induced neurotoxicity. Given that statins may provide benefits beyond the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A （HMG-CoA） reductase, these drugs may also improve the brain. Thus, statins may have beneficial effects on impaired insulin signaling by activating AMP-activated protein kinase （AMPK） in neuronal cells. They play a potential therapeutic role in targeting Aβ-mediated neurotoxicity.