Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an essential role in the degradation of low‐density lipoprotein C (LDL‐C) receptors, and PCSK9 inhibitors have recently emerged as a potential treatment option to reduce LDL‐C. Our paper reviewed the current available Phase II clinical trials of PCSK9 inhibitors for the treatment of dyslipidemia. A second objective of this review was to evaluate the potential clinical role of PCSK9 inhibitors in the management of dyslipidemia. Studies evaluating the efficacy and safety of any PCSK9 inhibitors in patients with dyslipidemia were included. The monoclonal antibodies REGN727/SAR236553 and AMG145 have the most published clinical data. Seven phase II trials were retrieved that evaluated the efficacy and safety of REGN727/SAR236553 or AMG145 in patients with either hypercholesterolemia or heterozygous familial hypercholesterolemia (HeFH). These two agents significantly decreased LDL‐C levels either as monotherapy or in combination with other lipid‐lowering agents. REGN727/SAR236553 and AMG145 have been well tolerated. The ongoing phase III trials of these two agents are summarized. REGN727/SAR236553 and AMG145 have demonstrated the potential to further decrease LDL‐C levels when added to conventional lipid‐lowering therapy. Morbidity and mortality data are required to define their roles in clinical practice. 相似文献
We tested to find out whether pravastatin restores the infarct size (IS)-limiting effect of ischemic preconditioning (IP) and if it has any effect on the IP-induced activation of adenosine producing enzyme ecto-5′-nucleotidase which plays a key role in the IP-induced cardioprotection.
BACKGROUND
The IS-limiting effect of IP is blunted by hypercholesterolemia. Recently, HMG-CoA reductase inhibitors are shown to have direct cytoprotective effects.
METHODS
Rabbits were fed with a normal or cholesterol (1%) added diet with or without pravastatin (5 mg/kg/day) treatment. Infarct size was measured after 30 min occlusion and 3 h reperfusion of circumflex coronary artery with or without the IP procedure (5 min occlusion and 10 min reperfusion). Additionally, ecto-5′-nucleotidase activities of ischemic and nonischemic myocardium were measured immediately after IP procedure.
RESULTS
This dose of pravastatin did not normalize the increased level of serum cholesterol. The IS-limiting effect of preceding IP (IS reduced from 36.7% to 9.6%, p < 0.001) was abolished by hypercholesterolemia (from 46.1% to 31.3%, p = NS) and restored by pravastatin treatment (from 35.2% to 9.4%, p < 0.001). Pravastatin treatment did not affect IS or the effect of IP under normocholesterolemia. The activation of ecto-5′-nucleotidase presented as the activity ratio of ischemic to nonischemic myocardium (3.1-fold in normocholesterolemia) was blunted by hypercholesterolemia (1.8-fold, p < 0.05) and restored by pravastatin treatment (2.9-fold).
CONCLUSIONS
Pravastatin, at the dose serum cholesterol was not normalized, restored the IS-limiting effect of IP and IP-induced ecto-5′-nucleotidase activation, which were both blunted by hypercholesterolemia. The activation of ecto-5′-nucleotidase may be worth further investigation as a possible mechanism for the hypercholesterolemia-induced retardation and pravastatin-mediated restoration of the cardioprotective effect of IP. 相似文献
Mushroom farm workers suffer from respiratory symptoms during the farming of mushrooms. The objective of this study was to analyze the effects of oyster mushroom (Pleurotus ostreatus) extract (OME) on isolated guinea pig tracheal smooth muscle in vitro. Isolated guinea pig tracheal tissue from 27 nonsensitized guinea pigs were studied. The OME was obtained from indoor mushroom growing fields and prepared as a 1:10 w/v aqueous solution. Dose-related contractions of nonsensitized guinea pig trachea were demonstrated using these extracts. The OME contained significant quantities of bacterial components (eg., endotoxin: 43,072.92 EU/mg). Parallel, pharmacological studies were performed by pre-treating the tissues with mediator-modifying agents including atropine, indomethacin, pyrilamine, BPB, acivicin, NDGA, captopril, TMB8 and capsaicin. Atropine consistently and strikingly reduced the contractile effects of this extract. These observations suggest an interaction of the OME with parasympathetic nerves or more directly with muscarinic receptors. Pretreatment with TMB8 (inhibitor of intracellular calcium mobilization) also significantly blocked the constrictor effect of OME, indicating a role of calcium mobilization in the constricting effect of OME. Inhibition of contraction by blocking of other mediators was less effective and varied depending on the drug. We conclude that OME causes a dose-related airway smooth muscle constriction by nonimmunological mechanisms involving a variety of airway mediators and possibly cholinergic receptors. This effect is not dependent on pre-sensitization of the guinea pigs. 相似文献
OBJECTIVE: To assess use of cholesterol-lowering therapy and related beliefs among middle-aged adults after myocardial infarction. DESIGN: Telephone survey and administrative data. SETTING: National managed-care company. PARTICIPANTS: Six hundred ninety-six adults age 30 to 64 surveyed in 1999, approximately 1 to 2 years after a myocardial infarction. MEASUREMENTS: Use of cholesterol-lowering drugs, beliefs about the importance of lowering cholesterol, and knowledge of personal cholesterol level, adjusting for demographic and clinical factors with logistic regression. MAIN RESULTS: Among respondents, 62.5% reported they were taking a cholesterol-lowering drug. In adjusted analyses, these drugs were used significantly less often by African-American patients and those with congestive heart failure or peripheral vascular disease, and more often by college graduates, patients with hypertension, and those who had seen a cardiologist since their myocardial infarction. Lowering cholesterol was viewed as "very important"; by 87.1% of patients, but significantly less often by smokers and more often by those who had undergone coronary angioplasty or bypass surgery. Only 42.5% of respondents knew their cholesterol level, and this knowledge was significantly less common among less-educated or less-affluent patients, African-American patients, and patients who smoked or had diabetes or peripheral vascular disease. CONCLUSIONS: Although most patients recognized the importance of lowering cholesterol after myocardial infarction, several clinical and demographic subgroups were less likely to receive cholesterol-lowering therapy, and many patients were unaware of their cholesterol level. Health-care providers and managed-care plans can use these findings to promote cholesterol testing and treatment for patients with coronary heart disease who are most likely to benefit from these efforts. 相似文献
BACKGROUND: Replacement of animal protein with soy protein in the diet is associated with decreased cholesterol levels. However, the effects of soy protein diet on endothelial function are not well known. HYPOTHESIS: The aim of the study was to investigate the effects of soy protein diet on plasma lipids and endothelial function parameters assessed by two different methods. METHODS: Twenty hypercholesterolemic, nonsmoker male patients (age 50.1+/-11.8 years), with a normal body mass index, were included. After calculating their daily requirements, a diet with 25-30% of energy from fats. 10-12% from proteins, and the rest from carbohydrates was instituted. Sixty percent of the animal source proteins of the diet were substituted by soy. The anthropometric measures, lipid parameters, and endothelial functions of the subjects were assessed at baseline and 6 weeks after soy protein diet. Flow-mediated endothelium-dependent dilatation (EDD) and plasma thrombomodulin (TM) levels were evaluated as endothelial function parameters. RESULTS: After diet, plasma total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, and triglyceride levels decreased significantly (p <0.001, p < 0.001, p = 0.039, and p = 0.001, respectively). The mean plasma TM levels were also significantly reduced with diet (p = 0.004). Studies of the brachial artery indicated a borderline dilatation in baseline brachial artery diameter (p = 0.05), however the diameter at reactive hyperemia was significantly larger after diet (p<0.001), resulting in a significant improvement of EDD (p = 0.002). CONCLUSION: Soy protein diet significantly improves plasma lipid profile in patients with hypercholesterolemia. Furthermore, the endothelial function, as judged by two different methods (EDD and plasma TM levels), also improves with soy protein diet. 相似文献
In this second of a 5-part Focus Seminar series, we focus on precision medicine in the context of vascular disease. The most common vascular disease worldwide is atherosclerosis, which is the primary cause of coronary artery disease, peripheral vascular disease, and a large proportion of strokes and other disorders. Atherosclerosis is a complex genetic disease that likely involves many hundreds to thousands of single nucleotide polymorphisms, each with a relatively modest effect for causing disease. Conversely, although less prevalent, there are many vascular disorders that typically involve only a single genetic change, but these changes can often have a profound effect that is sufficient to cause disease. These are termed “Mendelian vascular diseases,” which include Marfan and Loeys-Dietz syndromes. Given the very different genetic basis of atherosclerosis versus Mendelian vascular diseases, this article was divided into 2 parts to cover the most promising precision medicine approaches for these disease types. 相似文献
FH is a genetic disorder characterized by an increase in serum LDL and total cholesterol values. The afflicted patients are at increased risk of premature atherosclerosis and myocardial infarction. Different treatment modalities are present, including pharmacological agents and surgical procedures. The most effective method of therapy in refractive cases is liver transplantation. Herein, we report our experience on 36 cases of patients with FH undergoing liver transplantation in our center, the main referral center of liver transplantation in Iran. The clinical findings, hospital courses, post‐operative complications, and patient follow‐up are also described. 相似文献
We show the long‐term efficacy and safety of modified biliopancreatic diversion for the treatment of LPL‐deficiency. How this option compares with gene therapy is difficult to evaluate due to limited experience. Surgery may be the first option in patients in whom medical therapy is ineffective and gene therapy not applicable. 相似文献