(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Carotid-Stenosis

Carotid artery stenosis is narrowing of the carotid arteries. Asymptomatic carotid stenosis is when this narrowing occurs in people without a history or symptoms of this disease. It is caused by atherosclerosis; that is, the build-up of fats, cholesterol, and other substances in and on the artery walls. Atherosclerosis is more likely to occur in people with several risk factors, such as diabetes, hypertension, hyperlipidaemia, and smoking. As this damage can develop without symptoms, the first symptom can be a fatal or disabling stroke, known as ischaemic stroke. Carotid stenosis leading to ischaemic stroke is most common in men older than 70 years. Ischaemic stroke is a worldwide public health problem.. To assess the effects of pharmacological interventions for the treatment of asymptomatic carotid stenosis in preventing neurological impairment, ipsilateral major or disabling stroke, death, major bleeding, and other outcomes.. We searched the Cochrane Stroke Group trials register, CENTRAL, MEDLINE, Embase, two other databases, and three trials registers from their inception to 9 August 2022. We also checked the reference lists of any relevant systematic reviews identified and contacted specialists in the field for additional references to trials.. We included all randomised controlled trials (RCTs), irrespective of publication status and language, comparing a pharmacological intervention to placebo, no treatment, or another pharmacological intervention for asymptomatic carotid stenosis.. We used standard Cochrane methodological procedures. Two review authors independently extracted the data and assessed the risk of bias of the trials. A third author resolved disagreements when necessary. We assessed the evidence certainty for key outcomes using GRADE.. We included 34 RCTs with 11,571 participants. Data for meta-analysis were available from only 22 studies with 6887 participants. The mean follow-up period was 2.5 years. None of the 34 included studies assessed neurological impairment and quality of life. Antiplatelet agent (acetylsalicylic acid) versus placebo Acetylsalicylic acid (1 study, 372 participants) may result in little to no difference in ipsilateral major or disabling stroke (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.47 to 2.47), stroke-related mortality (RR 1.40, 95% CI 0.54 to 3.59), progression of carotid stenosis (RR 1.16, 95% CI 0.79 to 1.71), and adverse events (RR 0.81, 95% CI 0.41 to 1.59), compared to placebo (all low-certainty evidence). The effect of acetylsalicylic acid on major bleeding is very uncertain (RR 0.98, 95% CI 0.06 to 15.53; very low-certainty evidence). The study did not measure neurological impairment or quality of life. Antihypertensive agents (metoprolol and chlorthalidone) versus placebo The antihypertensive agent, metoprolol, may result in no difference in ipsilateral major or disabling stroke (RR 0.14, 95% CI 0.02 to1.16; 1 study, 793 participants) and stroke-related mortality (RR 0.57, 95% CI 0.17 to 1.94; 1 study, 793 participants) compared to placebo (both low-certainty evidence). However, chlorthalidone may slow the progression of carotid stenosis (RR 0.45, 95% CI 0.23 to 0.91; 1 study, 129 participants; low-certainty evidence) compared to placebo. Neither study measured neurological impairment, major bleeding, adverse events, or quality of life. Anticoagulant agent (warfarin) versus placebo The evidence is very uncertain about the effects of warfarin (1 study, 919 participants) on major bleeding (RR 1.19, 95% CI 0.97 to 1.46; very low-certainty evidence), but it may reduce adverse events (RR 0.89, 95% CI 0.81 to 0.99; low-certainty evidence) compared to placebo. The study did not measure neurological impairment, ipsilateral major or disabling stroke, stroke-related mortality, progression of carotid stenosis, or quality of life. Lipid-lowering agents (atorvastatin, fluvastatin, lovastatin, pravastatin, probucol, and rosuvastatin) versus placebo or no treatment Lipid-lowering agents may result in little to no difference in ipsilateral major or disabling stroke (atorvastatin, lovastatin, pravastatin, and rosuvastatin; RR 0.36, 95% CI 0.09 to 1.53; 5 studies, 2235 participants) stroke-related mortality (lovastatin and pravastatin; RR 0.25, 95% CI 0.03. Although there is no high-certainty evidence to support pharmacological intervention, this does not mean that pharmacological treatments are ineffective in preventing ischaemic cerebral events, morbidity, and mortality. High-quality RCTs are needed to better inform the best medical treatment that may reduce the burden of carotid stenosis. In the interim, clinicians will have to use other sources of information.. پیشینه: تنگی شریان کاروتید عبارت است از باریک شدن شریان‌های کاروتید. تنگی کاروتید بدون نشانه زمانی است که این تنگی در افراد بدون سابقه یا نشانه‌های این بیماری رخ می‌دهد. این عارضه ناشی از آترواسکلروز (atherosclerosis) است؛ یعنی تجمع چربی، کلسترول و دیگر مواد داخل و روی دیواره‌های شریان. احتمال بروز آترواسکلروز در افرادی که عوامل خطر متعددی دارند، مانند دیابت، هیپرتانسیون، هیپرلیپیدمی و مصرف سیگار، بیشتر است. از آنجایی که این آسیب می‌تواند بدون نشانه ایجاد شود، اولین نشانه می‌تواند یک سکته مغزی کشنده یا ناتوان کننده باشد که به عنوان سکته مغزی ایسکمیک شناخته می‌شود. تنگی کاروتید منجر به وقوع سکته مغزی ایسکمیک در مردان بالای 70 سال شایع‌تر رخ می‌دهد. سکته مغزی ایسکمیک یک مشکل سلامت عمومی در سراسر جهان است. اهداف: ارزیابی تاثیرات مداخلات دارویی در درمان تنگی کاروتید بدون نشانه به منظور پیشگیری از بروز‌اختلالات نورولوژیکی، سکته مغزی ماژور یا ناتوان کننده یک طرفه (ipsilateral)، مرگ‌ومیر، خونریزی شدید، و دیگر پیامدها. روش‌های جست‌وجو: پایگاه ثبت کارآزمایی‌های گروه سکته مغزی (stroke) در کاکرین، CENTRAL؛ MEDLINE؛ Embase؛ دو بانک اطلاعاتی دیگر، و سه پایگاه ثبت کارآزمایی را از زمان شروع به کار تا 9 آگوست 2022 جست‌وجو کردیم. هم‌چنین فهرست منابع مرورهای سیستماتیک مرتبط را که شناسایی شدند، بررسی کرده و برای یافتن منابع بیشتر برای کارآزمایی‌ها با متخصصان این زمینه تماس گرفتیم. معیارهای انتخاب: همه کارآزمایی‌های تصادفی‌سازی و کنترل شده (randomised controlled trials; RCTs) را بدون در نظر گرفتن وضعیت انتشار و زبان نگارش مقاله وارد کردیم، که به مقایسه یک مداخله دارویی با دارونما (placebo)، عدم درمان، یا مداخله دارویی دیگر در درمان تنگی کاروتید بدون نشانه پرداختند. گردآوری و تجزیه‌وتحلیل داده‌ها: از پروسیجرهای استاندارد روش‌شناسی (methodology) کاکرین استفاده کردیم. دو نویسنده مرور به‌طور مستقل از هم به استخراج داده‌ها و ارزیابی خطر سوگیری (bias) در کارآزمایی‌ها پرداختند. در صورت لزوم، نویسنده سوم اختلاف‌نظرات را حل‌وفصل کرد. قطعیت شواهد را برای پیامدهای کلیدی با استفاده از رویکرد درجه‌بندی توصیه، ارزیابی، توسعه و ارزشیابی (Grading of Recommendations Assessment, Development and Evaluation; GRADE) ارزیابی کردیم. نتایج اصلی: تعداد 34 RCT را با 11,571 شرکت‌کننده وارد کردیم. برای انجام متاآنالیز، داده‌هایی از فقط 22 مطالعه با 6887 شرکت‌کننده در دسترس بودند. میانگین دوره پیگیری 2.5 سال بود. هیچ یک از 34 مطالعه وارد شده اختلالات نورولوژیکی و کیفیت زندگی را ارزیابی نکردند. عامل ضد پلاکت (استیل‌سالیسیلیک اسید) در برابر دارونما استیل‌سالیسیلیک اسید (acetylsalicylic acid) در مقایسه با دارونما (1 مطالعه، 372 شرکت‌کننده) ممکن است تفاوتی اندک تا عدم تفاوت را در سکته مغزی ماژور یا ناتوان ک

Topics: Aspirin; Atherosclerosis; Atorvastatin; Carotid Stenosis; Chlorthalidone; Fluvastatin; Hemorrhage; Humans; Ischemic Stroke; Metoprolol; Pravastatin; Probucol; Rosuvastatin Calcium; Stroke; Warfarin

Cardiovascular disease, including coronary heart disease, is the leading cause of death both in men and in women in the United States. The purpose of this review is to describe the effectiveness of lipid-lowering therapy in reducing cardiovascular morbidity and mortality, which has recently been extended to patients with mild to moderate hypercholesterolemia, and the cost of providing therapy, which would be prohibitive if all persons with hypercholesterolemia received treatment. Cost-effectiveness analysis provides a rational means of allocating limited health care resources by allowing the comparison of the costs of lipid-lowering therapy, in particular, therapy with beta-hydroxy-beta-methylglutaryl-CoA (coenzyme A) reductase inhibitors (statins), with the costs of atherosclerosis that could be prevented by lowering cholesterol. To extend the benefits of treatment to the large number of persons not receiving therapy, we need to implement more cost-effective treatment by improving risk assessment, increasing treatment effectiveness, and reducing the cost of therapy.

Topics: Anticholesteremic Agents; Atorvastatin; Carotid Stenosis; Cerebrovascular Disorders; Clinical Trials as Topic; Coronary Disease; Cost-Benefit Analysis; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lovastatin; Pravastatin; Pyrroles; Simvastatin

High-risk patients with dyslipidemias resistant to diet and single-agent pharmacotherapy may require combination therapy to achieve target levels of low density lipoprotein, triglycerides, and high density lipoprotein. Combinations of fibrates and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are effective, but because of safety concerns related to myopathy and rhabdomyolysis, it is important to consider the possibility of pharmacokinetic interactions when such combinations are used. In this study, the area under the curve, maximum plasma concentration, and time to maximum concentration for fluvastatin and gemfibrozil are compared, when used alone and in combination, in patients with hyperlipidemia and either coronary or carotid atherosclerosis, or a family history of coronary artery disease. A total of 17 patients were studied in a random sequence, open-label, crossover study of fluvastatin at 20 mg twice daily, gemfibrozil at 600 mg twice daily, and the combination of the 2 drugs. No significant difference was observed in area under the curve, maximum plasma concentration, and time to maximum concentration when comparing the combination with each drug alone. These pharmacokinetic data add support to the clinical observations that the combination of fluvastatin and gemfibrozil is both effective and safe.

Topics: Anticholesteremic Agents; Arteriosclerosis; Carotid Stenosis; Coronary Artery Disease; Coronary Disease; Cross-Over Studies; Drug Combinations; Fatty Acids, Monounsaturated; Female; Fluvastatin; Gemfibrozil; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Indoles; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Pilot Projects; Placebos; Safety; Triglycerides

Interleukin (IL)-33, a member of the IL-1 family of cytokines, is involved in various inflammatory conditions targeting amongst other cells the endothelium. Besides regulating the maturation and functions of myeloid cells, granulocyte macrophage-colony stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) have been shown to play a role in such pathologies too. It was the aim of our study to investigate a possible influence of IL-33 on GM-CSF and M-CSF production by human endothelial cells. IL-33, but not IL-18 or IL-37, stimulated GM-CSF and M-CSF mRNA expression and protein production by human umbilical vein endothelial cells (HUVECs) and human coronary artery ECs (HCAECs) through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway in an IL-1-independent way. This effect was inhibited by the soluble form of ST2 (sST2), which is known to act as a decoy receptor for IL-33. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor fluvastatin could also be shown to moderately reduce the IL-33-mediated effect on M-CSF, but not on GM-CSF expression. In addition, IL-33, IL-1β, GM-CSF and M-CSF were detected in endothelial cells of human carotid atherosclerotic plaques using immunofluorescence. Upregulation of GM-CSF and M-CSF production by human endothelial cells, an effect that appears to be mediated by NF-κB and to be independent of IL-1, may be an additional mechanism through which IL-33 contributes to inflammatory activation of the vessel wall.

Topics: Carotid Stenosis; Cells, Cultured; Endothelial Cells; Fatty Acids, Monounsaturated; Fluvastatin; Granulocyte-Macrophage Colony-Stimulating Factor; Human Umbilical Vein Endothelial Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Inflammation Mediators; Interleukin-1; Interleukin-18; Interleukin-1beta; Interleukin-33; Macrophage Colony-Stimulating Factor; NF-kappa B; Recombinant Proteins; RNA, Messenger; Up-Regulation

Although it has been demonstrated that statins stabilize atherosclerotic lesions in animal models of advanced atherosclerosis, there is little evidence to suggest that statins have a preventive effect on plaque rupture itself. In the present study, we examined the effect of fluvastatin on plaque disruption using a simple and quick method of plaque disruption in carotid artery lesions in apolipoprotein E-deficient mice. Male apolipoprotein E-deficient mice received normal chow and underwent ligation of the left common carotid artery just proximal to its bifurcation. Four weeks later, a polyethylene cuff was placed around the artery immediately proximal to the ligation site. Fluvastatin (10mg/kg per day) was given by oral gavage every day starting at 3 days before cuff placement. The administration of fluvastatin suppressed atherosclerotic plaque disruption accompanied by luminal thrombi by 31.5% compared with controls at 4 days after the cuff was placed at the ligated carotid artery. Fluvastatin administration decreased matrix metalloproteinase-9 expression, gelatinolytic activity, endothelial adhesion molecules expression and neutrophil infiltration, and increased type I collagen content in the cuffed region. In summary, fluvastatin was found to prevent plaque disruption through pleiotropic effect on acute inflammation in an animal model using apolipoprotein E-deficient mice.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Carotid Stenosis; Disease Models, Animal; Fatty Acids, Monounsaturated; Fluvastatin; Gene Expression; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Inflammation; Male; Matrix Metalloproteinase 9; Mice; Mice, Knockout

The in vitro and in vivo activity of atorvastatin and other 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors (fluvastatin, pravastatin and simvastatin) has been investigated. Atorvastatin, fluvastatin, pravastatin and simvastatin caused a significant and dose-dependent (0.1-50 microM) reduction in cell multiplication of vascular smooth muscle cells (SMC) in cultures associated with the retardation of cycling cells in the G1 and G2/M compartments at 24 h, a phenomenon leading to apoptosis (programmed cell death) in several experimental in vitro models. The effects on the cell cycle resulted in a strong inhibition of cell proliferation at 48 h, followed by apoptosis when incubation was prolonged to 72 h as assessed by nuclei morphology and cytofluorimetric analysis of DNA. The apoptotic effect observed for the statins is completely prevented by the addition of exogenous mevalonate at a 100 microm concentration. in vivo SMC proliferation was stimulated by applying a silastic collar to the outside surface of carotid arteries in normocholesterolemic rabbits in the presence of an anatomically intact endothelium. The positioning of the collar promoted apoptosis in control vessels as assessed by Terminal Deoxynucleotidyl Transferase-dUTP-Biotin Nick-End Labeling (TUNEL) assay. The pre-treatment with 5 mg kg-1 per day of atorvastatin before collar insertion strongly increased the number of TUNEL-positive cells, suggesting a pro-apoptotic effect of HMGCoA reductase inhibitors also in vivo, even though cell DNA rearrangement still needs to be excluded. No apoptotic signal was detectable in sham operated arteries with no collar in either control or atorvastatin-treated rabbits. These data indicate that HMGCoA reductase inhibitors effect on the arterial wall may involve the modulation of both cell proliferation and programmed cell deaths supporting a possible role of statins in the prevention of early lesion and restenosis.

Topics: Animals; Apoptosis; Atorvastatin; Carotid Stenosis; Cell Division; Cells, Cultured; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Muscle, Smooth, Vascular; Pravastatin; Pyrroles; Rabbits; Simvastatin