Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (Ang II) plays a pivotal role in cardiovascular remodeling leading to hypertension, myocardial infarction, and stroke. Pitavastatin, an HMG-CoA reductase inihibitor, is known to have pleiotropic actions against the development of cardiovascular remodeling. The objectives of this study were to clarify the beneficial effects as well as the mechanism of action of pitavastatin against Ang II-induced organ damage. C57BL6/J mice at 10 weeks of age were infused with Ang II for 2 weeks and were simultaneously administered pitavastatin or a vehicle. Pitavastatin treatment improved Ang II-induced left ventricular hypertrophy and diastolic dysfunction and attenuated enhancement of cardiac fibrosis, cardiomyocyte hypertrophy, coronary perivascular fibrosis, and medial thickening. Ang II-induced oxidative stress, cardiac TGFbeta-1 expression, and Smad 2/3 phosphorylation were all attenuated by pitavastatin treatment. Pitavastatin also reduced Ang II-induced cardiac remodeling and diastolic dysfunction in eNOS-/- mice as in wild-type mice. In eNOS-/- mice, the Ang II-induced cardiac oxidative stress and TGF-beta-Smad 2/3 signaling pathway were enhanced, and pitavastatin treatment attenuated the enhanced oxidative stress and the signaling pathway. Moreover, pitavastatin treatment reduced the high mortality rate and improved renal insufficiency in Ang II-treated eNOS-/- mice, with suppression of glomerular oxidative stress and TGF-beta-Smad 2/3 signaling pathway. In conclusion, pitavastatin exerts eNOS-independent protective actions against Ang II-induced cardiovascular remodeling and renal insufficiency through inhibition of the TGF-beta-Smad 2/3 signaling pathway by suppression of oxidative stress.
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PMID:Pitavastatin, an HMG-CoA reductase inhibitor, exerts eNOS-independent protective actions against angiotensin II induced cardiovascular remodeling and renal insufficiency. 1796 81

Dietary changes associated with drug therapy can reduce high serum cholesterol levels and dramatically decrease the risk of coronary artery disease, stroke, and overall mortality. Statins are hypolipemic drugs that are effective in the reduction of cholesterol serum levels, attenuating cholesterol synthesis in liver by competitive inhibition regarding the substrate or molecular target HMG-CoA reductase. We have herewith used computer-aided molecular design tools, i.e., flexible docking, virtual screening in large data bases, molecular interaction fields to propose novel potential HMG-CoA reductase inhibitors that are promising for the treatment of hypercholesterolemia.
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PMID:Use of virtual screening, flexible docking, and molecular interaction fields to design novel HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia. 1804 55

Cerebral ischaemic stroke is frequently a relapsing, if not chronic, disease. Its incidence is age-dependent, and with the ageing of society the need for effective therapies increases. This review considers current and alternative hypotheses underlying secondary prevention of stroke. Currently, secondary stroke prevention is widely practiced with aspirin (acetylsalicylic acid), a drug that has been in use for more than 100 years. Newer drugs such as ticlopidine and clopidogrel have subsequently been developed, but their efficacy barely surpasses that of aspirin. Other drugs used in secondary stroke prevention include HMG-CoA reductase inhibitors and antihypertensive agents. The endovascular paradigm has shaped the thinking of secondary stroke prevention, and aspirin, ticlopidine and clopidogrel are known as 'platelet inhibitors'; however, their pharmacological and clinical effects are not fully explained within the platelet paradigm. Moreover, in recent years, reduction of stroke incidence has also been observed with HMG-CoA reductase inhibitors, regardless of their lipid-lowering effects. Hence, current understanding needs to be supplemented by considering mechanisms beyond platelet inhibition. Evidence has shown that aspirin, ticlopidine and clopidogrel share neuroprotective properties not explained by the platelet paradigm and that are reminiscent of a preconditioning effect. This neuroprotective mechanism is also shared with HMG-CoA reductase inhibitors.
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PMID:Secondary stroke prevention: inside the vessels and beyond. 1819 23

Type 2 diabetes is associated with a two to fourfold increased risk of both coronary heart disease and stroke. Dysfunction of endothelial cells (EC) is known to promote abnormal vascular growth such as that in atherosclerosis and arteriosclerosis and has been postulated as an initial trigger of the progression of atherosclerosis in patients with diabetes mellitus, and hyperglycemia is an independent risk factor for the development of cardiovascular disease. We and others have previously demonstrated that high D-glucose induced apoptosis through activation of the bax-caspase proteases pathway in human EC and the potential contribution of hepatocyte growth factor, as an anti-apoptotic factor, to the pathogenesis of endothelial dysfunction. The anti-apoptotic action of HGF was due to bcl-2-upregulation and the phosphatidylinositol 3-kinase pathway, which is involved in Akt activation. Although it has been known for years that cardiovascular tissues can release a large amount ROS, including superoxide, hydrogen peroxide, and nitric oxide, the role of oxidative stress in atherogenesis has received increasing attention in recent years. Recent work strongly suggests that NADPH oxidase is a major source of superoxide in cardiovascular cells, and oxidative stress can be involved in the process of endothelial dysfunction. NADPH oxidase can be activated in hyperglycemia through the protein kinase C pathway. From the viewpoint of these molecular mechanisms, HMG-CoA reductase inhibitors (statins) might inhibit the high glucose-induced NADPH oxidase activation through inhibition of Rac activity and finally prevent the increase in ROS production in diabetes. A recent clinical trial suggested that statins prevent several vascular events in patients with type 2 diabetes without a high concentration of LDL-cholesterol. These pleiotropic effects of statins can be expected to improve endothelial dysfunction through nitric oxide production and/or an anti-oxidant effect in diabetic patients.
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PMID:Endothelial dysfunction in hyperglycemia as a trigger of atherosclerosis. 1822 May 82

Statins, the inhibitors of HMG-CoA reductase, are currently among the most commonly prescribed agents for the prevention of cardiovascular disease. It is well established that statins reduce cholesterol levels and prevent coronary heart disease. Moreover, evidence suggests that statins have additional properties such as endothelial protection via actions on the nitric oxide synthetase system as well as antioxidant, anti-inflammatory and antiplatelet effects. There is evidence that all these actions might have potential therapeutic implications not only in stroke, but also in various neurological disorders, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and primary brain tumors. In this review, we summarize the protective effects of statins on various neurological diseases. Currently available data suggest that statins are safe and effective in the treatment of these neurological disorders, although further experiments and new data are required.
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PMID:Potential therapeutic role of statins in neurological disorders. 1845 39

The obvious strengths of fixed-dose drug combinations include the potential advantages of increased compliance, convenience, and cost savings. In contrast, potential disadvantages include reduced flexibility in dosing, exposure of some patients to therapies they do not require, and possible increased risks of adverse effects without added benefits. With respect to fixed-dose drug combinations of HMG-CoA reductase inhibitors (statins), the totality of evidence is far less for the non-statin component leading to possible over utilization of two drugs when single-agent efficacy will suffice to maximize the benefit and minimize the risks. The current US FDA policy for fixed-dose drug combinations was established in 1971. The policy states that "two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug." The FDA was concerned with several disadvantages associated with fixed-dose combination drugs, including the lack of flexibility in titration, exposure of patients to unnecessary drugs when one component alone would be effective, as well as the increased possibility of adverse reactions without increased efficacy. The FDA has considered novel fixed-dose combination drugs to be composed of component drugs at least one of which has not been previously approved, labeled for an indication that is new to at least one or more of the component drugs, or where no significant evidence exist to support concurrent use of the components in a patient population. Based on the current FDA regulatory approval process for fixed-dose drug combinations with statins, it was possible to gain regulatory approval with intermediate endpoints such as lipids for example niacin/lovastatin and ezetimibe/simvastatin and BP/lipids, for example, amlodipine/atorvastatin. Based on the more stringent criteria of additive benefits on clinical endpoints of myocardial infarction, stroke, and cardiovascular disease death, it was possible to gain regulatory approval for aspirin/pravastatin. In summary, the approvals of several fixed-dose drug combinations with statins have both strengths and limitations. The availability to the healthcare provider of many individual statins with varying potency on lipids as well as several fixed-dose drug combinations reinforces the fact that the final decision should be made on astute and individual clinical judgements based on randomized clinical trial data, guidelines and FDA approvals with evidence to do more good than harm to the patient.
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PMID:Fixed-dose combination therapy with statins: strengths, limitations, and clinical and regulatory considerations. 1853 36

Cardiovascular disease remains the leading cause of mortality in elderly patients. While coronary heart disease (CHD) morbidity and mortality have decreased over the last 25 years, the percentage reduction in elderly patients is nearly 50% lower than that for the general adult population. Therefore, aggressive primary and secondary prevention of CHD is imperative for our society, and hyperlipidaemia remains the major modifiable risk factor in the elderly population. However, there appears to be a reluctance among practitioners to treat hyperlipidaemia in elderly patients, a bias that is particularly important given the absolute benefits of treating such patients. While many of the major clinical trials involving HMG-CoA reductase inhibitors (statins) in patients with CHD focused on younger individuals, subsequent subgroup analyses of elderly patients have shown consistent reductions in all-cause mortality, major CHD events and numbers of revascularization procedures. Intensive statin therapy in the setting of acute myocardial infarction (MI) has also been shown to reduce the risk of death, MI, unstable angina, revascularization and stroke in elderly patients. Furthermore, three recent articles that have evaluated intensive lipid-lowering in the elderly population have extended the known benefits of such therapy to elderly patients with acute coronary syndrome and stable CHD.Elderly patients often take multiple medications and are at significant risk of drug-drug interactions. Several available statin medications are metabolized by cytochrome P450 (CYP) 3A4 and can therefore interact with commonly used medications such as amiodarone, macrolide antibacterials, calcium channel antagonists, fibric acid derivatives and ciclosporin. These interactions can result in an increased frequency of statin-related hepatotoxicity and myopathy.There are currently six commercially available statin medications on the US market, three of which, lovastatin, simvastatin and pravastatin, are available in generic formulations, and are thus less expensive. Of the commercially available statins, rosuvastatin, atorvastatin and simvastatin have the highest potency. While rosuvastatin currently lacks clinical event data, atorvastatin has the most clinical event data for CHD and even stroke prevention. Although pravastatin has lower potency than other described statins, it also has the lowest risk of drug-drug interactions involving CYP.
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PMID:Secondary prevention of coronary heart disease in elderly patients following myocardial infarction: are all HMG-CoA reductase inhibitors alike? 1866 58

Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which catalyzes the conversion of 3-HMG-CoA to mevalonate, a rate-limiting step in cholesterol synthesis. These drugs are currently used for the treatment of cardiovascular diseases and brain stroke. Recently it has been indicated that statins have cytostatic and cytotoxic properties on several type of cancer cell lines. Inhibition of the synthesis of isoprenoid intermediates of the mevalonate pathway has been thought to be an important mechanism whereby statins exert proapoptotic, antiangiogenic, and antimetastatic action on human tumor cells. This review describes the anticancer activity of statins on the basis of numerous in vitro and in vivo experiments and focuses on their clinical applications.
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PMID:[The anticancer properties of statins]. 1868 9

There is growing experimental and clinical evidence that by reducing downstream products of the mevalonate pathway other than cholesterol, HMG-CoA reductase inhibitors ('statins') have beneficial effects on endothelial function, coronary and cerebral blood flow, inflammation, and hemostasis. Statins have been shown in rodent models of acute ischemic stroke to reduce neuronal injury and infarct size in a dose-dependent fashion. The objective of this early phase trial will be to determine the maximal-tolerated dose of lovastatin for short-term acute stroke therapy. In this multicenter phase 1B dose-escalation and dose-finding study, 33 patients with acute ischemic stroke will be administered lovastatin in increasing doses from one to 10 mg/kg daily for 3 days beginning within 24 hours after symptom onset. The primary safety outcome will be occurrence of myotoxicity or hepatotoxicity, defined by clinical and laboratory criteria, and the study is designed to determine the highest dose of lovastatin that can be administered with <10% risk of myotoxicity or hepatotoxicity. The statistical design of the study utilizes an adaptive design, the Continual Reassessment Method, which is novel to stroke trials, to find the optimal dosage. The dose-toxicity model is calibrated such that the method will eventually select a dose that causes 7-13% dose-limiting toxicity (within 3% of target). A sample size of 33 will ensure that estimates of any binary variables will have a 95% confidence interval of width <or=0.34, and enable us to detect any unexpected toxicity that occurs at 5% rate (in a non-dose-dependent fashion) with probability 0.82. The probability of choosing a dose for further trials with 25% or higher likelihood of toxicity is no more than 23%. The presently described trial represents a new approach for treatment of acute ischemic stroke, as well as a novel way of conducting a phase I trial, evaluating safety and determining an optimal dose of a potential neuroprotectant drug.
Int J Stroke 2008 Aug
PMID:The Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART): an adaptive design phase I dose-escalation study of high-dose lovastatin in acute ischemic stroke. 1870 2

Older adults are not only at higher risk of experiencing stroke, but also have multiple co-morbidities that make treatment for secondary stroke prevention challenging. Very few clinical trials specifically related to secondary stroke prevention treatment efficacy have focused on the oldest-old (>or=85 years) and, therefore, evidence-based recommendations for treatment specific to this population are not available. Some of the special considerations for stroke prevention treatments in older patients include careful titration of blood-pressure-lowering drugs to avoid hypotension, the risk of haemorrhagic stroke with HMG-CoA reductase inhibitors (statins) and weighing the risk of recurrent ischaemia versus bleeding in patients taking antiplatelet or anticoagulant therapy. The risk of peri-procedural complications appears to be high with both carotid angioplasty and stenting and carotid endarterectomy in older patients with carotid stenosis. Other common issues in older patients include adverse drug events, recognizing the risk of dementia, depression and osteoporosis and deciding when to discontinue secondary stroke prevention. In this review, we provide the practitioner with the evidence related to specific approaches to secondary stroke prevention in older patients, and identify the knowledge gaps that currently limit our ability to appropriately treat this vulnerable population.
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PMID:Secondary stroke prevention strategies for the oldest patients: possibilities and challenges. 1935 17


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