Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antihypertensive agents of first choice include ACE-inhibitors, angiotensin receptor blockers, beta blockers, calcium antagonists and diuretic agents. For the selection of medicaments, the individual patient risk profile of decisive importance. In particular a metabolic syndrome, diabetes mellitus, disturbed renal function and/or a disturbed electrolyte household must be considered. For initial treatment monotherapy or a low-dose combination regime is suggested. If the response is inadequate, possible options include increasing the dose, changing the medicament, (sequential monotherapy) or, in the sense of stepped treatment, introduction of further combination drugs. Resistance to therapy should prompt consideration of a number of causes, in particular noncompliance on the part of the patient.
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PMID:[Medical treatment of hypertension--what treatment for what patients?]. 1537 6

There are a total of 17 families of drugs that are used for treating the heterogeneous group of cardiovascular diseases. We propose a comprehensive pharmacogenomic approach in the field of cardiovascular therapy that considers the five following sources of variability: the genetics of pharmacokinetics, the genetics of pharmacodynamics (drug targets), genetics linked to a defined pathology and its corresponding drug therapies, the genetics of physiologic regulation, and environmental-genetic interactions. Examples of the genetics of pharmacokinetics are presented for phase I (cytochromes P450) and phase II (conjugating enzymes) drug-metabolizing enzymes and for phase III drug transporters. The example used to explain the genetics of pharmacodynamics is glycoprotein IIIa and the response to antiplatelet effects of aspirin. Genetics linked to a defined pathology and its corresponding drug therapies is exemplified by ADRB1, ACE, CETP and APOE and drug response in metabolic syndrome. The examples of cytochrome P450s, APOE and ADRB2 in relation to ethnicity, age and gender are presented to describe genetics of physiologic regulation. Finally, environmental-genetic interactions are exemplified by CYP7A1 and the effects of diet on plasma lipid levels, and by APOE and the effects of smoking in cardiovascular disease. We illustrate this five-tiered approach using examples of cardiovascular drugs in relation to genetic polymorphism.
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PMID:Pharmacogenomics and drug response in cardiovascular disorders. 1546 3

To compare effects of antihypertensive and combined therapy on 24-hour blood pressure, biochemical parameters and chronic hyperinsulinemia in patients with metabolic syndrome. 54 patients with metabolic syndrome were observed during 8 weeks. 28 patients (group A) were treated with antihypertensive agents (calcium antagonists, and when required -- ACE inhibitors and diuretics). 26 patients (group B) received the same therapy plus metformin. There were no significant changes in parameters of lipid and carbohydrate metabolism in group A. In group B we found significant decrease in C-peptide (p<0.05) and triglyceride (p<0.1) levels and increase in high density lipoprotein cholesterol levels (p<0.01). The combined antihypertensive and metformin therapy has a significant effect on carbohydrate and lipid metabolism.
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PMID:[Assessment of efficacy of combined therapy with antihypertensive agents and biguanides in patients with metabolic syndrome]. 1547 88

The focus of current diabetes research is the clarification of the pathogenetic relationships between subclinical inflammation, diabetes and arteriosclerosis. Even minimal disturbances in glucose tolerance are associated with a chronic, generalized inflammatory reaction that links components of the metabolic syndrome and contributes to the development of diabetic complications as well as to the development and progression of arteriosclerosis. The most important mediators and markers of this inflammation cascade are NF-kappaB, TNF-alpha, IL-6, CRP and PAI-1. For the treatment of subclinical inflammation, substances with anti-inflammatory properties such as statins or ACE inhibitors are of increasing importance.
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PMID:[Inflammation and diabetes]. 1554 May 36

The role of the RAAS in development and maintenance of blood pressure is well established. In addition, the deleterious effects of angiotensin II on the heart, vasculature, and kidneys have been clearly defined. There seems to be a close relationship between endothelial dysfunction, insulin resistance (a precursor to diabetes and coronary artery disease) and angiotensin II. The signaling pathways for insulin in the vascular wall interacts with the angiotensin signaling, giving rise to potential mechanisms for development of diabetes and resulting harmful effects. A large number of clinical trials using ACE inhibitors or ARBs have shown significant reduction in secondary endpoints in the development of new onset of diabetes. Ongoing prospective studies involving ARBs (eg, the Nateglinide and Valsartan Impaired Glucose Tolerance Outcomes Research trial) and ACE inhibitors (eg, the Diabetes Re-duction Assessment with Ramipril and Rosiglita-zone Medication trial) are testing the ability of certain agents to prevent type 2 diabetes. In the meantime, it is important to recognize insulin resistance and metabolic syndrome as entities that increase the risk for cardiovascular disease. In addition to lifestyle modifications, managing endothelial dysfunction and protecting the vasculature will help prevent diabetes and cardiovascular disease.
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PMID:The renin angiotensin system as a therapeutic target to prevent diabetes and its complications. 1569 45

The various mechanisms that may explain the association between brain dysfunction and the pathogenesis of metabolic syndrome (MS) leading to cardiovascular disease and type 2 diabetes have been reviewed. A Medline search was conducted until September 2003, and articles published in various national and international journals were reviewed. Experts working in the field were also consulted. Compelling evidence was found that saturated and total fat and low dietary n-3 fatty acids and other long-chain polyunsaturated fatty acids (PUFAs) in conjunction with sedentary behavior and mental stress combined with various personality traits can enhance sympathetic activity and increase the secretion of catecholamine, cortisol and serotonin, all of which appear to be underlying mechanisms involved in MS. Excess secretion of these neurotransmitters in conjunction with underlying long-chain PUFA deficiency may damage the neurons in the ventromedial hypothalamus and insulin receptors in the brain, in particular during fetal life, infancy and childhood, and lead to their dysfunction. Since 30-50% of the fatty acids in the brain are long-chain PUFAs, especially omega-3 fatty acids which are incorporated in the cell membrane phospholipids, it is possible that their supplementation may have a protective effect. Omega-3 fatty acids are also known to enhance parasympathetic activity and to increase the secretion of anti-inflammatory cytokines as well as acetylecholine in the hippocampus. It is possible that a marginal deficiency of long-chain PUFAs, especially n-3 fatty acids, due to poor dietary intake during the critical period of brain growth and development in the fetus, and later in the infant and also possibly in the child, adolescent and adult may enhance the release of tumor necrosis factor-alpha (TNF-alpha) interleukin (IL)-1, 2 and 6 and cause neuronal dysfunction. Experimental studies indicate that ventromedial hypothalamic lesions in rats induce hyperphagia, resulting in glucose intolerance and insulin resistance. Treatment with neuropeptide Y abolished hyperphagia and ob mRNA (leptin mRNA) in this animal model. Long-term infusion of norepinephrine and serotonin into the ventromedial hypothalamus impaired pancreatic islet function inasmuch as ventromedial hypothalamic norepinephrine and serotonin levels were elevated in hyperinsulinemic and insulin-resistant animals. Treatment with insulin was associated with restoration of hypothalamic neurotransmitter abnormalities, indicating that ventromedial hypothalamus dysfunction can impair pancreatic beta cells resulting in metabolic abnormalities consistent with MS. Treatment with omega-3 fatty acids, beta blockers, ACE inhibitors, estrogen, and meditation may have a beneficial effect on insulin receptors and ventromedial hypothalamic dysfunction. However, no definite or precise insight into the pathophysiological link between MS, brain function and nutrition is available. Despite this, epidemiological studies and intervention trials indicate that treatment with n-3 fatty acids may be adopted in clinical practice and used to direct therapy for prevention of type 2 diabetes, hypertension, coronary artery disease (CAD), and atherosclerosis, thereby indicating that MS may also respond to this treatment.
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PMID:Can brain dysfunction be a predisposing factor for metabolic syndrome? 1575 41

Atherosclerosis is the major cause of death in the world. Fasting and postprandial hyperlipidaemia are important risk factors for coronary heart disease (CHD). Recent developments have undoubtedly indicated that inflammation is pathophysiologically closely linked to atherogenesis and its clinical consequences. Inflammatory markers such as C-reactive protein (CRP), leucocyte count and complement component 3 (C3) have been linked to CHD and to hyperlipidaemia and several other CHD risk factors. Increases in these markers may result from activation of endothelial cells (CRP, leucocytes, C3), disturbances in adipose tissue fatty acid metabolism (CRP, C3), or from direct effects of CHD risk factors (leucocytes). It has been shown that lipoproteins, triglycerides, fatty acids and glucose can activate endothelial cells, most probably as a result of the production of reactive oxygen species. Similar mechanisms may also lead to leucocyte activation. Increases in triglycerides, fatty acids and glucose are common disturbances in the metabolic syndrome and are most prominent in the postprandial phase. People are in a postprandial state most of the day, and this phase is proatherogenic. Inhibition of the activation of leucocytes, endothelial cells, or both, is an interesting target for intervention, as activation is obligatory for adherence of leucocytes to the endothelium, thereby initiating atherogenesis. Potential interventions include the use of unsaturated long-chain fatty acids, polyphenols, antioxidants, angiotensin converting enzyme inhibitors and high-dose aspirin, which have direct anti-inflammatory and antiatherogenic effects. Furthermore, peroxisome proliferator activating receptor gamma (PPARgamma) agonists and statins have similar properties, which are in part independent of their lipid-lowering effects.
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PMID:Lipaemia, inflammation and atherosclerosis: novel opportunities in the understanding and treatment of atherosclerosis. 1576 89

Prevalence of the Type 2 diabetes mellitus (DM2) has been rising in the whole word. It is assumed that before DM2 develops, patients undergo a stadium of impaired glucose tolerance (IGT) or they have impaired fasting glycaemia (IFG). The confirmed IFG or IGT represent strong predictors of DM2 manifestation and at the same time they are related with high cardiovascular risk, namely with IGT. Other significant risk factor (RF) of DM2 is the obesity and metabolic syndrome. Recent clinical studies have shown that some metabolic abnormalities, which precede development of DM2 can be positively influenced by the lifestyle changes, including improvement of the diet and increasing the physical activity. Such measures can prevent or at least to delay the development of type 2 diabetes mellitus and thus the development of cardiovascular diseases. Positive effect has also the administration of some drugs, already tested in clinical studies, namely glitasons, metromin, inhibitor of ACE, sartans and other.
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PMID:[Contemporary prospects of prevention of type 2 diabetes mellitus]. 1588 94

Type 2 diabetes mellitus is a public health problem of epidemic proportions and its prevalence is on the rise. The typical American born today has a one in three chance of developing type 2 diabetes. This diagnosis is associated with an adverse cardiovascular prognosis and is considered the risk equivalent of established coronary disease. Many risk factors, including the metabolic syndrome, have been implicated in its development. Even in high-risk individuals, type 2 diabetes is a preventable disease. Diet and exercise have been consistently shown to decrease the incidence of diabetes in large randomized controlled studies. Additionally, new-onset diabetes was reduced by several oral pharmacologic anti-diabetic agents including metformin, acarbose and troglitazone in randomized trials which studied patients with impaired glucose tolerance. More interestingly, multiple large prospective studies have also reported a reduction in the development of type 2 diabetes in patients treated with anti-hypertensive agents, predominantly angiotensin converting enzyme inhibitors and angiotensin receptor blockers. In this review, we will discuss some of these important trials and the speculative mechanisms whereby those medications prevent type 2 diabetes. Such observations, if proven to be true, may represent preventive strategies which can be considered in patients with pre-diabetic conditions such as the metabolic syndrome, hypertension, impaired fasting glucose, family history of diabetes, obesity, congestive heart failure or other risks for the development of type 2 diabetes.
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PMID:Strategies to prevent type 2 diabetes. 1600 80

Proteins are particularly attractive targets for product analysis, which is used to understand pathology. Protein modifications, such as advanced glycation end products (AGEs), serve as footprints of biochemical processes and also help in the search for novel agents that efficiently inhibit protein damage. Interestingly, several medical agents that are used clinically interfere with oxidative protein damage through different mechanisms characteristic of their chemical structures. We recently found that angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) lower the in vitro formation of the AGEs pentosidine and carboxymethyllysine. Their inhibition for AGE formation is more striking than aminoguanidine. Unlike aminoguanidine, ARBs and ACEIs do not trap reactive carbonyl precursors of AGEs. Rather, they inhibit AGE formation, possibly as a result of their potent ability to scavenge hydroxyl radicals and to chelate the transition metals necessary for the Fenton reaction. We tested their AGE-lowering ability in vivo in a unique type-2 diabetic model with nephropathic SHR/NDmcr-cp rats, which exhibits the metabolic syndrome (obesity, hyperglycemia, hyperlipidemia, hyperinsulinemia) in addition to hypertension. Obesity and associated metabolic derangements, in addition to hypertension, markedly accelerate renal injury. Expectedly, correction of hyperglycemia and hyperinsulinemia partially but significantly improves renal injury. A low-calorie diet greatly improves renal injury despite persistent hypertension. Among antihypertensive agents, ARBs, unlike nifedipine and atenolol, are renoprotective despite persistent metabolic syndrome, but their action is independent of blood pressure lowering and is observed in a dose-dependent manner despite the complete blockade of angiotensin II receptor. Interestingly, the improvement of renal injury by ARBs as well as a low-calorie diet is associated with a significant reduction in local oxidative stress and AGE formation in the kidney. During the characterization of the AGE-lowering profile of our chemical compound libraries ( approximately 2000), we identified several inhibitors of oxidative stress and advanced glycation. They are indeed renoprotective, independently of correction of hypertension and metabolic syndrome, in experimental diabetic nephropathy and other nephritis models. Altogether, our data are in good agreement with the recent therapeutic concept for diabetic nephropathy that multiple risk factor interventions are critical in the treatment of diabetic renal injury, and further implicate a therapeutic potential of inhibition of oxidative stress and advanced glycation.
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PMID:From molecular footprints of disease to new therapeutic interventions in diabetic nephropathy. 1603 1


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