Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular reactivity to nitric oxide (NO) is mediated by NO-sensitive soluble guanylyl cyclase (sGC). Since a diminished activity of vascular sGC has been reported in an animal model of type 2 diabetes, the sGC activity was assayed in vitro in internal mammary artery specimens obtained during bypass surgery from patients with and without type 2 diabetes. The sensitivity of sGC to NO, which is dependent on Fe(2+)-containing heme, was measured in vitro using stimulation with diethylamine NONOate (DEA/NO). In addition, the novel cyclic guanosine monophosphate-elevating compound HMR-1766 was used to test the stimulation of the oxidized heme-Fe(3+)-containing form of sGC. Basal activity of sGC and its sensitivity to stimulation by DEA/NO and HMR-1766 were not different between control and type 2 diabetic patients: maximum stimulation by DEA/NO amounted to 475 +/- 67 and 418 +/- 59 pmol. mg(-1). min(-1) in control and type 2 diabetic patients, respectively. The maximum effects of HMR-1766 were 95 +/- 18 (control subjects) and 83 +/- 11 pmol. mg(-1). min(-1) (type 2 diabetic patients). Hypertension, hyperlipidemia, drug treatment with statins, ACE inhibitors, or nitrates had no effect on sGC activity. In conclusion, the present findings do not support the hypothesis that desensitization of sGC contributes to the pathogenesis of diabetic vascular dysfunction in humans.
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PMID:Nitric oxide-sensitive soluble guanylyl cyclase activity is preserved in internal mammary artery of type 2 diabetic patients. 1544 95

When kidney disease of any aetiology results in substantial loss of nephrons, a common clinical syndrome, characterised by hypertension, proteinuria and a progressive decline in renal function, ensues. This observation suggests that common mechanisms may contribute to progressive renal injury and that therapeutic interventions that inhibit these common pathways may afford renal protection. Research to date has identified several mechanisms that may contribute to progressive renal injury including glomerular haemodynamic changes, multiple effects of angiotensin II and detrimental effects of excessive filtration of plasma proteins by injured glomeruli. Clinical trials over the past decade have identified several interventions that are effective in slowing the rate of progression of chronic kidney disease (CKD). The use of ACE inhibitors, angiotensin receptor antagonists or a combination of the two should be regarded as fundamental to any therapy for slowing the rate of CKD progression. Hypertension should be treated aggressively to achieve a blood pressure target of < 130/80 mm Hg. Reduction of proteinuria to < 0.5 g/day should be regarded as an independent therapeutic goal. Although inconclusive, there is some evidence to support moderate dietary protein restriction to 0.6 g/kg/day in appropriate patients. Hyperlipidaemia may contribute to CKD progression and should be treated to reduce cardiovascular risk and potentially improve renal protection. Smoking cessation should be encouraged and, where necessary, assisted. Among diabetic patients tight glycaemic control should be achieved (glycosylated haemoglobin < 7%). These interventions are simple and relatively inexpensive. If applied to all patients with CKD they will result in substantial slowing of renal function decline in many patients and thereby reduce the number who progress to end-stage renal disease and require renal replacement therapy.
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PMID:Slowing the progression of adult chronic kidney disease: therapeutic advances. 1545 27

Hyperglycemia is associated with excess mortality in AMI and should be treated aggressively in the intensive care setting. The exact goal of therapy is unclear because different blood glucose targets were used in earlier studies (eg, 215 mg/dL in DIGAMI versus 110 mg/dL in the Belgian study of critically-ill patients). In the setting of AMI, it is prudent to avoid excessive hypoglycemia and, thus, more modest goals for blood glucose may be considered until more definitive data are present. Aggressive therapy with continuous infusion of insulin seems to improve a host of metabolic and physiologic effects that are associated with acute hyperglycemia and improves mortality in the acute setting. Aggressive glycemic control should be coupled with appropriate use of reperfusion therapies, glycoprotein IIb/IIa inhibitors, aspirin, 1-blockers, ACE inhibitors, and antithrombotic agents. The role of intensive chronic glucose control in reducing CV events is less clear but earlier studies were not well-powered; did not achieve aggressive, durable glycemic control; and did not use insulin-sensitizing agents routinely. Given the results of the DIGAMI trial, the goal of therapy postdischarge should include strict glycemic control while future studies help to delineate the role of insulin-sensitizing agents versus insulin-providing agents in reducing recurrent macrovascular events. Careful attention also should be paid to aggressive lifestyle modifications and treatment of hypertension, hyperlipidemia, and left ventricular dysfunction, as well as appropriate use of anti-platelet and antithrombotic agents.
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PMID:The role of intensive glycemic control in the management of patients who have acute myocardial infarction. 1569 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

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

Nephrotic syndrome is an important chronic disease in children, characterized by minimal change disease in the majority. Research on pathogenesis has emphasized the importance of T lymphocyte dysregulation and vascular permeability factors that might alter podocyte function and permselectivity. While mutations in genes that encode important podocyte proteins have also been identified, a hypothesis unifying available evidence on pathogenesis is yet to be proposed. Patients with nephrotic syndrome are at risk for life threatening infections and thromboembolic episodes. Long-term effects of persistent hyperlipidaemia and prolonged steroid therapy are increasingly recognized. Remission of proteinuria following corticosteroid therapy has greater prognostic value, in relation to long-term outcome, than the precise renal histology. Prospective studies show that prolonged duration of therapy for the initial episode results in sustained remission and reduced frequency of relapses. Treatment with levamisole, cyclophosphamide, cyclosporine and mycophenolate mofetil is beneficial in a variable proportion of patients with frequent relapses or steroid dependence. The management of steroid-resistant nephrotic syndrome is difficult; most patients failing to achieve remission show progressive renal damage. Calcineurin inhibitors (cyclosporine, tacrolimus) are capable of inducing remission in a significant proportion of patients, but at risk of nephrotoxicity. Reduction of proteinuria is also possible, in children, using angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers. Prospective trials are necessary to identify effective and safe therapies for patients with frequent relapses, steroid dependence and resistance.
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PMID:Nephrotic syndrome in children. 1610 86

Heart failure studies have suggested important differences between women and men both in heart failure etiology and in survival. Clinical trials and long-standing perceptions of the typical heart failure patient have related far more to men than to women, while more women than men in the United States may be hospitalized with heart failure. The goal of this study was to analyze ADHERE Registry data, the largest database of acute decompensated heart failure (ADHF) patient hospitalizations available, to gain insight into the effect of gender on medical history, clinical characteristics, and discharge counseling. This preliminary study analyzed the 85,617 ADHF hospitalizations in the ADHERE Registry as of October 2003, with 44,340 (52%) women and 41,276 (48%) men included. Women were significantly older (mean age 74.6 +/- 13.7 years) than men (mean age 70.2 +/- 13.9 years, P < .0001). Women were more likely to have a history of hypertension (75% vs. 69%, P < .0001) and a systolic blood pressure > 140 mm Hg (56% vs. 44%, P < .0001). History of coronary artery disease was more common in men (64% vs. 51%, P < .0001). Other risk factors for atherosclerosis, including smoking (17% vs. 10%, P < .0001) and hyperlipidemia (37% vs. 32%, P < .0001), were also more common in men. Men had a significantly lower mean left ventricular ejection fraction (32.9%, N = 30,831) than women (42.1%, N = 29,744); 51% of women had preserved left ventricular function (EF > 40%) compared to only 28% of men (P < 0.0001). At discharge, adherence to 3 of the 4 JCAHO standardized measures of quality of care far heart failure patients were documented more frequently for men than for women. A significantly smaller proportion of women received discharge instructions on management of diet, weight, and medications (30.1% vs. 32.8%); received or were scheduled for assessment of left ventricular function (81.5% vs. 85.6%); or were discharged with an angiotensin converting enzyme inhibitor prescription if appropriate (72.6% vs. 73.9%). Real-world data from the ADHERE Registry may lead to better recognition of the signs and symptoms of heart failure in women, increase the proportion of women who are correctly diagnosed, and may help to support gender-specific considerations in heart failure guidelines.
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PMID:Reshaping our perception of the typical hospitalized heart failure patient: a gender analysis of data from the ADHERE Heart Failure Registry. 1648 29

Effect of dietary supplementation of two types of rice bran fraction on blood pressure (BP), lipid profile, and glucose metabolism in stroke-prone spontaneously hypertensive rats was studied. Male 4-week-old rats were divided into one group fed the AIN-93M-based control (C) diet and two groups fed diet supplemented with 60 g/kg of Driselase and ethanol fractions (DF and EF, respectively) of rice bran. After 8 weeks feeding, the BP decreased in the DF and EF groups in comparison with the C group (p < 0.01). Plasma ACE inhibitory activity, BUN, BUN/creatinine ratio, albumin, triglyceride, and glucose levels were lower in the DF and EF groups than in the C group (p < 0.01). Plasma nitric oxide and urinary 8-hydroxy-2'-deoxyguanosine levels were lower in the DF and EF groups than in the C group (p < 0.01). Rice bran fractions appear to have a beneficial dietary component that improves hypertension, hyperlipidemia, and hyperglycemia.
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PMID:Rice bran fractions improve blood pressure, lipid profile, and glucose metabolism in stroke-prone spontaneously hypertensive rats. 1650 53

We aimed to investigate prognostic factors for a composite end-point of end-stage renal disease (ESRD) and the progression of renal disease in Japanese patients with chronic renal disease. Using a composite end-point comprising a doubling of serum creatinine (sCr), an increase in sCr level to 6.0 mg/dL, or initiation of dialysis and renal transplantation caused by ESRD, we examined data obtained in a prospective cohort study. The present study consisted of 641 patients who were 20 years of age or older with chronic renal disease caused by diabetic nephropathy, glomerulonephritis, or nephrosclerosis, and who had baseline sCr levels of 5.0 mg/dL or less. The following criteria were examined as prognostic factors: sex; age; elapsed time from initial diagnosis; disease underlying the nephropathy (diabetic or non-diabetic); complications with hypertension, hyperlipidemia, or anemia; baseline sCr level; therapeutic regimen, including use of ACE inhibitors or Ca2+ -channel blockers; and diet. A log-rank test was used for univariate analysis, and Cox regression analysis was used for multivariate analysis. Underlying disease (diabetic or non-diabetic), baseline sCr level, and Ca2+ -channel blocker therapy were significantly related to event incidence. In the present study, we identified underlying disease and baseline sCr level as important prognostic factors for a composite end-point in a predialysis patient population in both the early and middle stages of renal disease. These factors should be considered as balancing variables for randomization in future clinical studies.
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PMID:Prognostic factors for a composite end-point of renal outcomes in patients with chronic kidney disease. 1655 40

New-onset diabetes mellitus in a previously non-diabetic transplant recipient is a serious adverse event that confers significant morbidity and mortality. The most significant consequences of post-transplant diabetes mellitus (PTDM) in solid organ transplant recipients include decreased patient and graft survival, an increased risk of infectious complications, and morbid cardiovascular events. The development of PTDM in the elderly is of particular concern because this group is already at increased risk of progression of cardiovascular disease. Because the elderly, especially those aged >65 years, are the fastest-growing segment of the renal transplant population, attention needs to be given to PTDM risk reduction and post-transplant management. PTDM develops as a consequence of both impaired insulin production and enhanced peripheral insulin resistance. A number of non-modifiable factors such as age, race, family history, hepatitis C, polycystic kidney disease and emerging genetic causes have been identified as risk factors for PTDM. However, a number of modifiable factors can be targets for intervention in high-risk patients, including bodyweight (through dietary restriction and exercise), hypertension, hyperlipidaemia and the effects of certain immunosuppressive agents. The two agents most responsible for PTDM are tacrolimus and corticosteroids, especially when used in combination. Attempts to modify doses and regimens designed to eliminate or avoid these drugs should be considered. Use of HMG-CoA reductase inhibitors ('statins') and ACE inhibitors is particularly helpful in controlling hypertension and hyperlipidaemia in the elderly because these agents confer protection against future adverse cardiovascular events. Bisphosphonates are also advantageous in controlling the progression of osteoporosis and possible increased risk of bone fractures. Future trials in the elderly should focus on such endpoints as PTDM, post-transplant neoplasia, cardiovascular events and bone fracture events in order to identify the safest regimens that provide the optimal control of rejection while limiting the morbidity from these secondary events.
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PMID:Post-transplant diabetes mellitus: risk reduction strategies in the elderly. 1706 82


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