UMLS:C0042373 - FACTA Search

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Using measurements of fibrin fibre thickness (microT) derived from turbidity and permeability (tau) of clotted plasma, it has been found that glucose in vitro added to plasma decreases permeability of the network despite unaltered fibrinogen conversion. Fibrin fibre thickness (microT) in uncontrolled diabetes is found significantly reduced. In diabetic plasma the degree of conversion to fibrin is similar to that in age and sex matched plasma from non-diabetics: the effect on fibrin network and fibre thickness probably arises from glycosylation of fibrinogen. Studies with Gliclazide, Metformin, Glibenclamide and insulin have shown that while all other drugs tested have no effect, Gliclazide increases fibrin fibre thickness (microT) significantly, diminishes tensile strength and reduces permeability. In separate experiments lysability of 125I-labelled fibrin networks developed in the presence of all four hypoglycaemic agents by tissue activator was tested. Networks developed in the presence of Metformin were found to lyse more quickly, followed by insulin and Gliclazide. Alterations induced in fibrin networks in diabetes may be nullified by some oral hypoglycaemic agents such as Gliclazide and not by others. Whether nullification of such changes has long-term effects in reducing the incidence of vascular disease in diabetics remains to be established.
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PMID:Studies on fibrin network structure in human plasma. Part II--Clinical application: diabetes and antidiabetic drugs. 178 32

The clinical studies have demonstrated that patients showed significant improvements in their oxidative status after 3 months treatment. This improvement in oxidative status which was associated with a reduction in platelet reactivity, remained constant for the rest of the study period. The effect was independent of glycaemic control. The demonstration of a benefit to clinical vascular disease has proved difficult to achieve in all studies of non-insulin dependent diabetes. This is due to the multifactorial nature of complications and the long duration of disease required before microvascular complications such as retinopathy became apparent. The Japanese Diabetic Retinopathy Program24 studied the progression of retinopathy over a 5 year period comparing Gliclazide with other sulphonylureas and with placebo. The study suggested that with equivalent metabolic control there was a trend towards a lower rate of deterioration of retinopathy and a significantly lower incidence of pre-proliferative retinopathy in the group receiving Gliclazide compared with patients receiving other sulphonylureas or placebo. There is little comparative evidence on the effect of specific sulphonylureas on large vessel disease. Although improvement in parameters of hyperglycaemia is associated with an improvement in morbidity from large vessel disease. In Type II diabetes atherosclerosis coexists in the majority of patients and often predates the clinical diagnosis of diabetes. The presence of atherosclerosis which often determines the ultimate fate of the patient, further increases the level of lipid peroxidation of oxidative stress, amplifying the effects of hyperglycaemia and potentiating vascular damage. In diabetes, therefore where increased glycation and oxidation are fundamental in the pathogenesis of diabetic vascular disease agents such as Gliclazide with anti-oxidant activities may have an enhanced therapeutic role.
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PMID:The potential of gliclazide, a sulphonylurea to influence the oxidative processes within the pathogenesis of diabetic vascular disease. 777 Dec 62

ATP-dependent potassium channel blockers used as hypoglycaemic agents may have effects on vascular disease in diabetes mellitus beyond their effect on blood glucose control. This study was designed to determine the effects of treatment with gliclazide on the isolated abdominal aorta of diabetic rabbits in which endothelium-dependent relaxation is impaired by a mechanism involving oxygen-derived free radicals. After induction of diabetes with alloxan, there was no effect of gliclazide (10 mg x kg(-1) day(-1) orally) on blood glucose or insulin levels over a 6 week period. Hence, this permitted an examination of the vascular effects of gliclazide in diabetic rabbits exclusive of metabolic effects. Acetylcholine- and nitric oxide-induced relaxation in aortae from rabbits treated with or without gliclazide were measured in the absence or presence of the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine (L-NAME). Diabetes was associated with significant impairment of acetylcholine-induced endothelium-dependent relaxation of the abdominal aorta which was not significant in diabetic rabbits treated with gliclazide in vivo. Aortae from diabetic rabbits studied in the presence of L-NAME showed an exaggerated contraction to acetylcholine which was prevented in rabbits treated with gliclazide. Gliclazide treatment did not affect the response to acetylcholine of normal rabbit aorta, and gliclazide when added in vitro had no effect on the response of diabetic rabbit aorta, suggesting that the effect of gliclazide was specific to the abnormality arising with diabetes and was not due to an acute effect of the drug. These data indicate that gliclazide, aside from either a direct antioxidant action or an effect on insulin or glucose levels, may ameliorate diabetic endothelial cell dysfunction.
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PMID:Vascular action of the hypoglycaemic agent gliclazide in diabetic rabbits. 949 23

The burden of Type II diabetes is growing rapidly worldwide, across high-, middle- and low-income countries. This burden is associated primarily with increased risks of macrovascular and microvascular diseases, and it is agreed that multifactorial treatment regimens are required to reduce it. ADVANCE (Action in Diabetes and Vascular disease: Preterax and Diamicron-MR Controlled Evaluation) is a large-scale, 2 x 2 factorial, randomised clinical trial. It will investigate the potential benefits of blood pressure lowering, using a fixed low-dose combination of perindopril and indapamide vs placebo, and of tighter glucose control, using an intensive gliclazide-MR-based glucose control regimen vs a standard guidelines-based regimen, separately and together. The two primary outcomes are a composite macrovascular end point of nonfatal stroke, nonfatal myocardial infarction and cardiovascular death; and a composite microvascular end point of new or worsening nephropathy or microvascular eye disease. Following successful recruitment and randomisation of 11,140 participants by March 2003, the study is currently half way through its planned follow-up of 4.5 years. Adherence to randomised study treatment is good; and loss to follow-up is minimal. It is hoped that the study will answer a number of unresolved issues. The blood pressure lowering arm will investigate the possible reduction in major vascular disease in patients with Type II diabetes whether or not they have hypertension, and the possible benefits of blood pressure lowering in such patients already receiving background therapy with the ACE inhibitor perindopril. The glucose control arm will investigate the possible reduction in both macrovascular and microvascular disease achieved with tighter glucose control, targeting an HbA1c of 6.5% and a fasting blood glucose of 6.0 mmol/l. Finally, the factorial design will enable investigation of the combined effects of more intensive glucose control and tighter control of blood pressure.
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PMID:ADVANCE: action in diabetes and vascular disease. 1607 30

Pharmacological treatment of hypertension represents a cost-effective way of preventing cardiovascular and renal complications. To benefit maximally from antihypertensive treatment, blood pressure should be brought to below 140/90 mmHg in every hypertensive patient, and even lower (< 130/80 mmHg) if diabetes or renal disease co-exists. Such targets cannot usually be reached using monotherapies. This is especially true in patients who present with a high cardiovascular risk. The co-administration of two agents acting by different mechanisms considerably increases the blood pressure control rate. Such combinations are not only efficacious, but are also well tolerated, and some fixed low-dose combinations even have a placebo-like tolerability. This is the case for the preparation containing the angiotensin-converting enzyme inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), a fixed low-dose combination that has been shown in controlled trials to be more effective than monotherapies in reducing albuminuria, regressing cardiac hypertrophy and improving the stiffness of large arteries. Using this combination to initiate antihypertensive therapy has been shown in a double-blind trial (Strategies of Treatment in Hypertension: Evaluation; STRATHE) to normalize blood pressure (< 140/90 mmHg) in significantly more patients (62%) than a sequential monotherapy approach based on atenolol, losartan and amlodipine (49%) and a stepped-care strategy based on valsartan and hydrochlorothiazide (47%), with no difference between the three arm groups in terms of tolerability. An ongoing randomized trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; ADVANCE) is a study with a 2 x 2 factorial design assessing the effects of the fixed-dose perindopril-indapamide combination and of the intensive gliclazide modified release-based glucose control regimen in type 2 diabetic patients, with or without hypertension. A total of 11 140 patients were randomly selected. Within the first 6 weeks of treatment (run-in phase), the perindopril-indapamide combination lowered blood pressure from 145/81 +/- 22/11 mmHg (mean +/- SD) to 137/78 +/- 20/10 mmHg. Fixed-dose combinations are becoming more and more popular for the management of hypertension, and are even proposed by hypertension guidelines as a first-line option to treat hypertensive patients.
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PMID:Managing hypertension in high-risk patients: lessons and promises from the STRATHE and ADVANCE trials. 1672 62

Sulphonylureas, such as glybenclamide and gliclazide, are classical blockers of ATP-dependent potassium channels (K(ATP)). Closure of K(ATP) channels in vascular smooth muscles by sulphonylureas would lead to membrane depolarization and vasoconstriction but this hypothesis has not been consistently proved in different types of vascular tissues. Our present study examined mouse vascular contractility changes induced by sulphonylureas using a wire myograph. The phenylephrine-precontracted aorta (n=6), super mesenteric arteries (n=10) and third-order mesenteric artery (n=10) from C57BL mice were relaxed by glybenclamide with IC(50) of 116+/-13.0, 61.8+/-5.5, and 41.4+/-1.3 microM, respectively. Gliclazide or U37883A (a vascular K(ATP) blocker structurally different from that of sulphonylureas) had similar vasorelaxant effects on mesenteric arteries with IC(50) of 14.8+/-1.5 microM (n=5) or 15.6+/-1.3 microM (n=9), respectively. The presence of Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME, 300 microM, n=8), apamin+charybdotoxin (n=4), or 1H-[1, 2, 4]-oxadiazolo[4, 3-a]quinoxalin-1-one (ODQ) (10 microM, n=10) partially reduced vasorelaxant effect of glybenclamide on mesenteric arteries. Removal of endothelium (n=7) or precontraction with 100 mM [K(+)](o) (n=10) also significantly reduced vasorelaxant effect of glybenclamide on mesenteric arteries. The relaxation of mouse resistance arteries by K(ATP) channel blockers calls for further investigation into the selectivity and suitability of these drugs in treatment of different vascular disease.
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PMID:Sulphonylureas induced vasorelaxation of mouse arteries. 1794 9

Blood pressure is an important determinant of the risk of macro- and microvascular vascular complications in patients with type 2 diabetes. Current European guidelines for the management of hypertension recommend lowering blood pressure in patients with type 2 diabetes to reduce the risk of cardiovascular events. The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial (n = 11,140), is the first trial designed to address the issue of whether routine blood pressure lowering with the fixed combination of perindopril/indapamide is beneficial in patients with diabetes with a broad range of baseline blood pressure values. In addition, it aimed to determine if clinical benefit is achieved over and above that observed with background angiotension-converting enzyme inhibitor therapy. In the perindopril/indapamide arm, the reduction in blood pressure led to significant clinical benefits in patients with type 2 diabetes, irrespective of baseline blood pressure values, and subsequently improved mortality rates, and macro- and microvascular outcomes, beyond the improvements associated with patients' existing antihypertensive therapies. ADVANCE is a robust well-designed trial, the results of which are directly applicable to current clinical practice. The ADVANCE study defines the relevant blood pressure goals for patients with type 2 diabetes who are at high risk of cardiovascular events and underscores the benefits of aggressive blood pressure reduction even in normotensive patients with diabetes. It is likely that these findings will have a significant impact on the management of patients with type 2 diabetes. In view of the evidence indicating that clinical benefits obtained with the perindopril/indapamide combination can be expected even in patients who are normotensive, vascular risk rather than initial blood pressure should be employed to determine appropriate treatment protocols in patients with type 2 diabetes.
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PMID:Implications of the ADVANCE study for clinical practice. 1936 50

Whether glycaemic control may result in a reduction of cardiovascular (CV) risk has been a matter of continuous discussion and investigation. Epidemiological analyses have extensively suggested a relationship between glycaemic control and CV events; however, the results of intervention trials have been less conclusive. The UKPDS reported a 16% reduction in the risk of myocardial infarction, but this reduction was not statistically significant. The results of the Kumamoto and PROactive studies could not allow any firm conclusions to be drawn either, because of limited size and the defined primary endpoint, respectively. The results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trials and the Veteran Administration Diabetes Trial (VADT) were published in rapid succession over the second half of 2008 and at the beginning of 2009. A total number of almost 25,000 type 2 diabetic patients were recruited in these three trials, which assessed the effect of intensive glycaemic control vs conventional treatment on well-defined CV endpoints. In spite of the achievement and maintenance of strict glycaemic control (HbA(1c) <7.0%), no beneficial effect of intensive therapy was apparent in any of the studies. At the same time these results were presented, the results of an analysis of the 10 year follow-up of the UKPDS also became available and provided a more optimistic view of the potential benefit of achieving good glycaemic control. The relative risk reductions for myocardial infarction and all-cause mortality were significantly lower in the patients who initially received the intensive treatment compared with those in the conventional treatment arm. Moreover, the initial benefit in terms of microvascular complications observed at the end of the intervention trial remained unaltered at follow-up. Once again the debate on the importance of glycaemic control in preventing macrovascular complications remains unsettled. These results, however, require some reconciliation, and the objective of this commentary is to analyse a series of elements, including the changes in the treatment approach to CV risk factors in type 2 diabetes, the effect of glucose-lowering agents, and the characteristics of the patients included in the different trials, that should be taken into account when interpreting the results of intervention trials in type 2 diabetes.
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PMID:Megatrials in type 2 diabetes. From excitement to frustration? 1937 46

Cardiovascular disease is the predominant cause of death in diabetic patients, and reducing the risk of cardiovascular disease in diabetics has recently been the focus of several highly publicized large trials, including ACCORD (Action To Control Cardiovascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), and VADT (Veterans Affairs Diabetes Trial). These studies randomized high-risk diabetic patients into either intensive treatment or standard treatment. The glycemic control arm of ACCORD was terminated 17 months before the planned end of the study because of a finding of significantly increased all-cause and cardiovascular mortality in the intensive treatment group. These findings were not duplicated in either ADVANCE or VADT. Multiple possible explanations have been brought forward, including a higher incidence of death from unrecognized hypoglycemia, effects due to increased exposure to particular antidiabetic medications, adverse effects of rapid correction of hyperglycemia, weight gain, and differences in baseline characteristics. None of these were validated in post hoc analyses of the trial data, and the cause of the increased mortality remains elusive. Subgroup analyses suggest that those who start off with better control of their diabetes or without preexisting cardiovascular disease may have the most to gain from tight glycemic control. Reducing the risk of macrovascular disease and death in diabetic patients requires not only attention to glucose control but also meticulous attention to control of nonglycemic risk factors, including hypertension, hyperlipidemia, smoking, lack of exercise, and unhealthy diet as well as timely prescription of medications with proven preventative benefits, such as aspirin and statins.
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PMID:Glycemic targets for patients with type 2 diabetes mellitus. 1942 66

The relative importance of various blood pressure indices on cardiovascular risk in people with type 2 diabetes mellitus has not been established. This study compares the strengths of the associations between different baseline blood pressure variables (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse pressure [PP], and mean arterial pressure) and the 4.3-year risk of major cardiovascular events in the Action in Diabetes and Vascular Disease: Preterax and Diamicron-Modified Release Controlled Evaluation Study. Mean (SD) age for the 11 140 participants was 65.8 years (6.4 years). During follow-up, 1000 major cardiovascular events, 559 major coronary events, and 468 cardiovascular deaths were recorded. After adjustment for age, sex, and treatment allocation, the hazard ratios (95% CIs) associated with 1 increment in SD for the risk of major cardiovascular events were 1.17 (1.10 to 1.24) for SBP; 1.20 (1.13 to 1.28) for PP; 1.12 (1.05 to 1.19) for mean arterial pressure; and 1.04 (0.98 to 1.11) for DBP. The areas under the receiver operating characteristic curve were slightly higher for SBP and PP compared with mean arterial pressure and DBP for major cardiovascular and coronary events. Using achieved instead of baseline blood pressure values marginally improved the effect estimates for SBP, DBP, and mean arterial pressure, with no significant differences in the areas under the receiver operating characteristic curve between models with SBP and those with PP. In conclusion, SBP and PP are the 2 best and DBP is the least effective determinant of the risk of major cardiovascular outcomes in the relatively old patients with type 2 diabetes mellitus participating in the Action in Diabetes and Vascular Disease: Preterax and Diamicron-Modified Release Controlled Evaluation Study. However, SBP may be the simplest and most useful predictor across a wider range of age groups and populations.
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PMID:Blood pressure variables and cardiovascular risk: new findings from ADVANCE. 1947 Aug 69

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