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: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin converting enzyme (ACE) inhibitors not only reduce angiotensin II (ANG II) levels but also inhibit kinin degradation. The relative roles of ANG II and bradykinin in the acute action of ACE inhibitors on renal hemodynamic parameters in rats after 3 wk of diabetes were explored using antagonists of the ANG II type 1 (AT1) and the bradykinin B2 receptors. Conscious control and streptozotocin diabetic male Sprague-Dawley rats were randomized to receive vehicle, the ACE inhibitor, ramiprilat, the B2-receptor blocker, HOE-140, the AT1-receptor blocker, valsartan, or the combination of ramiprilat and HOE-140. Systolic blood pressure, glomerular filtration rate (GFR), renal plasma flow (RPF), filtration fraction and urinary flow, and sodium excretion were assessed before and during treatment. Diabetic animals had higher GFR and a tendency toward increased RPF and filtration fraction compared with control animals. Acute ramiprilat infusion decreased GFR significantly in diabetic but not in control animals. Valsartan and the combination of ramiprilat and HOE-140 reduced blood pressure to a similar degree to ramiprilat alone, yet did not reduce GFR. No decrease in GFR was observed in any control rat groups. Ramiprilat decreased RPF in diabetic rats but increased RPF in control rats. No such effects on RPF were observed with valsartan. HOE-140 alone did not influence any renal parameter in the diabetic rats. Diabetic rats had increased urinary flow and sodium excretion, but these parameters were not influenced by any drug regimen.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acute renal hemodynamic effects of ACE inhibition in diabetic hyperfiltration: role of kinins. 773 15

Essential hypertension is a major Public Health issue. Although the number of treated hypertensive patients has increased, only 25% of treated patients have their blood pressure levels under control. The benefit of treating hypertension has been proven, but cardiovascular morbidity and mortality rates remain high. The ideal antihypertensive drug should not only normalize blood pressure levels, but also reduce the associated cardiovascular morbidity and mortality rates. The role of angiotensin II in systemic hypertension and its complications has been recently redefined. The potent trophic effects of angiotensin II on blood vessels and on cardiac cells have been well demonstrated, especially the role of angiotensin II in left ventricular hypertrophy, vascular hypertrophy, endothelial dysfunction, and congestive heart failure. Of all ongoing mortality and morbidity trials in systemic hypertension, VALUE (Valsartan Antihypertensive Long-term Use Evaluation) is the only one comparing an angiotensin II antagonist (valsartan) with a third-generation calcium channel blocker (amlodipine). The main hypothesis of the VALUE trial is that, for an equivalent decrease in blood pressure, valsartan will be more effective than amlodipine in decreasing cardiac mortality and morbidity. VALUE is a prospective, multinational, multicentre, double-blind, randomized, active-controlled, 2-arm parallel group comparison with a response-dependent dose titration scheme. VALUE involves 14,400 patients in over 30 countries, who will be followed for 4 years or until 1450 patients experience a primary endpoint. The population to be included in VALUE consists of hypertensive men and women, aged 50 years or older, and at a relatively high risk of sustaining a cardiovascular event. The high risk profile is defined taking into account age, gender, and a list of cardiovascular risk factors and disease factors. Risk factors are cigarette smoking, hypercholesterolaemia, diabetes mellitus, uncomplicated left ventricular hypertrophy, proteinuria, and high serum creatinine. Disease factors include documented history of myocardial infarction, peripheral vascular disease, stroke or transient ischaemic attack, or the presence of left ventricular hypertrophy with strain on the ECG. A unique feature of VALUE is the assessment of the predictive power of this cardiovascular risk factor scale in a large population of treated hypertensive patients. The trial started on 10 September 1997.
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PMID:The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial of cardiovascular events in hypertension. Rationale and design. 975 88

The study compared valsartan 80 mg or 160 mg o.d. with captopril 25 mg t.i.d. or placebo on plasma lipids in normotensive and treated hypertensive patients with type II diabetes and microalbuminuria. One hundred and twenty-two adult outpatients were randomised to receive either valsartan 80 mg or 160 mg, captopril 25 mg or placebo for 360 days. Changes from baseline to endpoint in plasma lipid parameters were measured. The primary criterion for tolerability was the incidence of adverse events. All treatment groups showed minor changes in lipid parameters. Triglyceride increased by 2.7% (valsartan 160 mg) to 9.1% (placebo). Total cholesterol decreased under valsartan 80 mg, while other groups showed increases of up to 0.031 mmol/l. Decreases in total cholesterol (p = 0.018), apolipoprotein B (p = 0.042) and apolipoprotein A1 (p = 0.025), were significant for the comparison of 80 mg valsartan and captopril. Valsartan 80 mg or 160 mg o.d. does not cause deleterious changes in the diabetic lipid profile and, unlike captopril, is not associated with dry cough.
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PMID:The effect of valsartan and captopril on lipid parameters in patients with type II diabetes mellitus and nephropathy. 1069 51

Successful treatment of hypertension entails not only normalizing high blood pressure, but also addressing the associated risk factors that increase the likelihood of cardiovascular morbidity and mortality. Hypertension often occurs in a setting of insulin resistance, hyperinsulinemia, dyslipidemia, and a prothrombotic state. A number of epidemiologic studies have shown that the clustering of these abnormalities is associated with increased risk of cardiovascular morbidity and mortality. Therefore, it is rational to direct therapy at moderating these risk factors as well as at lowering blood pressure in hypertensive patients. This is particularly important in patients with comorbidities such as diabetes, cardiovascular disease, or renal insufficiency. Many physicians prescribe only diuretics and beta-blockers, agents that have demonstrated efficacy in long-term randomized controlled trials. However, this approach does not consider the potential benefits of newer agents for which long-term outcome data are not yet available. The ongoing Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, in which the angiotensin II subtype 1 receptor blocker valsartan is compared with the third-generation calcium channel blocker amlodipine, should provide important evidence on the long-term efficacy of these newer agents. A unique feature of VALUE is that it is specifically enrolling into the only current trial, now under way, hypertensive men and women at a relatively high risk for a cardiovascular event to determine the benefits of complete blockade of angiotensin II beyond those of the control of blood pressure.
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PMID:Treating high-risk hypertensive patients. 1083 Jul 92

Blood pressure reduction is the most significant factor in delaying onset and progression of renal disease. Blockade of the renin-angiotensin system (RAS) using angiotensin-converting enzyme inhibitors (ACEIs) delays renal disease progression. More recently, agents that block the RAS by preventing angiotensin II from binding to its subtype 1 receptor (ARBs) have been developed in an effort to prevent deleterious consequences of pathologic levels of angiotensin II and to reduce the adverse effects of RAS blockade associated with ACEIs. Human studies with a variety of ARBs have clearly demonstrated the antihypertensive and antiproteinuric efficacy of these agents in patients with progressive renal diseases. Moreover, the effects of ARBs are similar or identical to those of ACEIs. Ongoing long-term clinical trials are designed to determine whether ARBs also preserve renal function similar to ACEIs. Specifically, the role of ARBs in patients with hypertension and type 2 diabetes is being evaluated in 3 large trials, including Appropriate Blood Pressure Control in Diabetes-Part 2 With Valsartan, the Losartan Renal Protection Study, and the Irbesartan Diabetic Nephropathy Trial. Definitive evidence of the long-term protective effects of ARBs in chronic progressive renal disease is expected from these important studies.
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PMID:Angiotensin II subtype 1 receptor blockers and renal function. 1142 96

The rising incidence of stroke, congestive heart failure (CHF) and end stage renal disease (ESRD) has signalled a need to increase awareness, treatment and control of hypertension. There continues to be a need for effective antihypertensive medications since hypertension is a major precursor to various forms of cardiovascular disease. The renin-angiotensin (AT) aldosterone system (RAAS) is a key component to the development of hypertension and can be one target of drug therapy. Angotensin II (ATII) receptor blockers (ARBs) are the most recent class of agents available to treat hypertension, which work by by inhibiting ATII at the receptor level. Currently, national consensus guidelines recommend that ARBs should be reserved for hypertensive patients who cannot tolerate angiotensin converting enzyme (ACE) inhibitors (ACEIs). ARBs, however, are moving to the forefront of therapy with a promising role in the area of renoprotection and CHF. Recent trials such as the The Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes Trial (IDNT), the Effect of Irbesartan on the Development of Diabetic Nephropathy in Patients with Type 2 Diabetes (IRMA2), and The Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy (RENAAL) study have demonstrated the renoprotective effects of ARBs in patients with Type 2 diabetes. The Valsartan Heart Failure Trial (Val-HeFT) adds to the growing body of evidence that ARBs may improve morbidity and mortality in CHF patients. As a class, ARBs are well tolerated and have a lower incidence of cough and angioedema compared to ACEIs. This article reviews the differences among the ARBs, existing efficacy data in hypertension, and explores the role of ARBs in CHF and renal disease.
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PMID:Angiotensin II receptor blockers for the treatment of hypertension. 1182 17

The Heart Outcomes Prevention Evaluation (HOPE) study conclusively demonstrated that ramipril, an angiotensin-converting enzyme (ACE) inhibitor, reduces the risk of cardiovascular death, myocardial infarction (MI), and death in patients at risk for cardiovascular events but without heart failure. The Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E (SECURE) substudy demonstrated that ramipril also reduced atherosclerosis. These results suggest that the renin-angiotensin system (RAS) has a more important role in the development and progression of atherosclerosis than previously believed, and they indicate the need for further clinical studies to define the range of benefits available from modifying the RAS. Achieving maximum benefit may require treatment with both an ACE inhibitor and an angiotensin II type-1 receptor blocker (ARB). The Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) study indicated that combining an ACE inhibitor with an ARB decreased blood pressure and improved the ejection fraction more than treatment with either drug alone in patients with congestive heart failure. The Valsartan in Heart Failure Trial (Val-HeFT) showed that the combination of an ACE inhibitor and an ARB reduced hospitalization for heart failure in patients with congestive heart failure by 27.5%, although no decrease in all-cause mortality was observed. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) is a large, long-term study (23,400 patients, 5.5 years). It will compare the benefits of ACE inhibitor treatment, ARB treatment, and treatment with an ACE inhibitor and ARB together, in a study population with established coronary artery disease, stroke, peripheral vascular disease, or diabetes with end-organ damage. Patients with congestive heart failure will be excluded. In a parallel study, patients unable to tolerate an ACE inhibitor will be randomized to receive telmisartan or placebo (the Telmisartan Randomized Assessment Study in ACE-I Intolerant Patients with Cardiovascular Disease [TRANSCEND]). The primary endpoint for both trials is a composite of cardiovascular death, MI, stroke, and hospitalization for heart failure. Secondary endpoints will investigate reductions in the development of diabetes mellitus, nephropathy, dementia, and atrial fibrillation. These 2 trials are expected to provide new insights into the optimal treatment of patients at high risk of complications from atherosclerosis.
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PMID:From the HOPE to the ONTARGET and the TRANSCEND studies: challenges in improving prognosis. 1183 7

In this article, 2 leading physicians debate the strength of outcome data on the efficacy of angiotensin-converting enzyme (ACE) inhibitors versus angiotensin II receptor blockers (ARBs) for reducing the incidence of cardiovascular, cerebrovascular, and renovascular events. Dr. Stephen G. Ball notes that the efficacy of ACE inhibitors for reducing the risk for myocardial infarction independent of their effects on blood pressure is controversial. In the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril treatment in high-risk patients was associated with a 20% reduction in the risk for myocardial infarction; mean reduction in blood pressure was 3 mm Hg for systolic blood pressure and 1 mm Hg for diastolic blood pressure. The HOPE investigators propose that the 20% reduction was much greater than would be expected based on the observed blood pressure reduction. However, a meta-regression analysis of blood pressure reduction in >20 antihypertensive therapy outcome trials found that the reduction in myocardial infarction risk with ramipril observed in HOPE was consistent with the modest blood pressure reduction seen with that agent. Nevertheless, there are convincing data for prevention of myocardial infarction with ACE inhibitors in patients with heart failure, including those with heart failure after myocardial infarction, as well as supportive evidence from studies in patients with diabetes mellitus and concomitant hypertension. On the other hand, Dr. William B. White takes the position that ARBs are well-tolerated antihypertensive agents that specifically antagonize the angiotensin II type 1 (AT(1)) receptor and provide a more complete block of the pathologic effects of angiotensin II-which are mediated via the AT(1) receptor-than ACE inhibitors. The Evaluation of Losartan in the Elderly (ELITE) II study and the Valsartan Heart Failure Trial (ValHeFT) suggest that ARBs reduce the risk for mortality in patients with congestive heart failure. The Losartan Intervention for Endpoint (LIFE) Reduction in Hypertension trial also demonstrated beneficial effects of ARBs in the prevention of stroke events. The Irbesartan in Patients with Diabetes and Microalbuminuria (IRMA) study, the Irbesartan Diabetic Nephropathy Trial (IDNT), and the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study demonstrated significant reductions in the rate of progression of renal disease in patients receiving ARBs, independent of effects on blood pressure. These data support the use of ARBs, in addition to the standard of care, in hypertensive patients with heart failure who are intolerant of ACE inhibitors, and also provide compelling evidence for their use in patients with hypertension and type 2 diabetes.
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PMID:Debate: angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers--a gap in evidence-based medicine. 1451 6

Restenosis rates after coronary stent implantation in complex lesions are between 30 and 50%. Neointimal hyperplasia promoted by complex interaction between cellular and acellular elements, such as cytokines and growth factors, is thought to be the primary process responsible for restenosis. The risk of in-stent restenosis is increased in patients with a history of restenosis after percutaneous transluminal coronary angioplasty, in long lesions, in total occlusions, in patients with diabetes mellitus, in small vessels, in the proximal parts of the left anterior descending coronary artery and in cases of stent oversizing. In-stent restenosis represents a serious economic burden on society because treatment strategies include expensive approaches such as cutting-balloon angioplasty, rotational atherectomy and brachytherapy. A number of pharmacological agents, including ACE inhibitors, have been unsuccessful in preventing restenosis. Alternative procedures such as brachytherapy, radioactive stents and drug-eluting stents are under evaluation. Although sirolimus- or paclitaxel-eluting stents have been associated with very low restenosis rates over durations of 6 to 12 months, the long-term efficacy and tolerability of this approach is currently being investigated. Although ACE inhibitors have failed in reducing restenosis rates, the selective angiotensin II type 1 (AT(1)) receptor antagonist valsartan has shown encouraging results in the single-center Valsartan for Prevention of Restenosis after Stenting of Type B2/C lesions trial (ValPREST). The ValPREST trial is the first randomized, placebo-controlled study to have evaluated the effect of an angiotensin receptor antagonist on in-stent restenosis in a moderate number of patients. Compared with ACE inhibitors, angiotensin receptor blockers exert additional effects on the pathophysiological processes which lead to restenosis. Angiotensin receptor antagonists may affect several mechanisms involved in neointimal hyperplasia such as decreasing circulating cytokine and growth factor levels and reducing neutrophil activation, especially after stenting in acute coronary syndromes, but the results need to be confirmed in a large multicenter trial. The question whether long-term therapy, with an oral angiotensin receptor antagonist, is cost-effective and whether angiotensin receptor antagonists should be used as an add-on therapy to drug-eluting stents, requires clarification.
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PMID:Can angiotensin receptor antagonists prevent restenosis after stent placement? 1472 76

Hypertension is a major risk factor for cardiovascular morbidity and mortality. Monotherapy of hypertension is often ineffective, since it controls approximately 50% of the blood pressure of hypertensive patients. For lowering blood pressure to less than 140/90 mmHg (or <130/80 mmHg among people with diabetes or chronic renal disease) according to JNC-7 guidelines, combination therapy of two or more drugs is often necessary. The combination of a diuretic with an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) is effective and provides the additional benefit of blocking the effects of angiotensin II, which is responsible for cardiovascular remodeling and its complications. ARBs may have an advantage over the ACEIs because they block the action of all angiotensin II directly, whereas ACEIs are ineffective in blocking angiotensin II generated by nonclassical ACE pathways. Valsartan (Diovan, Novartis) is one of the seven currently approved ARBs in the USA for the treatment of hypertension, and it has been shown to be very effective in controlling blood pressure given once-daily in doses of 80-160 or 320 mg. Its fixed combination with hydrochlorothiazide (HCT) is even more effective in controlling blood pressure in 70% of the cases. The most commonly used combinations are valsartan/HCT (Diovan/HCT), 80/12.5 and 160/12.5 mg given once-daily.
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PMID:Fixed combination therapy of hypertension: focus on valsartan/hydrochlorothiazide combination (Diovan/HCT). 1503 Feb 62


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