Gene/Protein Disease Symptom Drug Enzyme Compound
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The prevalence of primary and secondary hypertension and of heart and kidney involvement was thoroughly studied in 689 hypertensive subjects derived from a blood pressure screening examination of a total population sample of Swedish men (n = 7,452). The prevalence of secondary hypertension was found to be only 5%, the prevalence of surgically curable hypertension being even lower. Left ventricular hypertrophy and slight heart enlargement were each found in about one-third of the hypertensive patients, while severe heart enlargement, left ventricular hypertrophy on ECG, proteinuria, abnormal serum creatinine and urinary sediment were each found in about 5%. On the basis of these findings, a minimum pre-treatment workup in uncomplicated hypertension is proposed.
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PMID:Pre-treatment workup for antihypertensive treatment. 127 68

When captopril was first introduced, it was used in high doses for severe hypertension, often in the presence of renal insufficiency, and side effects such as proteinuria, rash, neutropenia, and altered taste sensation were noted. Upon analysis, these effects were most commonly seen in patients with renal disease, autoimmune disease, or collagen vascular disease. These complications usually reversed rapidly upon discontinuation of treatment. In contrast, the growing use of the angiotensin converting enzyme inhibitors, captopril and enalapril, for treating mild to moderate hypertension and the trend toward the use of lower doses has shown these agents to be well tolerated with a low frequency of troublesome adverse effects. In fact, the original spectrum of adverse effects has virtually disappeared with the use of lower doses in patients with uncomplicated hypertension. In low doses, the converting enzyme inhibitors produce remarkably few incidences of symptomatic discomfort; the most common is skin rash, which often responds to dosage reduction. Cough and rare occurrences of angioedema have also been reported. Moreover, evidence is evolving that indicates that the converting enzyme inhibitors may sometimes decrease proteinuria and improve renal function; these effects may be especially important in diabetic hypertensive patients. Of note, these drugs can also attenuate the unwanted metabolic side effects of concurrent diuretic treatment.
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PMID:Safety issues during antihypertensive treatment with angiotensin converting enzyme inhibitors. 306 5

Circulating immune complexes (CICs) were measured in sera of pregnant women with pre-eclampsia and other hypertensive disorders of pregnancy and pregnant women with renal disease, using four different CIC assays: platelet 125I-labelled staphylococcal protein A test ( PIPA ), conglutinin-binding ELISA, C1q-binding ELISA and rheumatoid factor binding inhibition ELISA. CICs were shown to be present in the sera of 47% of women with severe pre-eclampsia, in 20% with mild pre-eclampsia and in 18% of women with normal pregnancy using the PIPA test. The PIPA test was capable of discriminating between patients with renal disease, which were all positive, and women with uncomplicated hypertension, which were all negative. All patients positive in the PIPA test, and most patients with a positive RFbI -ELISA test, had various amounts of proteinuria. Although half of the women with severe pre-eclampsia showed the presence of CICs in the PIPA test, the amount of these complexes was low and not constant in serial samples from the same patient.
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PMID:Circulating immune complexes in hypertensive disorders of pregnancy. 673 68

1. Platelet-activating factor is a phospholipid with potent vasodilator and platelet-activating properties. To test the hypothesis that a generalized change in cellular platelet-activating factor metabolism may be involved in the systemic vasodilatation of normal pregnancy or pregnancy-induced hypertension, we studied platelet-activating factor and eicosanoid synthesis in isolated leucocytes obtained from pregnant women before and after delivery compared with age-matched non-pregnant control subjects. Parallel observations were carried out in age- and gestation-matched women with uncomplicated hypertension in pregnancy and in women with pregnancy-induced hypertension and a further set of normotensive pregnant control subjects. 2. Leucocyte counts were higher in all pregnant groups compared with non-pregnant control subjects. Neutrophil production of platelet-activating factor and metabolites of prostacyclin, prostaglandin E2 and thromboxane in response to calcium ionophore stimulation were all lower in pregnant women compared with non-pregnant control subjects, but returned to similar levels 6 weeks post partum. There was no significant difference between essential hypertensive and normotensive groups. When women with pregnancy-induced hypertension were a priori sub-divided into those with or without proteinuria, subjects with proteinuria showed significantly lower levels of neutrophil platelet-activating factor synthesis. 3. Plasma levels of the platelet-activating factor metabolite (lyso-platelet-activating factor) were also lower in pregnancy, suggesting alterations in the activity of enzymes controlling synthesis or degradation of this phospholipid in pregnancy. In pregnancy-induced hypertension the levels of plasma lyso-platelet-activating factor were higher than in normal pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neutrophil platelet-activating factor in normal and hypertensive pregnancy and in pregnancy-induced hypertension. 814 97

Outcome trials are the scientific method of determining if an antihypertensive agent really works; and for a therapy to work well, it should reduce mortality. The FDA requires only that blood pressure be controlled safely, but current evidence-based medicine demands answers to the mortality/morbidity question. We need this outcome trial information on all the classes of antihypertensives, including calcium channel blockers. For example, we often rely on surrogate endpoints such as control of blood pressure or control of PVCs. If we treat hypertensives with PVCs using beta-blockers or calcium channel blockers, we may see both control of blood pressure and suppression of PVCs. However, as we learned from the CAST trial with flecainide and encainide, PVCs can be controlled, but mortality may increase. On the other hand, the Lewis trial demonstrated that captopril, an ACE inhibitor, reduced proteinuria, which is another surrogate endpoint in diabetic hypertensives with nephropathy, although blood pressure was controlled with diuretic and conventional therapy. Importantly, captopril also reduced morbidity and mortality without influencing blood pressure. Unfortunately, there are no outcome trials measuring mortality endpoints for most of the antihypertensive agents in use today, especially in patients with uncomplicated hypertension.
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PMID:Toward improved antihypertensive therapy with calcium channel blockers. 959 54

The goals of antihypertensive therapy are to lower blood pressure and prevent end-organ damage without side effects, which affect quality of life. The antihypertensive drugs, regardless of class, all lower blood pressure, but they vary in their mechanisms of action, side-effect profiles, suitability for patients with other comorbid conditions, and ability to protect against the long-term sequelae of hypertension. The Sixth Report of the Joint National Committee on Prevention, Evaluation, and Treatment of High Blood Pressure (JNC-VI) recommends diuretics and beta-blockers as first-line therapy for uncomplicated hypertension, with diuretics also being strongly preferred for patients with isolated systolic hypertension or hypertension and heart failure and beta-blockers being strongly preferred for patients who have had a myocardial infarction (MI) and those with hypertension and angina, atrial tachycardia, or atrial fibrillation. Because angiotensin-converting enzyme (ACE) inhibitors have been shown to be cardioprotective and renoprotective in patients with diabetes or impaired left ventricular (LV) function, the JNC-VI recommends them as first-line therapy in patients with diabetes with proteinuria, heart failure, and MI complicated by LV dysfunction. It recommends calcium channel blockers for hypertensive patients with angina, long-acting dihydropyridines for those with isolated systolic hypertension, and the nondihydropyridines for those with atrial tachycardia or fibrillation, diabetes, and proteinuria. The angiotensin II receptor blockers (ARBs) share many of the organ-protective effects of ACE inhibitors when studied in animal models. They are effective in lowering blood pressure and have a very benign side-effect profile; however, these agents have not been available long enough to ascertain their efficacy in protecting against long-term complications.
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PMID:Clinical overview of antihypertensive classes--clinically relevant differences: myths or facts? Based on a presentation by Alan H. Gradman, MD. 1097 60

Therapeutic goals for the treatment of hypertension and the ability of various angiotensin-converting-enzyme (ACE) inhibitors to meet these goals are presented. The 1997 Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI) does not recommend ACE inhibitors for first-line therapy in the treatment of hypertension; however, these guidelines do identify compelling indications for ACE inhibitor therapy, including diabetes mellitus (type 1) with proteinuria, heart failure, or previous myocardial infarction with systolic dysfunction. Since the JNC-VI guidelines were developed, the results of a prospective randomized clinical trial in patients with uncomplicated hypertension have demonstrated that ACE inhibitor therapy is as effective as conventional treatment in the prevention of cardiovascular morbidity and mortality. In hypertensive patients with diabetes, therapy with captopril, enalapril, fosinopril, or ramipril has resulted in significant reductions in cardiovascular events. In addition, tight blood pressure control with an ACE inhibitor has resulted in a greater reduction in the risk of macrovascular and microvascular complications of diabetes than was seen with less tight control. Recent study results support broader use of ACE inhibitors for hypertension than was recommended in the JNC-VI guidelines.
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PMID:Role of angiotensin-converting-enzyme inhibitors in the treatment of hypertension. 1103 17

Some evidence suggests that long-term angiotensin-converting enzyme (ACE) inhibition may become less effective, thereby increasing angiotensin II levels, which could be inhibited by the addition of an angiotensin receptor blocker. We conducted a meta-analysis of randomized trials with searches of MEDLINE, EMBASE, and Cochrane databases. Overall, the combination of an ACE inhibitor and an angiotensin receptor blocker reduced ambulatory blood pressure by 4.7/3.0 mm Hg (95% confidence interval [CI], 2.9 to 6.5/1.6 to 4.3) compared with ACE inhibitor monotherapy and 3.8/2.9 mm Hg (2.4 to 5.3/0.4 to 5.4) compared with angiotensin receptor blocker monotherapy. Clinic blood pressure was reduced by 3.8/2.7 mm Hg (0.9 to 6.7/0.8 to 4.6) and 3.7/2.3 mm Hg (0.4 to 6.9/0.2 to 4.4) compared with ACE inhibitor and angiotensin receptor blocker, respectively. However, the majority of these studies used submaximal doses or once-daily dosing of shorter-acting ACE inhibitors and, when a larger dose of shorter-acting ACE inhibitor was given or a longer-acting ACE inhibitor was used, there was generally no additive effect of the angiotensin receptor blocker on blood pressure. Proteinuria was reduced by the combination compared with ACE inhibitor and angiotensin receptor blocker monotherapy, an effect that was independent of blood pressure in several studies, suggesting that the combination could have benefits in proteinuric nephropathies. None of the studies was of sufficient size and duration to determine whether there may be safety concerns. In conclusion, although there is a small additive effect on blood pressure with an ACE inhibitor-angiotensin receptor blocker combination, the routine use of this combination in uncomplicated hypertension is not recommended until more carefully controlled studies are performed.
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PMID:Systematic review of combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade in hypertension. 1580 63

Hypertension is common in chronic renal disease and is a risk factor for the faster progression of renal damage, and reduction of blood pressure (BP) is an efficient way of preventing or slowing the progression of this damage. International guidelines recommend lowering BP to 140/90 mm Hg or less in patients with uncomplicated hypertension, and to 130/80 mm Hg or less for patients with diabetic or chronic renal disease. The attainment of these goals needs to be aggressively pursued with multidrug antihypertensive regimens, if needed. The pathogenesis of hypertensive renal damage involves mediators from various extracellular systems, including the renin-angiotensin system (RAS). Proteinuria, which occurs as a consequence of elevated intraglomerular pressure, is also directly nephrotoxic. As well as protecting the kidneys by reducing BP, antihypertensive drugs can also have direct effects on intrarenal mechanisms of damage, such as increased glomerular pressure and proteinuria. Antihypertensive drugs that have direct effects on intrarenal mechanisms may, therefore, have nephroprotective effects additional to those resulting from reductions in arterial BP. Whereas BP-lowering effects are common to all antihypertensive drugs, intrarenal effects differ between classes and between individual drugs within certain classes. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have beneficial effects on proteinuria and declining renal function that appear to be mediated by factors additional to their effects on BP. These RAS inhibitors are recommended as a first-line antihypertensive approach in patients with chronic kidney disease. The addition of diuretics and calcium channel antagonists to RAS inhibitor therapy is also considered to be a rational strategy to reduce BP and preserve renal function. Calcium channel antagonists are a highly heterogeneous class of compounds, and it appears that some agents are more suitable for use in patients with chronic renal disease than others. Manidipine is a third-generation dihydropyridine (DHP) calcium channel antagonist that blocks both L and T-type calcium channels. Unlike older-generation DHPs, which preferentially act on L-type channels, manidipine has been shown to have beneficial effects on intrarenal haemodynamics, proteinuria and other measures of renal functional decline in the first clinical trials involving hypertensive patients with chronic renal failure. Preliminary results from a trial in diabetic patients who had uncontrolled hypertension and microalbuminuria despite optimal therapy with an ACE inhibitor or an ARB suggest that manidipine may be an excellent antihypertensive drug in combination with RAS inhibitor treatment in order to normalise BP and albumin excretion in patients with diabetes.
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PMID:Renal protection in hypertensive patients: selection of antihypertensive therapy. 1639 60

The present report highlights the key messages of the 2009 Canadian Hypertension Education Program (CHEP) recommendations for the management of hypertension and the supporting clinical evidence. In 2009, the CHEP emphasizes the need to improve the control of hypertension in people with diabetes. Intensive reduction in blood pressure (to less than 130/80 mmHg) in people with diabetes leads to significant reductions in mortality rates, disability rates and overall health care system costs, and may lead to improved quality of life. The CHEP recommendations continue to emphasize the important role of patient self-efficacy by promoting lifestyle changes to prevent and control hypertension, and encouraging home measurement of blood pressure. Unfortunately, most Canadians make only minor changes in lifestyle after a diagnosis of hypertension. Routine blood pressure measurement at all appropriate visits, and screening for and management of all cardiovascular risks are key to blood pressure management. Many young hypertensive Canadians with multiple cardiovascular risks are not treated with antihypertensive drugs. This is despite the evidence that individuals with multiple cardiovascular risks and hypertension should be strongly considered for antihypertensive drug therapy regardless of age. In 2009, the CHEP specifically recommends not to combine an angiotensin-converting enzyme inhibitor with an angiotensin receptor blocker in people with uncomplicated hypertension, diabetes (without micro- or macroalbuminuria), chronic kidney disease (without nephropathy [micro- or overt proteinuria]) or ischemic heart disease (without heart failure).
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PMID:2009 Canadian Hypertension Education Program recommendations: the scientific summary--an annual update. 1941 57


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