trandolapril and Kidney-Failure--Chronic

Verapamil blocks the rapid influx of calcium into the cardiac myocytes of the cardiac conduction system and smooth muscle of the vasculature, resulting in decreased myocardial contractility, prolonged conduction time, and vascular relaxation. A sustained-release form, verapamil SR (or ER), is available that contains higher levels of medication and requires only once-daily dosing. The majority of reported fatal cases of verapamil toxicity are due to massive, intentional overdoses. Herein, we present an unusual case of fatal verapamil SR toxicity in a 57-year-old female that resulted from accidental overdose of only 3 tablets (720 mg), as witnessed by the decedent's daughter. In spite of the low dose ingested, the postmortem cardiac blood verapamil level was clearly toxic (6000 ng/mL, or 6 mg/L). Her preexisting medical conditions included hypercholesterolemia, hypertension, iron deficiency anemia, diabetes mellitus, and associated mild chronic renal failure. Complicating factors, which likely include the decedent's preexisting renal and cardiac disease, and a review of the available literature will be discussed.

Topics: Accidents; Antihypertensive Agents; Calcium Channel Blockers; Drug Combinations; Drug Overdose; Female; Forensic Toxicology; Humans; Hypercholesterolemia; Hypertension; Indoles; Kidney Failure, Chronic; Middle Aged; Verapamil

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diet, Protein-Restricted; Disease Progression; Humans; Hypokalemia; Indoles; Japan; Kidney Failure, Chronic; Losartan; Renal Dialysis

The renin-angiotensin-aldosterone system has an important role in the progression of both diabetic and non-diabetic nephropathy. COOPERATE was set up to determine whether dual blockade of angiotensin-converting-enzyme (ACE) and the AT-1 receptor was more efficacious than either ACE inhibition or AT-1 antagonism alone in non-diabetic renal disease. The combined primary end point was of time to doubling of serum creatinine concentration or end stage renal disease. By year 3, 10 of 85 (11%) of the combination patients had reached the primary end point. This was significantly less than the 20 of 86 (23%) and 20 of 85 (23%) in the losartan and trandolapril groups, respectively. Combination treatment should be considered in non-diabetic renal disease especially if the disease is progressing with ACE treatment alone.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Creatinine; Drug Therapy, Combination; Endpoint Determination; Humans; Indoles; Kidney Failure, Chronic; Losartan; Renin-Angiotensin System

SEVERAL MECHANISMS: The progression in renal failure first implies hemodynamic mechanisms and among which angiotensin II has a central role, but also an increase in proteinuria and the induction of many inflammatory and mitogenic mediators that enhance fibrosis (TGF-beta), an effect stimulating the thrombotic mechanism. Among these factors of progression in renal failure, hypertension and proteinuria are the two major factors. Proteinuria is "nephrotoxic" and leads to glomerular and tubulo-interstitial lesions. THE ROLE OF ANGIOTENSIN-CONVERTING ENZYME INHIBITORS: Angiotensin-converting enzyme inhibitors (ACE) affect the different mechanisms that lead to glomerulosclerosis: antihypertensive effect, with the normalisation of blood pressure having demonstrated its determining role in the production of nephrosis in various epidemiological studies; hemodynamic effect with a decrease in glomerular capillary pressure, in the filtration fraction, and inhibition of the bradykinin deterioration; antiproteinuric effect superior to that of other anti-hypertensive drugs (excepting angiotensin II-receptor antagonists). Two indications ACE inhibitors have demonstrated their efficacy in slowing the progression of renal failure in two large pathological fields: diabetic nephropathy in which this effect is demonstrated in type I diabetes, although the results are not as obvious in type II diabetes in which the nephropathy is multi-factor. The recent French and American recommendations are that ACE inhibitors should be used in first intention in diabetic nephropathies and aimed at tight blood pressure control; non-diabetic nephropathies Two pivotal studies have demonstrated the efficacy of ACE inhibitors in nephropathies whatever their type. These data have led to propose ACE inhibitors in first intention in patients exhibiting chronic nephropathies, whether hypertensive or not THE COMBINATION WITH OTHER HYPERTENSIVE DRUGS: Calcium channel blockers have a beneficial trophic effect in renoprotection and can be combined with ACE inhibitors, particularly in the case of diabetic nephropathies. ACE inhibitors and angiotensin II-receptor antagonists have comparable effect on hemodynamics and glomerulosclerosis factors. Clinically, the decrease in proteinuria is identical. Endothelin antagonists have also been studied in renoprotection and appear to have a beneficial effect when combined with ACE inhibitors. GLOBALLY: ACE inhibitors remain the only treatment with demonstrated lon

Topics: Amlodipine; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Biphenyl Compounds; Calcium Channel Blockers; Clinical Trials as Topic; Cohort Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Endothelins; Hemodynamics; Humans; Hypertension; Indoles; Irbesartan; Kidney; Kidney Failure, Chronic; Proteinuria; Randomized Controlled Trials as Topic; Receptors, Angiotensin; Renin-Angiotensin System; Tetrazoles; Verapamil

Hemodialysis patients have uremic dyslipidemia, represented by elevated serum intermediate-density lipoprotein cholesterol (IDL-C) levels, and an increased cardiovascular mortality rate. This study was performed to determine the low-dose effects of the angiotensin II receptor blocker losartan and the angiotensin-converting enzyme inhibitor trandolapril on pulse wave velocity (PWV), which predicts cardiovascular morbidity and mortality in hemodialysis patients.. Serum lipid levels and PWV were monitored for 12 months in 64 hemodialysis patients who were administered low doses of losartan or trandolapril or a placebo.. At the start of the study, there were no differences in patient characteristics among the 3 groups. PWV tended to increase in the placebo group during the 12-month study period, but decreased significantly in the losartan and trandolapril groups, and decreases in PWV were similar in the losartan and trandolapril groups. There were no changes in blood pressure, hematocrit, erythropoietin dose, ankle-brachial index, serum lipid levels, serum 8-isoprostane levels, or serum C-reactive protein levels during the 12-month study period, but there was an increase in serum triglyceride levels in the losartan group and a decrease in serum IDL-C levels in the losartan and trandolapril groups.. In hemodialysis patients, trandolapril is as effective as losartan in decreasing PWV independent of its depressor effect and in suppressing elevated IDL-C levels. Long-term blockade of the renin-angiotensin system may have a beneficial effect on the acceleration of atherosclerosis and uremic dyslipidemia.

Topics: Aged; Anemia; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; C-Reactive Protein; Cardiovascular Diseases; Cholesterol; Comorbidity; Dinoprost; Drug Therapy, Combination; Erythropoietin; Female; Follow-Up Studies; Hematocrit; Humans; Hyperlipidemias; Indoles; Kidney Failure, Chronic; Lipids; Lipoproteins; Lipoproteins, LDL; Losartan; Male; Middle Aged; Prospective Studies; Renal Dialysis; Treatment Outcome; Vascular Resistance

Arterial hypertension is a common finding in patients with end stage renal disease (80% patients are hypertensive). Cardiovascular diseases are the main cause of death in haemodialysis. The present study was performed to asses' successful treatment in hypertensive chronic haemodialysis patients by ultra filtration only and ultra filtration combined with medics. We studied 80 hypertensive adult patients who had been on regular haemodialysis treatment for at least 12 months (average duration of 41 months). All subjects were divided in two different antihypertensive treatment groups including 40 subjects each. The first group of patients were treated with trandolapril and ultra filtration, and the second group of patients were only treated with ultra filtration (control group). Blood pressure measurements before and after HD sessions were performed for each patient. Blood pressure control was defined using World Health Organization criteria 140/90 mm Hg. Average systolic blood pressure levels, after haemodialysis, were in the first group of patients 146.33 +/- 9.7 mm Hg, and in the control group 157,86 +/- 10.33 mm Hg. Average diastolic blood pressure was 87.83 +/- 8.11 mm Hg in the first group of patients and, in the control group it was 91.03 +/- 10.67 mm Hg. There were significant differences between systolic blood pressure level in the first group of patients and the control group of patients as well as in diastolic blood pressure (p < 0.05). We conclude that an antihypertensive therapy by trandolapril is more effective than ultra filtration alone in hypertensive patients on chronic haemodialysis.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Cardiomegaly; Female; Humans; Hypertension, Renal; Indoles; Kidney Failure, Chronic; Male; Renal Dialysis

Microalbuminuria is an early marker of diabetic nephropathy, and its prevention can be considered to be the primary prevention of diabetic nephropathy. Angiotensin converting enzyme inhibitors and non-dihydropyridinic calcium antagonists have specific renoprotective properties in diabetes, and preliminary evidence is available that their combination can delay the onset and limit the progression of nephropathy in experimental diabetes more effectively than either of the two agents alone.. The Bergamo Nephrologic Diabetes Complication Trial is a prospective, randomized, double-blind, parallel-group study aimed at evaluating the possibility of preventing the onset of nephropathy in 2400 hypertensive non-insulin-dependent diabetes mellitus patients who have a normal albumin excretion rate. During phase A of the study, patients will be randomized to one of the following treatments for 3 years: a non-dihydropyridinic calcium antagonist (slow-release verapamil 240 mg/day), an angiotensin converting enzyme inhibitor (trandolapril 2 mg/day), the combination of these drugs (verapamil 180 mg/day plus trandolapril 2 mg/day) and placebo. Other antihypertensive agents will be allowed in order to achieve and maintain systolic and diastolic blood pressures consistently below 140 and 90 mmHg, respectively, in all patients. The primary efficacy variable of phase A will be progression to microalbuminuria. In phase B progression to macro-albuminuria will be evaluated in patients who became microalbuminuric in phase A. These patients will be randomized to 2 years of treatment with trandolapril (2 mg/day) alone or combined with verapamil (180 mg/day).

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Drug Combinations; Humans; Indoles; Kidney Failure, Chronic; Prospective Studies; Verapamil

A new, long-acting angiotensin-converting enzyme (ACE) inhibitor, trandolapril, was administered daily for 10 days to 13 patients with chronic renal failure [CRF; creatinine clearance (CLCR) 7-55 ml/min/1.73 m2) and 8 healthy volunteers (CLCR > 80 ml/min/1.73 m2)]. Plasma ACE inhibition parameters were the same, irrespective of the degree of renal insufficiency, although renal failure tended to prolong ACE inhibition. The pharmacokinetics of trandolapril were not affected by CRF; hence, no accumulation of trandolapril was detected. After single or repeated administration the active metabolite, trandolaprilat, showed an inverse correlation between maximal plasma concentrations (Cmax) and CLCR (r = -0.676 day 1 and r = -0.864 day 10) and area under the concentration-time curve (AUC) and CLCR (r = -0.635 day 1 and r = -0.794 day 10). The renal clearance of trandolaprilat showed significant linear correlation (r = > 0.885, p < 0.0001) with CLCR after single (r = 0.879) and repeated administration (r = 0.957). Significantly reduced excretion of trandolaprilat was seen only when the CLCR was < 30 ml/min/1.73 m2. A steady state had been achieved by 7 days in all patients, and extrapolation suggested that this was achieved in most cases after 4 days. The drug was well tolerated. The effect of CRF on the pharmacokinetics and pharmacodynamics of trandolaprilat is of significance only when CLCR is < 30 ml/min/1.73 m2. Hence, in these patients the standard dose should be reduced.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Female; Humans; Indoles; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Middle Aged

1. Hypertension plays a critical role in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD), but it has also been postulated that antihypertensive drugs that block the renin-angiotensin system (RAS) show class-specific renoprotective actions beyond their blood pressure (BP)-lowering effects. 2. Because this notion has recently been questioned, in the present study we compared the effects of a RAS-dependent antihypertensive therapy (a combination of trandolapril, an angiotensin-converting enzyme inhibitor (ACEI) and losartan, an angiotensin-II (AngII) receptor subtype 1A receptor antagonist) with a 'RAS-independent' antihypertensive therapy (a combination of labetalol, an alfa- and beta-adrenoreceptor antagonist with the diuretics, hydrochlorothiazide and furosemide) on the progression of CKD after 5/6 renal ablation (5/6 NX) in Ren-2 renin transgenic rats (TGR), a model of AngII-dependent hypertension. Normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats after 5/6 NX served as controls. 3. RAS-dependent and -independent antihypertensive therapies normalized BP and survival rate, and prevented the development of cardiac hypertrophy and glomerulosclerosis to the same degree in 5/6 NX HanSD rats and in 5/6 NX TGR. The present findings show that renoprotection, at least in rats after 5/6 NX, is predominantly BP-dependent. When equal lowering of BP was achieved, leading to normotension, cardio- and renoprotective effects were equivalent irrespective of the type of antihypertensive therapy. 4. These findings should be taken into consideration in attempts to develop new therapeutic approaches and strategies aimed to prevent the progression of CKD and to lower the incidence of ESRD.

Topics: Aldosterone; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Cardiomegaly; Creatinine; Diabetic Nephropathies; Diuretics; Drug Therapy, Combination; Furosemide; Hydrochlorothiazide; Hypertension; Indoles; Kidney Failure, Chronic; Labetalol; Losartan; Proteinuria; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Renin; Renin-Angiotensin System

The activation of both the renin-angiotensin-aldosterone and endothelin (ET) system in uremia contributes to the development of cardiovascular disease. The combination of ET receptor antagonists and inhibitors of the angiotensin-converting enzyme (ACE) or angiotensin II type 1 (AT,) receptor could therefore inhibit atherogenesis. We studied the effects of different medications on growth-factor-induced proliferation of vascular smooth muscle cells (VSMC) isolated from uremic rats.. Subtotally nephrectomized rats (SNX) were treated with an ETA receptor antagonist, losartan, trandolapril, or the combinations of an ETA receptor antagonist and losartan or trandolapril for 12 weeks. Proliferation induced by different growth factors in isolated aortal SMC was measured using a BrdU-ELISA.. Maximum proliferation in response to PDGF-BB, bFGF, and TNF-alpha which was higher in untreated SNX than in controls (PDGF-BB: 486.60 +/- 8.27% versus 346.74 +/- 4.60%, n=8), was reduced after monotherapy with losartan or the ETA receptor antagonist. VSMC from trandolapril-treated rats showed an increased response to all growth factors (PDGF-BB: 663.48 +/- 7.00%, n=8). After combined therapy with the ETA receptor antagonist and trandolapril, maximum proliferation was lower than in untreated SNX (PDGF-BB: 162.6 +/- 1.40%; n=8; p < or = 0.01). Combined treatment with losartan and the ETA receptor antagonist attenuated the maximum levels of VSMC proliferation induced by PDGF-BB, bFGF, and TNF.. In contrast to an increased response after trandolapril monotherapy, combined treatment of SNX with an ETA receptor antagonist and trandolapril reduced growth-factor-induced VSMC proliferation in vitro. Further investigations in uremic patients have to clarify whether the combination of endothelin receptor antagonists and ACE inhibitors inhibits atherogenesis.

Topics: Analysis of Variance; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Drug Therapy, Combination; Indoles; Kidney Failure, Chronic; Losartan; Male; Muscle, Smooth, Vascular; Nephrectomy; Probability; Rats; Rats, Sprague-Dawley; Risk Factors; Sensitivity and Specificity; Uremia

Detection of podocytes in the urinary sediments of children with glomerulonephritis has been shown to indicate severe injury to the podocytes. The aim of the present study was to determine whether podocytes are present in the urine sediments of adult patients with diabetes with and without nephropathy and whether trandolapril is effective for podocyte injury.. Fifty diabetic patients (10 with normoalbuminuria, 15 with microalbuminuria, 15 with macroalbuminuria and 10 with chronic renal failure) and 10 healthy controls were studied. Urinary podocytes were examined by immunofluorescence using monoclonal antibodies against podocalyxin, which is present on the surface of podocytes. In addition, we studied plasma metalloproteinase (MMP)-9 concentrations in all patients.. Urinary podocytes were absent in healthy controls, diabetic patients with normoalbuminuria and diabetic patients with chronic renal failure. Podocytes were detected in the urine of eight diabetic patients with microalbuminuria (53%) and of 12 patients with macroalbuminuria (80%). The number of podocytes in the urine of patients with macroalbuminuria was significantly greater than in patients with microalbuminuria (P:<0.01). However, there was no relationship between urinary albumin excretion and urinary podocytes. In addition, plasma MMP-9 concentrations were significantly correlated with the number of urinary podocytes (P:<0.01). Twelve diabetic patients with macroalbuminuria and eight patients with microalbuminuria who had urinary podocytes were treated with the angiotensin-converting enzyme inhibitor trandolapril. Urinary albumin excretion, the number of podocytes and plasma MMP-9 concentrations were reduced by the trandolapril treatment.. Podocytes in the urine may be a useful marker of disease activity in diabetic nephropathy. Trandolapril may be effective for podocyte injury.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Monoclonal; Basement Membrane; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Fluorescent Antibody Technique; Humans; Indoles; Kidney Failure, Chronic; Male; Matrix Metalloproteinase 9; Middle Aged; Osmolar Concentration; Reference Values; Sialoglycoproteins; Urine

1. The pharmacokinetics and pharmacodynamics of a single dose of trandolapril, an angiotensin converting enzyme (ACE) inhibitor with an active metabolite, trandolaprilat, which is in part further metabolised prior to renal elimination, were evaluated in 31 subjects with a wide range of renal function (creatinine clearance 4-112 ml min-1 1.73 m-2). 2. The pharmacokinetics of trandolapril were unaffected by differences in renal function. 3. In contrast, there was a close correlation between the renal clearance (0-96 h) of trandolaprilat and creatinine clearance (r = 0.95, P = 0.0001). The maximum plasma concentration of trandolaprilat, and the area under the concentration curve (0-96 h) correlated inversely with creatinine clearance (r = -0.59, P < 0.001; and r = -0.61, P < 0.001 respectively). 4. Significant changes in plasma trandolaprilat concentrations were seen only in patients with creatinine clearances of 30 ml min-1 1.73 m-2 or less, suggesting that a dose reduction in trandolapril might be advisable in severe renal impairment. 5. However, the majority of parameters of ACE inhibition were unrelated to creatinine clearance, although area under the curve for ACE inhibition (0-336 h) showed a weak negative correlation (r = -0.49, P < 0.01). Similarly, weighted mean changes in blood pressure were not influenced by renal function. 6. Therefore, while the pharmacokinetic parameters of trandolaprilat correlated with creatinine clearance, pharmacodynamic measurements (ACE inhibition and blood pressure changes) in general showed no such relationship, indicating that dose adjustment of ACE inhibitors in renal impairment should be based on pharmacokinetic results only in conjunction with pharmacodynamic data.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Creatinine; Female; Humans; Indoles; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged