Hyperlipidemia and progressive renal disease.

Experimental studies have suggested an important role for abnormal lipid metabolism as an integral factor in modulating progressive renal damage. Dietary induced hypercholesterolemia induced relatively modest glomerular injury. However, in the presence of reduced nephron population or in the presence of underlying renal diseases, such as diabetes, nephrotic syndrome, and hypertension, nephron injury can be markedly exaggerated. These experimental results suggest that an important interaction may occur between renal disease and the occurrence of abnormalities of lipid metabolism. Additional support for the role of lipids in progressive renal injury can be obtained from studies in which pharmacological interventions reduced circulating lipids and this led to decreased glomerular damage. The mechanisms whereby lipids may amplify glomerular injury are not completely understood but may include an interaction with macrophages, alteration in vascular and mesangial functions, changes in production of mediator substances or alterations in membrane fluidity. Local glomerular modification of lipoproteins could also occur and contribute to the development of glomerular pathologic changes. Clinically, few data are available that provide insights into the potential role of renal-related lipid abnormalities in the progression of human renal disease.

Large prospective study of ramipril in patients with hypertension. CARE Investigators.

The results of controlled trials demonstrate that ramipril lowers blood pressure in hypertensive patients, has a long duration of action suitable for once-daily administration in most patients, and is well tolerated. To assess the efficacy and safety of ramipril in a large cross-section of patients, we conducted a multicenter, open-label, prospective study, in which 591 men or women with essential hypertension (diastolic blood pressure > or = 95 and < or = 114 mmHg) received ramipril on a regimen of 1.25 to 10 mg once daily for 8 weeks. Forty-one percent of the patients required 2.5 mg and 81% required < or = 5 mg once daily at study completion. Compared with baseline, ramipril reduced mean systolic/diastolic blood pressure by 19.9/14.7 mmHg (P < 0.001/P < 0.001). Ramipril reduced diastolic blood pressure to < or = 90 mmHg or by at least 10 mmHg in 84.1% of the patients. Response rates were similar regardless of age, gender, and race. No patient stopped ramipril because of an adverse event or experienced an unexpected adverse event. In our real-world study, low-dose ramipril given once daily controlled blood pressure in most patients and was well tolerated.

Double-blind, placebo-controlled study of ramipril in diabetics with mild to moderate hypertension.

Although hypertension and diabetes mellitus frequently appear as comorbidities, the pharmacotherapy of hypertension in patients with diabetes mellitus can aggravate underlying carbohydrate and lipid abnormalities. To evaluate the efficacy and safety of the long-acting angiotensin converting enzyme inhibitor ramipril in patients with insulin-dependent or non-insulin-dependent diabetes mellitus, the authors conducted a double-blind, placebo-controlled study. After a single-blind washout period, 58 patients were randomly assigned to receive 2.5 mg of ramipril or a 2.5-mg placebo, each once daily. Each patient underwent titration and maintenance phases for a total treatment period of 12 weeks. By the end of maintenance, 54% of patients maintained the target blood pressure 24 hours after receiving ramipril compared with 19% in the placebo group (P = 0.008). Between baseline and the end of maintenance, ramipril decreased mean supine systolic/diastolic blood pressure (SBP/DBP) measured 24 hours after the last dose by 9/8 mmHg (P < or = 0.001/P < or = 0.001); placebo decreased SBP/DBP by 2/4 mmHg (NS/P < or = 0.05). Between-group differences were significant (P < 0.05). During this time, blood glucose, hemoglobin Alc, lipoproteins, and biochemistry were unchanged in the ramipril group. There were no between-group differences in the number or types of adverse events. In our study of patients with diabetes mellitus, once-daily ramipril controlled blood pressure, was well tolerated, and had no effects on carbohydrate or lipid metabolism.

Radioimmunoassays for the enantiomeric components of indacrinone and their phenolic metabolites.

MK-286 is a 90:10 mixture of the (+) and (-)-enantiomers of indacrinone, a combination which induces diuresis while maintaining isouricemia. The principal (phenolic) metabolites also possess pharmacological activity and assays for the four entities were needed for clinical studies. Antisera were produced with the stereospecificity required to measure one enantiomer in the presence of the others, but significant cross-reactivity between drug and metabolite necessitated the separation of these two species by means of Sep-Pak cartridges. Recovery was assessed by concurrently fractionated reference samples. The radioligand in each case was a [I-125]-L-iodotyrosine conjugate of the analyte. Absolute assay sensitivities ranged from 2-20 pg/assay tube, corresponding to 0.2-2.0 ng/ml in serum samples. The assay was also applied to urine with analytes at concentrations greater than 16 ng/ml.

Long-term renal effects of enalapril therapy in patients with renal insufficiency.

Angiotensin-converting enzyme inhibitory therapy is widely used to treat hypertension. With long-term use, it is now being shown to have a beneficial effect on renal function and proteinuria in patients with renal insufficiency. When hypertensive patients with renal insufficiency are treated with enalapril, glomerular filtration rate is maintained, effective renal plasma flow is increased, and microalbuminuria and gross proteinuria are reduced. These beneficial renal changes with enalapril therapy differ from those of most other conventional antihypertensive medications. Clinical awareness of potential problems with hyperkalemia and increasing azotemia, particularly in the setting of salt/volume depletion, is important to assure optimal patient management. When these problems occur, they are nearly always reversible by correcting salt/volume status and/or interrupting enalapril therapy.

The study of the effect of intensity of blood pressure management on the progression of type 1 diabetic nephropathy: study design and baseline patient characteristics. Collaborative Study Group.

A randomized, prospective, clinical trial has been initiated to continue follow-up in a subset of the patients previously enrolled in the recently completed Study of Angiotensin-Converting Enzyme Inhibition (ACEi) in Type 1 Diabetic Nephropathy. In that study, the use of captopril was associated with a 48% reduction in the risk of doubling the serum creatinine and a 50% reduction in the risk of experiencing dialysis, transplantation, or death, compared with the use of placebo. These effects were independent of captopril's effect on the blood pressure. This study is designed to determine whether the level of mean arterial blood pressure (MAP), using the ACE inhibitor ramipril as the primary therapy, is associated with an improved prognosis of diabetic nephropathy with respect to (1) the rate of decline in renal function; (2) the rate of progression to end-stage renal failure; (3) the clinical course of proteinuria; (4) morbidity; and (5) mortality. Patients are randomized into one of two distinct blood pressure control groups, an Intensive Group #1, MAP < or = 92 mm Hg; and a Moderate Group #2, MAP 100 to 107 mm Hg. Patients previously enrolled in the "Study of ACEi in Type 1 Diabetic Nephropathy" whose serum creatinine was less than 4.0 mg/dL (354 mumol/L) were eligible for randomization into this study. All patients will receive ramipril (2.5 to 10.0 mg/day) as the primary therapy, with the addition or removal of other antihypertensive agents as needed to achieve the assigned blood pressure goal.(ABSTRACT TRUNCATED AT 250 WORDS)

Tolerability of long term therapy with enalapril maleate in patients resistant to other therapies and intolerant to captopril.

Patients with severe hypertension and/or congestive heart failure (n = 281) who were unresponsive to other therapies and intolerant to captopril received enalapril treatment (mean dose 19.5 mg/day) under study conditions as part of a Compassionate Use Program. Many of these patients had serious concurrent disorders known to predispose them to a greater risk of adverse experiences and death. The mean duration of enalapril treatment was 29 weeks, with a range of 1 day to approximately 3.5 years. Enalapril was generally well tolerated, and the estimated long term probability of patients terminating enalapril therapy because of adverse effects was low. 20 patients had discontinued captopril treatment because of low white blood cell counts; during subsequent enalapril treatment these reactions resolved in 14 patients, persisted in 2 patients, and could not be evaluated in 4 patients. Captopril-related proteinuria improved or resolved in 9 and persisted in 2 of 15 patients, taste disturbances resolved in 35 and persisted in 2 of 38 patients; and rash resolved in all but 7 of 178 patients during enalapril treatment. 18 patients (6%) discontinued enalapril treatment because of lack of efficacy; 6 of these 18 patients died due to a progression of heart failure, and another 11 patients died for other reasons. The deaths were considered unrelated to therapy with enalapril. Adverse reactions were the reason for discontinuation of enalapril treatment in 53 patients (19%). The most common adverse experiences that resulted in discontinuation of enalapril were: impairment of renal function (5%), hypotension (2%) and rash (2%). No neutropenia, proteinuria, or new taste disturbances were recorded as reasons for discontinuation.(ABSTRACT TRUNCATED AT 250 WORDS)