In patients with severe CRI, a continuous intravenous infusion of bumetanide is more effective and less toxic than conventional intermittent bolus therapy. Continuous administration will probably be useful in patients with severe CRI who have not achieved an adequate natriuresis or who show evidence of drug toxicity with standard diuretic dosing regimens. A similar benefit may occur in selected diuretic-resistant patients with cardiac or hepatic disease, and studies in these patients seem warranted.
We studied the pharmacokinetics and effects of recombinant human superoxide dismutase (rhSOD) in 32 normal human volunteers after intravenous bolus doses from 1 mg/kg to 45 mg/kg in a single-blind, placebo-controlled, crossover design. The drug was well tolerated. Neither cardiovascular nor renal function, such as the echocardiographically determined cardiac index, insulin or para-aminohippurate clearance, or the urinary excretion of beta 2-microglobulin or N-acetylglucosaminidase, was affected. Pharmacokinetic analysis by use of noncompartmental methods showed an overall half-life of rhSOD to be about 4 hours for doses from 3 mg/kg to 45 mg/kg. The peak concentrations ranged from 24 to 837 mg/L, and urinary excretion increased from 3% to 57% of total dose after single intravenous bolus administrations of the drug from 1 mg/kg to 45 mg/kg. The mean renal clearance of rhSOD initially increased with dose then plateaued at the highest dose, whereas the nonrenal clearance decreased with dose to a plateau; total clearance remained essentially constant. The progressive increase in renal clearance may be explained by saturation of the tubular reabsorption and degradation of the protein, a mechanism previously described in animal models.
The pharmacokinetics and pharmacodynamics of torasemide were studied in 24 subjects with chronic renal insufficiency. The subjects were divided into two groups of patients, half having a creatinine clearance < 30 ml/min and the other half having a creatinine clearance between 30 and 60 ml/min. Three different intravenous doses were studied in each patient group. Pharmacokinetic analysis revealed dose proportionality when relating area under the concentration curve to dose. There was a progressive decrease in renal clearance of torasemide with declining renal function. In contrast, there was no difference in serum elimination half-life among the patients. In addition, this half-life was not different from that observed in healthy young or elderly control subjects. In previous reports on patients with congestive heart failure and liver disease, serum half-life values were prolonged compared to that of control subjects, presumably due to decreased hepatic, nonrenal clearance of torasemide. Supportive of this hypothesis is the considerably increased area under the serum vs. concentration time curve in such patients. In summary, this study has shown that the serum half-life of torasemide would be unchanged in patients with renal disease. The ceiling dose for torasemide (i.e., the dose above which no further drug-induced natriuresis is obtained) has been preliminarily found to be a single 100-mg intravenous dose in patients with moderate renal insufficiency and a single 200-mg intravenous dose in patients with severe disease.
1. To test the hypothesis that basal renin angiotensin aldosterone system (RAAS) activity impairs the acute natriuretic response to frusemide in patients with mild or moderate congestive heart failure (CHF), we studied eight adult volunteers with preserved renal function, stable New York Heart Association Class II or III CHF, and echocardiographic evidence of left ventricular dysfunction due to myocardial infarction, hypertension, or both causes. 2. All patients received three dosing regimens administered in random order: (a) intravenous frusemide: 40 mg bolus then 40 mg h‐1 for 3 h, (b) captopril: two 12.5 mg oral doses separated by 2 h, (c) combined dosing: the first captopril dose preceded the frusemide bolus by 30 min. Sodium balance on an 80 mmol day‐1 sodium diet was documented prior to each dosing regimen. Sodium excretion was quantitated in urine collected at intervals until 3.5 h after initiating drug administration. During this time, urine output was replaced intravenously with an equivalent volume of 0.45% saline. 3. Captopril significantly lowered plasma angiotensin converting enzyme (ACE) activity and plasma aldosterone concentration, and raised inulin clearance. The drug had essentially no effect on the time course of magnitude of frusemide's natriuretic effect. Maximal fractional sodium excretion during frusemide infused by itself and in combination with captopril was 24.7 +/‐ 1.9% vs 28.2 +/‐ 3.8%, respectively (difference 3.5%; 95% CI, ‐4.0 to 11.0%; P > 0.05). Cumulative sodium excretion ending at 3.5 h was 429 +/‐ 53 mmol when frusemide was given alone and 455 +/‐ 69 mmol when captopril was added (difference, 26 mmol; CI, ‐121 to 174 mmol; P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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