Tolvaptan vs. furosemide-based diuretic regimens in patients hospitalized for heart failure with hyponatremia (AQUA-AHF).

AIMS: Hyponatremia is associated with poorer outcomes and diuretic response in patients hospitalized for heart failure. This study compared a tolvaptan-based vs. furosemide-based diuretic regimen on short-term clinical responses in hyponatremic acute heart failure. METHODS AND RESULTS: Prospective, randomized, open-label, parallel-group, single-centre study comparing oral tolvaptan vs. continuous infusion furosemide. Thirty-three subjects requiring hospitalization for acute congestive heart failure, and a serum sodium < 135 mmol/L, were randomized to tolvaptan 30 mg orally daily or furosemide 5 mg/h intravenously for initial 24 h, after which treatments could be escalated. Median daily dose throughout was tolvaptan 30 mg and furosemide 120 mg, with four subjects in each group requiring dose escalation. Urine output and net fluid balance were not different between groups at 24 h or subsequent time points up to 96 h. Changes in estimated glomerular filtration rate were comparable. Cystatin C improved at 24 h with tolvaptan compared with furosemide (-6.4 ± 11.8 vs. 4.1 ± 17.2% change, P = 0.036), but the effect was transient. No significant between group differences were seen for NT-proBNP, plasma renin activity, or urinary neutrophil gelatinase-associated lipocalin:Cr. Serum sodium, as well as copeptin levels, increased with tolvaptan compared with furosemide. CONCLUSIONS: Oral tolvaptan was associated with similar, but not superior, diuresis compared with intravenous furosemide for acute heart failure with concomitant hyponatremia.

Estimating aminoglycoside clearance and creatinine clearance in underweight patients.

PURPOSE: An adjustment factor (AF) was developed and evaluated to determine the best method for estimating aminoglycoside clearance (CL(amino)) and creatinine clearance (CL(cr)) in underweight patients. METHODS: This study was a retrospective, multicenter, chart analysis of aminoglycoside pharmacokinetic data obtained between January 2000 and August 2006 at the University of Southern California University Hospital and Cedars-Sinai Medical Center. Adult patients were included in this study if they had received inpatient aminoglycoside therapy, were at least 60 inches tall, and were at least 10% below their ideal body weight (IBW). CL(cr) and CL(amino) were estimated and compared to actual CL(amino) using the Cockcroft-Gault equation with actual serum creatinine (SCr) (CG(SCr)), Cockcroft-Gault equation with SCr rounded to 1 mg/dL (CG(rnd)), and Cockcroft-Gault equation multiplied by an AF (CG(AF)). Results An AF of 0.69 was determined from 52 patients and tested in 53 separate patients. The CG(AF) method was more precise and less biased than the CG(SCr) equation; the CG(rnd) equation was less biased than the CG(SCr) equation; the CG(AF) method was more precise and less biased than the CG(rnd) equation, but this difference was not statistically significant. In underweight patients with an SCr concentration of > or = 1 mg/dL, the CG(AF) method had less bias compared with the CG(SCr) equation. CONCLUSION: Both the CG(rnd) and CG(AF) methods of predicting CL(amino) in underweight patients were superior to the CG(SCr) equation. The CG(AF) method was more accurate in patients exhibiting greater differences between IBW and actual body weight.

Pharmacokinetics of Ibuprofen in children with cystic fibrosis.

An exaggerated inflammatory response is responsible for the decline of lung function in patients with cystic fibrosis (CF). Ibuprofen is a potent anti-inflammatory agent that demonstrates inhibition of neutrophil activity in vitro at concentrations between 50 and 100 mg/L, whereas lower concentrations result in an increase in inflammatory mediators. Significant decline in the rate of deterioration of pulmonary function and increased nutritional status were observed in children with CF who were administered long-term high-dosage ibuprofen therapy. As with many other drugs, CF patients appear to exhibit altered pharmacokinetics of ibuprofen (reduced bioavailability, increased volume of distribution, and more rapid clearance) when compared with healthy controls. However, the absence of studies with intravenous ibuprofen as well as protein binding measurements in patients with CF currently limits the ability to compare the pharmacokinetics with those in other populations. Current studies indicate that there is high interpatient variability in ibuprofen pharmacokinetics among CF patients. Some of this variability can be explained by differences in ibuprofen formulation administered. Therapeutic drug monitoring of high-dosage ibuprofen therapy is recommended because of the biphasic response to inflammatory mediators demonstrated in vitro as well as the high interpatient variability in pharmacokinetics. Due to the differences in absorption characteristics between ibuprofen formulations, the timing of obtaining blood samples for pharmacokinetic analysis is critical. Maximum a posteriori Bayesian analysis has been shown to provide more accurate and precise estimates of the pharmacokinetic parameters of ibuprofen in children with CF, and may also be a useful tool to further investigate the relationship between measures of drug exposure and efficacy/toxicity outcomes.