Pharmacokinetic disposition and protein binding of furosemide in newborn infants

Aranda, Jacob V.; Perez, J.; Sitar, Daniel S.; Collinge, Judith M.; Portuguez-Malavasi, Ana; Duffy, B. J.; Dupont, Claire

doi:10.1016/s0022-3476(78)81181-0

Cited by 71 publications

(33 citation statements)

References 23 publications

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“…Therefore, it is interesting to speculate that the furosemide-induced di uresis would also change rapidly at slightly older ages than used in the present study. Finally, whereas the time course of the re sponses to acctazolamide, chlorothiazide and amiloride was similar at all ages, the response to furosemide was prolonged in the 2-day-old pups as compared to the 6-and 10-day-old pups which may be related to the increased plasma half-life of the drug in the newborn [21].…”

Section: Discussionmentioning

confidence: 80%

Pharmacologic Probing of Renal Development in the Neonatal Rat

Gray¹,

Kavlock²

1986

Neonatology

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This study was designed to examine the ontogeny of renal functions in the neonatal rat using various pharmacologic agents as probes. The renal responses of 2-, 6-, and 10-day-old rats to diuretic agents known to act on proximal tubules, loops of Henle and distal tubules were assessed. These included acetazolamide, furosemide, mercaptomerin, chlorothiazide and amiloride. Following administration of a diuretic agent, urine was collected at 90-min intervals for 6 h and urine volume, osmolality, chloride and pH were measured. Acetazolamide, furosemide, chlorothiazide and amiloride induced diuresis at each age indicating that the respective reabsorptive mechanisms were present and functional by 2 days of age. At all ages furosemide evoked a maximal response in eliminating the interstitial fluid gradient as indicated by the formation of an isosmotic urine in treated pups. However, the volume of the diuresis at 2 days of age was half those at 6 and 10 days, reflecting enhanced activity of the countercurrent multiplication apparatus in the maturing pups. Administration of mercaptomerin did not produce pharmacologic diuresis, but rather resulted in acute renal failure; although the nephrotoxicity was to a lesser extent in 2-day-old pups. The ability of the neonatal rat to respond to these pharmacologic probes demonstrates that the integrity of these renal functions is established in this species early in postnatal life.

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Section: Discussionmentioning

confidence: 80%

Pharmacologic Probing of Renal Development in the Neonatal Rat

Gray¹,

Kavlock²

1986

Neonatology

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“…2, 1-and 10-min plasma concentrations were lower [27,28] for doses with surfactant. The curves then cross at 30 min and the surfactant curve has higher plasma concentrations thereafter.…”

Section: Intratracheal Installation With Surfactantmentioning

confidence: 82%

“…Furosemide half-life is much shorter and clearance more rapid in the guinea pig than the reported values for the human neonate 196 Smith/Pillers/Gilhooly/Wall/Olsen Intratracheal Pharmacokinetics [27,28]. The neonatal values vary widely and are dependent on gestational age.…”

Section: Discussionmentioning

confidence: 96%

Furosemide Pharmacokinetics following Intratracheal Instillation in the Guinea Pig

Smith

Pillers

Gilhooly³

et al. 1995

Neonatology

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Inhaled furosemide has been shown to attenuate bronchospasm in asthmatics and to increase lung compliance in infants with bronchopulmonary dysplasia (BPD). The reports involving BPD used a dose of 1 mg/kg and some have failed to show an effect with that dose. We determined the pharmacokinetics of furosemide administered directly to the airway in 7 young adult male guinea pigs who received intravenous and intratracheal doses of furosemide. Each animal received a 3 mg/kg i.v. bolus, 1, 3 and 6 mg/kg i.t. in 2 ml/kg normal saline and 3 mg/kg i.t. in 2 ml/kg bovine extract surfactant. Blood was sampled multiple times after each dose. The mean fraction of the intratracheal dose absorbed was 0.50–0.60 for all doses. Surfactant delayed the absorption of furosemide but did not alter the fraction absorbed.

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“…A 30 M concentration of furosemide approximates the plasma concentration expected in a newborn after i.v. administration of 1 mg/kg furosemide (17,18). Data analysis.…”

Section: Methodsmentioning

confidence: 99%

Loop Diuretics and In Vitro Relaxation of Human Fetal and Newborn Mouse Airways

2001

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This study was designed to test the hypotheses that furosemide directly causes relaxation in human fetal airway and that delivery of loop diuretics to either the adventitial or epithelial surface of newborn mouse airway results in equivalent relaxation. Isometric tension changes were measured in human fetal (11-16 wk) trachea and mainstem bronchus rings exposed to furosemide (300 M) or saline after acetylcholine or leukotriene D 4 constriction. Significant decreases in isometric tension to furosemide were demonstrated after constriction with acetylcholine or leukotriene D 4 . To examine the site of effect and mimic aerosolized and systemic administration, furosemide (3-300 M) and bumetanide (0.3-30 M) were applied separately to epithelial and adventitial surfaces of newborn mouse airways. No differences in airway diameter changes to epithelial or adventitial furosemide or bumetanide were observed, but a 10-fold difference in potency was found. In summary, human fetal airway relaxed to furosemide when constricted with either neurotransmitter or inflammatory mediator in vitro. Further, no differences in relaxation to equimolar epithelial and adventitial furosemide were observed in isolated newborn mouse airway. Taken together, this provides evidence that furosemide has a direct, nonepithelial-dependent effect on airway smooth muscle tone. Systemically administered furosemide improves pulmonary mechanics and gas exchange in infants with chronic lung disease independent of its diuretic effects (1, 2). Studies demonstrating a reduction of bronchoconstrictive responses in pediatric (3) and adult asthmatics (4, 5) with aerosolized furosemide further support the notion that a nondiuretic effect may produce improvements in pulmonary function. Indeed, the in vitro airway relaxation to furosemide that is observed in animal models (6 -8) suggests that there may be a direct effect on airway smooth muscle.However, a bronchodilatory response to inhaled furosemide is not consistently observed in infants with chronic lung disease (9, 10). Although aerosolized administration of furosemide could minimize systemic effects while producing localized bronchodilation, it is not widely accepted that inhaled furosemide has therapeutic efficacy during acute bronchoconstriction. Taken together, it is presently unclear whether these inconsistent results are because of species differences or inadequate concentrations of drug that reach the airway with aerosolized treatment, or because furosemide in fact does not act via a mechanism of direct airway smooth muscle relaxation (11). Therefore, the potential relevance of previous in vitro animal findings requires validation by the study of human airway response (12), with the first objective to test the hypothesis that furosemide causes direct relaxation of human fetal airway.In addition to demonstrating a direct relaxing effect on airway smooth muscle, further support for the bronchodilatory response to furosemide via aerosolization would require evidence that mechanisms can be activated from th...

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Pharmacokinetic disposition and protein binding of furosemide in newborn infants

Cited by 71 publications

References 23 publications

Pharmacologic Probing of Renal Development in the Neonatal Rat

Pharmacologic Probing of Renal Development in the Neonatal Rat

Furosemide Pharmacokinetics following Intratracheal Instillation in the Guinea Pig

Loop Diuretics and In Vitro Relaxation of Human Fetal and Newborn Mouse Airways

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