No abstract

Argatroban, a direct thrombin inhibitor, is approved in the United States in adults as an anticoagulant for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT) and in adults with or at risk for HIT undergoing percutaneous coronary intervention. The authors conducted a literature analysis to characterize the uses, dosing patterns, and safety of argatroban anticoagulation in pediatric patients. A comprehensive literature search identified nine articles describing 34 patients aged 1 week to 16 years who received argatroban anticoagulation for prophylaxis or treatment of thrombosis, cardiac catheterization, hemodialysis, extracorporeal membrane oxygenation or ventricular assist device support, or cardiopulmonary bypass. Most (85%) patients had HIT, a history of HIT, and/or HIT antibodies. For HIT thromboprophylaxis or treatment, argatroban dosing varied widely (0.1-12 mcg/kg/min), with no obvious relationship between patient age and dosage requirement. Overall, in these pediatric patients, therapeutic levels of anticoagulation were achieved despite the wide range of doses used. For pediatric patients undergoing cardiac catheterization, argatroban doses lower than those recommended in adults appeared to provide therapeutic anticoagulation. There was an unacceptably high bleeding risk with argatroban anticoagulation during pediatric cardiopulmonary bypass. Due to the limitations of case reports and/or case series, prospective studies with pharmacokinetic analyses are needed to evaluate the use of argatroban in pediatric patients.

No abstract

Fenoldopam, a dopamine agonist, was evaluated in renal clearance studies during water diuresis after oral doses of 25, 50, and 100 mg. After the 100-mg dose there was an increase in urine flow rate, paraaminohippurate clearance, free water clearance, and an increase in the fractional excretion of sodium, calcium, and uric acid. These effects were evident within the first hour, peaked during the second hour, and lasted about 3 hr. Doses of 50 and 25 mg induced smaller increases. There was no significant change in inulin clearance at any dose. To elucidate the mechanism of action, the studies were repeated after treatment with a dopamine-receptor antagonist (metoclopramide). Metoclopramide greatly diminished the renal effects of fenoldopam. These findings indicate that fenoldopam is an active renal vasodilator in man and increases urine volume, free water clearance, and fractional excretion of sodium by stimulation of renal dopamine receptors.

Fenoldopam, a dopaminergic agonist, was administered intravenously to 18 healthy male subjects in doses ranging from 0.025 to 1.0 microgram/kg/min for 2 hours. Three subjects were studied in a three-way crossover of fenoldopam at doses of 0.025, 0.10, and 0.50 microgram/kg/min. Fenoldopam decreased diastolic blood pressure and increased pulse rate without changing systolic blood pressure. Fenoldopam produced dose-related increases in para-aminohippuric acid clearance up to 75% at the 0.50 microgram/kg/min dose. This increase in renal blood flow was accompanied by increases in urine volume, water, and solute excretion; glomerular filtration rate was unchanged. Doses greater than 0.25 microgram/kg/min caused flushing and nasal congestion. The dopamine receptor antagonist metoclopramide (0.1 mg/kg/hr) did not block the systemic hemodynamic effects of fenoldopam but attenuated the increase in para-aminohippuric acid clearance. Fenoldopam plasma levels achieved steady state between 30 and 120 minutes after the start of the infusion and were linear with respect to infusion rate. Our findings show that intravenous fenoldopam causes systemic arteriolar vasodilation, accompanied by renal vasodilation and increased sodium excretion.

Pranlukast (SB 205312; ONO-1078), a potent, orally active selective cysteinyl-leukotriene receptor antagonist (LTRA), was developed in Japan for the treatment of asthma. This article reports results of the initial U.S. clinical evaluation of pranlukast. The primary objective of this multicenter study was to evaluate the safety and tolerability of pranlukast administered at doses of 337.5 mg b.i.d. and 450 mg b.i.d. in 65 patients with mild to moderate asthma. Pranlukast, a novel LTRA, is safe and well tolerated at doses of 337.5 mg b.i.d. and 450 mg b.i.d. Pranlukast has demonstrated clinical activity in patients with asthma.

Abstract. SKF 82526-J, or fenoldopam, a benzazepine derivative, is a selective dopamine-1 (DA-1) agonist devoid of activity at dopamine-2, alpha-or beta-adrenergic receptors. We studied SKF 82526-J in 10 patients with essential hypertension and five normal control subjects on constant 150-meq sodium, 60 meq potassium intake. In the hypertensive patients, during a 6-d placebo period supine blood pressure and heart rate were stable at 156±6/105±4 mmHg and 76±5 beats/ min, respectively. In response to a single oral dose of 100 mg of SKF 82526-J, supine blood pressure decreased to a nadir of 141±5/89±8 mmHg (P < 0.0001) at 90 min and remained decreased at 145±6/99±3 mmHg (P < 0.0001) at 4 h. Heart rate increased to 91±5 beats/ min (P < 0.002), but returned to control levels (82±5 beats/min) at 4 h. Renal blood flow increased from 371±57 to a peak of 659±104 ml/min and renal vascular resistance fell from 34±5 to 19±2 dyn sec cm-5 X 103 (P < 0.01). Urine volume, sodium and fractional sodium excretion, and plasma renin activity were increased as a result of SKF 82526-J administration. During the ensuing 3 wk of SKF 82526-J, blood pressure remained decreased and returned to control levels after placebo administration. In These results suggest that reduced dopaminergic activity expressed at the peripheral DA-1 receptor may contribute to the pathophysiology and/or maintenance of increased blood pressure in essential hypertension. In addition, the results suggest that peripheral DA-1 receptor stimulation with SKF 82526-J may be efficacious in the treatment of human essential hypertension.

To evaluate the effect of acute histamine H2-receptor blockade on renal function, renal function studies were performed in a control state and after cimetidine. Studies included acid excretion in response to acid loading, bicarbonate reabsorption during bicarbonate infusion, and urinary concentrating ability. Cimetidine produced no significant effect on any of these functions. During bicarbonate infusion, inulin clearance remained constant while creatinine clearance fell, possibly because of an effect on tubular creatinine secretion.