Hemodynamic effects of N-acetylamrinone in a porcine model of group B streptococcal sepsis.

High plasma concentrations of N-acetylamrinone, a primary metabolite of amrinone, are measured in some children during prolonged amrinone infusion. The purpose of this investigation was to determine if N-acetylamrinone has direct hemodynamic effects independent of amrinone. Twenty neonatal piglets received an infusion of 6 x 10(9) colony-forming units/kg of group B Streptococcus to induce sepsis. Subsequently, they were divided into 1 of 3 groups and received a 1-hr infusion of either normal saline (N = 4); 8 mg/kg amrinone, followed by 20 micrograms/kg/min (N = 9); or 8 mg/kg N-acetylamrinone, followed by 20 micrograms/kg/min (N = 7). Hemodynamic measurements and arterial/venous blood-gas determinations were obtained every 30 min during the study. Systemic vascular resistance and pulmonary vascular resistance were calculated. One milliliter of blood was obtained every 30 min during drug administration to determine plasma amrinone and N-acetylamrinone concentrations. The mean amrinone plasma concentrations measured at 30 and 60 min during the infusion time in the group receiving amrinone were 8.8 +/- 1.1 and 6.9 +/- 0.7 micrograms/ml, respectively. These animals experienced a significant decrease in mean pulmonary artery pressure and pulmonary vascular resistance, compared with saline controls after a 30-min infusion of amrinone. The mean N-acetylamrinone plasma concentrations measured at 30 and 60 min during the N-acetylamrinone infusion were 7.3 +/- 0.8 and 5.7 +/- 0.6 micrograms/ml, respectively. There was no difference between any hemodynamic parameter measured in these animals, compared with saline controls at any time during the infusion. We conclude that amrinone, but not N-acetylamrinone, causes pulmonary vasodilation in a porcine model of sepsis and that the parent drug is the sole active component in amrinone.

HPLC micromethod for amrinone and metabolites in patients receiving concurrent cephalosporin therapy.

Amrinone (AMR), a bipyridine derivative, is receiving increasing use in postoperative cardiac patients as an inotrope and vasodilator. The hemodynamic response to amrinone in adults is linearly related to AMR concentrations, warranting therapeutic drug monitoring. We report a rapid microsample HPLC method for monitoring AMR and its principal metabolites, N-acetyl (N-ac) and N-glycolyl (N-gly) AMR. Serum was precipitated with acetonitrile, and the supernatant fluid was then injected into a C18 narrow-bore column. The mobile phase consisted of a 0.1 mol/L sodium phosphate buffer (pH 6) with a gradient of acetonitrile going from 50 to 100 mL/L of eluent. Detection with a diode-array detector (DAD) concurrently monitored the absorbances at 320 and 345 nm. Monitoring 320 nm allows optimal quantification of AMR, N-gly, and N-ac. Patients often receive concurrent cephalosporin therapy, which is detectable at 320 nm but not 345 nm. Because cephalosporins coelute with AMR or metabolites, monitoring at 345 nm allows separation of these antibiotics from AMR and metabolites while retaining a detection limit of 0.5 mg/L.

Oral dimercaptosuccinic acid and ongoing exposure to lead: effects on heme synthesis and lead distribution in a rat model.

Lead (Pb) exposure and subsequent toxicity continues to be a significant problem in the United States. Treatment with meso-2,3-dimercaptosuccinic acid (DMSA) has been reported to be effective in reducing the body's Pb burden, with fewer adverse side effects than other chelating agents. The oral availability and relative safety of DMSA presents the controversial option of treating patients with Pb poisoning on an outpatient basis. Despite recommendations that children be removed from the Pb contaminated environment, some children will inevitably be exposed to environmental Pb while receiving oral DMSA therapy. The study hypothesized that oral DMSA chelation therapy is beneficial even when faced with continued dietary Pb. Sprague-Dawley rats were exposed to Pb in water for 35 days and then placed in various treatment groups, including groups administered oral DMSA with and without concurrent Pb exposure. The concentration of Pb in blood and critical organs and Pb diuresis were measured. The effect of Pb on heme synthesis was determined by assaying the urinary delta-aminolevulinic acid (delta-ALA), and blood zinc protoporphyrin (ZPP). DMSA reversed the hematological effects of Pb, decreased the blood, brain, bone, kidney, and liver Pb concentration, and produced a marked Pb diuresis, even when challenged with ongoing Pb exposure. In conclusion, even though DMSA treatment without exposure to Pb is optimal, oral DMSA could be beneficial even when challenged with ongoing Pb exposure.

Age-related amrinone pharmacokinetics in a pediatric population.

OBJECTIVES: To measure the plasma concentrations of amrinone and N-acetyl-amrinone achieved using current pediatric dosing recommendations. To examine the pharmacokinetics of amrinone in an extended age range of pediatric patients. To examine any age-related differences in the relative contribution of hepatic metabolism vs. renal elimination of amrinone. DESIGN: Prospective study. SETTING: A pediatric intensive care unit in a tertiary care teaching hospital. PATIENTS: Thirty-one patients aged 4 days to 15 yrs who required a constant infusion of amrinone. INTERVENTIONS: Blood samples were obtained 15 mins after each 0.75 mg/kg loading dose, and every 6 hrs during a constant infusion of amrinone to measure plasma amrinone, N-acetyl-amrinone and N-glycolyl-amrinone concentrations by high-performance liquid chromatography. Blood samples to measure amrinone, N-acetyl-amrinone, and N-glycolyl-amrinone concentrations during elimination were also obtained at regular intervals after discontinuation of the infusion. Six-hour urine collections were obtained to measure amrinone renal clearance. MEASUREMENTS AND MAIN RESULTS: Plasma amrinone concentrations > or = 2 micrograms/mL were obtained in 13 of 14 patients after a 3-mg/kg loading dose. There was a six-fold variability in steady-state plasma amrinone concentrations in patients receiving the same ordered infusion rate. There was a significant (p = .001) difference between the ordered and measured amrinone infusion rates. Six (19.4%) of 31 patients had steady-state plasma amrinone concentrations of < or = 2 micrograms/mL. There was a large variability in the volume of distribution, clearance, and elimination half-life which did not appear to be age-related. Renal clearance of amrinone ranged between 0.4 and 2.18 mL/kg/min, and did not increase with age. There was no increase in the proportion of children with a high plasma steady-state N-acetyl-amrinone/amrinone ratio over time from 1 to 24 months of life. CONCLUSIONS: Administering a 3-mg/kg amrinone loading dose in four divided doses over 1 hr resulted in relatively rapid therapeutic plasma concentrations without excessively high concentrations and good clinical tolerance. The wide interindividual variation in clearance and volume of distribution resulted in a variable dose-concentration relationship; children receiving lower amrinone infusion rates may-have subtherapeutic plasma steady-state concentrations. There did not appear to be any age-related change in renal clearance or hepatic metabolism of amrinone in children aged 1 to 24 months.

Amrinone-associated thrombocytopenia: pharmacokinetic analysis.

Amrinone-associated thrombocytopenia is thought to result from nonimmune-mediated peripheral platelet destruction. Platelet destruction may be a concentration-dependent toxic effect of amrinone or its principal metabolite N-acetylamrinone. Eighteen children receiving amrinone after heart surgery were prospectively evaluated to correlate the pharmacokinetics of amrinone and N-acetylamrinone with thrombocytopenia. Amrinone and N-acetylamrinone plasma concentrations were determined by HPLC during loading, infusion, and terminal elimination, with concurrent monitoring of platelet counts. Thrombocytopenia developed in eight patients (platelet count, 66 +/- 17 x 10(9) platelets/L [mean +/- SD]). Peak and steady-state amrinone plasma concentration, amrinone total dose, duration of amrinone exposure, and amrinone area under curve (AUC) were similar between patients with and without thrombocytopenia. N-Acetylamrinone peak concentration, steady-state concentration, N-acetylamrinone AUC, and ratio of N-acetylamrinone to amrinone were greater in patients with thrombocytopenia. This association suggests that N-acetylamrinone, and not amrinone, may be the mediator of thrombocytopenia in children receiving amrinone.

Hepatic clotrimazole concentrations and hepatic drug metabolizing enzyme activities in adult male Sprague-Dawley rats.

A single high dose, 75 mg/kg, of clotrimazole (CloTZ) was administered intragastrically (i.g.) to adult male Sprague-Dawley rats. Hepatic CloTZ concentrations were determined in organic extracts of whole liver homogenate, by high-performance liquid chromatography (HPLC). The peak liver CloTZ concentration was found at 2.5 h post dose, and the liver t1/2 was 11 h. With the present procedure CloTZ was detectable in the liver for up to 40 h and during this period, the hexobarbital sleep-time in these treated rats was prolonged. Between 40 and 120 h following a single dose of CloTZ, hexobarbital sleep-times were less than in untreated rats. The shortened sleep-time coincided with cytochrome P-450 induction which could be demonstrated in microsomal fractions obtained from the livers. Cytochrome P-450 catalyzed p-nitroanisole-demethylase activity in the microsomal fractions in vitro was inhibited in the first 24 h and induced in microsomes prepared after that time.