Enantiomer-selective pharmacokinetics and metabolism of ketorolac in children.

OBJECTIVE: To compare the pharmacokinetics and metabolism of R(+)- and S(-)- ketorolac in children. METHODS: Children from 3 to 18 years old received 0.6 mg/kg racemic ketorolac intravenously. Serial blood samples were obtained for 12 hours, and urine was collected for 12 to 24 hours. Racemic ketorolac was measured in plasma, and racemic ketorolac, para-hydroxyketorolac, and ketorolac glucuronide were measured in urine by HPLC. S(-)- and R(+)-ketorolac were measured in plasma; S(-)- and R(+)-ketorolac and ketorolac glucuronide were measured in urine by chiral HPLC separation. Plasma pharmacokinetic parameters for racemic drug and both enantiomers were determined for each patient. RESULTS: Clearance of racemic ketorolac in children was approximately 2 times the clearance reported in adults. Clearance of the S(-) enantiomer was 4 times that of the R(+) enantiomer. Terminal half-life of S(-)-ketorolac was 40% that of the R(+) enantiomer, and the apparent volume of distribution of the S(-) enantiomer was greater than that of the R(+) form. Recovery of S(-)-ketorolac glucuronide was 2.3 times that of the R(+) enantiomer. CONCLUSION: The higher clearance in children suggests that the weight-adjusted dose of ketorolac may have to be greater for children to achieve plasma concentrations comparable to those of adults. Because of the greater clearance and shorter half-life of S(-)-ketorolac, pharmacokinetic predictions based on racemic assays may overestimate the duration of pharmacologic effect. Enantiomeric pharmacokinetic differences are best explained by stereoselective plasma protein binding. Selective glucuronidation of the S(-) enantiomer suggests that stereoselective metabolism may also be a contributing factor.

An improved method for the quantitation of phencyclidine (PCP) in biological samples utilizing nitrogen-detection gas chromatography.

A simplified method for the quantitation of phencyclidine using nitrogen-detection gas chromatography is described. The samples are extracted twice with n-butyl chloride containing benzphetamine as an internal standard. A 0.5 mL sample is required for detection of as little as 5 ng/mL PCP. The assay is easy, fast and reliable. Due to the relatively small volume required, this method is suitable for analysis of pediatric samples.

A rapid and sensitive high-performance liquid chromatography assay for rofecoxib in human serum.

Rofecoxib is a selective cyclooxygenase (COX)-2 inhibitor that is approved for the treatment of acute pain and osteoarthritis in adults. A sensitive and rapid high-performance liquid chromatographic (HPLC) method of determining rofecoxib in human serum is described. Alkalinized plasma samples are extracted into an organic solvent containing an internal standard and evaporated under nitrogen. The dried sample residues are reconstituted with mobile phase and analyzed by HPLC. The method uses 100 microL of the sample and is linear from 20 to 2000 ng/mL of rofecoxib. Precision and accuracy studies are performed. Stability of the drug in serum over four weeks is documented. This new method is simple, sensitive, precise, and accurate. Its use will translate into faster laboratory turnaround time, and the small sample volume required (100 microL) makes this assay suitable for pediatric patients. This assay will expedite pharmacokinetic studies and the therapeutic drug monitoring of rofecoxib and possibly other COX-2 inhibitors.

Analysis of caffeine: comparison of the manual enzyme multiplied immunoassay (EMIT), automated EMIT, and high-performance liquid chromatography procedures.

Caffeine has been recommended for the treatment of apnea in newborn children. Most of the current methods for measurement of caffeine in newborns have used high-performance liquid chromatography (HPLC) because analysis can be performed on as little as 50 microliter of serum, an important factor when obtaining multiple blood samples for routine drug monitoring in infants and children. We evaluated the manual Syva enzyme multiplied immunoassay technique (EMIT) caffeine procedure and compared the assay results with our HPLC caffeine method. The EMIT procedure was also automated, and these results were compared with those of the manual and HPLC procedures. The 7-micrograms/ml calibrator was analyzed 20 times to establish within-run precision for the manual procedure. The mean +/- SD was 6.97 +/- 0.33, and the coefficient of variation (CV) was 4.80%. Reproducibility was tested by multiple analysis of the 11-micrograms/ml control. The mean +/- SD (CV) for the manual system was 11.3 +/- 0.45 (4%), n = 17; for the HPLC system, 10.58 +/- 0.89 (8.4%), n = 10; and for the automated system, 10.4 +/- 0.78 (7.5%), n = 12. Samples from 32 patients were analyzed by each of the above procedures. There was a good correlation among all three procedures. The correlation coefficient (r) for HPLC vs. manual EMIT was 0.98; for HPLC vs. automated EMIT, 0.97; and for automated EMIT vs. manual EMIT, 0.96. We conclude that the new Syva EMIT caffeine method is reliable and reproducible and can be applied to automated analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic and pharmacodynamic study of midazolam in children during esophagogastroduodenoscopy.

We undertook a prospective study to evaluate the relationship between the onset and degree of sedation and the midazolam plasma concentration in children between 6 and 18 years of age during esophagogastroduodenoscopy. Thirteen boys and seven girls (median age 13.5 years) were studied. Midazolam was injected intravenously for 5 minutes, and the dose was titrated to sedation or a maximum dose of 0.1 mg/kg was given. Plasma midazolam concentration was determined just before and at 5, 10, 15, 30, 45, and 60 minutes after the start of midazolam injection. The patient's level of sedation was evaluated by an assistant at each blood sampling time. Clearance, volume of distribution, and terminal elimination (beta) half-life were estimated from a biexponential fit of the serial plasma midazolam concentrations. Mean beta half-life of midazolam was 47 +/- 26 minutes and mean clearance was 10.0 +/- 5.0 ml/min per kilogram of body weight. Maximum level of sedation occurred at 5 minutes after initiation of the injection and corresponded to a mean peak midazolam serum concentration of 229 +/- 39 micrograms/L. Thereafter, a decline of mean sedation scores paralleled the decrease in midazolam concentration. Mean oxygen saturation remained greater than 94% during the study. We conclude that children metabolize and excrete midazolam more rapidly than adults do and that sedation adequate for endoscopy is safely achieved in the majority of children with a midazolam dose of 0.05 to 0.1 mg/kg and a mean peak midazolam concentration greater than 200 microgram/L.

Simultaneous measurements of acetaminophen and salicylate in plasma by liquid chromatography.

We describe a "highly-performance" liquid chromatographic method in which 8-chlorotheophylline is used as an internal standard to determine acetaminophen and salicylate simultaneously in plasma samples. Therapeutic as well as toxic concentrations can be determined on samples as small as 50 micro L, which makes the method particularly useful for determinations on samples from young children. The procedure requires a simple extraction of the drugs, and the chromatography is completed in 6 min.

Flumazenil in children after esophagogastroduodenoscopy.

OBJECTIVE: Our aim was to evaluate if the routine use of the benzodiazepine antagonist flumazenil would shorten postprocedure recovery times after esophagogastroduodenoscopy in pediatric patients receiving standard intravenous conscious sedation with the benzodiazepine diazepam in combination with meperidine. METHODS: Upper endoscopy was performed using intravenous conscious sedation with standardized doses of diazepam and meperidine on 29 children, age range 6-18 yr. Patients were randomized in a double-blind fashion to receive either intravenous normal saline (placebo) or 0.01 mg/kg (maximum, 1.0 mg) flumazenil within 5 min of procedure completion. Evaluation of the degree of sedation using a modified Observer' s Assessment of Alertness/Sedation Scale was performed presedation, immediately before reversal solution administration, and serially over 60 min after reversal solution injection. RESULTS: Fifteen patients received flumazenil and 14 received placebo; patient group composition did not vary significantly in age and weight. Fifty-four percent of flumazenil patients and 30% of control patients achieved full alertness within 10 min of reversal solution injection. However, this difference between groups was not significant (p > 0.45). Resedation or side effects directly attributable to flumazenil were not observed. CONCLUSIONS: A single postsedation dose of flumazenil is well-tolerated in children >6 yr old. However, its routine use after esophagogastroduodenoscopy is of questionable benefit in shortening recovery time in this age group.

Relative bioavailability of intravenous chloramphenicol succinate and oral chloramphenicol palmitate in infants and children.

The relative bioavailability of intravenously administered chloramphenicol succinate and orally administered chloramphenicol palmitate was compared in 18 children, age 2 months to 14 years. The area under the serum concentration vs time curve of chloramphenicol and urinary excretion of chloramphenicol succinate were determined in each child under steady-state conditions while receiving chloramphenicol succinate and again while receiving chloramphenicol palmitate. The mean AUC was significantly greater during oral therapy compared to intravenous therapy (110 vs 78 mg hr/L, P less than 0.001). The relative bioavailability of chloramphenicol succinate was 70% compared to chloramphenicol palmitate. This could be explained by the mean loss of 36% of the intravenous dose in the urine as unhydrolyzed chloramphenicol succinate. The intravenous dose of chloramphenicol succinate did not correlate with AUC (r = 0.193). However, there was a significant correlation between the oral dose of chloramphenicol palmitate and AUC (r = 0.429, P = 0.025). The bioavailability of orally administered chloramphenicol palmitate is superior to that of chloramphenicol succinate given intravenously. Furthermore, there is a greater correlation between dose and amount of active drug in the body when the oral preparation is used. Oral administration of chloramphenicol palmitate appears to offer significant therapeutic advantages in patients who can tolerate medication given orally.

Diffusion of moxalactam into the cerebrospinal fluid in children with bacterial meningitis.

We studied the penetration of moxalactam into the cerebrospinal fluid of 16 children (age range one month to 4 1/2 years) who were being treated for bacterial meningitis. Two hours after single intravenous doses of 15 or 25 mg/kg, moxalactam was detectable in the CSF in only one of 11 instances; however, following three doses (50 mg/kg each) moxalactam was detectable in eight of 17 instances. In these eight instances CSF concentrations of moxalactam ranged between 1.5 and 18.9 micrograms/ml (mean 7.7) and the CSF/plasma ratio ranged from 2.6 to 36% (mean 17.7). There was no relation between the stage of meningitis or the CSF cell count and the diffusion of the drug into the CSF. However, the diffusion of the drug significantly correlated with the CSF protein content. In view of the unpredictability of moxalactam penetration into CSF, caution should be exercised in using it alone in the treatment of meningitis.

Pharmacokinetic and clinical evaluation of moxalactam in infants and children.

37 patients ranging in age from 9 months to 14 years, with various infections, were treated with moxalactam. The pharmacokinetics of the drug were studied in 18 patients. The mean plasma concentration 1 h after a 25 mg/kg intravenous dose was 41.4 micrograms/ml +/- 15.6 SD, the half-life was 1.5 h +/- 0.4 SD and the mean Vd was 550 ml/kg +/- 239 SD. The total body clearance of moxalactam was 4.1 ml/min/kg +/- 1.5 SD and the mean renal clearance 4.5 ml/min/kg +/- 2.8 SD. Between 52 and 107% of the administered dose was recovered in the urine within 8 h after administration. The pharmacokinetics after the first and multiple doses of moxalactam were similar, indicating no accumulation of the drug with repeated administration. The clinical response was adequate in 35 of 37 patients. Moxalactam was well tolerated and only minor and transient hematological abnormalities were observed.