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Linezolid (Zyvox), the first of a new class of antibiotics, the oxazolidinones, is approved for treatment of Gram-positive bacterial infections, including resistant strains. The disposition of linezolid in human volunteers was determined, after a 500-mg (100-microCi) oral dose of [(14)C]linezolid. Radioactive linezolid was administered as a single dose, or at steady-state on day 4 of a 10-day, 500-mg b.i.d. regimen of unlabeled linezolid (n = 4/sex/regimen). Mean recovery of radioactivity in excreta was 93.8 +/- 1.1% (range 91.2-95.2%, n = 15), of which 83.9 +/- 3.3% (range 76.7-88.4%) was in urine and 9.9 +/- 3.4% (range 5.3-16.9%) was in feces. There was no major difference in rate or route of excretion of radioactivity by dose regimen. Linezolid was excreted primarily intact, and as two inactive, morpholine ring-oxidized metabolites, PNU-142586 and PNU-142300. Other minor metabolites were characterized by high-performance liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry and (19)F NMR spectroscopy. After the single radioactive dose, linezolid was the major circulating drug-related material accounting for about 78% (male) and 93% (female) of the radioactivity area under the curve (AUC). PNU-142586 (T(max) of 3-5 h) accounted for about 26% (male) and 9% (female) of the radioactivity AUC. PNU-142300 (T(max) of 2-3 h) accounted for about 7% (male) and 4% (female) of the radioactivity AUC. Overall, mean linezolid and PNU-142586 exposures at steady-state were similar across sex. In conclusion, linezolid circulates in plasma mainly as parent drug. Linezolid and two major, inactive metabolites account for the major portion of linezolid disposition, with urinary excretion representing the major elimination route. Formation of PNU-142586 was the rate-limiting step in the clearance of linezolid.

Background Linezolid is an oxazolidinone antibiotic with excellent in vitro activity against a number of Gram-positive organisms including antibiotic-resistant isolates. The safety and pharmacokinetics of intravenously administered linezolid were evaluated in children and adolescents to examine the potential for developmental dependence on its disposition characteristics. Methods Fifty-eight children (3 months to 16 years old) participated in this study; 44 received a single 1.5-mg/kg dose and 14 received a single 10-mg/kg dose of linezolid administered by intravenous infusion. Repeated blood samples (n = 10 in children > or = 12 months; n = 8 in children 3 to 12 months) were obtained during 24 h after drug administration, and linezolid was quantitated from plasma by high performance liquid chromatography with mass spectrometry detection. Plasma concentration vs. time data were evaluated with a model independent approach. Results Linezolid was well-tolerated by all subjects. The disposition of linezolid appears to be age-dependent. A significant although weak correlation between age and total body clearance was observed. The mean (+/- SD) values for elimination half-life, total clearance and apparent volume of distribution were 3.0 +/- 1.1 h, 0.34 +/- 0.15 liter/h/kg and 0.73 +/- 0.18 liter/kg, respectively. Estimates of total body clearance and volume of distribution were significantly greater in children than historical values of adult data. As such maximum achievable linezolid plasma concentrations were slightly lower in children, and concentrations 12 h after a single 10-mg/kg dose were below the MIC90 for selected pathogens with in vitro susceptibility to the drug. Conclusion Based on these data a linezolid dose of 10 mg/kg given two to three times daily would appear appropriate for use in pediatric therapeutic clinical trials of this agent.

Editor—We report two sibs with an unbalanced translocation of chromosomes 2 and 10 resulting in distal 2p trisomy. We feel that this sib pair could help to delineate the common features that may result from duplication of this specific region, in particular to show that arachnodactyly is a key feature. We suggest that the combination of arachnodactyly with developmental delay should prompt investigation of this region within the differential diagnosis. This sib pair was first seen in 1995 aged 8 years (male) and 11 years (female). They were referred with a combination of speech and language delay, poor coordination, and concordant dysmorphic features. The male sib (fig 1) was born at 38 weeks' gestation weighing 3200 g (25th centile). He was noted to have gross motor delay with hypotonia and walked at 22 months. Speech development was severely delayed necessitating Makaton from the age of 2 years. He attended a school for moderate learning difficulties and required intensive speech therapy. His motor development is still delayed and at the age of 11, he cannot ride a bicycle, catch a ball, or fasten shoe laces. He continues to require considerable supplemental educational input and speech therapy. Figure 1 Male sib aged 8 years showing facial dysmorphism and arachnodactyly. His height has followed the 90th centile with weight between the 25th and 50th centile and head circumference on the 50th. There is no limb or body segment disproportion. Joint flexibility is normal. He has arachnodactyly (palm length 10.5 cm (75th centile), middle finger length 8.0 …

To investigate glyburide pharmacokinetics in patients with well-controlled noninsulin-dependent diabetes mellitus (NIDDM), and test the hypothesis that intersubject variability in the glyburide dose is due to patient differences in the drug's pharmacokinetics.Prospective, open-label study.University-affiliated, internal medicine outpatient clinic.Fifty-one patients with NIDDM (11 women, 40 men, mean age 56.7 +/- 15.3 yrs) receiving oral glyburide and with well-controlled glycohemoglobin levels 10.0% or below.After fasting overnight, patients ingested their regular morning dose of glyburide and then ate breakfast. Blood samples were drawn before dosing and between 0.5-2 hours, 2-5 hours, and 5-10 hours after dosing.Serum glyburide was assayed by high-performance liquid chromatography and pharmacokinetics by NONMEM. Glyburide clearance was proportional to weight and greater in older patients (60 yrs).Variability in the glyburide dose was not primarily due to intersubject differences in the drug's pharmacokinetics.

X-ray fluorescence (XRF) has been used to determine in vivo the percutaneous absorption of 5-iodouracil (5IU) in dimethyl sulfoxide (DMSO) on female Sprague-Dawley rats. An average absorption rate constant of 122 +/- 34 micrograms/cm2-hr was obtained from the XRF measurements on four rats. A comparative study was performed with radiolabeled (125I) 5IU in which the absorption rate constant was determined to be 126 +/- 20 micrograms/cm2-hr. The XRF system described provides a simple, noninvasive means of measuring the percutaneous absorption rate of select compounds by the surface disappearance method.

The bioavailability of three formulations of medroxyprogesterone acetate (MPA) was assessed in 30 healthy male volunteers in a three-way, open-label, cross-over-designed trial. Each subject received one Provera 500-mg tablet, one Farlutal 500-mg tablet, and one Provera 500-mg granule packet according to a randomized schedule, with each treatment separated by a 21-day washout period. Serum MPA levels were determined using both radioimmunoassay (RIA) and high-performance liquid chromatography techniques. Based on the results of RIA analysis, Farlutal tablets produced significantly lower serum MPA concentrations compared with Provera tablets at most sampling times, resulting in statistically lower AUC0-144 for the Farlutal tablet (544 vs 768 ng.hr/ml; -29.2%). The Farlutal tablet also had a significantly lower maximum concentration than the Provera tablet (27.8 vs 47.4 ng/ml; -41.4%). However, there was no significant difference in time of maximum concentration between the tablet formulations (3.71 vs 3.41 hr), indicating that the rates of absorption of the two tablet formulations were comparable. Provera granules provided significantly higher serum MPA levels than Provera tablets at 0.5, 1, 1.5, 2, and 6 hours, and the AUC0-144 for Provera granules was higher by 5.47% (810 vs 768 ng.hr/ml). There were no differences in terminal elimination rate constants among the dosage forms. No significant adverse events were noted during the trial. The relative bioavailabilities of Provera granules and Farlutal tablets were 105% and 71.2%, respectively, compared with Provera tablets.

The buccal absorption of flurbiprofen was evaluated in nine normal volunteers. Twenty milliliters of 2.5 mg/ml flurbiprofen solution (pH 8.03) was administered as a 1-min mouthwash or a 5-min mouthwash or swallowed. Serum was harvested from blood samples taken at specified times over a 12-hr period. Serum flurbiprofen concentration data indicate that the extent, but not the rate, of drug absorption was dependent upon the time of exposure of the flurbiprofen solution to the buccal membrane. Following the 1- and 5-min mouthwash treatments, 5.2 and 9.4% of the administered doses were absorbed, respectively.

Editor—Slack and Schapira1 are correct in drawing attention to a problem that is recognised and documented but not fully addressed or understood. Their suggestion that further studies are required to determine the optimum timing of immunisation for extremely preterm infants is sound (even though the adequate immunological response of these babies to vaccinations is well documented). However they state that the presumed cause of the apnoeas is the pertussis component, with neither reference nor explanation of why they think this is the case. As the four antigens are given simultaneously it is not possible to identify the culprit. The American studies quoted2 3 could not identify whether one or a combination of antigens was …

The effect of antacid administration on the pharmacokinetics of ibuprofen was evaluated in a randomized, crossover study of eight healthy volunteers. Doses of 62 mL of aluminum and magnesium hydroxide suspension and single doses of ibuprofen 400 mg were used. Subjects received each of the following treatments at one-week intervals: ibuprofen alone; ibuprofen administered concurrently with one dose of antacid; antacid administered one hour after the ibuprofen dose; and antacid administered concurrently with the ibuprofen dose, plus three more antacid doses given every five hours. Blood samples were taken at various time intervals up to 24 hours after the ibuprofen dose. Serum samples were assayed for ibuprofen content using high-performance liquid chromatography. Values for AUC, Cmax, tmax, and k were not significantly different among treatment groups. The ranges of mean (+/- S.D.) values were 113.97 +/- 21.5 to 127.53 +/- 29.3 micrograms.hr/mL for AUC, 35.30 +/- 6.40 to 41.00 +/- 10.00 micrograms/mL for Cmax, 0.95 +/- 0.30 to 1.28 +/- 0.54 hr for tmax, and 0.346 +/- 0.026 to 0.388 +/- 0.040 hr-1 for k. For the doses used, concurrent administration of aluminum and magnesium hydroxide suspension and ibuprofen does not alter ibuprofen pharmacokinetics.