Clinical pharmacokinetics of carboplatin in children

The present study was undertaken to evaluate in children the plasma pharmacokinetics of free carboplatin given at different doses and schedules and to evaluate the inter- and intrapatient variability and the possible influence of schedule on drug exposure. A total of 35 children (age range, 1-17 years) with malignant tumors were studied. All patients had normal renal function (creatinine clearance corrected for surface body area, above 70 ml min-1 m-2; range, 71-151 ml min-1 m-2) and none had renal involvement by malignancy. Carboplatin was given at the following doses and schedules: 175, 400, 500, and 600 mg/m2 given as as a 1-h infusion; 1,200 mg/m2 divided into equal doses and infused over 1 h on 2 consecutive days; and 875 and 1,200 mg/m2 given as a 5-day continuous infusion. A total of 57 courses were studied. Carboplatin levels in plasma ultrafiltrate (UF) samples were measured both by high-performance liquid chromatography and by atomic absorption spectrophotometry. Following a 1-h infusion, carboplatin free plasma levels decayed biphasically; the disappearance half-lives, total body clearance, and apparent volume of distribution were similar for different doses. In children with normal renal function as defined by creatinemia and blood urea nitrogen (BUN) and creatinine clearance, we found at each dose studied a limited interpatient variability of the peak plasma concentration (Cmax) and the area under the concentration-time curve (AUC) and a linear correlation between the dose and both Cmax (r = 0.95) and AUC (r = 0.97). The mean value +/- SD for the dose-normalized AUC was 13 +/- 2 min m2 l-1 (n = 57).2+ The administration schedule does not seem to influence drug exposure, since prolonged i.v. infusion or bolus administration of 1,200 mg/m2 achieved a similar AUC (13.78 +/- 2.90 and 15.05 +/- 1.44 mg ml-1 min, respectively). In the nine children studied during subsequent courses a limited interpatient variability was observed and no correlation (r = 0.035) was found between AUC and subsequent courses by a multivariate analysis of dose, AUC, and course number. The pharmacokinetic parameters were similar to those previously reported in adults; however, a weak correlation (r = 0.52, P = 0.03) between carboplatin total body clearance and creatinine clearance varying within the normal range was observed.(ABSTRACT TRUNCATED AT 400 WORDS)     

Are there special considerations in the prescription of serotonin reuptake inhibitors for women?

The aim of this study was to evaluate and compare the pharmacokinetics of naftidrofuryl (CAS 3200-06-4) after single oral administration of a 200 mg naftidrofuryl tablet (Praxilene) in Caucasian male and female elderly healthy volunteers versus young healthy volunteers. Thirty healthy volunteers were included in a randomised phase I trial in 3 parallel groups of 10 subjects aged 18-35 years (group 1), 60-70 years (group 2) and 70-80 years (group 3). Blood samples were taken over a period of 24 h after dosing for evaluation of the pharmacokinetics of naftidrofuryl. The Cmax, tmax, AUC0-t parameters were measured and t1/2 and AUC0-alpha were calculated by a model independent method. The mean (+/- SD) pharmacokinetic parameters of naftidrofuryl after single oral administration of 200 mg of naftidrofuryl for group 1 were as follows: tmax 3.5 h (median), Cmax 284 +/- 136 ng/ml, t1/2 3.69 +/- 1.30 h, AUC0-t 1865 +/- 905 h.ng/ml and AUC0-inf 2055 +/- 901 h.ng/ml; for group 2: tmax 2.75 h (median), Cmax 282 +/- 165 ng/ml, t1/2 3.03 +/- 1.08 h, AUC0-t 1783 +/- 1147 h.ng/ml and AUC0-inf 1856 +/- 1158 h.ng/ml; for group 3: tmax 2.5 h (median), Cmax 271 +/- 86 ng/ml, t1/2 3.50 +/- 1.29 h, AUC0-t 1742 +/- 544 h.ng/ml and AUC0-inf 1834 +/- 549 h.ng/ml. Statistical analysis was performed on the pharmacokinetic parameters with one-way ANOVA in order to compare each age group. The results of the pharmacokinetic and statistical analysis showed no significant difference between each age group. The mean pharmacokinetic parameters of naftidrofuryl after single oral administration of 200 mg of naftidrofuryl in the whole population were as follows: tmax 2.75 h (median), for Cmax 279 +/- 128 ng/ml, t1/2 3.41 +/- 1.22 h, AUC0-t 1797 +/- 870 h.ng/ml for AUC0-inf 1910 +/- 877 h.ng/ml. In conclusion, advanced age did not appear to influence the pharmacokinetic profile of oral naftidrofuryl, and therefore it is not necessary to adjust the dosage of naftidrofuryl in this population.     

The growth hormone response to hexarelin in patients with Prader-Willi syndrome

Hexarelin (Hex) is a synthetic hexapeptide with potent GH-releasing activity in both animals and men. Aim of this study was to evaluate the GH response to a maximal dose of Hex and GH-releasing hormone (GHRH) in a group of patients with Prader-Willi syndrome (PWS). Seven patients (4 boys and 3 girls, age 2.4-14.2 yr) with PWS, 10 prepubertal obese children (7 boys and 3 girls, age 7.5-12.0 yr), and 24 prepubertal short normal children (11 boys and 13 girls, age 5.9-13 yr) with body weight within +/- 10% of their ideal weight were studied. All subjects were tested on two occasions with GHRH 1-29 at the dose of 1 microgram/Kg i.v., and with Hex at the dose of 2 micrograms/Kg i.v. In the PWS patients the GH response to GHRH (peak = 6.4 +/- 2.0 micrograms/l, p < 0.0001; AUC = 248 +/- 70 micrograms min/l, p < 0.0001) was significantly lower than that observed in the short normal children and similar to that observed in the obese children. In the PWS children the GH response to Hex (peak = 7.5 +/- 1.6 micrograms/l; AUC = 309 +/- 53) was similar to that observed after GHRH and significantly lower than that observed in the obese children (p < 0.05). The results of this study show that PWS patients have a blunted GH response to the administration of a maximal dose of Hex. Whether these findings reflect a more severe pituitary GH deficiency in PWS than in obese children or a deranged hypothalamic regulation of GH secretion need further investigation.     

Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus

This study evaluated the safety, tolerability, and pharmacokinetics of zidovudine administered intravenously and orally to infants born to women infected with the human immunodeficiency virus. Thirty-two symptom-free infants were enrolled before 3 months of age. The pharmacokinetics of zidovudine were evaluated in each infant after single intravenously and orally administered doses of zidovudine on consecutive days, and during long-term oral administration of the drug for 4 to 6 weeks. As new patients were enrolled, doses of zidovudine were progressively increased from 2 to 4 mg/kg. Therapy was continued for up to 12 months in 7 of the infants proved to be infected with human immunodeficiency virus. Zidovudine was generally well tolerated; 20 children (62.5%) had anemia (hemoglobin level < 10.0 gm/dl) during therapy and 9 (28.1%) had neutropenia (neutrophil count < or = 750 cells/mm3); these hematologic abnormalities usually resolved spontaneously. The total body clearance of zidovudine increased significantly with age, from an average of 10.9 ml/min per kilogram in infants < or = 14 days of age to 19.0 ml/min per kilogram in older infants (p < 0.0001). Concurrently, there was a significant decrease in serum half-life from 3.12 hours in infants < or = 14 days to 1.87 hours in older infants (p = 0.0002). Oral absorption was satisfactory and bioavailability decreased significantly with age, from 89% in infants < or = 14 days to 61% in those > 14 days of age (p = 0.0002). Plasma concentrations of zidovudine were calculated to be in excess of 1 mumol/L (0.267 micrograms/ml) for 4.12 +/- 1.86 hours and 2.25 +/- 0.78 hours after oral doses of 2 mg/kg in infants younger than 2 weeks and 3 mg/kg in older infants, respectively. We conclude that zidovudine administered at oral doses of 2 mg/kg every 6 hours to infants aged less than 2 weeks and 3 mg/kg every 6 hours to infants older than 2 weeks resulted in plasma concentrations that are considered virustatic against human immunodeficiency virus. Zidovudine was well tolerated by infants at these doses.     

Pharmacokinetics and pharmacodynamics of growth hormone-releasing peptide-2: a phase I study in children

Administration of GH-releasing peptide-2 (GHRP-2) represents a potential mode of therapy for children of short stature with inadequate secretion of GH. Requisite information to determine the dosing route and frequency for GHRP-2 consists of the pharmacokinetics (PK) and pharmacodynamics (PD) for this compound, neither of which have been previously evaluated in children. The purpose of this study was to characterize the PK and PD of GHRP-2 in children with short stature. Ten prepubertal children (nine boys and one girl; 7.7 +/- 2.4 yr old) received a single 1 microg/kg i.v. dose of GHRP-2 over 1 min, followed by repeated (n = 9) blood sampling over 2 h. GHRP-2 and GH were quantitated by specific RIA methods. PK parameters were calculated from curve fitting of GHRP-2 and GH vs. time data. Posttreatment plasma GH concentrations (normalized for pretreatment values) were used as the effect measurement. PD parameters were generated using the sigmoid Emax model. Disposition of GHRP-2 best fit a biexponential function. GHRP-2 PK parameters (mean +/- SD) were: alpha = 13.4 +/- 9.7 h(-1), beta = 1.3 +/- 0.3 h(-1), t(1/2beta) = 0.55 +/- 0.14 h, AUC(0-infinity) = 2.02 +/- 1.37 ng/mL x h, Cmax = 7.4 +/- 3.8 ng/mL, plasma clearance = 0.66 +/- 0.32 L/h x kg, and apparent volume of distribution = 0.32 +/- 0.14 L/kg. PK parameters for GH were: appearance rate constant = 5.9 +/- 3.1 h(-1), elimination t(1/2) = 0.37 +/- 0.15 h, lag time = 0.05 +/- 0.01 h, Cmax = 50.7 +/- 17.2 ng/mL, Tmax = 0.42 +/- 0.16 h, and AUC(0-infinity) = 47.9 +/- 26.1 ng/mL x h. PD parameters for GHRP-2 were: Ke0 = 1.13 +/- 0.94 h(-1), gamma = 13.15 +/- 9.44, E0 = 6.63 +/- 4.86 ng/mL (GH), Emax = 67.5 +/- 23.5 ng/mL (GH), and EC50 = 1.09 +/- 0.59 ng/mL. We concluded that 1) GHRP-2 produced a predictable and significant (i.e. compared to pretreatment values) increase in plasma GH concentrations; 2) the PK-PD link model enabled quantitative assessment of GHRP-2 modulation of serum GH levels; and 3) definition of the EC50 for GHRP-2 will enable PD and PK evaluations of extravascular dosing regimens for children.     

Refined genetic localization of the Best disease gene in 11q13 and physical mapping of linked markers on radiation hybrids

In the framework of the system of monitoring the environmental impact on population health, the concentration of lead, cadmium and selenium in blood and cadmium in urine was measured in adults (n = 670), children (n = 599) and umbilical blood (n = 549) using atomic absorption spectrophotometry. Furthermore, cytogenetic analysis of peripheral lymphocytes in all population groups under study was investigated. The median blood Pb level for the overall group of adults (47.8 micrograms/l, i.e. 0.23 mumol/1) was significantly higher in men (51.5 micrograms/l, i.e. 0.25 mumol/l). Smoking significantly influenced the blood Pb level in women. The 90th percentile in no group exceeded the value of 100 micrograms/l (0.48 mumol/l). The median blood Cd level in adults (0.9 microgram/l, i.e. 0.008 mumol/l) depends on smoking habit (1.25 micrograms/l, i.e. 0.01 mumol/l). The median urine Cd level was 0.585 microgram/g creatinine (0.59 mumol/mole creatinine) in adults and 0.37 microgram/g creatinine (0.37 mumol/mole creatinine) in children. The median blood Se level (53.5 micrograms/l, i.e. 0.68 mumol/l) was found to be higher in the group of non-smokers (57.5 micrograms/l, i.e 0.73 mumol/l). Lead and selenium level were significantly lower in the umbilical blood. Cytogenetic analysis results showed age-dependent average percentages of aberrant cells: 1.1% in umbilical blood, 1.27% in children and 1.71 in adults in line with the reference values for the Czech population.     

Pantoprazole does not interact with the pharmacokinetics of carbamazepine

OBJECTIVE: Pantoprazole is a H+/K+-ATPase inhibitor with a minimized potential of interaction with the cytochrome P450 system. Imidazole derivatives such as cimetidine and omeprazole have been shown to markedly interact with carbamazepine, a major anticonvulsant with a narrow therapeutic range. Therefore, the influence of steady-state pantoprazole on the pharmacokinetics of carbamazepine was investigated. SUBJECTS AND METHODS: N = 20 healthy volunteers (12 male/8 female) completed a double-blind, placebo-controlled, randomized crossover study. During the test period they received 40 mg pantoprazole p.o. once daily for 11 days and concomitantly a single oral dose of 400 mg carbamazepine on day 5. In the reference period placebo was administered instead of pantoprazole. RESULTS: Serum concentrations of carbamazepine and its active metabolite carbamazepine-10,11-epoxide were measured until day 11. Geometric means of AUC (extent characteristic) and Cmax/AUC (rate characteristic) of carbamazepine were 292 and 287 mgxh/l, and 0.0150 and 0.0144 l/h (reference and test), respectively. Point estimates and 90% confidence intervals of the ratios were 0.98 (0.95, 1.01) for AUC, and 0.96 (0.92, 1.00) for Cmax/AUC, respectively. Since the 90% confidence intervals of the primary characteristics, AUC and Cmax/AUC were entirely within the predefined equivalence range of 0.80 - 1.25, lack of interaction of pantoprazole with the pharmacokinetics of carbamazepine was demonstrated. Equivalence was also demonstrated for carbamazepine-10,11-epoxide using the characteristics AUC and Cmax. CONCLUSION: No dose adjustment of carbamazepine is therefore required during concomitant treatment with pantoprazole.     

Fluorides in the body of the mother and in the fetus. III. Fluorides in amniotic fluid

Fluoride concentrations in amniotic fluid as well as in venous and arterial cord blood serum were determined in 20 women during the perinatal period. The mean concentrations of fluoride from amniotic fluid, venous cord blood serum and arterial cord blood serum were 1,6 +/- 0,18 mumol/l, 3,2 +/- 0,28 mumol/l and 2,9 +/- 0,39 mumol/l respectively. Amniotic fluid fluoride concentrations were significantly higher in the older age group of pregnancies (39-42 weeks) in comparison with the younger age group of pregnancies (34-38 weeks) p < 0,01. The reasons for mentioned relations were discussed.     

True post-micturition urinary incontinence of the male

The effect of food on the bioavailability of brofaromine hydrochloride was investigated in a randomized cross-over study. Eight healthy male volunteers were given single peroral doses of 75 mg brofaromine hydrochloride after overnight fasting or a fat- and protein-rich breakfast. Mean (+/- SD) areas under the plasma concentration-time curves (AUC) were 9.66 (2.35) mumol l-1 h when given to the fasted volunteers and 11.82 (3.78) mumol l-1 h (p = 0.0413) when given after a substantial breakfast. Mean (+/- SD) maximum plasma concentrations (Cmax) were 0.71 (0.13) mumol l-1 when given to the fasted volunteers and 0.85 (0.22) mumol l-1 (p > 0.05) when given after breakfast. Thus, both the average AUC and Cmax were increased by approximately 20 per cent when brofaromine hydrochloride was given with food. The times when Cmax was reached (tmax) as well as the elimination half-lives were not influenced by concomitant intake of food. The tolerability was the same whether brofaromine was given before or after food in healthy volunteers. The slight effect of food on the bioavailability of brofaromine should be of little therapeutic consequence because of the observed wide inter-subject variability of the plasma levels.     

Pharmacokinetics and extracellular distribution to blood, brain, and muscle of alovudine (3'-fluorothymidine) and zidovudine in the rat studied by microdialysis

Microdialysis was applied to sample the free drug concentration in the extracellular fluid in brain, muscle, and blood of rats given alovudine (n = 6) (3'-fluorothymidine) or zidovudine (n = 5) (25 mg/kg s.c.). Alovudine and zidovudine were analyzed by means of high performance liquid chromatography (HPLC) with UV detection. The assay for zidovudine was validated by a radioimmunoassay. In addition, the plasma protein binding of the drugs was measured by microdialysis in vitro. The concentrations attained in blood and muscle were similar for each drug, with a Cmax of 57 microM (blood) and 54 microM (muscle) for alovudine and 38 and 46 microM, respectively, for zidovudine. In contrast the Cmax in brain was 8 microM for alovudine and 4 microM for zidovudine. The peak concentration was attained 20-40 min after injection in blood and muscle and 40-60 min after injection in the brain. The half-lives of zidovudine in both blood and muscle were 37 min and in brain 69 min. For alovudine the corresponding half-lives were significantly longer: 61, 58, and 105 min, respectively. The ratio of the AUC0-180 brain/blood was 0.257 for alovudine and 0.186 for zidovudine. The plasma protein binding of zidovudine was 10%, while alovudine was virtually unbound.     

Sertraline treatment of children and adolescents with obsessive-compulsive disorder or depression: pharmacokinetics, tolerability, and efficacy

OBJECTIVE: To evaluate the pharmacokinetics, safety, and efficacy of sertraline in children (6 to 12 years old) and adolescents (13 to 17 years old). METHOD: Children (n = 29) and adolescents (n = 32) with major depression, obsessive-compulsive disorder (OCD), or both received a single dose of 50 mg of sertraline followed, 1 week later, by 35 days of sertraline treatment as follows: (1) either a starting dose of 25 mg/day titrated to 200 mg/day in 25-mg increments or (2) a starting dose of 50 mg/day titrated to 200 mg/day in 50-mg increments. Sertraline and desmethylsertraline pharmacokinetics were determined approximately weekly, and efficacy measures were assessed before drug administration and at the end of treatment. RESULTS: Mean area under the plasma concentration-time curve (AUC), peak plasma concentration (Cmax), and elimination half-life (t1/2) for sertraline and desmethylsertraline were similar to previously reported adult values. No titration-dependent pharmacokinetic or safety differences were seen. While Cmax and AUC0-24 were greater for children versus adolescents, these differences disappeared after parameters were normalized for body weight. Sertraline was well tolerated in both children and adolescents, with adverse experiences similar to those previously reported by adult patients. Efficacy measurements indicated improvement (p < .001) in depression and OCD symptomatology. CONCLUSIONS: Sertraline can be safely administered to pediatric patients using the currently recommended adult titration schedule.     

Serum androgen levels in women who have recurrent miscarriages and their correlation with markers of endometrial function

The dose proportionality of lubeluzole, a drug in clinical development for the treatment of acute ischemic stroke, was evaluated in a Phase I, single-center, open-label, randomized-dosing-sequence, three-way crossover clinical trial in 12 healthy adults. An equal number of male and female volunteers were enrolled in the trial, with a mean weight (+/- SD) of 73.2 +/- 11.9 kg, mean height (+/- SD) of 66.8 +/- 4.6 inches, and a mean age of 36.1 +/- 5.2 years. Subjects received intravenous infusions of 5 (A), 10 (B), and 15 mg (C) of lubeluzole over 1 hour on three separate occasions, with a minimum washout period of 2 weeks. The treatment sequences were A-B-C; A-C-B; B-A-C; B-C-A; C-A-B; and C-B-A. One male and one female were assigned to each sequence. After the 5-, 10-, and 15-mg doses, maximum concentration (Cmax) was 58.1, 113, and 138 microg/L, respectively, and the area under the curve from 0 to (AUC(0-infinity)) was 771, 1384, and 2025 microg x h/L. There were no statistically significant differences among the groups in mean terminal half-life, steady-state volume of distribution, total plasma clearance, or dose-normalized AUC(0-infinity). Dose-normalized values of Cmax differed significantly between the groups. No serious adverse events were reported, and no changes were observed in cardiac function, as judged by the QT(c) interval. The pharmacokinetics of lubeluzole appear to be linear at intravenous infusion doses of 5, 10, and 15 mg, and these doses are well tolerated by healthy adults.     

The renal clearance of free and conjugated pyridinium cross-links of collagen

We developed a sensitive reversed-phase high performance liquid chromatography (HPLC) assay to measure free and total Pyridinoline (Pyr) and Deoxypyridinoline (Dpyr) in serum. The method was used to measure total serum levels in seven premenopausal women (ages 52.2 +/- 2.4 years) and to investigate the renal clearance of free and conjugated Pyr and Dpyr in two groups of children (group 1: 13 girls, ages 11-13 years; group 2: 18 older children [2 male, 16 female], ages 13-18 years). Blood and 24-h urine samples were collected from the younger group to measure the renal clearance, and blood and 2-h morning urine samples from the older group were collected to investigate the fractional clearance. Total Pyr and Dpyr in the premenopausal women was 4.08 +/- 0.91 and 1.18 +/- 0.39 nmol/l, respectively. Free and total Pyr and Dpyr in serum and urine was elevated in both groups of children. The free serum levels were 16 and 18% in young and older children, respectively, compared with 40 and 46% in the urine. The percentage of free Dpyr in serum decreased with total urinary Pyr excretion (r = -0.56, p < 0.005, n = 31). The renal clearance of the free cross-link fraction in both groups was 4-fold higher than the conjugated fraction. The fractional clearance of the free fraction was greater than 1 (p < 0.001) and the conjugated fraction less than 1 (p < 0.001). The fractional excretion of free Dpyr increased with total urinary Pyr excretion (r = 0.66, p < 0.005, n = 13). We conclude that HPLC can be used to measure free and total Pyr and Dpyr in serum and that some free Pyr and Dpyr excreted in urine is produced by the kidney.     

Pretreatment with somatostatin analog SMS 201-995 potentiates growth hormone (GH) responsiveness to GH-releasing factor in short children

Previous studies in children have shown inconsistent, poorly reproducible GH responses to exogenous GH-releasing factor (GRF), with wide individual variability. In the present study, we tested the hypothesis that prior administration of the long-acting somatostatin analog, SMS 201-995 (SMS), will enhance GH responsiveness to a subsequent GRF challenge. Two study protocols were employed in 37 children with short stature [M = 31, F = 6, ages 11.8 +/- 1.6 yr (mean +/- SEM), height -2.25 +/- 0.55 SDS (SD scores)]. In both studies, each subject served as his/her own control. In the first study, which was designed to determine optimal SMS dose and regimen, SMS, in doses ranging from 0.8-2.2 micrograms/kg sc, was randomly administered or omitted at 0800 h after an overnight fast, and a GRF bolus (50 micrograms, iv) was given 4 h later. In the second study, we employed a protocol identical to study 1 except for the use of standard doses of SMS (1 microgram/kg, sc) and GRF (1 microgram/kg, iv) and an additional 1-h delay of the GRF injection. Plasma GH levels were measured every 20 min from 0800 h until 2 h after the GRF injection in both studies. In study 1 (n = 12; M = 10, F = 2), SMS significantly suppressed spontaneous GH secretion (expressed as the mean +/- SEM GH AUC during the 4-h SMS-GRF interval, AUC 1:2.2 +/- 0.4 vs. 6.2 +/- 0.9 micrograms/L.h; P < 0.001), GH responsiveness to GRF (GH AUC during the 2 h after the GRF injection, AUC 2: 41.5 +/- 7.8 vs. 85.0 +/- 13.5 micrograms/L.h; P < 0.001), and the GH peak response (17.4 +/- 3.1 vs. 36.0 +/- 6.2 micrograms/L; P < 0.001), compared to control tests. In contrast, in study 2 (n = 25; M = 21, F = 4), whereas spontaneous GH secretion was still suppressed during the 5-h SMS-GRF interval (AUC 1:3.8 +/- 0.4 vs. 7.4 +/- 1.1 micrograms/L.h; P < 0.001), both the GH peak response (56.7 +/- 5.5 vs. 30.5 +/- 3.0 micrograms/L; P < 0.0001) and the GH AUC (AUC 2: 103.7 +/- 10.3 vs. 77.5 +/- 6.8 micrograms/L.h; P < 0.05) after GRF administration were significantly augmented by pretreatment with SMS, compared to control tests. Taken together, these results indicate that a priming SMS dose of 1 microgram/kg has a significant permissive effect on GH responsiveness to exogenous GRF administered 5 h later.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of three types of half-limb casts on in vitro bone strain recorded from the third metacarpal bone and proximal phalanx in equine cadaver limbs

This open-label, non-randomized, parallel-group trial investigated the pharmacokinetics of raltitrexed (Tomudex, formerly ZD1694) after a single intravenous dose of 3.0 mg m(-2), comparing eight cancer patients with mild to moderate renal impairment (creatinine clearance 25-65 ml min(-1)) with eight cancer patients with normal renal function (creatinine clearance >65 ml min(-1)). The primary end points were area under the plasma raltitrexed concentration-time curve from the start of the infusion to the last determined concentration (AUC(0-tldc)) and AUC to infinity (AUC(0-infinity)); secondary end points were peak concentrations of raltitrexed (Cmax) and elimination half-life (t(1/2gamma)). The groups were compared statistically using analysis of covariance. The AUCs were greater for patients with renal impairment than for patients with normal renal function (2452.2 compared with 1247.3 ng h ml(-1) for AUC(0-tldc) (ratio 1.97; 95% CI 1.36-2.84); 2961.5 compared with 1457.0 ng h ml(-1) for AUC(0-infinity) (ratio 2.03; 1.25-3.29). These differences were statistically significant (P = 0.002 and P = 0.008 for AUC(0-tldc) and AUC(0-infinity) respectively. Terminal half-life was longer for the renally impaired patients (271.2 compared with 143.3; P = 0.030). There was no significant statistical difference between the groups for Cmax (652.9 compared with 564.7 ng ml(-1) for patients with impaired and normal renal function respectively: ratio 1.16; 0.91-1.46; P = 0.204). There was a clear relationship between raltitrexed clearance and creatinine clearance. Adverse events, severe (WHO grade 3 or 4) toxicity and hospitalization due to adverse events were more frequent in the group with renal impairment. Therefore, a reduction in raltitrexed dose and increased interval between doses is recommended for patients with mild to moderate renal impairment.     

Pharmacokinetics of propofol after a single dose in children aged 1-3 years with minor burns. Comparison of three data analysis approaches

BACKGROUND: No complete pharmacokinetic profile of propofol is yet available in children younger than 3 yr, whereas clinical studies have demonstrated that both induction and maintenance doses of propofol are increased with respect to body weight in this age group compared to older children and adults. This study was therefore undertaken to determine the pharmacokinetics of propofol after administration of a single dose in aged children 1-3 yr requiring anesthesia for dressing change. METHODS: This study was performed in 12 children admitted to the burn unit and in whom burn surface area was less than or equal to 12% of total body surface area. Exclusion criteria were: unstable hemodynamic condition, inappropriate fluid loading, associated pulmonary injury, or burn injury older than 2 days. Propofol (4 mg.kg(-1))plus fentanyl (2.5 microg.kg(-1)) was administered while the children were bathed and the burn area cleaned during which the children breathed spontaneously a mixture of oxygen and nitrous oxide (50:50). Venous blood samples of 300 microl were obtained at 5, 15, 30, 60, 90, and 120 min, and 3, 4, 8, and 12 thereafter injection; an earlier sample was obtained from 8 of 12 children. The blood concentration curves obtained for individual children were analyzed by three different methods: noncompartmental analysis, mixed effects population model, and standard two-stage analysis. RESULTS: Using noncompartmental analysis, total clearance of propofol (+/-SD) was 0.053+/-0.013l.kg(-1).min(-1), volume of distribution at steady state9.5 +/- 3.7l.kg(-1),and residence time 188 +/- 85 min. Propofol pharmacokinetics were best described by a weight-proportional three-compartmental model in both population and two-stage analysis. Estimated and derived pharmacokinetic parameters were similar using these two pharmacokinetic approaches. Results of population versus two-stage analysis are as follow: systemic clearance 0.049 versus 0.048 l.kg(-).min(-1), volume of central compartment 1.03 versus 0.95 l.kg(-1), volume of steady state 8.09 versus 8.17 l.kg(-1). CONCLUSIONS: The volume of the central compartment and the systemic clearance were both greater than all values reported in older children and adults. This is consistent with the increased propofol requirements for both induction and maintenance of anesthesia in children 1-3 yr. (Key words: Anesthesia: pediatric. Pharmacokinetics: propofol.)     

Sudden deafness: a randomized comparative study of 2 administration modalities of hyperbaric oxygenotherapy combined with naftidrofuryl

The pharmacokinetics of a single, oral dose of 750 mg of ciprofloxacin were studied in 35 subjects with various degrees of renal function (Group 1, Clcr > or = 80 ml/min; Group II, Clcr 50-79 ml/min; Group III, Clcr 10-49 ml/min) and on hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Blood, urine and CAPD dialysate samples were collected over a period of 48 hours after dosing. Data were fitted using non-linear, least squares regression. The mean Cmax was 3.4 +/- 1.0 mg/l and tmax was 2.3 +/- 0.9 hours. The mean AUC in Group I was 14.7 mg.h/l, Group II was 33.7 (p < 0.001), Group III 63.8 (p < 0.001), HD 57.9 (p < 0.0001) and CAPD 44.3 (p < 0.001). Half-life in Group I was 4.6 h, and was shorter than Group III (11.1 h, p < 0.001), HD (13.4 h, p < 0.001) and CAPD (8.9 h, p < 0.001). Total body clearance and renal clearance demonstrated significant differences also. The dialysis clearance in CAPD patients was 0.53 +/- 0.39 l/h. Peritoneal effluent concentrations varied from 0.6 mg/l during the first exchange, to a peak of 2.2 mg/l during the second, to 0.13 mg/l in the 48 hour (9th) exchange. Dosage adjustments of ciprofloxacin in the presence of renal insufficiency are indicated for subjects with a Clcr < 20 ml/min/1.73m2.     

Pharmacokinetics of mefloquine, when given alone and in combination with artemether, in patients with uncomplicated falciparum malaria

The pharmacokinetics of mefloquine at a single oral dose of 750 mg, when given alone or 24 hours after a single oral dose of artemether (300 mg) was investigated in 27 Thai patients with acute uncomplicated falciparum malaria (17 with mefloquine alone, 10 with the combination). The oral bioavailabiiity of mefloquine was significantly decreased when administered 24 hours after an oral dose of artemether. This was evident by the significantly lower values of Cmax, AUC[0-24 h], AUC[0-48 h], AUC[0-72 h], as well as total AUC[Cmax: 1,290 (827-2,619) vs 1,820 (1,283-2,531) ng.ml-1; AUC[0-24 h]: 0.99 (0.64-1.41) vs 1.33 (1.07-1.95) micrograms.day.ml-1; AUC[0-48 h]: 1.78(1.23-2.58) vs 2.67 (2.09-3.84) micrograms.day.ml-1; AUC[0-72 h]: 2.74 (1.63-3.6) vs 4.54 (2.88-5.38) micrograms.day.ml-1; AUC: 11.11 (6-20.96) vs 15.29 (9.3-36.71) micrograms.day.ml-1]. Tmax was also delayed with the combination regimen [14 (5-24) vs 6 (4-16) h]. Terminal elimination half-lives were comparable [t1/2z: 11.1 (6.8-14.3) vs 13.4 (10.5-19.1) h].     

Genotypically dependent effects of cyromazine on reproduction and offspring development in the Australian Lucilia cuprina (Diptera: Calliphoridae)

Various factors may influence bioavailability and blood concentrations of cyclosporine, a problem that may be compounded by diseases such as cystic fibrosis in which impaired absorption through the gastrointestinal tract is common. Neoral, a microemulsion formulation of cyclosporine, has improved bioavailability and more stable blood concentrations than earlier formulations. We conducted a prospective, open, crossover study to examine whether these findings held true in 12 clinically stable patients with cystic fibrosis who had undergone lung transplantation at least 6 months earlier. In the first arm, patients continued their usual dosage of cyclosporine twice/day. In the second arm they received Neoral for at least 1 week before having blood studies. For each arm whole blood trough concentrations were drawn for 7-10 successive days, together with a pharmacokinetic study with concentrations drawn at times zero, 1, 2, 3, 4, 6, 12, and 24 hours. Variance was assessed from morning concentrations. Area under the curve from zero to 12 hours (AUC12), maximum concentration (Cmax), and time to Cmax (Tmax) were calculated for each arm. Eleven subjects completed the protocol. The daily variance for Neoral was significantly less than for cyclosporine (p=0.04). The AUC12 for Neoral and cyclosporine were 4164+/-1467 and 5318+/-1670 microg x L/hour (p=0.09), respectively. Respective Cmax were 613+/-242 and 931 +/-458 microg/L (p=0.08) and relative Cmax and AUC12 were 1.91 and 1.47 (p<0.05). Thus Neoral had a superior pharmacokinetic profile and less day-to-day variability in patients with cystic fibrosis who had undergone lung transplantation.     

Interobserver variability in recognizing arousal in respiratory sleep disorders

BACKGROUND: The study was designed to investigate the influence of haemodialysis on the pharmacokinetics of the non-ionic contrast medium iopentol and the outcome of radiocontrast nephropathy in patients at risk undergoing angiography. METHODS: We prospectively studied 30 patients with reduced renal function (mean serum creatinine concentration (+/- SEM), 2.4 +/- 0.16 mg/dl (212 +/- 14 mumol/l)). Patients were randomly assigned to receive either a haemodialysis procedure for 3 h, started as soon as possible (63 +/- 6 min) after administration of contrast medium, or a conservative treatment. Serum concentrations of iopentol and creatinine were followed for up to 14 days. RESULTS: The extracorporal plasma clearance of contrast medium was 71 +/- 2.5 ml/min. The fraction of the dose eliminated was 32 +/- 3%. The rate of radiocontrast nephropathy (defined as serum creatinine increase of > or = 0.5 mg/dl (44 mumol/l) within 48 h) after administration of contrast medium was similar in both groups (53 and 40% in group 1 (haemodialysis) and group 2 (conservative treatment) respectively). The course of absolute changes in serum creatinine over the whole observation period was not different in both groups. CONCLUSIONS: The data indicate that haemodialysis eliminates contrast medium effectively, but it may not influence the incidence or outcome of contrast induced nephropathy.