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B G Charles

Publications and source records attributed to B G Charles.

At least 37 records · Page 2Linked to original sources
PubMed1999

A procedure for generating bootstrap samples for the validation of nonlinear mixed-effects population models.

A method is presented for automated preparation of bootstrap data samples and their presentation to NONMEM for use in the validation of population pharmacokinetic or pharmacodynamic models, which have been developed with relatively small numbers of subjects. The bootstrap sampling procedure involves the use of an MS-DOS batch file and a script file for use with the public-domain text processing program, AWK, which is a single EXE file (48k in size for the version used in this report). A UNIX version of AWK is also available and UNIX users can adapt the process to their needs. Its use obviates the need for expensive, high-end statistical packages and associated script files written using in-built programming languages. The method can easily be adapted to bootstrap sampling requirements in other biomedical modelling applications.

Computer Simulation↗
PubMed1999

Development of HPLC conditions for valid determination of hydrolysis products of cisplatin.

In water, the antineoplastic drug cisplatin, cis-[PtCl2(NH3)2] (1) hydrolyses slowly to the aqua complexes cis-[Pt(NH3)2Cl(H2O)]+ (2) and, to a small extent, cis-[Pt(NH3)2(H2O)2]2+ (3), which are thought to play an important role in the metabolism of cisplatin. HPLC is a useful technique for monitoring 2 and 3, but only if the components of the mobile phase used in the reverse phase HPLC technique are unreactive toward these aqua complexes under the conditions of the experiment. 15N Nuclear magnetic resonance (NMR) with samples highly enriched (>98%) in 15N has been used to check the reactivity of 2 and 3 toward substances commonly used as components of the mobile phase. The results reported herein indicate that acetonitrile, often used as an organic modifier, reacts readily with 2 and 3. Methanol, also commonly employed, is much less reactive. Carboxylic acids RCO2H (R = CH3, H, CF3), which are frequently used to adjust pH of the mobile phase, also react readily with 2 and 3. Trifluoromethanesulfonic acid ("triflic acid"), CF3SO3H, is unreactive. Neither hexanesulfonic acid nor sodium dodecyl sulfate (SDS), used as "ion-pairing agents", reacts significantly with 2 or 3 under the experimental conditions, but SDS gives better peak separation. Commercial SDS must, however, be purified from chloride contamination. From our studies, optimal conditions for HPLC separation of 1, 2, and 3, with a C18 stationary phase at 37 degrees C, require an aqueous mobile phase with 3% v/v methanol, 0.05 mM SDS, and pH 2.5 (adjusted with triflic acid). This technique was then used to measure levels of 1, 2, and 3 in ultrafiltered serum after incubation for various times with cisplatin at 37 degrees C.

Acetonitriles↗
PubMed1999

Population pharmacokinetic modeling in very premature infants receiving midazolam during mechanical ventilation: midazolam neonatal pharmacokinetics.

BACKGROUND: Midazolam is used widely as a sedative to facilitate mechanical ventilation. This prospective study investigated the population pharmacokinetics of midazolam in very premature infants. METHODS: Midazolam (100 microg/kg) was administered as a rapid intravenous bolus dose every 4-6 h to 60 very premature neonates with a mean (range) gestational age of 27 weeks (24-31 weeks), a birth weight of 965 g (523-1,470 g), and an age of 4.5 days (2-15 days). A median (range) of four (one to four) blood samples, 0.2 ml each, were drawn at random times after the first dose or during continuous treatment, and concentrations of midazolam in serum were assayed by high-performance liquid chromatography. A population analysis was conducted using a two-compartment pharmacokinetic model using the NONMEM program. RESULTS: Average parameter values (interpatient percent coefficient of variation) for infants with birth weights 1,000 g or less were total systemic clearance (Cl(T)) = 0.783 ml/min (83%), intercompartmental clearance (Cl(Q)) = 6.53 ml/min (116%), volume of distribution of the central compartment (V1) = 473 ml (70%), and volume of distribution of the peripheral compartment (V2) = 513 ml (146%). For infants with birth weights more than 1,000 g they were as follows: Cl(T) = 1.24 ml/min (78%), Cl(Q) = 9.82 ml/min (98%), V1 = 823 ml (43%), and V2 = 1,040 ml (193%). The intrapatient variability (percent coefficient of variation) in the data was 4.5% at the mean concentration midazolam in serum of 121 ng/mL. CONCLUSIONS: Serum concentration-time data were used in modeling the population pharmacokinetics of midazolam in very premature, ventilated neonates. Clearance of midazolam was markedly decreased compared with previous data from term infants and older patients. Infants weighing less than 1,000 g at birth had significantly lower clearance than those weighing more than 1,000 g.

Anesthetics, Intravenous↗
PubMed1998

Pharmacokinetics of cisapride in the horse.

The purpose of this study was to determine the pharmacokinetics and absolute bioavailability of cisapride after intravenous (i.v.) and intragastric (i.g.) administration in healthy, adult horses. Five animals received single doses of 0.1 mg/kg, 0.2 mg/kg and 0.4 mg/kg cisapride by the i.g. route in an open, randomized fashion on different occasions separated by a washout period of at least 48 h. Four of these horses were also given a single i.v. dose of 0.1 mg/kg cisapride. Jugular venous blood was collected periodically up to 24 h after dosing. Plasma cisapride concentrations were measured by high-performance liquid chromatography. There was considerable inter individual variability in pharmacokinetic parameters. The mean (SD) values for systemic clearance (CI) and steady-state volume of distribution (Vss) were 494 (43.6) mL/h/kg and 1471 (578) mL/kg, respectively. Although the rate of cisapride absorption was quite rapid, only about half the i.g. dose was absorbed systemically. The average terminal half-life (t1/2) calculated over three i.g. doses was 2.06 h and that for i.v. administration was 2.12 h. The pharmacokinetics of cisapride from 0.1 mg/kg to 0.4 mg/kg were independent of the i.g. dose.

Animals↗
PubMed1998

NONMEM population pharmacokinetic modeling of orally administered cyclosporine from routine drug monitoring data after heart transplantation.

The population pharmacokinetics of cyclosporine (CsA) in adult recipients of cardiac transplants were determined from sparse, retrospective drug monitoring data accumulated for at least 3 months after surgery. All were receiving oral CsA twice daily, and morning trough levels in whole-blood were measured by high-performance liquid chromatography. Additional data included height, weight, gender, age, ethnicity, hematocrit, total bilirubin, and concurrent drug use. Population modeling was performed using NONMEM on 36 randomly selected patients, assuming a one-compartment model with first-order absorption and elimination. Improved fits were obtained by incorporating the following expression in the model to adjust oral bioavailability as a function of postoperative day (POD): F = 0.2 + 10 x ABS (POD - 7)/([POD + 10] x 60). Interpatient variability (CV%) in clearance (CL) was 20.2%. There was a mean bias of 8.5% at the average CsA concentration of 250 ng/ml when the predictive performance was assessed statistically in a reserved subset of 33 patients who received cardiac transplants. For the entire population (n = 69 patients), the average CsA CL and terminal half-life (T1/2) were, respectively: CL (l/h) = 0.256 x weight (kg); T1/2 = 11.0 hours, or CL (l/h) = 0.184 x weight (kg); T1/2 = 14.7 hours, if there was concomitant diltiazem administration. These results compared favorably with those reported elsewhere for studies of postcardiac transplant kinetics using the traditional multiple blood sampling approach.

Administration, Oral↗
PubMed1998

Effect of oral levodopa treatment on articulatory function in Parkinson's disease: preliminary results.

To quantify lip function in 16 patients with Parkinson's disease, a computerized semiconductor lip pressure transducer system was used prior to subjects being administered oral levodopa and at approximately 0.5 hr, 1.5 hr, and 3.0 hr postmedication. Two blood samples were taken from each subject at varying times during the levodopa dosage interval, and the exact time and dosage of levodopa were noted. Lip function measurements were expressed as percentage changes from baseline and were plotted for each subject against time and levodopa concentrations to determine the effects of levodopa therapy on articulatory function. The results supported the effectiveness of levodopa therapy in improving lip function. In particular, lip pressures recorded during both speech and nonspeech tasks tended to improve after levodopa administration, the lip measures improving somewhat in parallel with the rise and fall of blood plasma levodopa concentrations. Evidence of a hysteresis effect was noted.

Aged↗
PubMed1997

Population pharmacokinetics of intravenous amoxicillin in very low birth weight infants.

The population pharmacokinetics of amoxicillin were determined in 40 very premature infants (< or = 32 week gestational age, < 1500 g birth weight) who were receiving intravenous amoxicillin (50 mg/ kg, every 12 h) during the first days after birth. Serum amoxicillin concentrations were measured by HPLC. Clearance (CL) and volume of distribution (Vd) were modeled alone and under the influence of demographic and clinical covariates with a 1-compartment model with first-order elimination. The final population models with influential covariates were: CL(L/h) = 0.0000610 x body weight (g) and CL (L/h) = 0.0000805 x body weight (g), for infants also receiving gentamicin and not receiving gentamicin, respectively; Vd(L) = 0.678. The interpatient standard deviation (SD) for CL was 0.0351 L/h, and for Vd was 0.365 L. The intrapatient variability (SD) among observed and model-predicted serum concentrations was 13.7 mg/L. Evaluation of the predictive performance of this model in another group of infants (n = 16) indicated statistically insignificant bias (p > 0.05) of 3 mg/L among pairs of observed and Bayesian-predicted amoxicillin concentrations. The average population CL was smaller, but the average Vd and terminal half-life (t1/2) were larger than previously reported for healthy adults.

Amoxicillin↗
PubMed1997

Haemodynamic responses and population pharmacokinetics of midazolam following administration to ventilated, preterm neonates.

OBJECTIVE: To evaluate the effects of intravenous midazolam on haemodynamic variables and cerebral blood flow velocity (CBFV) and to determine the pharmacokinetics using a population approach in very low birthweight (VLBW) ventilated infants. METHODOLOGY: Physiological variables were measured at predetermined times in 10 infants with birthweight < or = 1500 g following a bolus dose of intravenous midazolam (0.1 mg/kg). Heart rate, mean arterial blood pressure (MAP) and transcutaneous CO2 (TcPCO2) were recorded and CBFV was assessed by Doppler ultrasound. Midazolam concentrations were also measured and pharmacokinetic parameters determined using a population modelling package. RESULTS: No change in heart rate occurred during the study period, while the MAP decreased by 3 mmHg 5 min after midazolam administration compared to baseline values. A non-significant fall in TcPCO2 was seen at 20 min. Mean CBFV decreased from the baseline by 12% at 5 min, then returning to predose values. Midazolam concentrations were in the range shown to be effective in sedation of paediatric intensive care infants with the elimination being delayed in comparison to older children. CONCLUSIONS: As only minor cerebral and haemodynamic effects were found with the use of midazolam in stable ventilated preterm infants, it appears to be a safe, short-term sedative agent.

Analysis of Variance↗
PubMed1996

Population pharmacokinetics and pharmacodynamics of oral levodopa in parkinsonian patients.

OBJECTIVE: The population pharmacokinetics and pharmacodynamics of a standardised oral test dose of levodopa have been determined in patients with mild to severe Parkinson's disease using parametric, non-linear mixed effect modelling with the program NON-MEM. Levodopa plasma concentration data and motor effect behaviour (tapping times) were obtained from 46 patients, for whom a total of 970 observations were available (approximately 21 pharmacokinetic and pharmacodynamic observations per patient). The pharmacokinetic-pharmacodynamic model used was a one-compartment first-order absorption model linked to the sigmoid EMax representation of the Hill equation via an equilibration rate-constant, ke0. The model was also tested via a reduction in the number of pharmacokinetic and pharmacodynamic data points to a total of four to eight per patient. RESULTS: In the final regression models the Hoehn and Yahr (HY) status of the patient and duration of disease (DUR) were found to be important determinants of the pharmacodynamic parameters for levodopa. The pharmacokinetic parameters were not significantly affected by any covariates. A test group of 16 additional parkinsonian patients was used to evaluate the predictive performance of the population parameters. The predictive performance of the pharmacokinetic-pharmacodynamic modelling using the full and reduced data sets was evaluated in NONMEM using posthoc, Bayesian forecasting. Statistically insignificant bias existed among predicted and observed levodopa concentrations, whereas the pharmacodynamic model underpredicted the observed tapping times. There was little difference in the pharmacokinetic-pharmacodynamic predictive performance among results for the full and the reduced data sets. CONCLUSION: In a clinical setting knowledge of the population pharmacokinetic and pharmacodynamic parameters for oral levodopa may prove useful in estimating the duration of the drug's beneficial motor activity in patients with mild to severe Parkinson's disease (Hoehn and Yahr status I-IV).

Administration, Oral↗
PubMed1996

Copper(II) complexes of the fluoroquinolone antimicrobial ciprofloxacin. Synthesis, X-ray structural characterization, and potentiometric study.

Reaction of the fluoroquinolone antimicrobial ciprofloxacin with copper(II) nitrate in the presence of 2,2'-bipyridine resulted in the isolation of the complex [Cu(cip)(bipy) (Cl)0.7(NO3)0.3] (NO3).2H2O. Reaction of an aqueous solution of ciprofloxacin.HCl and NaCl with CuCl2 at pH 5.0 resulted in the isolation of [Cu(cip)2]Cl2.11H2O. The complex [Cu(cip) (bipy)(Cl)0.7(NO3)0.3] (NO3).2H2O crystallizes in the monoclinic space group P2(1)/n, with a = 13.955(8), b = 14.280(8), c = 14.192(6) A, beta = 93.10(4) degrees, Z = 4 with R = 0.046. The selective broadening of resonances in the 13C NMR spectrum of ciprofloxacin by the addition of Cu2+(aq) was employed to probe metal ion binding sites in the ligand. The protonation constants of norfloxacin and ciprofloxacin, and the formation constants with copper(II), were determined by potentiometric titrations at 25 degrees C. The additions of ciprofloxacin to metal to form ML and ML2 complexes exhibit stepwise formation constants of log K1 6.2(1) and log K2 11.1(3), respectively.

Anti-Infective Agents↗
PubMed1996

Interaction of norfloxacin with divalent and trivalent pharmaceutical cations. In vitro complexation and in vivo pharmacokinetic studies in the dog.

The formation constants of the fluoroquinolones norfloxacin and ciprofloxacin with Mg2+ (log beta 1 = 2.97(4), log beta 2 = 5.6(2)), Zn2+ (log beta 1 = 3.77(2), log beta 2 = 7.59(3)), and Fe2+ (log beta 1 = 3.99(5), log beta 2 = 7.2(5)) were determined by potentiometric titration. The pH at which precipitation occurred in the titration solutions was compared for the metal ions Ca2+, Mg2+, Zn2+, Fe2+, Cu2+, and Al3+. The formation constants were used to predict a rank order of metals that may be expected to hinder the gastrointestinal absorption of the fluoroquinolones, in vivo. The effects of metal ions on the pharmacokinetics of orally-administered norfloxacin in the dog were investigated. Norfloxacin (12 mg/kg) was administered alone or with equimolar doses of each of the chloride salts of Ca2+, Mg2+, Zn2+, Fe2+, and Al3+. Statistically significant reductions in serum norfloxacin concentrations were observed after analysis by HPLC. The Cmax was reduced 29-85%, while the area under the norfloxacin serum concentration-time curve (AUC0-infinity) was reduced by 29-79%. The extent of the reduction in AUC0-infinity was correlated with the magnitude of the formation constant of the 1:1 norfloxacin:metal chelate complex for the divalent metal ions. On coadministration of 12 mg/kg norfloxacin with various doses of Mg2+ (chloride) the AUC0-infinity and Cmax decreased with increasing Mg2+ dose. The interaction peaked at a Mg2+:norfloxacin ratio of 1:2 suggesting the formation of a 1:2 Mg:norfloxacin complex. Formation constant data were used to simulate the percentage of norfloxacin complexed at pH 6.5. Combinations of metal ion and norfloxacin which result in only a small extent (< 20%) of norfloxacin complex formation can result in relatively large decreases in oral bioavailability of this antimicrobial agent.

Administration, Oral↗
PubMed1996

Saliva as a valid alternative to serum in monitoring intravenous caffeine treatment for apnea of prematurity.

Caffeine is a potentially useful alternative to theophylline for the treatment and prevention of apnea of prematurity because of its lower toxicity and longer terminal half-life. Monitoring of salivary caffeine concentrations is less invasive than blood sampling, especially in very sick premature neonates. Caffeine citrate-3 mg/kg, 15 mg/kg, or 30 mg/kg-was administered once daily for 7 days in a randomized, parallel design to 59 newborn, premature infants with an initial loading dose of twice the maintenance dose. Serum and saliva samples (131 pairs) were collected and assayed by high-performance liquid chromatography (HPLC) for caffeine content. Measurable caffeine concentrations in serum ranged from 0.28 to 93.3 mg/L and in saliva from 0.35 to 91.5 mg/L. The mean ratio of the saliva-to-serum concentrations was 0.924. There was no significant difference in precision between the serum and salivary data. The mean serum caffeine concentration was 29.9 mg/L, and the mean salivary concentration was 27.7 mg/L, indicating a small negative bias for saliva versus serum monitoring. Salivary caffeine concentration monitoring is a satisfactory alternative to blood sampling across a wide range of caffeine doses used to treat apnea.

Apnea↗
PubMed1996

Theophylline population pharmacokinetics from routine monitoring data in very premature infants with apnoea.

1. Theophylline is commonly used in neonatology for the treatment and prophylaxis of apnoea of prematurity, and during ventilator weaning. 2. NONMEM was used to study the population pharmacokinetics of intravenous and oral theophylline from retrospective drug monitoring data in 82 premature neonates, weighing < 1500 g at birth, and < or = 32 weeks gestational age. 3. Clearance (CL), volume of distribution (V), and oral bioavailability (F1) from liquid preparations were modelled alone, and under the influence of demographic and clinical covariates, assuming a 1-compartment model with first-order elimination. 4. The final population models with influential co-variates were as follows: CL (1h-1) = 0.0000123 *body weight (g) + 0.000377 *postnatal age (days); V (1) = 0.000937 *body weight (g); F = 0.918. 5. The CL was lower and V was higher than previously reported for less premature neonates, term babies, and older children. 6. Predictive performance of the population models was evaluated by Bayesian forecasting in a similar, but independent cohort of 30 infants. There was statistically insignificant bias and imprecision between measured and predicted serum theophylline concentrations. 7. Based on the validated population models, recommended maintenance theophylline dosages are provided for infants aged between 2 and 50 days, and weighing 700 to 2000 g.

Apnea↗
PubMed1995

Rapid and economical high-performance liquid chromatographic method for the determination of norfloxacin in serum using a microparticulate C18 guard cartridge.

A rapid and economical high-performance liquid chromatographic assay is described for norfloxacin in serum. Samples (100 microliters) containing N-ethylnorfloxacin as the internal standard were extracted into 1 ml of chloroform. Chromatography was performed at 30 degrees C on a 40 x 3.2 mm I.D. C18 guard cartridge (3 microns spherical particles) using a mobile phase of 11% (v/v) acetonitrile in 0.01 M phosphate buffer (pH 2.5) containing 0.001 M triethylamine, and pumped at 1 ml/min. Detection was at 279 nm. The retention times of norfloxacin and internal standard were 1.9 and 2.9 min, respectively. Calibration curves were linear (r > 0.999) from 0.1 mg/l to at least 2.0 mg/l. Within-day and between-day precision (C.V.) were 8.6% or less, and accuracy was 5.3% or less. Absolute assay recovery of norfloxacin was over 70%.

Anti-Infective Agents↗
PubMed1995

Determination of the angiotensin-converting enzyme inhibitor lisinopril in urine using solid-phase extraction and reversed-phase high-performance liquid chromatography.

A simple, accurate and precise high-performance liquid chromatographic method is described for assaying lisinopril in human urine. Urine (1 ml) containing lisinopril and enalaprilat (internal standard) was acidified with 10 microliters of 6 M nitric acid, passed through a Sep-Pak C18 cartridge and eluted with 3 ml of 10% acetonitrile, followed by 6 ml of distilled water. the separations were carried out using a mu Bondapak c18 column with a mobile phase comprising acetonitrile (60 ml), methanol (10 ml) and tetrahydrofuran (10 ml) in 15 mM phosphate buffer (920 ml) at pH 2.90. Separations were performed at 40 degrees C and detection was at 206 nm. Standard calibration plots of lisinopril in urine were linear (r > 0.998) and recovery was greater than 64%. The lowest quantifiable concentration was 0.5 micrograms/ml. Within-day and between-day imprecision (coefficient of variation) ranged from 2.51% to 9.26%, and inaccuracy was less than 8.3%.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Analysis of cisapride in neonatal plasma using high-performance liquid chromatography with a base-stable column and fluorescence detection.

A simple, selective, sensitive, and precise high-performance liquid chromatographic plasma assay for the prokinetic drug cisapride is described. Alkalinised samples of plasma (100 microliters) were extracted with 1.0 ml of 10% (v/v) isopropanol in chloroform, dried, redissolved in mobile phase and injected. Chromatography was performed at 20 degrees C by pumping a mobile phase of acetonitrile (370 ml) in pH 5.2, 0.02 M phosphate buffer (630 ml) at 1.0 ml/min through a C8 Symmetry column. Cisapride and the internal standard were detected by fluorescence monitoring at 295 nm (excitation) and 350 nm (emission), and were eluted 5 min and 8 min, respectively, after injection. Calibration plots in bovine serum albumin (3% w/v) were linear (r > 0.999) from 5 to 250 ng/ml. Intra-day and inter-day precision (C.V.) was 9.5%, or less, and the accuracy was within 5.5% of the nominal concentration over the range 8-200 ng/ml. Total assay recovery was above 82%. Endogenous plasma components, the major cisapride metabolite (norcisapride), and other drugs used in neonatal pharmacotherapeutics did not interfere.

Anti-Ulcer Agents↗
PubMed1994

Rapid column liquid chromatographic analysis of flucloxacillin in plasma on a microparticulate pre-column.

A rapid, sensitive, accurate and precise high-performance liquid chromatographic assay is described for flucloxacillin in plasma. Samples (100 microliters) containing dicloxacillin (internal standard) were extracted with ethyl acetate (2 ml). The mobile phase of acetonitrile (18%, v/v) in phosphate buffer (0.01 M, pH 7) was pumped at 1.2 ml/min through a 40 x 3.2 mm I.D. column (3 microns particles). Detection was at 220 nm. Calibration plots were linear (r > 0.9995) from 0.2 to 40 mg/l. Within-day and between-day coefficients of variation were less than 9% (n = 6). The detection limit was 0.05 mg/l and the limit of quantitation was 0.3 mg/l. Of 24 drugs tested, only phenytoin and carbamazepine may interfere in some patients' samples.

Acetates↗