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OBJECTIVE: To establish the role of patient characteristics in estimating doses of digoxin for neonates using routine therapeutic drug monitoring data. METHOD: The steady-state blood level data (n = 129) after repetitive oral administration in 71 hospitalized neonates were analysed using Nonlinear Mixed Effects Modelling (nonmem), a computer program designed for analysing drug pharmacokinetics in study populations through pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a one-compartment open pharmacokinetic model. The effect of a variety of developmental and demographic factors on digoxin disposition was investigated. RESULTS: Estimates generated by nonmem indicated that the clearance of digoxin (CL/F; L/h) was influenced by the demographic variables: total body weight (TBW), gestational age (GA) and neonate clearance factor (trough serum concentration of digoxin; Conc). These influences could be modelled by the equation CL/F = 0.0261 x TBW (kg)0.645 x Conc (ng/mL)(-0.724) x GA (weeks)0.8. The interindividual variability in digoxin clearance was modelled with proportional errors. The estimated coefficient of variation was 7.0%, and the residual variability was 13.1%. CONCLUSION: Clinical application of the model to patient care may permit selection of an appropriate initial maintenance dose, thus enabling the clinician to achieve the desired therapeutic effect. However, the digoxin dosage regimen for the individual patient should be based on a careful appraisal of their clinical need for the drug.

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The population pharmacokinetics of phenobarbital was evaluated using 69 serum concentration measurements obtained from the routine phenobarbital monitoring of 35 neonates and infants. The data were analysed using the nonlinear mixed effects model. A one-compartment open pharmacokinetic model with first-order elimination was used. Covariates screened were current bodyweight (TBW), gestational age, postnatal age (PNA), postconceptional age and gender. The final pharmacokinetic parameters were CL/F (mL/h) = 3.41.TBW (kg) + 1.64. PNA (weeks), Vd/F(L) = 1.09.TBW.(kg) [corrected] and F = 0.406 for oral administration and F = 1 for suppository. Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target phenobarbital concentrations, thus enabling the clinician to achieve the desired therapeutic effect in neonates and infants.

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We tested the antimicrobial activity of orthophthalaldehyde (OPA) against 21 strains (16 species) of pathogenic microorganisms that cause hospital-associated infections. Changes in hepatitis B surface antigen (HBs-Ag) resulting from the addition of OPA to HBs-Ag-positive serum were measured using a radioimmunoassay. We also examined the effect of immersing medical instruments in OPA (0.55%) for 168 h at room temperature. OPA (0.5%, 0.37% and 0.25%) killed 11 strains of vegetative bacteria within 15 s, and it killed the test micro-organisms faster than 3.0% glutaraldehyde (GTA). Incubation with OPA or GTA caused levels of HBs-Ag to fall below a cut-off value within 30 s. OPA did not adversely affect instruments made from various materials. OPA demonstrated more effective antimicrobial activity than GTA against a range of microorganisms. We conclude that OPA should replace GTA as the first-choice high-level disinfectant for endoscopes, considering its antimicrobial efficacy and low inhalation toxicity.

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OBJECTIVE: To clarify the observed variability of digoxin disposition by performing a population pharmacokinetic analysis in a Japanese population. DESIGN: Retrospective analysis of clinical pharmacokinetic data. PATIENTS AND PARTICIPANTS: Data were obtained from 106 patients with heart failure and atrial fibrillation (43 males and 63 females). METHODS: Digoxin concentrations in serum were measured by fluorescence polarisation immunoassay. Population pharmacokinetic analysis was performed using a 2-compartment open pharmacokinetic model with the computer program NONMEM. RESULTS: 246 serum concentrations were obtained. Final pharmacokinetic parameters were: CL (L/h) = (0.036 x TBW + 0.112 x CL(CR)) x 0.77SPI x 0.784CCB, V1 = 1.83 L/kg, V2 = 22.6 L/kg and Q = 0.629 L/h/kg, where CL is total body clearance, V1 and V2 are the apparent volumes of distribution in the central and peripheral compartments, Q is intercompartmental clearance, TBW is total bodyweight (in kg), CL(CR) is creatinine clearance (in ml/min), SPI = 1 for concomitant administration of spironolactone (and zero otherwise) and CCB = 1 for concomitant administration of calcium antagonists (and zero otherwise). Concomitant administration of digoxin and spironolactone resulted in a 23% decrease in digoxin clearance. Concomitant administration of digoxin and calcium antagonists (diltiazem, nicardipine, nifedipine or verapamil) resulted in a 21.6% decrease in digoxin clearance. CONCLUSIONS: The estimated population parameter values may assist clinicians in the individualisation of digoxin dosage regimens.

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OBJECTIVE: The steady-state concentrations of digoxin at trough levels were studied to establish the role of patient characteristics in estimating doses for digoxin using routine therapeutic drug monitoring data. METHOD: The data (n = 448) showing steady state after repetitive oral administration in 172 hospitalized neonates and infants were analyzed using Nonlinear Mixed Effect Model (NONMEM), a computer program designed to analyze pharmacokinetics in study populations by allowing pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a simple steady-state pharmacokinetic model. The effects of a variety of developmental and demographic factors on the clearance of digoxin were investigated. RESULTS: Estimates generated using NONMEM indicated that clearance of digoxin (l.h-1) was influenced by the demographic variables of age, total body weight, serum creatinine, the coadministration of spironolactone, and the presence or absence of congestive heart failure. The interindividual variability in digoxin clearance was modeled with proportional errors with an estimated coefficient of variation of 32.1%, and the residual variability was 28.9%. In the validation set of 66 patients, the performance (bias, precision) of the final population model was good (mean prediction error -0.04 ng.ml-1; mean absolute prediction error 0.20 ng.ml-1).

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BACKGROUND AND OBJECTIVES: Information about the pharmacokinetics of digoxin in paediatric patients is limited. We therefore aimed to investigate the effects of physiological factors on the digoxin clearance in Japanese paediatric patients. METHOD: We used routinely collected therapeutic drug monitoring data (n=544), derived from the steady-state serum concentrations of digoxin in 181 hospitalized paediatric patients. RESULTS: Of those physiological factors which have been examined in this study, age and total body weight were most closely correlated with digoxin clearance. Data on neonates within the first postnatal month indicated a tendency towards lower clearance for premature neonates than full-term neonates (P<0.01). Digoxin clearance was reduced by spironolactone in patients younger than 4 months (P<0.05). Patients with congestive heart failure showed a lower digoxin clearance than the others (P<0.001). Serum creatinine and gender did not have a statistically significant effect on digoxin clearance. CONCLUSION: Age and total body weight are important factors influencing digoxin clearance in children. Spironolactone affected digoxin clearance and needs to be considered when dosing paediatric subjects.

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A simple, rapid and highly sensitive high-performance liquid chromatographic method with fluorescence detection for determining the enantiomers of methamphetamine and its major metabolites, amphetamine and p-hydroxymethamphetamine, in urine samples was developed. Using a newly developed reagent for amines, namely, 4-(4,5-diphenyl-1H-imidazol-2-yl)benzoyl chloride, six enantiomers were derivatized under mild conditions (i.e., 10 min at room temperature, pH 9.0) and separated isocratically on a cellulose tris(3,5-dimethylphenylcarbamate) coated silica gel column following a pre-separation on an ODS column within 42 min, and the effluent was monitored at 440 nm (lambda ex 330 nm). Calibration curves for these derivatives using spiked human urine were linear in the range 0.05-100 mumol dm-3 with correlation coefficients > or = 0.999. The detection limits at a signal-to-noise ratio of 3 were 2.8-8.8 fmol per 5 microliters injection. The relative standard deviations of within- (n = 6) and between-day (n = 5) variations were < or = 7.4%. The method was successfully applied to discriminate between (S)-(+)-methamphetamine and its corresponding metabolites found in abusers' urine and their antipodes in a sample taken from a Parkinsonian patient on selegiline (Deprenyl) therapy.

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Both S-(-)- and R-(+)-enantiomers of 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), a main oxidative metabolite of the achiral antiepileptic drug phenytoin, could be determined simply, sensitively and accurately using reversed phase high-performance liquid chromatography by using a methanol-monopotassium phosphate eluent containing beta-cyclodextrin. Using this assay procedure, it was determined that an S-(-)-enantiomer was formed predominantly by the oxidation of phenytoin in isolated rat hepatocytes.

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The substrate labeled fluorescent immunoassay technique (SLFIA method) was examined in terms of clinical utility for the determination of blood levels of valproic acid (VPA) by comparing it to the enzyme-multiplied immunoassay technique (EMIT method). Both accuracy and precision were very high, and the correlation between the two was excellent (r = 0.985). Practically, the presence of hemoglobin in the sample had little influence on the accuracy. Results show that the SLFIA method is a useful means for the determination of blood concentration of VPA in epileptic patients.

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Two commercial sustained release preparations of isosorbide dinitrate (ISDN), capsules (preparation A) and tablets (preparation B), were tested for content uniformity and dissolution pattern. The deviations in contents of the single doses from the declared content ranged from -7.7% to +9.7% which conformed to the standard (+/- 15%) of the Japanese Pharmacopeia X (JP X). Dissolution tests were performed using the rotating basket method described in JP X. The dissolution medium were No. 1 and 2 solutions (pH 1.2 and 6.8, respectively) specified in JP X disintegration test, and 0.05 M phosphate buffer solutions (pH 3.0 and 5.0). The dissolution patterns of both preparations were independent on the pH of the medium. However, there was a marked difference between the dissolution rates of the two: after 8 hr of the test, the rates of preparation A were 85-89%, but those of preparation B were only 42-50%. From preparation A a somewhat constant release of ISDN continued until the 6 hr. ISDN was determined by the HPLC method.

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