The smaller population interindividual CV% estimates with IT2B on the clinical dataset are probably the result of assuming Gaussian parameter distributions and/or of using the FOCE approximation. NPEM and NPAG, having no constraints on the shape of the population parameter distributions, and which compute the likelihood exactly and estimate parameter values with greater precision, detected the more likely greater diversity in the parameter values in the population studied. In the first Monte Carlo study, NPAG and PEM had more precise parameter estimates than either IT2B FOCE or NONMEM FOCE, as well as much more precise estimates than NONMEM FO. In the second Monte Carlo study, NPEM easily detected the bimodal parameter distribution at this initial step without requiring any further information. Population modelling methods using exact or accurate computations have more precise parameter estimation, better stochastic convergence properties and are, very importantly, statistically consistent. Nonparametric methods are better than parametric methods at analysing populations having unanticipated non-Gaussian or multimodal parameter distributions.

The relationship of L-DOPA plasma level, parameters of ERG and severity of extrapyramidal symptoms after a single dose of L-DOPA was investigated in 11 patients suffering from parkinsonism of idiopathic or arteriosclerotic origin. After a drug-free night, each patient received his/her usual morning dose of L-DOPA. In the subsequent 3 h, the ERG recordings, blood levels and clinical ratings of extrapyramidal symptoms significantly dropped after a delay of 60 min in relation to the occurrence of the peak plasma L DOPA level. The initial "b" wave amplitudes as well as initial serum potassium values were abnormally high. There was a statistically significant correlation between the decrease of "b" wave amplitude (delta "b") and the potassium "normalization index" (i.e. the ratio between the observed decrease of serum potassium and the pretreatment difference from the middle normal potassium value). A definite interpretation of the data cannot be provided until more knowledge about the origin of "b" wave of ERG is available. It can be concluded tentatively that dopaminergic processes influence electrophysiological reactivity of the retina.

No abstract

The efficiencies of two dosage schedules of amikacin (2 x 10 mg/kg of body weight per 24 h and 1 X 20 mg/kg/24 h intramuscularly for 5 days) against Pseudomonas aeruginosa sepsis in rabbits were compared. Blood samples were drawn at various times after the first application, and amikacin concentrations in serum were assayed microbiologically. The dynamics of the bactericidal effect of amikacin was simulated in vitro with the same strain of P. aeruginosa. No regrowth was found with the 20-mg/kg dose when the bacterial inoculum was in contact with experimental and theoretically predicted serum amikacin concentrations. The killing effect was present even when the drug levels decreased considerably below the MIC. The interrelationship between simulated amikacin concentrations in serum and the corresponding average killing rates was described appropriately by the standard Emax model. The higher amikacin dose performed its bactericidal effect faster and the drug persisted longer in the blood. The two amikacin regimens were therapeutically equivalent, but the once-daily schedule had some advantages over the twice-daily drug administration which became evident when both the pharmacokinetic and the pharmacodynamic parameters of the drug were considered.Aminoglycoside antibiotics play a major role in the therapy of severe gram-negative infections. Pseudomonas aeruginosa sepsis continues to have a high mortality rate (26), so therapeutic strategies to overcome this problem were investigated. Aminoglycoside antibiotics are potent antipseudomonal agents having rapid and concentration-dependent bactericidal activity, but because of their narrow safety margins new approaches are necessary in order to optimize their therapeutic efficacy. One such approach is reducing the frequency of aminoglycoside administration (25). The pharmacodynamic background for once-daily dosing of amikacin includes concentrationdependent bactericidal activity (24), postantibiotic effect (5, 6), and low incidence of resistant subpopulations when concentrations in plasma above the threshold (8 to 10 times the MIC) are achieved (1, 21). An optimal regimen for aminoglycoside therapy would assure an adequate initial drug level, thus minimizing the opportunity for adaptive resistance, reducing the need for drug monitoring, and avoiding severe drug toxicity (18). A wide variety of animal models has been investigated, and the findings suggest that the less frequent dosing does not alter drug effectiveness (27,34). The efficiencies of two dosage schedules of amikacin (2 x 10 mg/kg of body weight per 24 h and 1 x 20 mg/kg/24 h given intramuscularly) against experimental P. aeruginosa sepsis in rabbits were compared. An attempt to correlate pharmacokinetic and pharmacodynamic features of the drug simulating its bactericidal in vitro activity was made.MATERIALS AND METHODS Animals. Chinchilla rabbits divided into three groups (six animals each) with a mean body weight of 3.12 ± 0.36 kg were included in the study.Pseudomonas infection model. Sepsis was induced by ...

Collectively, the results show that the NPEM method is suitable and relevant for large-scale epidemiological studies of population phenotyping for cancer susceptibility and for abnormal liver function by monitoring CYP1A2 activity based on sparse caffeine data.