A combined pharmacokinetic/pharmacodynamic model of levodopa motor response and dyskinesia in Parkinson's disease patients.

PURPOSE: Levodopa is the reference treatment for Parkinson's disease. However, after several years of treatment, dyskinesia may occur and strategies to overcome this side effect still need to be explored. We identified a unique population pharmacokinetic/pharmacodynamic model in Parkinson's disease to investigate the relationship and dissociability of motor response and dyskinesia. METHODS: Thirty parkinsonian patients (Hoehn and Yahr stages 3-4), treated with levodopa and suffering from peak-dose dyskinesia, were included in a prospective open-label study. They received a single dose of levodopa equal to 150 % of their usual daily dose. Blood samples, motor evaluations (UPDRS III scale) and peak-dose dyskinesia (Goetz scale) were examined after administration. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed using NONMEM software. RESULTS: Pharmacokinetic analysis identified a one-compartment model with the following parameter values [bootstrap 95 % CI]: absorption rate constant (KA) 1.86 1/h [1.08-3.25], clearance 36.6 L/h [31.3-42.8], and volume of distribution 42.9 L [34.3-52.3]. Between-subject variability was 122 % [71-183] and 38 % [26-47] for KA and clearance, respectively. Residual variability was 1120 µg/L [886-1290]. UPDRS III and dyskinesia were best described with an effect compartment and similar KE0 values of 1.37 1/h [1.01-1.77]. For UPDRS III, the E0, EC50, Emax, and Hill coefficient were 31.4 [28.4-35.3], 1410 µg/L [1200-1700], 0.72 [0.71-0.75], and 4.26 [3.20-5.58], respectively. For dyskinesia, the EC50 and Emax were 6280 µg/L [3420-37,900] and 17.9 [12.3-80.8], respectively. Residual variability was 3.15 [2.75-3.53] for UPDRS III and 2.66 [1.94-3.51] for dyskinesia. No covariates influenced the parameters. CONCLUSIONS: In patients treated with levodopa and suffering from dyskinesia, the motor response and dyskinesia have close onsets and duration effects. Maximal motor response tends to be inevitably associated with dyskinesia.

Penetration of ertapenem into muscle measured by in vivo microdialysis in mechanically ventilated patients.

Ertapenem at 1 g once daily has been suggested to be underdosed in intensive care unit (ICU) patients to attain optimal concentrations in target tissues. Therefore, our study aimed to assess the kinetics of ertapenem in plasma and skeletal muscle in ICU patients using microdialysis. Average muscle free-ertapenem concentrations were above the MIC values of targeted pathogens. In a few patients, the concentrations were below the MIC values. The clinical efficiency of ertapenem at 1 g once daily should be evaluated in a large population of ICU patients.

Vancomycin prescription in neonates and young infants: toward a simplified dosage.

BACKGROUND: There is no consensus on vancomycin dosing in newborns and young infants. OBJECTIVE: The first objective was to assess the efficiency of a simplified dosing regimen with a cohort study. The secondary objective was to examine pharmacokinetic data to determine how this simplified dosing could be improved. METHODS: All neonates admitted to our intensive care unit and treated with vancomycin were included in the pharmacokinetic study (PK group, 83 treatments, 156 measurements). The vancomycin dosing regimen consisted of a loading dose of 7 mg/kg, followed by a constant continuous dose of 30 mg/kg/day. The target serum vancomycin concentration ranged from 10 mg/l to 30 mg/l. Data from patients whose medications followed the scheduled dosing without modifications or prescription errors (actual dosing group: 62 treatments, 108 measurements) were analysed separately. A population pharmacokinetic analysis was performed (PK group) to simulate several vancomycin dosings. RESULTS: Prescription errors were found in 10 of 83 treatments (12%). In the actual dosing group, 89.2% of vancomycin measurements were within the target range. Serum creatinine remained stable throughout treatment. Vancomycin concentrations varied widely. The modified regimen for a target vancomycin concentration of 25 mg/l consisted of a bolus of 20 mg/kg followed by continuous infusion of 30 mg/kg. CONCLUSION: Our pharmacokinetic data and bedside results suggest that a simplified schedule of vancomycin can achieve the targeted drug concentrations in most patients while avoiding secondary renal toxicity. The proposed new dosing scheme should be validated in a drug survey, but due to pharmacokinetic variability, still requires therapeutic drug monitoring.

Causative organisms of infective endocarditis according to host status.

A prospective study of infective endocarditis (IE) was conducted between 1994 and 2000 in Marseilles, France, and included 170 definite cases diagnosed with the use of modified Duke criteria. Classification of IE based on the aetiological agent was related to epidemiological characteristics, including age, gender and the nature of the injured valve. Enterococci and Streptococcus bovis were identified more frequently in older subjects (p 0.02), and S. bovis was also associated with mitral valve infection (p 0.03). Streptococcus spp. were found to be associated with native valves (p < 10(-3)), whereas coagulase-negative staphylococci and Coxiella burnetii were associated with intracardiac prosthetic material (p < 0.05). S. bovis and Staphylococcus aureus were the predominant species associated with presumably healthy valves (p < 0.05), whereas oral streptococci caused IE exclusively in patients with previous valve damage. The basic host status of IE patients has been linked to specific microorganisms, and this may be of value when empirical treatment is needed in patients who have received previous antibiotic therapy and whose blood cultures are negative.