R. Le Verge

Preparation and characterization of bupivacaine-loaded polylactide and polylactide-co-glycolide microspheres

Abstract Various bupivacaine-loaded microsphere systems have been prepared from polylactide-co-glycolide (PLGA) and from blends of different molecular weight polylactide (PLA) by a solvent evaporation-extraction method. In vitro drug release profiles displayed significant differences between polymers. Among PLA microspheres, the initial release was accelerated with increasing proportion of low molecular weight PLA. Preliminary pharmacokinetic studies following intrathecal and intraperitoneal administration of different bupivacaine-loaded microspheres in rabbits illustrated the controlled release of this drug.

In vitro controlled release kinetics of local anaesthetics from poly(D, L-lactide) and poly(lactide-co-glycolide) microspheres

Poly(D,L)lactide and polylactide-co-glycolide drug-loaded microspheres were prepared with lipopholic (bupivacaine and etidocaine) and hydrophilic (mepivacine and lidocaine) local anaesthetics. Formulations of drug-loaded microspheres were characterized by the drug content, the in-vitro release kinetics and by the physical state of the drug within the microspheres. Release rates of the local anaesthetics from the microspheres were different and could not be accounted for by the intrinsic dissolution rates of the drugs. The encapsulation efficiency was highly dependent on the lipophilicity of the drugs, reaching the maximum for the lipophilic drugs and the poly(lactide-co-glycolide) polymers. The influence of the molecular weight of the poly(lactide-co-glycolide) polymers on the release rate and on the release mechanism depended on the drug studied and its physical state within the polymeric matrices. Diffusion-controlled release was evidenced in various formulations as a result of the linearity of the release as a function of the square root of time.

High-performance liquid chromatographic determination of bupivacaine in plasma samples for biopharmaceutical studies and application to seven other local anaesthetics.

A sensitive analytical procedure for bupivacaine dosing in plasma samples by reversed-phase high-performance liquid chromatography is described. After a two-step extraction, the analysis was performed using a C18 column and a mobile phase of 0.01 M sodium dihydrogen-phosphate (pH 2.1)-acetonitrile (80:20, v/v). The extraction yield of bupivacaine from plasma was 73.5 +/- 5.1% (mean +/- S.D., n = 10). The within-day and between-day reproducibilities at a concentration of 100 ng/ml were 2.1% and 5.6%, respectively (n = 10). Calibration curves were linear (r2 = 0.9996) between 5 and 1000 ng/ml. The limit of detection, defined by a signal-to-noise ratio of 3:1, was 2 ng/ml. The accuracy at a concentration of 100 ng/ml was 2.3%. This method could be applied to the plasma analysis of seven other local anaesthetics (articaine, etidocaine, lidocaine, mepivacaine, pramocaine, procaine and tetracaine). The procedure was used in bioavailability studies of bupivacaine-loaded poly(D,L-lactide) (i.e. PLA) and poly(D,L-lactide-co-glycolide) (i.e. PLGA) microspheres after subcutaneous and intrathecal administrations in rabbits.

Antinociceptive effect of bupivacaine encapsulated in poly(D,L)-lactide-co-glycolide microspheres in the acute inflammatory pain model of carrageenin-injected rats.

Encapsulating bupivacaine in poly(D,L)-lactidecoglycolide microspheres may prolong analgesia and diminish systemic toxicity. The antinociceptive effect of bupivacaine-loaded microspheres (1, 2.5, and 5 mg) and plain bupivacaine solutions (1, 2.5, and 5 mg) were compared using the vocalization threshold to paw pressure test (VTPP) in rats. Local anesthetic solutions were injected subcutaneously in the plantar hindpaw. First, the biological inactivity of the vehicle and drug-free microspheres (DFM) was evaluated in normal (n = 8) or carrageenin-injected rats (n = 24). Second, onset of antinociception was evaluated in normal rats (n = 16). We then evaluated the duration of antinociception induced by the different local anesthetic solutions in carrageenin-injected rats (n = 56). Neither the vehicle nor the DFM induced any modification of the VTPP. Onset of antinociception was 5 min for all local anesthetic solutions. Duration of antinociception was 60 min with plain bupivacaine (1 mg) and increased to 90, 120, and 180 min, respectively, for the different doses of bupivacaine-loaded microspheres (1, 2.5, and 5 mg). Larger doses of plain bupivacaine (2.5 and 5 mg) induced systemic toxicity. The encapsulation of bupivacaine in microspheres induced a dose-dependent increase in duration of antinociception as compared with plain bupivacaine. (Anesth Analg 1997;84:90-4)

Non steady state and steady state PKS Bayesian forecasting and vancomycin pharmacokinetics in ICU adult patients.

The pharmacokinetics of vancomycin was investigated in adult ICU patients after the first administration and at steady state. Then the predictive performance of a two-compartment Bayesian forecasting program was assessed in these patients by using population-based parameters and three non steady state vancomycin concentrations as feedback information. Finally a prospective investigation was carried out to search potential covariates. At steady state, a significant decrease (around 30%) in clearance (CL) was observed, while creatinine clearance (CLcr) was stable and a significant increase (around 30%) in volume of distribution (V(SS)) was observed. A two-fold increase in elimination half-life was found. CL was weakly correlated with CLcr at onset of therapy and at steady state. The Bayesian program tended to overpredict vancomycin peak and trough concentrations. A larger mean prediction error and a poorer precision were observed when population-based parameter estimates were used (no feedback) compared to feedback prediction, but the differences were not significant. Mechanical ventilation and concurrent opioid therapy may be pertinent covariates of vancomycin pharmacokinetics. The current work has shown that vancomycin pharmacokinetics in ICU patients displayed a significant variability and a significant change in both clearance and distribution during the course of therapy. Further investigation is necessary to clarify these findings. Moreover, the use of the Bayesian forecasting PKS program in our patients led to a prediction with low bias but rather poor precision. This outcome highlights the need to implement a population modeling approach, to determine the vancomycin pharmacokinetic parameters and covariates in our ICU patients, and to apply this information to provide more accurate concentration predictions.

Non linear disposition of thiopentone following long-term infusion

SummaryThe pharmacokinetics of thiopentone administered at infusion rates ranging 4.5–11.5 mg.kg−1. h−1 for 50–130 h was studied in 6 patients with neurologic evidence of severe cerebral damage. Arterial plasma concentrations of thiopentone were measured during and after discontinuation of the infusion. The postinfusion plasma concentrations were fitted to the one compartment Michaelis-Menten model. At the end of the infusion, the level of saturation of the enzymatic systems ranged 67.0–95.7%. Vm was on average 0.93±0.57 mg.l−1. h−1. The mean plasma clearance was 2.0±1.4 ml.min−1. kg−1. The apparent half-life of the terminal phase was 5.5±3.9 h.

Effect of dexamethasone on motor brachial plexus block with bupivacaine and with bupivacaine-loaded microspheres in a sheep model.

Background and objective: It has been suggested that dexamethasone potentiates the sensory block produced by bupivacaine when both drugs are loaded in microspheres. The aim of the study was to evaluate the effect of dexamethasone on the brachial plexus block obtained with plain bupivacaine and bupivacaine-loaded microspheres. Methods: Dexamethasone alone (Group 5) or added to plain bupivacaine (75 mg) with (Groups 3 and 4) and without pH correction (Group 2) was compared with plain bupivacaine (75 mg; Group 1). The effect of a small dose of dexamethasone (0.42 mg) was then evaluated on the brachial plexus block obtained with bupivacaine (750 mg) as bupivacaine-loaded microspheres (Group 6). Dexamethasone was added either in the suspending medium (Group 7) or incorporated with bupivacaine into microspheres (Group 8). The motor block was evaluated in a plexus brachial sheep model. Results: Dexamethasone alone did not produce any motor block. When added to plain bupivacaine without pH correction, complete motor block could not be obtained. When the pH was corrected, addition of dexamethasone to plain bupivacaine seemed to delay the onset of motor block and did not prolong its duration, and it had no effect on the pharmacokinetics of bupivacaine. With bupivacaine-loaded microspheres, the duration of complete motor block was reduced when a small dose of dexamethasone was added in the suspending medium. However, the duration of motor block was significantly prolonged when dexamethasone was incorporated with bupivacaine into microspheres. Conclusions: Despite the delayed onset of motor block, the incorporation of dexamethasone in bupivacaine-loaded microspheres dramatically increases the duration of action (700 ± 485-5160 ± 2136 min), which could be clinically relevant when such a drug-delivery system will be available.

Cerebrospinal fluid and plasma disposition of yohimbine and 11-hydroxy- yohimbine in young and older healthy subjects, and Alzheimer's disease patients

AbstractObjective: The plasma and cerebrospinal fluid (CSF) disposition of yohimbine (YO) and 11-hydroxy-yohimbine (11-OH-YO), after oral administration of a single dose of YO (0.65 mg · kg−1) were studied in young and older healthy subjects and in patients with Alzheimers disease (AD). Results: Plasma disposition of YO displayed large variability; no significant differences among subject groups were observed. In contrast, 11-OH-YO Cmax and AUC were significantly lower in the older normal subjects than in the young normal or AD subjects. A strong positive correlation between CSF and plasma YO concentrations was observed. A weak positive correlation between CSF and plasma concentrations of 11-OH-YO was also observed. CSF to plasma concentration ratios for yohimbine and 11-OH-YO were low (approximately 2%).