Roger Le Verge

Spray-dryed bupivacaine-loaded microspheres: in vitro evaluation and biopharmaceutics of bupivacaine following brachial plexus administration in sheep

Microspheres could be used as a drug delivery system to prolong the duration of action of bupivacaine and to reduce its systemic absorption leading to high plasma concentrations related to central nervous and cardiovascular toxicity. Bupivacaine-loaded microspheres were made by spray-drying using polylactide-co-glycolide polymers from different sources and with different bupivacaine-polymer ratio. The characterization of microspheres concerned the shape and size, the bupivacaine drug-content (DC) and the cumulative release profiles. We evaluated in sheep the bupivacaine pharmacokinetics: (i) after short intravenous infusion of 75 mg bupivacaine solution; and (ii) following brachial nerve plexus injections of 75 mg bupivacaine solution alone, with the addition of 75 microg epinephrine, with the addition of 150 microg epinephrine and of bupivacaine (750 mg)-loaded microspheres. Release profiles showed a biphasic pattern whatever the DC. After i.v. infusion the mean clearance value was 1.53+/-0.53 l/min and the mean elimination half-life was 120.5+/-73.1 min. Following brachial plexus nerve injection, bupivacaine C(max) were lower than 100 ng/ml following either solution or microspheres administration. Ninety percent of the 75 mg bupivacaine given as a solution were absorbed in 5.8+/-1.0 h (bupivacaine alone) compared to 24.6+/-1.2 h following microsphere administration.

Alkalinization of intracuff lidocaine improves endotracheal tube-induced emergence phenomena.

UNLABELLED We sought to evaluate the effect of filling an endotracheal tube cuff with 40 mg lidocaine alone (Group L) or alkalinized lidocaine (Group LB) in comparison to an Air Control group (Group C) on adverse emergence phenomena in a randomized controlled study (n = 25 in each group). The incidence of sore throat was decreased for Group LB in comparison to Group L during the 24 postextubation hours. The difference between Group L and Group C remained significant in the two postextubation hours only. Plasma lidocaine levels increased when lidocaine was alkalinized (C(max) were 62.5 +/- 34.0 ng/mL and 3.2 +/- 1.0 ng/mL for Groups LB and L, respectively). Cough and restlessness before tracheal extubation were decreased in Group LB compared with Group L and in Group L compared with Group C. Nausea, postoperative vomiting, dysphonia, and hoarseness were increased after extubation in Group C compared with the liquid groups, and a better tolerance was recorded with Group LB compared with Group L. The increase of arterial blood pressure and cardiac frequencies during the extubation period was less in the liquid groups than in the control group and less in Group LB compared with Group L. We concluded that use of intracuff alkalinized lidocaine is an effective adjunct to endotracheal intubation. IMPLICATIONS Use of 40 mg of alkalinized lidocaine, rather than lidocaine or air, to fill the endotracheal tube cuff reduces the incidence of sore throat in the postoperative period. This approach also decreases hemodynamic effects, restlessness, dysphonia, and hoarseness.

Ex vivo and in situ PLGA microspheres uptake by pig ileal Peyer's patch segment.

We investigated the ability of pig ileal Peyers patch segments to transport intestinal poly (D,L-lactide-co-glycolide) microspheres (PLGA MS) from intestinal lumen across the mucosae using in situ and ex vivo segments with confocal laser scanning microscopy (CLSM) and transmission electronic microscopy (TEM). From a global aspect, CLSM suggested that PLGA MS were translocated by M cells labelled with a FITC-conjugated anti-cytokeratin peptide 18, and transported through the follicle-associated epithelium (FAE) in the dome area in both types of experiments. At the ultrastructural level, TEM showed the traffic of PLGA MS throughout M cells, their transport into the basolateral invaginations of the M cells and their subsequent migration into the dome area and the follicular area in contact with macrophages and lymphatic vessels. Although in situ experiments allowed following the migration of PLGA MS until mesenteric lymph nodes, an ex vivo model could be used as a useful tool to study the targeting ability of PLGA MS formulations to the gut-associated lymphoid tissue (GALT).

PLGA microspheres phagocytosis by pig alveolar macrophages: influence of poly(vinyl alcohol) concentration, nature of loaded-protein and copolymer nature.

The study aimed to investigate on a pig alveolar macrophage culture model the influence of: (1) poly(D,L-lactide-co-glycolide) characteristics, (2) the residual poly(vinyl alcohol) (PVA) and (3) the nature of encapsulated proteins, immunoglobulin Y (IgY) or bovine serum albumin, on the microspheres phagocytosis efficiency. The phagocytosis evaluation was performed by flow cytometry and has allowed a screening of microspheres formulations. The hydrophilicity of microspheres resulting from the nature of the polymer and/ or from the residual hydrophilic surface agent (PVA) led to a decrease of phagocytosis intensity. The phagocytosis results of IgY-loaded microspheres strongly suggested that the phagocytosis was increased when the phagocytic cell possessed a receptor for this protein on its surface.

The pharmacokinetics and pharmacodynamics of bupivacaine-loaded microspheres on a brachial plexus block model in sheep.

UNLABELLED: We evaluated bupivacaine-loaded microspheres (B-Ms) using a brachial plexus block model in sheep. In the first step, pharmacokinetic characterization of 75 mg bupivacaine hydrochloride (B-HCl) (IV infusion and brachial plexus block) was performed (n = 12). In the second step, a brachial plexus block dose response study of B-HCl was performed with 37.5 mg, 75 mg, 150 mg, 300 mg, and 750 mg. As a comparison, evaluations were performed using a 750-mg bupivacaine base (B). In the third step, evaluations of brachial plexus block were performed with B-Ms (750 mg of B as B-Ms) using two formulations, 60/40 and 50/50 (w/w %); drug-free microspheres were also evaluated. Toxicity evaluations were also performed after IV administration of B-HCl (750 mg and 300 mg), B-Ms (750 mg), and drug-free microspheres (30 mL over 1 min). As the B-HCl dose increased, the time of onset of block decreased and the duration of complete motor blockade increased at the expense of an increase in bupivacaine plasma concentrations. The time of maximum concentration appeared to be independent of the B-HCl dose. In brachial plexus block, a 37.5-mg dose of B-HCl did not induce motor blockade whereas a dose of 750 mg of B-HCl was clinically toxic. In the case of IV administration, doses of 300 mg of B-HCl were as toxic as 750 mg of B-HCl. Compared with the 75 mg of B-HCl administration for brachial plexus block, administration of 750 mg of B as B-Ms increased the duration of complete motor blockade without significant difference in maximum concentration. No significant clinical difference between the two formulations of B-Ms was demonstrated. The IV administration of B-Ms was safe. We conclude that the controlled release of bupivacaine from microspheres prolonged the brachial plexus block without obvious toxicity. IMPLICATIONS: Administration of 750 mg of bupivacaine as loaded-microspheres resulted in prolongation of brachial plexus block in sheep. The peak plasma concentration was not significantly larger than that obtained with 75 mg of plain bupivacaine. The motor blockade was increased more than six times compared with 75 mg plain bupivacaine.

Inclusion complexation of amide-typed local anaesthetics with β-cyclodextrin and its derivatives. I. Physicochemical characterization

Qualitative aspects of the inclusion complexation of two local anaesthetics of the amide-type (LAs), bupivacaine (BVC) and lidocaine (LDC) with three cyclodextrins (CDs), β-cyclodextrin (βCD) and its alkylated derivatives 2-hydroxypropyl-β-cyclodextrin (HPβCD) and heptakis (2,6-di-o-methyl)-β-cyclodextrin (DMβCD), were studied in the solid state by infrared spectroscopy (IR) and differential scanning calorimetry (DSC). The LDC-βCD couple was also investigated in aqueous solution by nuclear magnetic resonance (1H-NMR and 13C-NMR). This first part of a study dealing with improvement in LA administration provided clear indications about LA-CD complexation. Qualitative modifications in a number of peaks or bands obtained from spectral methods as well as thermal analysis signed the inclusion, showing that the freeze-drying method was suitable for obtaining inclusion complexes of LAs with CDs.

Inclusion complexation of amide-typed local anesthetics with β-cyclodextrin and its derivatives. III. Biopharmaceutics of bupivacaine-SBE7-βCD complex following percutaneous sciatic nerve administration in rabbits

Abstract The effect of a new modified β -cyclodextrin derivative, sulfobutylether7- β -cyclodextrin (SBE7- β CD) on the biopharmaceutics of local anesthetic bupivacaine (BVC) was studied in a rabbit sciatic model. Phase-solubility study revealed the formation of a 1:1 complex of the Al type between BVC and SBE7- β CD, with an apparent stability constant of 149±7 M −1 . Then, BVC hydrochloride (BVC-HCl) and BVC complexed with SBE7- β CD (BVC-SBE7- β CD) were administered around the sciatic nerve both as solutions, in a randomized cross-over design in six New Zealand rabbits. The plasma concentrations of BVC, the onset and duration of motor blockade were evaluated. For the dose of BVC injected (5 mg in 2.5 ml), complexation with SBE7- β CD led to a decrease in the maximum plasma concentration ( C max ) of BVC, while the time to reach C max ( T max ) was increased. Complexation also delayed the onset of motor block and did not modify its duration. This decrease in absorption rate of BVC following complex administration was confirmed by Loo-Riegleman absorption analysis. The effect of SBE7- β CD concerned mainly the faster absorption phase, responsible for side effects, but had also an impact on the slower phase, even if not stastistically significant, shown by a flip-flop in the elimination constant. Complexation may be useful to improve the therapeutic index of local anesthetics, allowing greater amounts of drug to be injected in order to prolong nerve blockade.

Motor and blood pressure effects of epidural sustained-release bupivacaine from polymer microspheres: a dose-response study in rabbits.

The incorporation of local anesthetics into injectable polymer microspheres can be useful in providing prolonged regional effects.This randomized study was designed to compare the effects of bupivacaine and bupivacaine-loaded microspheres on the time course of motor block in rabbits injected epidurally. Bupivacaine-loaded microspheres and drug-free microspheres 1-10 micro meter in size were devised from poly-d,l-lactic acid by using a solvent evaporation/extraction method. The effects of bupivacaine and of similar amounts of bupivacaine-loaded microspheres were studied in 26 rabbits as follows: 0.9% sodium chloride, followed by drug-free microspheres, then 1.25 mg of bupivacaine and 1.25 mg of bupivacaine-loaded microspheres (Group I; n = 8); 2.5 mg of bupivacaine, then 2.5 mg of bupivacaine-loaded microspheres (Group II; n = 8); and 5 mg of bupivacaine and 5 mg of bupivacaine-loaded microspheres (Group III; n = 10). Motor block was evaluated blindly by observation of walking disturbances, using a scale from 0 (free movements) to 3 (total limb paralysis). A period of 3 days elapsed between each injection. No limitation on movements was observed after 0.9% sodium chloride and drug-free microsphere injection. With 5 mg, both bupivacaine solutions provided complete motor block which was significantly more prolonged (+244% +/- 129%, mean +/- SD) with bupivacaine-loaded microspheres than bupivacaine. With 2.5 and 1.25 mg, block intensity was less marked, and block duration was shorter after administration of bupivacaine-loaded microspheres than after bupivacaine. We concluded that blocks resulting from bupivacaine-loaded microspheres are highly influenced by the amount of drug initially released by the polymer. (Anesth Analg 1995;81:519-24)

Biopharmaceutics and metabolism of yohimbine in humans

The biopharmaceutics of yohimbine (YO) and the pharmacokinetics of 10-hydroxy-yohimbine (10-OH-YO) and 11-hydroxy-yohimbine (11-OH-YO) were investigated in healthy subjects following i.v. (5 mg) and oral (8 mg) dosing. One subject was found as a slow hydroxylator of YO. The mean (+/-S.D.) oral absolute bioavailability of YO was 22.3+/-21. 5%. Total plasma clearance (CL) and renal clearance (CL(r)) of YO following i.v. dosing were 0.728+/-0.256 ml/min and 0.001+/-0.002 ml/min, respectively. Based on the steady-state volume of distribution (V(ss)), YO had a relatively low distribution (V(ss) = 32.2+/-12.1 l). The overall renal excretion of YO, 10-OH-YO and 11-OH-YO, expressed as percent of the dose of YO administered, were not different following i.v. and oral dosing, and were around 0.1, 0.2 and 14%, respectively. Following i.v. dosing of YO, the mean apparent terminal half-life of 11-OH-YO (347+/-63 min) was almost four times higher than that of YO (91.0+/-33.6 min) suggesting an elimination rate-limited kinetics for 11-OH-YO.

Determination of yohimbine and its two hydroxylated metabolites in humans by high-performance liquid chromatography and mass spectral analysis

The existence of at least two metabolites of yohimbine (YO) in humans is demonstrated. Combined high-performance liquid chromatographic (HPLC), NMR and mass spectral analyses permitted them to be identified as hydroxylated metabolites at the C-10 and C-11 positions. A normal-phase HPLC method allowing the simultaneous determination of YO and its main metabolite, 11-hydroxyyohimbine (11-OHYO), in biological samples is described. This assay was performed using a LiChrosorb Si 60 column and a mobile phase consisting of 0.02 M sodium acetate (pH 5)-methanol (5:95, v/v) at a flow-rate of 1 ml/min. Detection was achieved by a fluorimetric method (excitation at 280 nm and emission at 320 nm). The extraction yields of YO, 10-OHYO and 11-OHYO from plasma were 91.8, 45.3 and 17.8%, respectively, and their respective within-day reproducibilities were 3.8, 1.4 and 5.9%. The between-day reproducibility for YO at the concentrations of 1 and 10 ng/ml were 8.9 and 6.4%, respectively. The accuracy of the method for YO at concentrations of 1 and 10 ng/ml were 5.1 and 2.3%, respectively. The limits of determination of YO, 10-OHYO and 11-OHYO were 0.1, 0.5 and 1 ng/ml, respectively. The method was used in bioavailability study of YO following oral and intravenous administration in humans.