[Endobronchial ultrasound with transbronchial needle aspiration: Evaluation of clinical practice]. / Échobronchoscopie avec ponction transbronchique à l'aiguille : évaluation des pratiques.

INTRODUCTION: Endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) has undergone a large increase in France since 2007. The aim is to study the evolution of the indications for EBUS-TBNA in our region during the period 2008-2013. MATERIAL AND METHODS: We conducted a retrospective observational study including all the patients who underwent an EBUS-TBNA procedure in Picardie from 2008 to 2013. The respective proportion for each indication was noted. RESULTS: During the study period, 1036 EBUS-TBNA procedures were performed with a continuous increase in number (86 in 2008 versus 275 in 2013). We observed an increase in the proportion of procedures performed for a suspected diagnosis of sarcoidosis (OR=1.31; IC 95% [1.09-1.58]; P=0.005) and for the simultaneous diagnosis and staging of lung cancer (OR=1.12; IC 95% [1.02-1.24]; P=0.022). For the diagnosis of sarcoidosis, we observed an improvement in the diagnostic yield between the periods [2008-2010] and [2011-2013] (42.9% versus 72.5%). CONCLUSION: A continuous increase in the number of EBUS-TBNA procedures was observed during the period 2008-2013. It was associated with a modification in practice with an increased proportion of procedures performed for the diagnosis of sarcoidosis.

In vitro delivery of a sparingly water soluble compound from PLA50 microparticles.

The administration of a sparingly soluble drug is always problematic, especially when the drug has to be released from the degradable matrix of a polymeric drug delivery system. Attempts were made to achieve the complete release of 1-[2-(fluorobenzoyl) aminoethyl]-4-(7-methoxynaphtyl)piperazine (FAMP), a potential anxiolytic and antidepressor hydrophobic compound, from racemic poly(lactic acid) (PLA50)-based microparticles, 100% release was required at a low rate in order to allow monthly repeated S.C. or I.M. injections of this potent compound. FAMP-polymer combinations were made in the form of microspheres by the solvent evaporation technique. Release profiles were investigated under dynamic conditions by using a constant flow rate of pH 7.4 0.15 M phosphate buffer, used as a model of body fluids. Under these conditions, none of the microsphere compositions led to total release within a month, even when hydrophilic excipients, namely fructose and PEG were added. PLA50-FAMP microparticles with compositions and sizes similar to those of the microspheres, were then made by direct blending in dichloromethane, evaporation of the solvent, grinding and sieving. These formulations also failed in providing total drug release within 30 days, even at a high drug load. FAMP/PLA50/water-soluble additive, ternary grounded particles were finally prepared with fructose, PLA50 oligomers or poly(ethylene glycol) (PEG) as the additive. Only PLA50 grounded particles with percolating FAMP-PEG microdomains allowed 100% release of FAMP over a 30 day period, at a quasi constant rate which depended primarily on solubility and channelling provided the flow was slow enough. Data are discussed in terms of the accessibility of the entrapped drug to the aqueous medium.

The use of additives to modulate the release of a sparingly water soluble drug entrapped in PLA50 microparticles: in vivo investigation.

Sustained and total release of the sparingly water soluble compound, namely 1-[2-(4-fluorobenzoyl)aminoethyl]-4-(7-methoxynaphthyl) piperazine hydrochloride (FAM), from poly (DL-lactic acid) (PLA50) microparticles was previously shown to be feasible if the particles are obtained by grinding a solid mixture composed of the polymer and a percolating array of the compound mixed with an additive. Such microparticles, where the additive was poly (ethylene glycol) (PEG), dimyristoylphosphatidylcholine (DMPC), or Poloxamer 6800, were administrated subcutaneously to rats either as depot or using a liquid vehicle. The variations of the plasma concentration vs time determined by high pressure liquid chromatography and fluorometric detection, were plotted for the various microparticle systems, blood being taken twice from each animal and each measurement being triplicated. Data were analysed by non-compartmental analysis, in order to evaluate the elimination constant, the half-life, the area under the curve and the bioavailability for each system. Kinetics experiments were performed over 24h and also for 7 days. It was found that, for the selected formulations, the release of the sparingly water soluble compound depends on the dissolution rate in vivo and on the physicochemical characteristics of the additive, including solubility and micelle formation. Data correlated well with the results of previous in vitro investigation.

The use of additives to modulate the release of a sparingly water soluble drug entrapped in PLA50 microparticles.

One of the major problems raised by the microencapsulation of drugs which are sparingly soluble in water is the difficulty to achieve a controlled and total release of the drug. It was previously shown that the microencapsulation of a model water insoluble drug, namely 1-[2-(4-fluorobenzoyl)aminoethyl]-4-(7-methoxynaphthyl) piperazine hydrochloride (FAMP) with a hydrophilic additive like low molar mass poly(ethylene glycol)s (PEG) can fulfil these requirements, provided all the drug + additive matter is in contact with the surrounding liquid medium via open pores and percolating channels. In this paper, PEG was replaced by other additives, selected because of their potential ability to increase the solubility of FAMP in pH = 7.4 isosomolar phosphate buffer (PBS). The idea was that increasing the solubility locally in microparticles could allow the drug to be released, despite its poor solubility in aqueous media like body fluids, and be absorbed before recrystallization. The solubility in PBS of FAMP mixed with additive, in the form of solid dispersions, was determined for various additives, namely citric acid, dimyristoyl DL-alpha-phosphatidyl choline (DMPC), poloxamer copolymers of different compositions and poly(dodecyl L-lysine citramidate) (PLCAC12(100)), an aggregate-forming hydrophilic polyelectrolyte containing 100%, hydrophobizing ester groups which can accommodate lipophilic compounds in hydrophobic pockets present in the aggregates. PEG was taken as a reference. It was found that DMPC, some poloxamers and the hydrophobized polyelectrolyte do increase the solubility of FAMP in PBS. Investigation was made of the release of FAMP from ground microparticles, whose loads were composed of FAMP combined with these solubilization-promoting additives. It was found that the release rate of FAMP from such systems can be increased and modulated to achieve an in vitro sustained release over a 20-30 day period and secure exhaustion of the particles at the end of this period.

Use of the acyl azide method for cross-linking collagen-rich tissues such as pericardium.

Collagen biomaterials should be cross-linked in order to prevent biodegradation when they are used as implants. We have compared the cross-linking efficiencies of glutaraldehyde and acyl azide in pericardium. Glutaraldehyde is used currently, but it elicits a cytotoxic effect which reduces the biocompatibility of cross-linked tissue. We have attempted to overcome this problem by developing a cross-linking method that obviates incorporation of foreign agents. Our process involves transformation of free carboxyl groups on collagen into acyl azide groups, which react with free amino groups on adjacent side chains. We have shown that the greatest increase in the thermal stability of collagen, as measured by differential scanning calorimetry, is achieved when tissue swelling is inhibited by the addition of sodium chloride (1 M) during acyl azide formation. Under these conditions, the denaturation temperature (Td) of pericardial collagen treated with acyl azide is raised to 83.4 degrees C and that of tissue treated with glutaraldehyde to 85.1 degrees C. Moreover, acyl-azide-treated tissues have the same resistance as glutaraldehyde-treated tissues to chemical solubilization by cyanogen bromide and to enzymatic digestion by collagenase.