Assessing the non-ideality of the CO2-CS2 system at molecular level: a Raman scattering study.

The dense phase of CO2-CS2 mixtures has been analysed by Raman spectroscopy as a function of the CO2 concentration (0.02-0.95 mole fractions) by varying the pressure (0.5 MPa up to 7.7 MPa) at constant temperature (313 K). The polarised and depolarised spectra of the induced (ν2, ν3) modes of CS2 and of the ν1-2ν2 Fermi resonance dyad of both CO2 and CS2 have been measured. Upon dilution with CO2, the evolution of the spectroscopic observables of all these modes displays a "plateau-like" region in the CO2 mole fraction 0.3-0.7 never previously observed in CO2-organic liquids mixtures. The bandshape and intensity of the induced modes of CS2 are similar to those of pure CS2 up to equimolar concentration, after which variations occur. The preservation of the local ordering from pure CS2 to equimolar concentration together with the non-linear evolution of the spectroscopic observables allows inferring that two solvation regimes exist with a transition occurring in the plateau domain. In the first regime, corresponding to CS2 concentrated mixtures, the liquid phase is segregated with dominant CS2 clusters, whereas, in the second one, CO2 monomers and dimers and CO2-CS2 hetero-dimers coexist dynamically on a picosecond time-scale. It is demonstrated that the subtle interplay between attractive and repulsive interactions which provides a molecular interpretation of the non-ideality of the CO2-CS2 mixture allows rationalizing the volume expansion and the existence of the plateau-like region observed in the pressure-composition diagram previously ascribed to the proximity of an upper critical solution temperature at lower temperatures.

Carbon dioxide in 1-butyl-3-methylimidazolium acetate. I. Unusual solubility investigated by Raman spectroscopy and DFT calculations.

The unusual solubility of carbon dioxide in 1-butyl-3-methylimidazolium acetate (Bmim Ac) has been studied by Raman spectroscopy and DFT calculations. It is shown that the solubility results from the existence of two distinct solvation regimes. In the first one (CO(2) mole fraction ≤ 0.35), the usual Fermi dyad is not observed, a fact never reported before for binary mixtures with organic liquids or ionic liquids (IL). Strong experimental evidence complemented by effective DFT modeling shows that this regime is dominated by a chemical reaction leading to the carboxylation of the imidazolium ring accompanied by acetic acid formation. The reactive scheme proposed involves two concerted mechanisms, which are a proton exchange process between the imidazolium cation and the acetate anion and the carboxylation process itself initiated from the formation of "transient" CO(2)-1-butyl-3-methylimidazole 2-ylidene carbene species. In that sense, CO(2) triggers the carboxylation reaction. Moreover, this dynamic picture circumvents consideration of a long-lived carbene formation in dense phase. The second regime is characterized by the detection of the CO(2) Fermi dyad showing that the carboxylation reaction has been strongly moderated. This finding has been interpreted as due to the interaction of the acetic acid molecules with the COO group of acetate anions involved in monodentate forms with the cation. The observation of the Fermi doublet allows us to infer that CO(2) essentially preserves its linear geometry and that the nature and strength of the interactions with its environment should be comparable to those existing in organic liquids and other IL as well. These results have been supported by DFT calculations showing that the CO(2) molecule interacts with energetically equivalent coexisting structures and that its geometry departs only slightly from the linearity. Finally, we find that the CO(2) solvation in Bmim Ac and 1-butyl-3-methylimidazolium trifluoroacetate (Bmim TFA) cannot be straightforwardly compared neither in the first regime due to the existence of a chemical reaction nor in the second regime because CO(2) interacts with a variety of environments not only consisting of ions pairs like in Bmim TFA but also with carboxylate and acetic acid molecule.

Transient complex formation in CO2-hexafluorobenzene mixtures: a combined raman and ab initio investigation.

The polarized and depolarized Raman spectra of CO2 in binary mixtures with hexafluorobenzene have been measured in the dense phase along the isotherm 313 K as a function of concentration (0.03-0.7 molar fraction in CO2) by varying the pressure (0.5-6.2 MPa). Experimental observations in the nu2 bending region, in the nu1-2nu2 Fermi resonance dyad, and in the spectral domain between the Fermi dyad peaks on CO2 are reported. These results are discussed in comparison with those obtained in previous studies on CO2-C6H6 and CO2-acetone mixtures. We conclude in agreement with previous investigations that CO2 molecules can probe two environments. In one of them carbon dioxide interacts "specifically" with hexafluorobenzene molecules to form a transient heterodimer, whereas in the other environment CO2 interacts "nonspecifically" with its neighbors. New ab initio calculations reported here allow rationalizing most of the experimental results. However, the observation of weak spectral features (bending mode and Fermi dyad regions) shows that a slight departure from the predicted structure (C6v symmetry) should exist in the dense phase. Finally, the greater solubility of CO2 in perfluorinated benzene versus perhydrogenated benzene has been discussed on the basis of this study in connection with thermodynamic measurements interpreted in the scaled particle theory framework.

Interaction of water highly diluted in 1-alkyl-3-methyl imidazolium ionic liquids with the PF6(-) and BF4(-) anions.

We have investigated water highly diluted in 1-alkyl-3-methyl imidazolium ionic liquids (ILs) with hexafluorophosphate {PF(6)(-)} and tetrafluoroborate {BF(4)(-)} anions using vibrational spectroscopic measurements in the nu(OH) spectral domain of water (3600-3800 cm(-1)) and DFT calculations. The measured profiles exhibit two well-defined bands at coinciding vibrational transitions assigned with the nu(1) symmetric and nu(3) antisymmetric OH stretching modes of monodispersed water. The local organization and the vibrational spectra of water diluted in ILs have been assessed by DFT calculations (using the B3LYP functional and 6-31+G** basis set). We show that the predicted structures of water interacting (minimally) with two anions in nearly "symmetric" structures of type (A...H-O-H...A) lead to spectral features consistent with the previous spectroscopic observations as well as with those reported here. We emphasize the role of the non additive interaction forces (especially the 3-bodies electrostatic interactions) in the structural organization taking place between the cation-anion couples and for determining preferentially (A...H-O-H...A) associations of water with the anions as well as their consequences on the vibrational spectra of water. We show that the doubly hydrogen-bonded character of water in such associations leads to well-defined spectral features, which are the shifts of the nu(1) and nu(3) stretching modes of water, the separation Delta nu(13) between them (about 80 cm(-1)), and the intensity ratio estimates R = I nu(3)/I nu(1) (IR absorption and Raman). Finally, we evoke the fact that the H-bond interactions of water diluted in these ILs involve a more noticeable electrostatic character than for H-bond interactions of water in usual molecular solvents. In this context, we emphasize that the appearance of the Raman band of the nu(3) mode of water originates from a significant polarization of water due to the local electrostatic fields induced by surrounding ions.

In vitro and in vivo characteristics of a thermogelling and bioadhesive delivery system intended for rectal administration of quinine in children.

The aim of this work was to improve the rectal bioavailability of quinine hydrochloride by designing thermosensitive and mucoadhesive gels intended for rectal delivery. The rheological and mucoadhesive properties of poloxamer 407 solutions have been modulated by addition of hydroxypropylmethycellulose (HPMC) and propanediol-1,2. In vitro release and rectal absorption of quinine have been highlighted by a dialysis dissolution testing method and by the determination of bioavailability of the different formulations in rabbits. Increasing the proportions of HPMC and poloxamer in the formulations resulted in a prolonged release of quinine. Indeed, compared to the DT 50% of a rectal solution and a simple HPMC gel (27 and 65 min, respectively) the DT 50% of thermosensitive ternary systems was increased and ranged between 80 and 138 min, depending on the system composition. The release rate depended strongly on the elasticity of the gels after thermogelation. The absolute rectal bioavailability of quinine determined in rabbits was significantly improved with these thermosensitive and adhesive systems. It increased from 62% for the rectal solution to 98% for a ternary system 16/0.5/30 (poloxamer (16%)/HPMC (0.5%)/propanediol-1,2 (30%)). As a result of combined bioadhesion and prolonged release of quinine in vivo, higher average values of MRT and t(max) (9.1+/-0.2h and 30 min, respectively) were obtained compared to the rectal solution (6.9+/-0.9h and 15 min, respectively). Moreover, these formulations presented a very good rectal tolerance. Modulation by HPMC of the viscoelastic and mucoadhesive properties of poloxamer 407 thermogelling solutions allowed a prolonged release of quinine hydrochloride and an improvement of bioavailability in rabbit.

Raman spectroscopy and ab initio investigations of transient complex formation in CO2-benzene mixtures.

The polarized and depolarized Raman spectra of CO(2) have been measured as a function of CO(2) concentration (0.02-0.7 molar fractions) in the dense phase of the binary mixtures obtained by introducing under pressure (from 0.2 up to 6.0 MPa) supercritical carbon dioxide (at 313 K) in liquid benzene. Four main experimental features are observed. A new weak polarized band centered at approximately 660 cm(-1) has been detected in the region of the Raman inactive nu(2) bending mode of carbon dioxide. The analysis of the polarized band shapes of the Fermi dyad shows that CO(2) molecules probe two environments. In one of them carbon dioxide interacts "specifically" with benzene molecules, whereas in the other it interacts "nonspecifically" with its neighbors. The analysis of the depolarized Fermi dyad profiles shows that the rotational dynamics of CO(2) specifically interacting with benzene is strongly hindered. Finally, a new weak polarized band has been detected between the two components of the dyad. These observations rationalized at the light of ab initio calculations show that CO(2)-benzene transient complexes are formed. It is argued that ab initio predictions, limited here to a pair of molecules, are still valid in dense phase because the elementary act of formation of the transient complex can be probed on the observation time and spatial range of vibrational Raman spectroscopy.

Liposomal formulation of a glycerolipidic prodrug for lymphatic delivery of didanosine via oral route.

Didanosine is a polar drug with poor membrane absorption and high hepatic first pass metabolism. This study aimed at developing a lipidic formulation of a glycerolipidic prodrug of didanosine in order to improve its bioavailability. In the course of a preformulation study, the glycerolipidic prodrug of didanosine was characterized by microscopy, DSC and XRDT. In anhydrous conditions, the prodrug displayed a polymorphic behaviour similar to that of triglycerides. Then, we evaluated three types of lipidic formulations (emulsions, mixed micelles and liposomes) in order to encapsulate the prodrug. Solubilities in water - even in the presence of taurocholate micelles - but also in some oils were very low (max 244 microg/mL) as the prodrug was found to be amphiphilic (log P=2). On the contrary, the prodrug was found to be perfectly incorporated in dipalmitoylphosphatidylcholine (DPPC) multilamellar liposomes up to a ratio of 1:5 (mol:mol) prodrug:DPPC as suggested by HPLC-UV and DSC experiments. Moreover, these liposomes could be freeze-dried whereas the chemical integrity of the prodrug was preserved. Then, the freeze-dried liposomal preparation could be formulated as gastro-resistant capsules to prevent didanosine from acidic degradation. Further experiments are on the way to evaluate in vitro the absorption of prodrug incorporated in liposomes by enterocytes.

Encapsulation of antiviral nucleotide analogues azidothymidine-triphosphate and cidofovir in poly(iso-butylcyanoacrylate) nanocapsules.

Nucleoside analogues are widely used in the treatment of various viral infections. However, the poor in vivo conversion of the nucleoside analogues like azidothymidine (AZT) into their active triphosphate nucleotide counterpart limits their pharmacological efficacy. This could be overcome by the direct administration of azidothymidine triphosphate (AZT-TP), but it requires an appropriate drug delivery approach. Besides nucleoside analogues, nucleotide analogues like cidofovir (CDV) are also used in the treatment of viral infections. CDV has raised recent interest because of its promising activity against smallpox, but its use is limited by its poor bioavailability and nephrotoxicity. Here again, a proper drug delivery system should address these issues. In this study, we investigated the encapsulation of the nucleotide analogues AZT-TP and CDV into poly(iso-butylcyanoacrylate) aqueous core nanocapsules, known to efficiently entrap oligonucleotides. We show here that the encapsulation of these mono-nucleotides is less efficient than with oligonucleotides and that a rapid release of AZT-TP from the nanocapsules occurred in vitro. This highlights the importance of the molecular weight of the entrapped molecules which, if they are too small, are diffusing through the thin polymer membrane of the nanocapsules. On the other hand, a good protection of the encapsulated AZT-TP was observed.

DFT Study of the Reaction Mechanisms of Carbon Dioxide and its Isoelectronic Molecules CS2 and OCS Dissolved in Pyrrolidinium and Imidazolium Acetate Ionic Liquids.

The reaction mechanisms of CO2 and its isoelectronic molecules OCS and CS2 dissolved in N-butyl-N-methylpyrrolidinium acetate and in 1-butyl-3-methylimidazolium acetate were investigated by DFT calculations in "gas phase". The analysis of predicted multistep pathways allowed calculating energies of reaction and energy barriers of the processes. The major role played by the acetate anion in the degradation of the solutes CS2 and OCS as well as in the capture of OCS and CO2 by the imidazolium ring is highlighted. In both ionic liquids, this anion governs the conversion of CS2 into OCS and of OCS into CO2 through interatomic S-O exchanges between the anion and the solutes with formation of thioacetate anions. In imidazolium acetate, the selective capture of CS2 and OCS by the imidazolium ring competes with the S-O exchanges. From the calculated values of the energy barriers a basicity scale of the anions is proposed. The (13)C NMR chemical shifts of the predicted adducts were calculated and agree well with the experimental observations. It is argued that the scenario issued from the calculated pathways is shown qualitatively to be independent from the functionals and basis set used, constitute a valuable tool in the understanding of chemical reactions taking place in liquid phase.

[Very preterm births in French Polynesia: update and proposal for follow-up]. / La grande prématurité en Polynésie française : évaluation et perspectives de prise en charge.

INTRODUCTION: The care of premature infants in French Polynesia is complicated by this country's geographic isolation. We undertook an evaluation of the medical care of very premature infants (VPIs) to find local solutions to this problem. OBJECTIVES: The objectives were to determine the incidence, mortality, and the short- and long-term outcome of very preterm infants in French Polynesia. METHODS: We retrospectively reviewed the medical charts of all infants born alive at<32 gestational age (GA) and>24 GA from January 2007 to December 2011. Perinatal characteristics and outcomes were examined by univariate and multivariate analysis. RESULTS: In total, 204 VPIs were born during the 5-year study period, comprising 0.9% of all births. Infants less than 28 GA comprised 0.1% of all births. Sixty-two percent of mothers were of extreme age including 43% less than 25 years old. Prematurity was attributed to spontaneous preterm labor in 63% of cases and preeclampsia in 29%. Spontaneous multiple pregnancies comprised 15% of the cases. Alcohol and tobacco consumption were frequently noted (>8% and 26% mothers, respectively). Seventy-eight percent of VPIs had received prenatal steroids. Intrauterine growth was normal in 89%. Mortality occurred in 9.3% (19 patients). Mortality was higher with lower gestational age (P<0.05) and absence of prenatal steroids (P<0.05) in univariate and multivariate analysis. The primary cause of death was sepsis. Hyaline membrane disease occurred in 44% of patients, 80% of whom received surfactant therapy. In total, 16.2% newborns developed bronchodysplasia, 3.4% necrotizing enterocolitis, 3% cerebral hemorrhage, and 1.5% leukomalacia. Long-term outcome was marked by 52% of the patients lost to follow-up by 2 years of age, mostly because of geographic isolation. For the 72 patients followed-up, four developed asthma and three cerebral palsy; 70% were attending school by 3 years of age. CONCLUSIONS: The incidence, mortality, and morbidity of very preterm birth in French Polynesia are comparable to reports from metropolitan centers in France. Conversely, nearly one-half of the patients were lost to follow-up, precluding meaningful information on intellectual development and other outcomes. We recommend organizing a long-term follow-up network to detect cognitive sequelae and adapting such a system to the geographical residence of French Polynesian families.

Prilocaine in arthroscopy: clinical pharmacokinetics and rational use.

Prilocaine pharmacokinetics were determined in 60 patients receiving the drug by two different routes of administration (intra-articular and subcutaneous) during arthroscopy under local anesthesia with controlled pressure irrigation. Resorption of prilocaine by subcutaneous tissues was slow and did not lead to high serum levels. On the contrary, prilocaine resorption by the synovium was fast and induced a sharp serum peak (265.8 +/- 163.5 ng/ml) in the hour after the end of the examination. The drug was completely eliminated from the blood after 24 hours, as the prilocaine t1/2 is about 5 hours. The first procedure was perfected to reduce the risk of methemoglobinemia, which occurred in four of 105 patients. Applied pressure was lowered to 100 mm Hg to prevent the escape of anesthetic solution into the soft tissue of the leg, the prilocaine concentration was reduced to 1 gm/L, and the arthroscope was only set up after a delay to allow the intra-articular anesthetic effect of prilocaine to become established. So far, 200 arthroscopies have been performed with this improved protocol without any problem.

Mechanosensitive ion channels and their mode of activation.

Mechanosensitive channels are ion channels whose activity is dependent on a mechanical stress on the membrane. They are believed to play a central role in mechanotransduction, the process by which mechanical energy is converted into electrical or chemical signals in biological cells. Recent progress, which has been made at the molecular level, is presented, and the two current models of activation of these channels are discussed.

Bacillus Calmette-Guérin infection after vaccination of human immunodeficiency virus-infected children.

The use of Mycobacterium bovis/Bacillus Calmette-Guérin (BCG) to vaccinate against tuberculosis remains controversial. The development of tuberculosis in human immunodeficiency virus (HIV)-infected children demands specific evaluation of the risk/benefit ratio of BCG vaccination in this situation. In our institution 9 of 68 HIV-infected children vaccinated with BCG before the diagnosis of HIV infection was suspected developed vaccine-related complications: 7 of these children had a large satellite adenopathy with or without skin fistulae, whereas the other 2 had disseminated BCG infection beyond the satellite ganglion (involvement of the spleen and mesenteric and mediastinal lymph nodes in one case and the liver and lungs in the other). The children were vaccinated soon after birth; no particular problems were observed at that time, but complications appeared 3 to 35 months later. All but one of these children had a rapidly progressive form of HIV disease. The possibility of delayed local or disseminated BCG infection must be considered in analysis of the risk/benefit ratio of vaccination of HIV-infected children. The prognosis of HIV infection must be taken into account, even if the child is asymptomatic when vaccination is being considered.

Systemic Candida infection in pediatric BM autotransplantation: clinical signs, outcome and prognosis.

Of the 393 children who underwent BM autotransplantation in the pediatric oncology unit of the Institut Gustave Roussy between February 1979 and September 1991, 14 (3.56%) developed disseminated Candida infection within 3 months. This incidence was far lower than in other published series. Eleven of the 14 patients recovered from the infection, giving a far higher survival rate (78%) than among adult BM transplant recipients (usually < 30%). All 14 patients had four or more risk factors and persistent BM aplasia (median, 25 days); six had Candida tropicalis infection. Four cases of deep visceral involvement were documented, two of which were lethal. Clinical signs were relatively uniform and included secondary high-grade fever (> 40 degrees C) for 8 days; half the patients developed cardiovascular impairment, respiratory distress, neurological disturbances (altered consciousness or delirium) and severe diarrhoea, within as little as 10 days after transplantation. Blood cultures rapidly became positive after the onset of clinical signs and this permitted prompt treatment with a combination of amphotericin B and 5-fluorocytosine; in addition, central catheters were removed. Blood cultures became sterile within 4 days of treatment in 10 of the 14 cases. The generally favourable outcome in this series could be related to the young age of the patients, the absence of GVHD, the absence of total body irradiation in the conditioning regimen, and early antifungal treatment.

Stealth PEGylated polycyanoacrylate nanoparticles for intravenous administration and splenic targeting.

The aim of the present work was to investigate the biodistribution characteristics of PEG-coated polycyanoacrylate nanoparticles prepared by the nanoprecipitation/solvent diffusion method using the previously synthesized poly(MePEGcyanoacrylate-hexadecylcyanoacrylate) copolymer. It was observed that [14C]-radiolabeled PEGylated nanoparticles remained for a longer time in the blood circulation after intravenous administration to mice, compared to the non-PEGylated poly(hexadecylcyanoacrylate) (PHDCA) nanoparticles. Furthermore, hepatic accumulation was dramatically reduced, whereas a highly increased spleen uptake was shown. The PEGylation degree of the polymer seemed not to affect the in vivo behavior of the nanoparticles, whereas previously obtained in vitro data have shown a modification of plasma protein adsorption depending on the density of PEG at the surface of the particles. Moreover, the study of the in vitro cytotoxicity of the nanoparticles revealed that the PEGylation of the cyanoacrylate polymer reduced its toxicity. These results open up interesting perspectives for the targeting of drugs to other tissues than the liver.

Diagnostic value of Western blotting in carbohydrate-deficient glycoprotein syndrome.

Carbohydrate-deficient glycoprotein syndrome (CDGS) is a newly recognized family of diseases characterized by the absence from the transferrin molecule of at least one glycan chain (type I) or an antenna of the glycan chain (type II). CDGS is currently diagnosed by studies of serum transferrin sialylation. We have developed an alternative Western blot-based method to detect serum transferrin species with reduced molecular masses due to altered glycosylation. Two additional bands are observed in type I CDGS, while a single lower band is observed in type II CDGS, relative to healthy subjects. N-glycanase treatment of serum from type I CDGS patients and normal subjects yields a single band of the same mass in the two cases, confirming that the glycan is the only moiety involved in the differential Western blot pattern. Similar results were found with serum alpha 1-acid glycoprotein, haptoglobin and alpha 1-antitrypsin. Western-blot analysis of one or more serum glycoproteins permits the differential diagnosis of CDGS.

Compaction of crystallographic forms of pharmaceutical granular lactoses. I. Compressibility.

Physico-chemical properties of a substance including the compaction behaviour are directly connected with the crystalline structure. The aim of this work is to compare the compaction behaviour in a group of excipient and in this first part, to display the influence of lactose structures on the compressibility. alpha-Lactose monohydrate (LalphaM), anhydrous beta-lactose (LbetaA), anhydrous alpha-lactose (LalphaA) and partly amorphous lactose (FF) were compressed using instrumented presses to investigate the densification behaviour under pressure. Force-displacement curves were associated to two energy parameters, specific cycle energy and specific expansion energy. This approach was used to class the four lactose species. It is possible to differentiate three groups with the specific energy cycle, FF, LalphaA/LbetaA and LalphaM in decreasing order of this energy. At the same time, the values of specific expansion energy are relatively low for FF and LalphaA contrary to LalphaM and LbetaA. Then, Heckel's plots were obtained with two compact geometries and the mean yield pressure was calculated from the in-die-method and the out-of-die-method. Two lactoses seem to differ, LalphaM appears to be the most ductile whereas LalphaA is more brittle than the others. Finally, it is concluded, that in the case of lactoses, pseudopolymorphism seems to affect the compressibility more than anomerisation or partial amorphisation.

Biodegradable microparticles for the controlled delivery of oligonucleotides.

Microspheres allowing the controlled release of the model oligonucleotide pdT16 were designed. The oligonucleotide, alone or associated with polyethylenimine (PEI) at different nitrogen/phosphate ratios, was encapsulated within poly(lactide-co-glycolide) microspheres prepared by the multiple emulsion-solvent evaporation technique. The introduction of PEI in the internal aqueous phase resulted in a strong increase of the oligonucleotide encapsulation efficiency. PEI affected also microsphere morphology inducing the formation of very porous particles and yielding to an accelerated release of pdT16. However, when incubated with HeLa cells, microspheres encapsulating pdT16/PEI complexes allowed an improvement of the intracellular penetration of the released oligonucleotide. The developed strategy appears to be a very interesting tool to obtain a sustained release system for oligonucleotides with an efficient cellular delivery.