Structural and electronic comparative analysis of aminopyridazines showing anti-GABA activity. Crystal structure of 2-(carboxy-3′-propyl)-3-amino-6-cyclohexylpyridazinium bromide.Ab initio Mulliken population analysis of the 6-phenyl-substituted analog compared to GABA

The crystal structure of 2-(carboxy-3-propyl)-3-amino-6-cyclohexylpyridazinium bromide has been determined by single-crystal X-ray diffraction techniques and refined by full-matrix least squares. The compound crystallized in the tri-clinic space groupP ¯1 witha=10.275(1),b=11.215(1),c=7.082(1) Å,=91.84(1),=102.21(1), =106.77(1)°, andZ=2. FinalR-factor is 0.045. The main structural results are very similar to the ones observed for the 6-phenyl analog. These two compounds are GABA-A antagonists.Ab initio molecular orbital calculations, with STO-3G and 4-31G basis sets, suggest that the exocyclic nitrogen accurately mimics the nitrogen atom of GABA.     

Determination of albendazole and its main metabolites in ovine plasma by liquid chromatography with dialysis as an integrated sample preparation technique

Albendazole is a benzimidazole derivative with a broad-spectrum activity against human and animal helminth parasites. In order to determine the main pharmacokinetic parameters in sheep after oral and intravenous administration of a new formulation of albendazole (an aqueous solution), a fully automated method was developed for the determination of this drug and its main metabolites, albendazole sulfoxide (active metabolite) and sulfone in ovine plasma. This method involves dialysis as purification step, followed by enrichment of the dialysate on a precolumn and liquid chromatography (LC). All sample handling operations were executed automatically by means of an ASTED XL system. After conditioning of the trace enrichment column (TEC) packed with octadecyl silica with pH 6.0 phosphate buffer containing sodium azide, the plasma sample, in which a protein releasing reagent (1 M HCl) containing Triton X-100 was automatically added, was loaded in the donor channel and dialysed on a cellulose acetate membrane in the static-pulsed mode. The dialysis liquid consisted of pH 2.5 phosphate buffer. By rotation of a switching valve, the analytes were eluted from the TEC in the back-flush mode by the LC mobile phase and transferred to the analytical column, packed with octyl silica. The chromatographic separation was performed at 35°C and the analytes were monitored photometrically at 295 nm. Due to the differences in hydrophobic character between albendazole and its metabolites, a gradient elution was applied. The mobile phase consisted of a mixture of acetonitrile and pH 6.0 phosphate buffer. The proportion of organic modifier was increased from 10.0 to 50.1% in 12.30 min, then from 50.1 to 66.9% in 1.70 min. First, the gradient conditions and the temperature were optimised for the LC separation using the DryLab software. Then, the influence of some parameters of the dialysis process on analyte recovery was investigated. Finally, the method developed was validated. The mean recoveries for albendazole and its metabolites were about 70 and 65%, respectively. The limits of quantification for albendazole and its metabolites were 10 and 7.5 ng/ml, respectively.     

Contribution of cyclodextrins in the development of different pharmaceutical formulations of a new matrix metalloproteinase inhibitor

Ro 28-2653 is a new synthetic inhibitor of matrix metalloproteinases. The ability of these enzymes to degrade various components of the extracellular matrix seems to play a major role in tumors progression and is potentially effective against bronchial remodeling in asthma and BPCO. Ro 28-2653 is very poorly soluble in water. This low solubility estimated at about 0.56 μg/ml in water at 25 °C gives rise to difficulties in pharmaceutical formulation of oral, injectable or nebulizable solutions. The purpose of our study is to prepare and to characterize inclusion complexes between Ro 28-2653 and cyclodextrins and to investigate the biopharmaceutical repercussion of the inclusion of the active substance. The complex formation was investigated by phase solubility studies. ¹H-NMR spectroscopy and molecular modeling studies were carried out to elucidate the structure of the inclusion complex between Ro 28-2653 and cyclodextrin. Oral, intravenous and nebulizable solutions of Ro 28-2653 were developed with cyclodextrin. The in vivo studies were performed on healthy sheep for the pharmacokinetic evaluation of the oral and intravenous formulations while the nebulization of the complex solution was studied by using an asthma model in mouse.     

In vivo Laser-induced Fluorescence Imaging of a Rat Pancreatic Cancer with Pheophorbide-a

Laser-induced fluorescence (LIF) of pheophorbide-a (Ph-a) was used for imaging of a rat pancreatic tumor. Using a dimensionless function (the ratio of Ph-a fluorescence by bluish autofluorescence), the fluorescence contrasts between excised tumors and their paired pancreas were investigated up to 48 h after a 9 mg kg^-1 Ph-a intravenous administration. Among five tested excitation wavelengths, 355 and 610 nm excitations gave the best distinctive contrasts, both 48 h after dye injection. The LIF imaging of six intrapancreatic tumors and six healthy pancreas was carried out in vivo using two laser excitations: 355 nm (Nd:YAG + tripling) for bluish autofluorescence and 610 nm (rhodamine 6G dye) for reddish autofluorescence and dye emission. Images were recorded through bandpass filters at 470 and 640 nm (autofluorescence) and at 680 nm (dye + autofluorescence) with an intensified charged-coupled device camera. Autofluorescence as Ph-a fluorescence images did not allow accurate LIF diagnosis of pancreatic carcinoma. An image processing, including for each pixel a computed division of Ph-a fluorescence (after subtraction of reddish autofluorescence) by bluish autofluorescence intensity generated poorly contrasted tumor images in five of six and false tumor localization in one of three of the tumor-bearing pancreas. A fitting of the digital 640 nm autofluorescence up to the mean 680 nm fluorescence intensity in pancreas prior to subtraction allowed a safe diagnosis to be made with well-contrasted tumor images. To assess automation ability of the processing, a same fitting coefficient (mean of individual values) was applied. In this way, false-negative (one of six) and false-positive (two of six) images were present in tumor-bearing animals as false-positive in one-half of the controls. A successful standardized procedure was then applied with a normalization of 640 and 680 nm pancreas intensities to a same set threshold prior processing. In opposition to thin-layered hollow organs, such as bronchial tube or digestive tract, LIF imaging of carcinoma inserted in a compact organ is exhausting. The use of a dye excitable in the red wavelength range (610 nm for Ph-a) may partly solve this problem, rendering LIF imaging more accurate and potentially automated.     

Inclusion Complexes of Cyproterone Acetate with Cyclodextrins in Aqueous Solution

Cyproterone acetate (CPA) is a steroidal antiandrogen with a progestogenic activity. Given that this molecule has a very poor water solubility (2.1 g/mL), different cyclodextrins (CDs) were tested to form inclusion complexes and to increase solubility. Two different techniques were compared to study the affinity between CPA and CDs: phase-solubility studies and NMR spectroscopy. The stoichiometry and the stability constant could be determined for most complexes with the aid of phase-solubility studies. The greatest increase in solubility was achieved with the methylated -CDs, but hydroxypropylated - and -CDs also gave enhanced solubilities. ¹H-NMR studies showed a solubility increase similar to that found with phase-solubility studies. The proof of inclusion in the2,6-dimethyl--CD (DIMEB) was shown by ¹H-NMR and t-ROESY spectra.     

X-ray crystal structures of three nonbenzodiazepinic ligands for the benzodiazepine receptor sites: SR95926, CMW1842, and L16317:nab initio MO study of the electronic properties

The crystal structures ofp-methoxyphenyl-3-triazolo [4,3-a] isoquinoline (SR95926),p-methoxyphenyl-3-triazolophtalazine (CMW1842), andp-methoxyphenyl-3-N-dimethoxyethylamino-6-triazolophtalazine (L16317) have been solved by direct methods from single-crystal X-ray diffraction data, and refined by full-matrix least squares. SR95926: monoclinic,P2₁/n,a=20.950(3),b=6.769(1),c=9.465(2) Å,=100.90(1)°. CMW1842: triclinic,P¯1,a=8.784(1),b=9.160(4),c=8.555(1) Å,=99.10(2),=93.90(1), =106.77(1)°. L16317: monoclinic,P2₁/_n,a=20.124(3),b=9.586(1),c=10.788(1) Å,=91.91(1)°. FinalR factors are 0.034, 0.037, and 0.053, respectively. Experimental geometries were used to perform STO-3Gab initio molecular-orbital calculations. A relationship between the electronic pattern within the molecules and the affinity of the benzodiazepine receptor sites is pointed out.     

Reduction electrochimique des oxydes de fer: Confrontation des caracteristiques electrochimiques et crist allographiques

Electrochemical properties of iron oxides, crystallographic data and examination of etching pits by scanning electron microscopy, suggest that ferric iron has electrochemical reactivity which differs according to its crystallographic position in the solid.     

Experimental and theoretical investigations of the electrical properties of undoped and magnesium-doped GaN layers

The ac characteristics of GaN : Mg and undoped GaN layers, grown by MOVPE on sapphire substrates, are measured for a wide range of temperature and bias conditions, in order to investigate the effect of the magnesium-related level on the transport properties. Two peaks, whose height and position depend on the measurement temperature, are observed in the admittance curves (G/ω versus frequency) of the Mg-doped samples, whereas only one peak appears in undoped samples. The study of the frequency dependence of the impedance, with a model including the two metallic Au/GaN junctions, the GaN layer itself, shows that, besides the effect of the differential resistance of the layer which plays a role in both sample types, the presence of a Mg-related deep level contributes to the observed variations of the peaks in the admittance curves of the p-doped samples. Results of a theoretical steady-state and small-signal analysis based on numerical modelling of the Au/GaN/Au heterostructure complete our analysis.