Summary version of the Standards, Options and Recommendations for the use of analgesia for the treatment of nociceptive pain in adults with cancer (update 2002).
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Adult↗
Biomedical subjects
R Duclos
Publications and source records attributed to R Duclos.
Progesterone freeze-dried systems in sublingual dosage form.
Various polymer matrices were tested to enhance progesterone bioavailability as part of an emergency therapy. Among the different polymers used, i.e. poly(N-vinylpyrrolidone) (PVP), poly(ethylene oxide) (PEO), Dextran T70 and partially saponified poly(methyl glyoxylate) (PMGz), the latter gives the fastest solubilization rate. The best results were obtained with the lyophilized dosage form instead of a simple mixture of the drug within the polymer matrix. A nearly instantaneous solubilization was observed with PMGz copolymers bearing 10-40% of carboxylic groups and containing up to 20% of the drug. The instantaneous solubilization of the PMGz matrix is due to the hydrophilic moieties, and the presence of hydrophobic zones in PMGz promotes good affinity with the drug and optimal dispersion into the matrix.
Administration, Sublingual↗
Stability assessment of ketoconazole in aqueous formulations.
Ketoconazole is an imidazole antifungal agent. It has a wide antifungal spectrum and possesses some antibacterial activity. In inappropriate formulations, especially in aqueous media, ketoconazole molecules may be unsteady. The stability of ketoconazole in aqueous media was assessed as a function of pH, antioxidant and ketoconazole concentrations. It was found that ketoconazole was least stable at pH 1 among the pH values studied (pH 1-9). Since the major degradation pathway was specific acid catalysis, based upon the transition-state theory, the entropy (DeltaS) of the activation was calculated and found to be negative indicating that the activated complex was more constrained than the individual species. The free energy of activation (DeltaG) was estimated to be 30 kcal mol(-1). The viscosity of the formulation was found to be more stable at high pH because carbopol is stable at basic pH and protected ketoconazole. It appears that the amount of ketoconazole in the formulation has a low influence on the degradation mechanisms. The increase of the butylated hydroxytoluene antioxidant levels from 0.05 to 0.4%, adversely affected the stability of ketoconazole. In conclusion, the expected shelf life of the final ketoconazole formulation (pH 7, 0.1% butylated hydroxytoluene) was 15 months.
Antifungal Agents↗
Rheology of polyol behenates and drug release from matrix monolithic capsules.
Three polyol behenates with similar melting points (MP) and different hydrophilic-lipophilic balances (HLB) were studied (MP/HLB: 70/02, 63/05 and 57/13). After melting at MP+30 degrees C, the rheological behaviour of behenates was determined by adjustment of the rheograms to the Ostwald power-law and by statistical assessment of the flow index. Behenates showed slight shear thickening. This shear thickening increased when HLB of behenates decreased. This behaviour accounted for a reorganization of the particles under the shear, which became easier when the proportion of the polyethylene glycol chains in the wax decreased. Proxyphylline was used to prepare suspensions at a concentration of 25% in the melted behenates, and to manufacture monolithic capsules by cooling. The suspensions had a shear-thinning behaviour with or without thixotropy. Colloidal particles and aggregates formed in these suspensions directly influenced the rheological properties, as observation of solidified suspensions by scanning electron microscopy confirmed. Extended release of proxyphylline was obtained with the three waxes. Behenates 63/05 and 70/02 gave inert matrices and released drug very slowly. Hydrodispersible behenate 57/13 swelled and made up a kind of hydrophilic matrix that released proxyphylline more quickly, due to slight erosion. In the three cases, the release mechanism was basically diffusional in nature.
Aminophylline↗
Rheological behavior of drug suspensions in Gelucire mixtures and proxyphylline release from matrix hard gelatin capsules.
Mixtures of Gelucires 50/02 and 50/13 showing different hydrophilic-lipophilic balances (HLB) and of proxyphylline were used to prepare suspensions at a concentration of 25% and to manufacture extended release hard gelatin capsules by cooling. The rheological behaviors of Gelucire mixtures with and without drug were determined by adjustment of the rheograms to the Ostwald power-law and by statistical assessment of the flow index. Pure Gelucire mixtures were very slightly shear thickening whereas proxyphylline suspensions had a thixotropic shear thinning behavior. These rheological behaviors can be explained by the chemical composition and by the ratio of the two Gelucires used. Extended release of proxyphylline was obtained with all these mixtures. Drug release increased with Gelucire mixture HLB owing to higher erosion. A viscosity-release relationship was found and allowed, with these two Gelucires of extreme HLB and viscosities, to define the formulations which will give an optimal drug release, by the determination of their suspension viscosity. Modeling of dissolution kinetics has generally shown the predominance of surface erosion of the plugs relative to drug diffusion inside the matrix. This was confirmed by the better linearization of percentage released, according to Hixson-Crowell as compared with Higuchi.
Aminophylline↗
Comparison of oral bioavailability of two dosage-forms of progesterone in women.
For poorly water soluble drugs, the dissolution process in biological fluids the rate limiting step in absorption. However, the utilization of some galenic processes such as solid dispersions (SD) leads to an improvement in quality and intensity of the drug gastro-intestinal absorption. In a previous work, the in vitro studies of the dissolution curves of both the pure micronized progesterone (MP) and the progesterone-PEG 6000 SD revealed marked increases in the progesterone dissolution rates for all the SD investigated compared to the pure MP. The aim of this work was to investigate the in vitro results after oral administration of the two pharmaceutical forms to menopaused volunteer women.
Administration, Oral↗
Increase of uterine motility and simultaneous decrease of progesterone concentrations in the rat after bilateral ovariectomy at mid-pregnancy.
Comparison of uterine activities recorded during the control period to those obtained during the two recording periods after ovariectomy (0-30 min and 30-60 min) showed an increase of the amplitude of uterine contractions (P less than 0.005) and a decrease of the interval between two successive uterine contractions (P less than 0.005) and the delay of electrical activities (P less than 0.005). Progesterone treatment (50 mg/kg i.m.) of ovariectomized rats prevented the abrupt fall in plasma progesterone concentrations, measured by RIA, which in turn inhibited the increase of uterine mechanical and electrical activities. A close relation between the increase of myometrial activity and the decrease of progesterone concentrations after ovariectomy is suggested. The activation of the myometrium would be principally induced by the fall of progesterone or by the variation of the oestrogen/progesterone ratio; these changes in sexual steroid hormones would augment the uterine sensitivity to physiological stimuli or modify the activity of other factors involved in the regulation of the myometrium.
Animals↗
Variation of myometrial activities and steroid sexual hormones following bilateral ovariectomy in the rat at midpregnancy.
The effects of bilateral ovariectomy on uterine motility and levels of progesterone, oestradiol, cAMP, adrenaline and PGF2 alpha were studied in the rat at midpregnancy. Animals were randomly divided into two groups, at least 15 rats in each, sham-operated serving as controls and ovariectomized. The spontaneous uterine mechanical activity of Wistar rats was recorded isometrically and the electrical activities were recorded simultaneously by two bipolar electrodes. Within 30 minutes of ovariectomy a significant increase of the amplitude of uterine contractions was observed and the simultaneity of electrical activity was significantly improved; these effects became more pronounced at 1h post-ovariectomy (p less than 0.005). Plasma progesterone levels decreased by 20% (p less than 0.01) at 30 min and by 50% (p less than 0.001) 1h after ovariectomy, whereas oestrogen levels remained unchanged. Levels of adrenaline, cAMP and PGF2 alpha in the uterine tissue 1h following ovariectomy were affected as follows: adrenaline (p less than 0.05) and cAMP (p less than 0.001) were reduced and PGF2 alpha augmented (p less than 0.05). It appears that variation of the ratio oestrogens/progesterone induces precociously the activation of uterine mobility and exerts an effect on some factors involved in the regulation of the rat myometrium at midpregnancy.
Animals↗
[Overload histiocytosis in 2 hemodialyzed patients. Possible role of dextran 40].
The authors report two cases of singular overloading histiocytosis, observed in patients treated with regular dialysis and undergoing feverish cachectic disease. The observations of the two patients show a same histiocytosis infiltration of ganglions, liver, muscles, lung, pleura and pericardium, consisting in an accumulation of PAS positive intracytoplasmic substance, refringent at polarisation, microcrystalline on electron microscopy and on ionic analysis. Clinical likeness appears with PVP thesaurismosis but the histochemical findings are different. A favorable issue occurred with corticosteroïd treatment. Nature of PAS positive substance is uncertain. An exogenous origin is undoubted, and some elements call for the responsibility of dextran 40.
Adult↗