Biomedical subjects
Publications and source records attributed to E Touitou.
A bacterial virus, suspended in three different vehicles, was introduced into the rectum of rabbits. The virus was detected in the circulating blood as early as 10 min after the administration. The quantity of virus found in blood and the duration of its presence, were enhanced when a non-ionic surfactant was used as vehicle of the virus.
Experiments performed in vitro with tablets and capsules indicate that the fungal polysaccharide scleroglucan is suitable for the formulation of sustained-release, oral dosage forms. Delivery of model drugs from the non-disintegrating matrix was studied in solutions buffered at different pH values. The effect on drug release of drug concentration, the physico-chemical properties of the drug, and the compression force used in the preparation of the matrix are reported, and the possible mechanisms of release are discussed.
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The in vitro skin permeation behaviour of idoxuridine (IDU) from a new preparation containing glycyrrhizin gel as carrier was tested and compared with that from a commercial IDU ointment (Virusan) at two temperatures on intact and stripped skin. At 34 degrees C the normalized flux (Fn) values were six times higher for the IDU glycyrrhizin gel than for Virusan when tested on intact hairless mouse skin. At 25 degrees C, Fn values were 22 and 25 times greater for the gel formulation using intact and stripped skin, respectively. These in vitro results, showing that IDU penetrates the skin more effectively when incorporated in the glycyrrhizin gel than in the ointment, correlate well with the previously reported efficacy of the gel tested in vivo.
We examined the effect of n-decylmethyl sulfoxide (n-decylMSO) on the resistance of the optic nerve sheath to the penetration of lidocaine hydrochloride. Three series of experiments were carried out in living cats, administering lidocaine with and without n-decylMSO. The visual evoked potential (VEP) and optic nerve response (ONR) were measured. The results obtained indicated that n-decylMSO increased the penetration of lidocaine. The presence of lidocaine (1%) and n-decylMSO (2.5%) decreased the ONR amplitude from 120 to 15 microV after a time lag of 105 min, and VEP decreased from 9.0 to 5.5 microV. This effect was preserved during the experiment. Histological examination showed only minimal changes in the optic nerve and the eye globe and its contents. Some infiltration of mononuclear cells was found around the optic nerve sheath.
The effect of sodium salicylate on the concentration-dependent self-association of insulin and 6-carboxyfluorescein (CF), as expressed by metachromasy, fluorescence, and changes in aqueous solubility, was learned. By decreasing the CF concentration from 12 to 0.48 microgram.ml-1, lambda max peaks shift from the shorter wavelengths (451, 474 nm), indicating the presence of oligomers, toward the monomer wavelength region (484 nm). Sodium salicylate shifts the peaks of a 12 micrograms.mL-1 CF solution towards the monomer region, eliminating the peak at the lower wavelengths and generating a spectrum with one peak at 490 nm, the effect being concentration dependent. The fluorescence of insulin and CF solutions increases with their concentration. Quenching of these solutions was observed, up to complete elimination of fluorescence, when various concentrations of salicylate were added. The water solubility of both molecules, CF and insulin, was considerably increased with the addition of increasing concentrations of salicylate to the solutions: at 37 degrees C, 2.5 M sodium salicylate solution increases the CF solubility 532 times from 12.2 to 6.5 mg.mL-1, and 1.5 M salicylate increases the solubility of insulin 7875 times, thus an aqueous solution containing 630 mg.mL-1 of insulin may be prepared. The results obtained here, together with our previously reported data, indicate that the interference between sodium salicylate and drug self-association behavior, by increasing drug solubility, may substantially contribute to the improved drug bioavailability mediated by salicylate.
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Sodium salicylate improves the rectal absorption of drugs which exhibit molecular self-association; it is suggested that salicylate may improve drug bioavailability by altering the drug self-association pattern. Methylene blue was chosen as a model molecule for investigating the interference of salicylate with drugs undergoing self-association. The effect of sodium salicylate on the concentration-dependent association of methylene blue as expressed by metachromasy was observed and compared with the effects of other additives: urea, sodium chloride, sodium acetate, sodium sulfate, and sodium benzoate. By increasing the methylene blue concentration from 10(-5) M to 2 X 10(-3) M, the lambda max peak shifts from the longer wavelength region (approximately 660 nm) of the monomer toward the shorter (approximately 600 nm) indicating the presence of dimers and other oligomers. Addition of increased concentrations of sodium salicylate had a deaggregative effect on a 10(-3) M methylene blue solution, shifting the peaks toward the monomer region. On the other hand, the addition of 0.5 M of any of the following salts: sulfate, acetate, or chloride, to a 10(-3) M, aqueous solution of methylene blue had the opposite effect, eliminating the lambda max peak at 660 nm and generating a spectrum with one peak at approximately 600 nm, which indicated a high degree of self-association. The sodium salicylate effect is concentration dependent, with a high excess (approximately 450 times on a molar scale) being necessary to reduce the self-association. At lower concentrations of salicylate, precipitation occurs in the system.(ABSTRACT TRUNCATED AT 250 WORDS)
This study was undertaken to compare the bioavailability and the in vitro release rates of theophylline from suppositories containing either theophylline or aminophylline. The absorption of theophylline from solution and from freshly prepared suppositories formulated with Suppocire and containing anhydrous theophylline 250 mg or aminophylline 300 mg was investigated in six healthy volunteers in a blind crossover design experiment. Venous blood samples were collected before drug administration and at 1, 2, 4, 6 and 8 h afterwards. Theophylline serum levels were measured spectrophotometrically. The pharmacokinetic parameters obtained: Cmax 6.7 and 5.4 micrograms ml-1, tmax 2 h, and F8h 0.79 and 0.83 for theophylline and aminophylline, respectively, show that the two formulations are almost bioequivalent, with a slightly higher Cmax for theophylline. The in vitro release rate of theophylline from freshly prepared formulations was, however, higher (4.8 mg min-1) from aminophylline suppositories relative to those containing theophylline (2.9 mg min-1). This lack of correlation between the in vitro and in vivo results is explained by the different drug thermodynamic activities in the processes of release and membrane penetration. Thus, a better water-solubility does not automatically point to a better rectal bioavailability. The release rate of aminophylline suppositories tested after 1-year storage at room temperature dropped from 4.8 to 0.5 mg min-1. The bioequivalence of theophylline and aminophylline freshly prepared suppositories and the stability problems associated with fatty-base aminophylline suppositories indicate that the choice of ethylenediamine derivative of theophylline is an empirical development, theoretically unjustified, and must be replaced by theophylline reformulations.
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Insulin injected intra-jejunally together with the non-ionic surfactant cetomacrogol was effective in streptozocin-induced diabetes in the rat, as measured by the hypoglycaemic effect. The reduction in blood sugar was maximal at about 2 h after administration but continued at a high level for the 4 h of the experiment. No hypoglycaemic effect was observed in controls injected with insulin or saline alone. Intestinal absorption of insulin has thus been effected by the addition of cetomacrogol, which appears to enhance membrane-permeability to insulin rather than to function as a protective agent preventing insulin degradation, as in liposome-encapsulation. In support of this, a significant hypoglycaemic action was still obtained when the insulin injection was given half-hour after that of the cetomacrogol, both intra-jejunally. Furthermore, oral administration of the surfactant followed by intra-jejunal injection of the insulin also gave a hypoglycaemic effect. The use of this agent to enhance insulin absorption offers the possibility of a new approach to oral insulin therapy.
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Dissolution rates of salicylamide in water and caffeine solutions under perfect sink conditions were predicted by theoretical diffusion equations applicable to dissolution in complexing media. Experimental dissolution rates were measured using a compartmentalized rotating-basket apparatus under two sets of conditions. Agreement was found between experimental and predicted rates. Use of the theoretical equation for estimating dissolution rates involves simple calculations of diffusion coefficients and diffusion layer thickness under the operative dissolution conditions. The increase in dissolution rate caused by addition of the complexant can be calculated for diffusion-controlled dissolution directly if the stability constant and the drug solubility in water are known or measured.
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The dissolution rate of compressed salicylamide discs has been measured in water and in caffeine solutions of increasing concentration at 15, 25, 37 and 45 degrees in an apparatus rotating at 48 rev min-1 or more. Dissolution rate profiles showed breaks indicative of a shift in the mechanism of dissolution from interfacial towards transport control. The shifts occurred at higher caffeine concentrations on increasing the agitation rate or temperature. The dependencies of dissolution rates on agitation rates typified the intermediate type of dissolution and Arrhenius plots indicated that interfacial and transport processes participated in salicylamide dissolution.
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The stability constants for formation of complexes of salicylamide with caffeine have been measured between 15 and 45degrees, by means of the solubility method. There was a linear solubility increase at all temperatures but phase diagrams indicated that at 15 and 25degrees an additional phase was formed which was found to be an insoluble 1 : 1 complex. The enthalpies and entropies of interactions were evaluated. They indicate that the interaction is exothermic and enthalpy controlled.