Pharmaceutica acta Helvetiae最新文献

The flavonoids, naringin and naringenin and the furanocoumarin, bergapten (5-methoxypsoralen), were detected in some fresh grapefruit and commercial grapefruit juices but were not detected in other fruit juices tested (orange; orange with apple base; dark grape; orange and mango with apple base; orange, peach, passion fruit juice). The contents of these three grapefruit constituents in commercial juice and fresh grapefruit varied from brand to brand and also from lot to lot. Juice was prepared from the fresh fruit via different methods (by hand, squeezer or blender). The naringin content, after hand-squeeze, ranged from 115 to 384 mg/l. With hand-squeeze juice production, bergapten was not detected (less than 0.5 mg/l) in two varieties of grapefruit, and naringenin was usually not in detectable levels (less than 2 mg/l) in three varieties. All three constituents were present in New Zealand grapefruit preparations (including juice by hand-squeeze) and different lots showed variation in content (1.5-, 2.3- and 4.7-fold for naringin, naringenin and bergapten, respectively). Differences in the concentrations of these three constituents, which have potential for drug interaction, may contribute to the variability in pharmacokinetics of CYP3A4 drugs and some contradictory results of drug interaction studies with grapefruit juice.

Inclusion complexes of gliclazide with β-cyclodextrin were prepared using different two methods: neutralization and recrysstalization. Host–guest interactions were studied in the solid state by X-ray diffractometry and infrared spectroscopy. The stability constant between gliclazide and β-cyclodextrin was calculated from the phase solubility diagram. It was found that the neutralization technique and a solid complex of gliclazide with β-cyclodextrin in a molar ratio of 1.5:1 could be used to prepare the amorphous state of drug inclusion complexes. The dissolution rates of gliclazide from the inclusion complex made by neutralization was much faster than the pure drug, physical mixture of drug and cyclodextrin, recyristalization system and also comparable to the data reported in literature. Results of this report indicate that β-cyclodextrin could be useful for the solid gliclazide formulations as it may results in a more rapid and uniform release of the drug.

Accelerated stability testing was performed on aspirin–magaldrate double layer tablets as well as aspirin–maalox marketed double layer tablets (Ascriptin®) in order to evaluate the effect of the presence of the alkaline moieties of the antacid (magaldrate and maalox) on the chemical stability of aspirin. The results were compared simultaneously with that obtained from the marketed Aspro® plain tablets. The results revealed that the presence of the alkaline moieties in the tested tablets has increased the rate of aspirin decomposition and reduced its shelf-life. This effect was more pronounced for aspirin tablets containing magaldrate antacid. Determination of shelf-lives at 25°C for the prepared and the marketed tablets was carried out using Arrhenius plots and the results showed that they were 35, 34.5 and 13.5 months for Aspro®, Ascriptin® and aspirin–magaldrate double layer tablets, respectively. The effect of storage for 50 days and at different temperatures, on the crushing strength and the disintegration time of the prepared and the marketed tablets showed a slight decrease in the disintegration time and the crushing strength of the tablets as the storage temperature increased. Aspro® tablets did not produce the same results. The in vitro release data of the prepared aspirin–magaldrate double layer tablets and the marketed Ascriptin® tablets stored for 50 days and at different storage temperatures as well as Aspro® tablets stored at 70°C were best fitted to the first-order kinetics model. The release data of Aspro® tablets stored at 50 and 60°C for 50 days were best fitted to Higuchi's model.

To improve the targeting efficiency of liposomes of indomethacin to the arthritic joints, circulation half-life of the liposomes was increased by grafting amphipathic polyethylene glycol-2000 to the bilayer surface. A comparative biodistribution study was performed between the conventional liposomes (PC:CH:PE — 1:0.5:0.16) and long-circulating liposomes (PC:CH:PE-PEG — 1:0.5:0.16) in arthritic rats. Pharmocokinetics of the drug changed significantly when administered in liposomal form. Pharmacokinetic parameters of the drug such as AUC_0-t (trapezoidal), clearance and t_1/2 (elimination half-life) changed significantly (p<0.05) when encapsulated in liposomes. Significant difference in pharmacokinetics was observed in AUC_0-t and clearance between the conventional liposomes and long-circulating liposomes. The increased AUC_0-t and reduced clearance of the durg with long-circulating liposomes, increased the availability of the drug by reducing RES uptake, in turn localization in arthritic paw tissue was also increased. A concentration of 0.33 μg of indomethacin/g of the tissue was achieved with S-liposomes after 24 h whereas it was only 0.26 μg of drug/g of the tissue with conventional liposomes. From the study, in may be concluded that the targeting efficiency of the long-circulating liposomes was about four times more than the conventional liposomes.

The contents of three quaternary alkaloids (berberine, palmatine, jatrorrhizine) in different parts of some plants of the genus Mahonia were determined by high-performance capillary electrophoresis (HPCE). The background electrolyte system composed of 0.1 M phosphate buffer (pH 7.0)–methanol (2:1 V/V) was found to be the most suitable solution for this separation. Brucine was used as internal standard. The linear calibration ranges were 0.004986–0.4986 mg ml⁻¹ (r=0.9990, n=5) for berberine, 0.005049–0.5049 mg ml⁻¹ (r=0.9996, n=5) for palmatine, and 0.005058–0.5058 mg ml⁻¹ (r=0.9984, n=5) for jatrorrhizine. The relative standard deviations were 1.56%, 1.02%, and 1.60% for berberine, palmatine, and jatrorrhizine (n=6), respectively. The recoveries were determined to be 96.00–101.66% for berberine, 100.15–102.97% for palmatine, and 96.68–102.44% for jatrorrhizine. By using proposed HPCE method, three alkaloids were well-separated within only 5.0 min.

Mannich bases of acetophenones have been disclosed to have antitumour and cytotoxic activities. 1-Phenyl-3-dimethylaminopropan-1-one hydrochloride, 1, and related piperidino, 2, and morpholino, 3, derivatives, and compound 4, which is a quaternary form of 1, were synthesized as mono Mannich bases derived from acetophenone. They were converted to corresponding bis Mannich bases, 5–8, to see whether it increases the bioactivity. The biological activity of the compounds was examined by cytotoxicity against mouse renal carcinoma (Renca) and transformed human T-lymphocyte (Jurkat) cell lines. Conversion of mono Mannich bases to corresponding bis Mannich bases remarkably increased the cytotoxicity in most cases. Quaternization procedure also improved the bioactivity in mono derivatives against Jurkat cells. Bis mannich bases 5–7 were found to be more active than 5-fluorouracil (6–23 fold) and melphalan (1.25–5 fold) against Renca cells. Except 2 and 8, the compounds synthesised were found to be more active than 5-fluorouracil (1.2–33 fold) against Jurkat cells.

The permeabilities of thyrotropin-releasing hormone (TRH) and insulin as model peptides were examined to characterize the tracheal epithelial barrier in in vitro experiments using excised rabbit trachea. TRH was not metabolized during 150 min duration of tracheal permeation and the apparent permeability coefficient (P_app) for TRH was about 3×10⁻⁷ cm/s. The tracheal permeability of TRH was increased about three times by 10 mM glycocholate as a permeation enhancer. Insulin showed a slight degradation during 150 min duration of tracheal permeation, the P_app for insulin was 7×10⁻⁹ cm/s. The tracheal permeability of insulin was significantly increased by 10 mM glycocholate, 1 mM bestatin (aminopeptidase B and leucine aminopeptidase inhibitor), and 10 000 KIU/ml aprotinin (trypsin and chymotrypsin inhibitor). The peptidase activities of rabbit tracheal epithelium were found to be the following; di-peptidyl-aminopeptidase IV (DPP IV)>Leu-aminopeptidase>cathepsin-B>trypsin. These activities were significantly lower than those of jejunal mucosal tissues. These results suggest that the tracheal absorption of peptide drugs through the respiratory tract may contribute to the systemic delivery of these drugs following the pulmonary administration of these drugs by intratracheal insufflation and instillation.

A correlation between the structure and lipophilicity has been carried out within the homologous members of two series of aliphatic bis(amides) and lipoamino acid conjugates of the anticancer drug methotrexate. Basing on their reversed-phase HPLC behaviour, the values of the experimental parameter R_Q, obtained by using different mobile phases with increasing concentration of acetonitrile, were considered as a parameter of lipophilicity of the tested compounds. A comparison with their calculated logPwas also performed.

A highly sensitive spectrofluorimetric procedure is developed for the analysis of certain 4-quinolone antibiotics: sparfloxacin (I), oxolonic acid (II), flumequine (III) and enrofloxacin (IV) in their pharmaceutical dosage forms or in biological fluids. This procedure is based upon the intrinsic fluorescence in acetonitrile for sparfloxacin or upon the highly enhanced fluorescence obtained by the interaction of the drugs with AlCl₃. The optimum pH for the maximum fluorescence intensity is 8–8.5 for I, 5–6 for II, III and pH 3.5 for IV. The different experimental parameters that affect the fluorescence intensity were carefully studied and incorporated into the procedure.