Acta pharmaceutica Nordica最新文献

The kinetics and mechanism of hydrolysis of 1,3-benzoxazine-2,4-dione and its N-methyl and N-benzoyl derivatives were studied in aqueous solution to provide basic information on the reactivity of the benzoxazinedione structure and to assess the potential of unsubstituted 1,3-benzoxazine-2,4-dione as a prodrug for salicylamide. The compounds were found to hydrolyze quantitatively to the parent salicylamide. The pH-rate profiles obtained at pH 1-11 were accounted for by a spontaneous or water-catalyzed reaction which predominated at pH 1-4 and a hydroxide ion-catalyzed reaction. The rates of hydrolysis were catalyzed slightly in the presence of human plasma and rat liver homogenate, the exception being the N-benzoyl derivative which was hydrolyzed very fast in plasma solutions to N-benzoylsalicylamide. The aqueous solubility and lipophilicity characteristics of 1,3-benzoxazine-2,4-dione were determined. The results obtained suggest that the latter may function as a prodrug for salicylamide with the potential of depressing the extensive first-pass metabolism of salicylamide following oral or rectal administration.

A labile intermediate in the photolytic rearrangement of the antibacterial drug tinidazole was isolated after photolysis of the drug in acetone. The intermediate was identified through structural studies as 1-[2-(ethylsulphonyl)ethyl]-2-methyl-4-hydroxyimino-5-oxo-im idazole. A second product was identified as N-[2-(ethylsulphonyl)ethyl]-5-methyl-1,2,4-oxadiazole-3-carboxa mid e. A different compound, N-[2-(ethylsulphonyl)ethyl]-oxamide, crystallized in an ethanolic solution of tinidazole exposed for four months on a sunny window sill. Tinidazole was hydrolyzed completely to 2-methyl-5(4)-nitroimidazole when refluxed in 0.1 M NaOH solution, and was converted to 4-nitro isomer when refluxed in water with a catalytic amount of base.

Various N-substituted 4-(aminomethyl)benzoate diesters of ganciclovir were synthesized and evaluated as prodrug forms with the aim of improving the delivery characteristics of ganciclovir. The esters were hydrolyzed enzymatically by human plasma to the parent drug, the hydrolysis proceeding through formation of the corresponding monoester. The nature of the amino substituents had a marked influence on the rate of enzymatic hydrolysis, the most enzymatically labile ester being the 4-(morpholinomethyl)benzoate derivative. All esters were more lipophilic than ganciclovir in terms of octanol-pH 7.4 buffer partition coefficients. These properties combined with good aqueous solubility and high chemical stability in weakly acidic solutions make the N-substituted 4-(aminomethyl)benzoate diesters a promising prodrug type for ganciclovir to enhance its delivery characteristics for e.g. parenteral administration.

The loss of nitroglycerin (GTN) during passage through a polyvinyl chloride (PVC) or polyethylene (PE) infusion set was investigated. The GTN concentration had no influence on the GTN loss in the PVC set. The study confirmed reports in the literature that the greatest loss of GTN occurs at the slowest rate of infusion. Interestingly, the lowest concentration of GTN is seen when the volume equivalent to the capacity of the infusion set has passed through the set. When we simulated the procedure recommended by the health authorities in Norway and Sweden, we observed a loss of up to 70% during infusion through the PVC set in the first 30 minutes, which decreased to 30% over the next seven hours. The loss from the PE set did not exceed 15% over eight hours.

Chewing gum and lozenges were evaluated as delivery systems for noscapine with the aim of developing improved antitussive preparations. The formulations studied were prepared with both the water-soluble hydrochloride salt of noscapine and with the poorly soluble embonate salt and noscapine free base. The release characteristics of the preparations were evaluated both in vitro and in vivo, and their taste properties examined. Only the formulations containing noscapine base were without any appreciable taste. Chewing gum containing this compound showed, however, a low level of drug release both in vitro and in vivo and is therefore not a suitable dosage form. Only a lozenge formulation containing noscapine base fulfilled the requirements of taste acceptability and adequate release properties.

The synthesis of two series of 1-(N-methylanilinoethyl)indoles is reported. The first arises from the N-alkylation of indole-3-acetic acid or its methylester, while the second was prepared by means of the Witting reaction on the appropriate aldehyde. The compounds were tested in mice (hot plate test and phenyl-p-benzoquinone induced writhing test) for their analgesic activity. None of the compounds was significantly active in the hot plate test. However, N-methylanilinoethyl 1-(N-methylanilinoethyl)-3-indolylacetate (7) was the most active one in the phenyl-p-benzoquinone induced writhing test, which indicates that 7 has a peripheral analgesic effect.

In this study, the particle size distribution and the droplet characteristics of the delivered aerosol cloud were first determined for two disodium cromoglycate inhalation aerosol preparations obtained from different manufacturers. In addition, the in vitro deposition properties and the clinical efficacy of these preparations were compared. The evaluation of the in vitro deposition was performed using a cascade impactor. The clinical efficacy was monitored by measuring the peak expiratory flow (PEF) values after the exercise test in fifteen asthmatic patients. The particle size and the spray characteristics of these two inhalation aerosol preparations were similar; the results of the in vitro test confirmed their similar physical properties. Both disodium cromoglycate preparations clearly alleviated the bronchoconstriction after the exercise test. According to the results of the clinical trial, supported by the laboratory scale studies, both disodium cromoglycate aerosols are of equal value in asthma inhalation therapy.

Sucralfate was labelled with 99mTc by the stannous reduction method. Tablets were compressed using 1 g of radioactive sucralfate and suitable additives. On the first test day, five fully informed healthy volunteers were given one radioactive tablet of sucralfate each, following 10 h fasting. On the second test day, the sucralfate tablet was given after a standard meal. The gastrointestinal transit of the 99mTc-labelled sucralfate was evaluated using gamma camera technique. The labelling of sucralfate with 99mTc by the stannous reduction method enables the deposition and the transition of sucralfate in the gastrointestinal tract to be monitored. The tablets disintegrated almost immediately after administration and the released sucralfate distributed homogenously over the entire stomach area, in both fasted and fed subjects. Transit from the stomach into the intestine was noted already 10 min after administration in fasted subjects, whereas the gastric emptying of sucralfate was markedly delayed in fed subjects. To achieve a wider and more homogenous distribution in the GI-tract, sucralfate tablets should be taken before eating.