Biomedical subjects
Publications and source records attributed to O N Gamst.
A female patient developed warfarin resistance after 2 years of satisfactory therapy. Only a third of orally administered warfarin was absorbed, the clearance of warfarin was normal. The patient was also resistant for dicoumarol, while phenandione had satisfactory effect on the prothrombin time (PT).
Two naproxen formulations were compared with regard to gastroduodenal endoscopic findings. Using a dose of 500 mg bid for one week, plain tablets were compared to enteric coated granules in a gelatine capsule in a randomized, cross over, double-blind, double dummy study in 16 healthy, male volunteers. Endoscopic evaluation revealed no difference between the two formulations. Since previous studies with enteric coated naproxen tablets indicated a favourable side effect profile compared to plain tablets, the present data indicates that enteric coated formulations are not all alike, and should be studied individually.
It is postulated that the gastroduodenal mucosal side effects of naproxen are partly based on topical toxicity. With enteric coated aspirin tablets as a model product, enteric coated naproxen formulations have been developed. The extent of absorption is the same for enteric coated and plain tablets. The onset of absorption is delayed as a result of retention of larger particles in the stomach and more so when taken along with food. The gastric emptying of enteric coated naproxen granules is less influenced by food intake, but so far without any verified reduction of gastroscopic findings. The gastro-intestinal transmit has been studied by use of gamma scintigraphy.
An enteric-coated, pellet formulation of naproxen has been evaluated in eight healthy subjects. Each volunteer was dosed with 153Sm-labelled, enteric-coated pellets on two occasions, once whilst fasted and once after breakfast. Gastrointestinal transit was followed using gamma scintigraphy and drug absorption compared with that from uncoated naproxen pellets dosed on a separate occasion. The pH in the stomach and intestines was monitored using radiotelemetry capsules. Gastric emptying was delayed by dosing after breakfast, but small intestinal transit of the enteric-coated formulation was the same on both occasions. The highest pH recorded from the stomach was 4.0 and in all subjects the pH rose to at least 7.3 in the small intestine. The onset of drug absorption was fastest from the uncoated formulation and slowest from the coated pellets taken after breakfast. The total amount of drug absorbed was the same on all three occasions.
The absorption of naproxen is dependent on the gastric emptying and the dissolution of the drug product in the small intestine. Enteric-coated granules designed to dissolve at pH 5.5 have a delayed absorption profile when given orally. Delivered directly into the duodenum, however, rapid absorption is obtained, indicating that the gastric emptying is the rate-limiting step. By varying the coating layer, it is possible to monitor the dissolution of enteric-coated products within a pH range from 4.5 to 7.0. The onset of absorption can be delayed by increasing the pH resistance of the coating, without affecting the extent of absorption.
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Bioavailability and absorption characteristics of naproxen sodium have been shown to be superior to that of naproxen in tablet formulations. In this study naproxen sodium suppositories were compared with naproxen tablets and naproxen suppositories with respect to plasma concentrations and bioavailability of naproxen. Eleven healthy volunteers participated in a randomized crossover study comparing naproxen sodium suppositories (equivalent to 500 mg naproxen) and naproxen suppositories (500 mg). Tmax (1.4 h) was significantly shorter after the administration of naproxen sodium suppositories than after naproxen tablets (2.4 h), whereas Cmax was higher after the tablet formulation. No difference was observed with respect to bioavailability and biologic half-life of naproxen. In a second crossover study in six volunteers suppositories containing either naproxen sodium or naproxen were compared. Tmax was shorter and Cmax significantly higher after administration of the sodium naproxen suppository formulation. The sodium naproxen suppositories were well tolerated and proved to be a safe and reliable way of administering naproxen, giving therapeutic naproxen concentrations within the 1st h after administration.
The absorption of theophylline from a suppository not containing ethylenediamine was tested in 9 healthy volunteers. AUC after rectal administration of anhydrous crystalline theophylline 250 mg (AUCrectal) was compared with the AUC after oral administration of microcrystalline theophylline 250 mg (Nuelin; AUCoral) in a randomized, cross-over study. The ratio AUCrectal/AUCoral was 0.75 at 10h, and the ratio AUCrectal x beta rectal/AUCoral x beta oral extrapolated to infinite time was 0.83. A mean concentration of 5.7 micrograms/ml was reached 3.7 h after a single rectal dose. The absorption studied were performed with suppositories stored for 15 weeks at 22 degrees C. No effect on the in vitro release rate of theophylline from the suppository was observed during storage at room temperature from 3 to 31 weeks after production. Since aminophylline suppositories are known to decompose upon storage, the results suggest that a formulation without ethylenediamine is preferable for the rectal administration of theophylline.
The intention of the present experiment was to study the effects of a possible interaction between fluoride and chlorhexidine when both agents were incorporated in the same vehicle. The amount of fluoride extractable from dentrifrices containing 0.1% NaF and the fluoride ion activity were not reduced by the addition of 2% chlorhexidine digluconate. Less than 50% of the added chlorhexidine was available when the dentifrices were dissolved in deionized water. This was not affected by the presence of fluoride. The in vitro antibacterial activity of the chlorhexidine-containing dentifrices was not reduced by the addition of fluoride. Approximately 40% of the chlorhexidine was retained in the human oral cavity after brushing for 1 min with both the chlorhexidine- and the chlorhexidine/fluoride-containing dentifrice. Thus the binding of chlorhexidine to vehicle ingredients when dissolved in water is probably too weak to affect the retention in the mouth.
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