Pharmacological activity, blood and tissue levels of indomethacin after single oral administration of two long-acting forms in the rat.

The duration of pharmacological action in the rat (carrageenin edema inhibition) of a long-acting indomethacin form (Dolcidium PL) was compared to that of a reference long-acting indomethacin form after a single oral dose (3 mg/kg) considered as the ED50 value and compatible with clinical use. Kinetic comparison of both forms was achieved in the blood and at the level of the inflammatory site. There was an identical bioavailability, but the rate of indomethacin release from the test preparation was significantly slower than that of the reference form. Greater pharmacological potency and significantly longer duration of action were also demonstrated for the former, indicating that this novel formulation exhibited better sustained release characteristics than the reference form, and thus exerted an optimal pharmacological effect (over 24 hr). Since there is a high degree of correlation of clinical efficacy with potency in the rat foot edema test, better effectiveness of Dolcidium PL should be expected in man. The reduction in peak plasma level of indomethacin should improve its tolerability as well.

Use of alveolar macrophages in antianoxic drug studies.

Alveolar macrophages are able to adapt their energy metabolism to very difficult survival conditions. Gaseous phase culture is adaptable to alveolar macrophages because it reproduces in vitro conditions very similar to in vivo conditions. It is easy to modify the incubation gas composition for hypoxia and anaerobiosis. Metabolic changes and cell injury were evaluated in three studies carried out after 24 hr of gaseous phase culture in normoxia and in anaerobiosis with a possible treatment with 0.01 microgram/ml vincamine: 1) ATP content assay by bioluminescence, the witness of cell vitality which decreases significantly in anaerobiosis; 2) Lactate assay which shows the metabolism derivation towards the anaerobic pathways; and 3) Tritiated deoxyglucose (DOG) incorporation, which shows glucose requirements after hypoxic incubation, maintaining or recovering a certain level of energetic activity. This incorporation greatly increases after anaerobic culture. Vincamine has no activity in normoxia. The three parameters are not significantly different from control, but in anaerobiosis, vincamine reveals an interesting protective effect. ATP content decreases under treatment and DOG incorporation increases. This demonstrates that vincamine is able to maintain cell metabolic activity for a longer period of time after the beginning of hypoxic trial. Cells can better use their energy storage and the metabolic pathways which enable them to restore themselves, thanks to vincamine treatment. It has been shown that cell membrane integrity was preserved by tests using cytochalasin B. DOG was not incorporated by cells treated with cytochalasin B after 24 hr of anaerobic culture and normally incorporated by control cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of anaerobiosis upon morphology and energy metabolism of alveolar macrophages cultured in gas phase.

Metabolic and morphological effects of anoxia were studied in alveolar macrophages obtained by lung lavage from guinea-pigs by means of an original method of cell culture allowing direct contact with air without interposition of liquid medium. After selection by glass adherence, alveolar cells were layered on a porous membrane applied to the surface of a reservoir filled with nutrient medium. Alveolar macrophages were then cultured in gas phase under either aerobic or anaerobic conditions for 24, 48 and 72 h. Cellular adenosine triphosphate (ATP) content, an indicator of cell vitality, significantly decreased by 68 and 88% after 48 and 72 h of exposure to anaerobic environment, respectively. Significant increases in lactate production (68% at 24 h) and in glucose uptake (125% at 24 h), evidence of marked glycolytic activity, occurred before these falls in intracellular ATP and parallel decreases in culture medium pyruvate level (76 and 85% at 48 and 72 h, respectively). The shift of energy metabolism resulted in cell death after 72 h, as noted by morphological degeneration and decreased cellular ATP content. Twenty-four hour re-exposure to normoxic atmosphere showed that recovery was possible when duration of anaerobiosis did not exceed 48 h. This reversibility in anoxic cell injury has been related to plasma membrane integrity. The results of these studies indicate that alveolar macrophage resistance to anaerobiosis is limited as ATP content falls and morphological degeneration occurs after 48 h. This novel approach of anaerobic effects at the cell level should be adaptable to investigations of activity and, in particular, the mechanisms of metabolic activity of antianoxic drugs.