ABSTRACT
The (R)-enantiomer of the NSAID ketoprofen was administered orally at 20 mg/kg to a series of 8 animal species. In all species, a highly significant degree of inversion occurred after 1 h which varied from 27% (gerbil) to 73% (dog) and persisted or increased in plasma samples obtained 3 h after drug administration. Although the (R)-enantiomer was inactive as an inhibitor of cyclooxygenase, the analgesic effects of that isomer was almost the same as the (S)-isomer in animal analgesic assays, following oral administration of the drugs to mice and rats. Taken together, the present results suggest that (R)-ketoprofen administered alone functioned primarily as a prodrug for (S)-ketoprofen under the experimental conditions of this study.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/blood , Ketoprofen/blood , Administration, Oral , Analgesics/blood , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Cricetinae , Dogs , Gerbillinae , Guinea Pigs , Humans , Ketoprofen/chemistry , Macaca fascicularis , Male , Mesocricetus , Mice , Mice, Inbred Strains , Rabbits , Rats , Rats, Sprague-Dawley , Species Specificity , StereoisomerismSubject(s)
Anti-Inflammatory Agents/toxicity , Oxazines/toxicity , Stomach Ulcer/chemically induced , Animals , Benzoxazines , Biotransformation , Fenoprofen/toxicity , Ibuprofen/toxicity , Indomethacin/toxicity , Male , Naproxen/toxicity , Oxazines/analogs & derivatives , Oxazines/metabolism , Peptic Ulcer Hemorrhage/chemically induced , Phenylbutazone/toxicity , Rats , Salicylates/toxicity , Time Factors , Tolmetin/toxicityABSTRACT
Meseclazone, 5-CSA and several representative NSAIDs caused concentration-dependent relaxation of the tracheal ring preparation and are listed in order of descending potency: isoproterenol greater than naproxen greater than ibuprofen greater than diflunisal greater than tolmetin approximately equal to fenoprofen approximately equal to indomethacin greater than phenylbutazone greater than meseclazone greater than 5-CSA greater than aspirin. This relaxation may be related to inhibition of prostaglandin synthetase, but relative potencies of NSAIDs in this test do not necessarily correspond to their potency in inhibiting PG synthethase in other tissue. Thus other factors may play a role.
Subject(s)
Airway Resistance/drug effects , Anti-Inflammatory Agents/pharmacology , Oxazines/pharmacology , Animals , Dose-Response Relationship, Drug , Guinea Pigs , In Vitro Techniques , Male , Muscle Relaxation/drug effects , Muscle Tonus/drug effects , Oxazines/analogs & derivatives , Trachea/drug effectsABSTRACT
Four benzodiazepines (diazepam, chlordiazepoxide, halazepam, lorazepam) were tested for their effects on the acquisition of a passive-avoidance task in mice. This was done to determine whether amnesic effects, as reported in humans after diazepam and lorazepam, could be demonstrated by blockade of passive-avoidance responding in mice and, if so, to investigate the possible causes of the blockade by studying the relationships between the blockade and times of drug administration. Each of these benzodiazepines, at doses that did not alter overt behavior, blocked acquisition of the passive-avoidance response when they were administered to mice prior to the training session, but not when they were administered after the training session or prior to testing 24 h later. The block of avoidance responding was reversed, however, when the drugs were administered prior to both training and test sessions. These results suggest that state-dependent learning occurred; i.e., apparent amnesia occurred in the test session with untreated mice that had undergone passive-avoidance learning 24 h earlier under the influence of drug.
Subject(s)
Anti-Anxiety Agents/pharmacology , Avoidance Learning/drug effects , Animals , Chlordiazepoxide/pharmacology , Diazepam/pharmacology , Dose-Response Relationship, Drug , Electroshock , Lorazepam/pharmacology , Mice , Time FactorsABSTRACT
The N-methyl-d-glucamine salt of flunixin (flunixin meglumine) is a potent non-narcotic analgesic agent after parenteral administration in mice, rats and monkeys. It is significantly more potent than pentazocine, meperidine and codeine in the rat yeast paw test after subcutaneous administration in saline. Activity on intramuscular administration is comparable to that after subcutaneous administration and is enhanced when dissolved in buffered saline as compared to nonbuffered saline. In addition, flunixin meglumine also had oral activity and differs from indomethacin in having more analgesic activity per unit of anti-inflammatory activity. In mice, flunixin meglumine is equipotent to pentazocine and more potent than meperidine and codeine in the abdominal constriction test. In primates, flunixin meglumine at 10 mg/kg i.m., produced a degree of analgesic efficacy comparable to that of a clinically effective dose of morphine (0.3 mg/kg). In contrast to codeine, tolerance to the analgesic action of flunixin meglumine was not observed. Furthermore, flunixin meglumine retained its activity in rats made tolerant to codeine. Unlike narcotics, the analgesic effect of flunixin meglumine is not antagonized by naloxone after acute administration in rats. These results indicate that flunixin meglumine is a parenterally and orally effective analgesic in animals and is unlikely to have narcotic or drug dependence liability.
