Dosing time optimizes sustained-release ketoprofen treatment of osteoarthritis.

A double-blind randomized parallel-group trial was undertaken to evaluate the influence of the dosing time of sustained-release ketoprofen (SRK) on its acceptability and efficacy. The SRK was prescribed for 2 weeks (200 mg once a day) to 117 outpatients with osteoarthritis of the knee and/or hip. One group received SRK in the morning (at 8 a.m.) and the other group in the evening (at 8 p.m.). The principal aim of the trial concerned the acceptability, whereas efficacy was its secondary aim. The principal trial criterion was defined as the number of spontaneous recordings of adverse effects. Results showed clearly that the acceptability of SRK in the SRK morning group was worse than that in the evening group (39% of patients with one or more adverse effects in the SRK morning group versus 19% in the evening group; p = 0.019). It is important to stress the difference concerning the number of adverse effects (48 for SRK morning group versus 23 for SRK evening group; p = 0.0234). The analgesic efficacy seemed to be similar, but one criterion was statistically significant: The duration of analgesic efficacy was more important for the SRK evening group than for the morning group (9.37 and 5.47 h, respectively; p = 0.001). To increase its acceptability, evening administration of SRK seems to be preferred over morning administration in osteoarthritis. However, other trials of the same type, assessing other antiinflammatory agents, are necessary before a general extrapolation of such results can be undertaken.

Acceptability and efficacy of two associations of paracetamol with a central analgesic (dextropropoxyphene or codeine): comparison in osteoarthritis.

A double-blind randomized parallel group trial was undertaken to compare the acceptability and efficacy of 2 forms of analgesic treatment, DI-Antalvic (Houde Laboratories, Puteaux, France) (30 mg dextropropoxyphene and 400 mg paracetamol per capsule) and Efferalgan-Codeine (UPSA Laboratories, Rueil Malmaison, France) (30 mg codeine and 500 mg paracetamol per tablet) prescribed for 1 week at doses of 6 capsules/day and 6 tablets/day, respectively, in 141 outpatients with active osteoarthritis of the knee or hip. The principal aim of the trial was concerned with acceptability, with efficacy as its secondary aim. The principal trial criterion was defined as overall assessment of acceptability by the patient at the end of the trial (success or failure) or by treatment dropouts because of an adverse effect (failure). Comparability of the groups was confirmed before any treatment regarding the physical characteristics of the patients, characteristics of osteoarthritis, and the initial level of pain and functional consequences of pain. Results show that the analgesic efficacy of the treatment was similar, but that the acceptability of Efferalgan-Codeine was significantly worse than that of DI-Antalvic: 53% failure with Efferalgan-Codeine versus 29% failure with DI-Antalvic (P = .005). Other trials of the same type would seem necessary (comparison of lower doses, other types of pain) before being able to generally extrapolate such findings.

[Biological rhythm and thromboembolic disease. Physiological, epidemiological and pharmacological aspects]. / Rythmes biologiques et maladie thromboembolique. Aspects physiologiques, épidémiologiques et pharmacologiques.

Arterial and venous thromboembolic disorders are the leading cause of death in most of the advanced nations. The study of physiologic, epidemiologic and pharmacologic relationships of these disorders to biological rhythms, may lead to a better understanding and perhaps a better treatment. Chronophysiologic studies have shown that hemostatic variables follow circadian rhythms. The level of platelets aggregation and of blood coagulation has been found to be increased in the morning and decreased at night, whereas fibrinolytic activity is lower in the morning than in the evening. Chronoepidemiologic studies demonstrated a morning peak for arterial thromboembolic disorders and an evening peak for cerebral bleedings. These facts might partially be explained by circadian variations in hemostasis and suggest a chronotherapeutic approach in thromboembolic disorders. Unfractionated heparin, because of its antithrombotic effect, is one of the major drugs used to treat this disease. However, with such a treatment venous thrombosis recurs or bleeding complications occur yet in about 30% of patients. Chronopharmacologic studies indicate that anticoagulant effect of heparin is minimum in the morning and maximum at night, following the physiologic circadian variation of blood coagulation. Such results suggest that the heparin doses should be modulated as a function of administration times in order to increase its effectiveness and to minimize both bleeding risk and thrombosis. Further studies are needed to evaluate such a proposal.

[Chronokinetics of ketoprofen administered orally and by continuous venous infusion]. / Chronocinétique du kétoprofène administré per os et en perfusion veineuse continue.

The aim of the study was to evaluate a possible chronokinetic phenomenon of ketoprofen administered orally and by continuous intravenous infusion. In the first part of the study, ketoprofen was administered orally to 8 healthy male volunteers aged between 25 and 45 years, at a dose of 2 X 50 mg at 7:00 a.m. (time I), 1:00 p.m. (time II), 7:00 p.m. (time III) and 1:00 a.m. (time IV), on the same day of the week at an interval of 2 weeks, during the first three months of the year. The order of administration was randomised, each subject acted as his own control and received ketoprofen at the four times mentioned above. A total of 14 venous blood samples were taken over 12 hours. The results indicate that the maximal serum concentration (Cmax) was significantly higher at time I (13.4 +/- 14.1) than at times II, III and IV (6.9 +/- 1.1, 7.2 +/- 0.7, 6.4 +/- 0.5 mg/l) (p less than 0.01). The time required to reach this concentration (Tmax) was significantly longer for time IV (135.0 +/- 16,8) than for times I, II and III (73,1 +/- 14.1, 75,0 +/- 16.6; 82.5 +/- 12.7 minutes) (p less than 0.05). The excretion half-life (t 1/2B) was significantly longer for time IV (4.3 +/- 0.6) than for times II and III (2.8 +/- 0.5, 2.5 +/- 0.2 hours) (p less than 0.05). Statistically significant differences were also observed in the area under the curve measured at midday (AUC 12) and in the total clearance (CIT) for the various sample times.(ABSTRACT TRUNCATED AT 250 WORDS)