The effect of the non-steroidal anti-inflammatory drug lysine clonixinate ([2-(3-chloro-o-toluidino) nicotinic acid]-L-lysinate, CAS 55837-30-4) on the pharmacokinetics and anticoagulant activity of phenprocoumon (4-hydroxy-3-(1-phenylpropyl)-coumarin, CAS 435-97-2) was investigated in an open, randomised, two-fold, cross-over study in 12 healthy male volunteers. These subjects received a single dose of 18 mg phenprocoumon without or with concomitant treatment with lysine clonixinate (125 mg five times a day for 3 days before and 13 days after ingestion of a single dose of phenprocoumon).Pharmacokinetic parameters of phenprocoumon following oral administration were: CL/f. 0.779 +/- 0.157 ml/min, half-life of elimination: 147.2 +/- 19.9 h; free fraction in serum: 0.51 +/- 0.20 %. These parameters were not significantly altered by concomitant treatment with lysine clonixinate. Prothrombin time increased from 13.3 +/- 1.3 s (at time 0) to 17.7 +/- 2.7 s following phenprocoumon and from 13.3 +/- 1.2 s to 18.0 +/- 2.2 s following combined administration.Prothrombin time returned to the pretreatment values 240 h after administration of phenprocoumon. The integrated effect (AUEC(0-288) h) was indentical following both treatments (4,303 461 and 4,303 312 s x h for phenprocoumon alone and phenprocoumon with lysine clonixinate, respectively). Thus, lysine clonixinate administered in therapeutic doses does not affect the pharmacokinetics and anticoagulant activity of phenproxoumon.

The aim of the present study was to investigate the pharmacokinetics of tilidine and its metabolites during the dialysis procedure and in the dialysis‐free interval. Tilidine is a prodrug that is metabolized presystemically into the active metabolite nortilidine. Nortilidine is degraded thereafter to bisnortilidine and several polar metabolites. Nine patients with a creatinine clearance < 5 ml/min were treated in a crossover design with single oral doses of 1.5 mg/kg on the day of dialysis (dialysis performed from 3 to 6 hours after drug administration) and on a day in the dialysis‐free interval. Blood samples were taken frequently and analyzed for tilidine, nortilidine, and bisnortilidine. Drug and metabolite concentrations were also measured in aliquots of dialysate collected during dialysis. Only negligible amounts of tilidine, nortilidine, and bisnortilidine (about 0.9% of the dose) were recovered from the dialysate. The pharmacokinetics of nortilidine and its inactive metabolite bisnortilidine was not affected by dialysis. The presystemic apparent clearance of the prodrug tilidine was decreased significantly during the dialysis‐free interval. A significant decrease of the rate of elimination and an increase of the AUC of bisnortilidine were observed if these parameters were compared with data obtained from healthy volunteers. The plasma concentrations of nortilidine were comparable in patients and normal volunteers. Thus, a reduction of the dose of tilidine in patients with severely impaired kidney function seems not to be required. Tilidine and its metabolites cannot be removed from the body by dialysis.

In this double‐blind, randomized, placebo‐controlled crossover study, the authors investigated the initial time course of effects of isosorbide‐5‐mononitrate (IS‐5‐MN) on hemodynamic parameters in 15 healthy male volunteers after administering a single oral dose of either an immediate‐release formulation (IS‐5‐MN 20 mg) or of a sustained‐release formulation (IS‐5‐MN 50 mg). The latter formulation released 15 mg IS‐5‐MN immediately, while 35 mg of the dose was sustained release. The onset of effect on the a/b‐ratio of the finger pulse curve (20 minutes after administration) and on heart rate following orthostatic challenge (30 minutes) was not different following ingestion of either the immediate‐release or the sustained‐release formulation. Only the systolic blood pressure following orthostatic challenge was affected earlier after ingestion of the immediate‐release form of IS‐5‐MN (10 vs. 30 minutes). There was no statistically significant difference in the maximum effect on the measured hemodynamic parameters between the two formulations. There was no significant difference with respect to the effect per dose between both of the active treatments (i.e., IS‐5‐MN 20 mg immediate release and IS‐5‐MN 50 mg sustained release) within 6 hours after administration. The hemodynamic findings were consistent with the observed rates of the increase of plasma concentrations of IS‐5‐MN following both formulations. Thus, the administration of the sustained‐release formulation of IS‐5‐MN 50 mg caused similar maximum effects when compared with an immediate‐release formulation (20 mg). While the onset of effect of IS‐5‐MN on the a/b‐ratio of the finger pulse curve and on heart rate following orthostasis was similar after administration of either the immediate‐ or the sustained‐release formulation, the onset of effect of the sustained‐release formulation on systolic blood pressure orthostasis was determined slightly later. However, the latter difference seems to be of minor clinical relevance.

Clinical Pharmacology & TherapeuticsVolume 65, Issue 2 p. 150-150 American Society for Clinical Pharmacology and Therapeutics Concentration-effect relationships of the new orally active RGD-type glycoprotein IIb/IIIa-Antagonist S1197 in man D. Trenk PhD, D. Trenk PhD Dept Clin Pharmacology, Herz-Zentnun, Bad KrozingenNonmember of the Society.Search for more papers by this authorE. Stengele MD, E. Stengele MD Dept Clin Pharmacology, Herz-Zentnun, Bad KrozingenNonmember of the Society.Search for more papers by this authorR. Adler MD, R. Adler MD Dept Clin Pharmacology, Herz-Zentnun, Bad KrozingenNonmember of the Society.Search for more papers by this authorM. Just MD, M. Just MD Hoechst Marion Roussel, Frankfurt, GermanyNonmember of the Society.Search for more papers by this authorD. Brockmeier PhD, D. Brockmeier PhD Hoechst Marion Roussel, Frankfurt, GermanyNonmember of the Society.Search for more papers by this authorM. Seibert-Grafe MD, M. Seibert-Grafe MD Hoechst Marion Roussel, Frankfurt, GermanyNonmember of the Society.Search for more papers by this authorE. Jähnchen MD, E. Jähnchen MD Dept Clin Pharmacology, Herz-Zentnun, Bad KrozingenNonmember of the Society.Search for more papers by this author D. Trenk PhD, D. Trenk PhD Dept Clin Pharmacology, Herz-Zentnun, Bad KrozingenNonmember of the Society.Search for more papers by this authorE. Stengele MD, E. Stengele MD Dept Clin Pharmacology, Herz-Zentnun, Bad KrozingenNonmember of the Society.Search for more papers by this authorR. Adler MD, R. Adler MD Dept Clin Pharmacology, Herz-Zentnun, Bad KrozingenNonmember of the Society.Search for more papers by this authorM. Just MD, M. Just MD Hoechst Marion Roussel, Frankfurt, GermanyNonmember of the Society.Search for more papers by this authorD. Brockmeier PhD, D. Brockmeier PhD Hoechst Marion Roussel, Frankfurt, GermanyNonmember of the Society.Search for more papers by this authorM. Seibert-Grafe MD, M. Seibert-Grafe MD Hoechst Marion Roussel, Frankfurt, GermanyNonmember of the Society.Search for more papers by this authorE. Jähnchen MD, E. Jähnchen MD Dept Clin Pharmacology, Herz-Zentnun, Bad KrozingenNonmember of the Society.Search for more papers by this author First published: 05 February 1999 https://doi.org/10.1016/S0009-9236(99)80133-7 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Abstract Clinical Pharmacology & Therapeutics (1999) 65, 150–150; doi: Volume65, Issue2February 1999Pages 150-150 RelatedInformation

Clinical Pharmacology & Therapeutics (1999) 65, 150–150; doi:

Objective: An enhanced response to warfarin and an increased risk of major bleeding has been observed in older patients. The reason for this increase in sensitivity remains unknown. It could be due to pharmacodynamic reasons, pharmacokinetic reasons, or both.