Pharmacokinetics of tiropramide after single doses in man.

The plasma levels and urinary excretions of (+/-) alpha-(benzoylamino)-4-[2-(diethylamino)ethoxy]-N, N-dipropyl-benzenepropanamide (tiropramide) and of some of its metabolites were studied in healthy volunteers after the following single-dose administrations of tiropramide hydrochloride: a) i.v. 50 mg, oral 100 mg or rectal 200 mg; b) i.v. 50 mg or i.m. 50 mg; c) oral 100, 200 or 400 mg. After i.v. bolus the plasma levels of tiropramide are consistent with a three-compartment open pharmacokinetic model. The steady-state volume of distribution is 221 l. The terminal elimination constant is 0.279 h-1 (t1/2 = 2.5 h). After i.m. injection the plasma levels increase rapidly (invasion t1/2 = 2 min) and then are similar to those found after i.v. bolus. After oral administration appreciable plasma levels are found after lag times of 18-27 min. They increase with an invasion t1/2 of 14-22 min. The peak is reached 1-1.7 h after administration and the elimination occurs with a constant of 0.20-0.23 h-1. After rectal administration appreciable plasma levels are found after a lag time of 11 min and increase with an invasion t1/2 of 6 min. The peak is reached at 2.2 h. The elimination constant is 0.21 h-1. Tiropramide and some of its metabolites can be determined in the urine by gas-liquid chromatography. The following percentages of the administered dose of tiropramide and tiropramide-related substances can be found in the 24-h urines. After i.v. bolus: 16.2; after i.m. injection: 17.0; after oral administration: 19.6; after rectal administration 13.1.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the safety of a new non-steroidal anti-inflammatory drug: protacine (CR 604).

The effects of 3'-(4-[2-(1-p-chlorobenzoyl-5-methoxy-2-methyl-indol-3-yl-acetoxy)-ethyl]-piperazinyl-1-yl)propyl-4-benzamido-N,N-dipropyl-glutaramate(+/-)dimaleate(protacine, CR 604) on gastrointestinal physiology and tolerance were investigated. The anti-inflammatory activities and the effects on the gastrointestinal tract showed a very good separation. Protacine showed a smaller influence on gastric prostaglandins and did not stimulate both basal and cAMP enhanced gastric acid output as did other antiinflammatory drugs. This may explain, at least in part, its gastrointestinal safety. Articular cartilage metabolism showed to remain practically unchanged by protacine both in in vitro and ex vivo experiments. All these results show that protacine has very good gastrointestinal safety indexes, that effects on articular cartilage metabolism are very low and that, from these points of view, it is superior to other non-steroidal anti-inflammatory drugs of similar potency.