An open-label, randomized, crossover study determined nicotine pharmacokinetics at steady state of a new Nicotine Transdermal System in 24 healthy adult male smokers. Three doses were each administered for 5 days: 7, 14 and 21 mg nicotine per day. Plasma nicotine concentrations reached steady state by the third day and were sustained throughout the 24-hour application periods. Mean steady-state nicotine and cotinine area under the curve (AUC0-24), maximum plasma concentration (Cmax), minimum plasma concentration (Cmin), average plasma concentration (Cavg), and total urinary cotinine were proportional to the dose of nicotine released in vitro from Nicotine Transdermal System. Time to reach peak concentration (tmax), half-life (t1/2), relative degree of fluctuation (DF) in steady-state plasma nicotine and cotinine concentrations, and renal cotinine clearance were similar for all three dosages, indicating linear pharmacokinetics and no change in nicotine metabolism with increasing dose. Findings from a second study also reflect the linear dose relationship for this Nicotine Transdermal System within the 7 to 21 mg/day dosage range. Bioequivalence based on the confidence interval test was demonstrated for a single application of Nicotine Transdermal System 21 mg/day and the same total dosage achieved by combined administration of Nicotine Transdermal System 7 mg/day plus Nicotine Transdermal System 14 mg/day, although there were small statistical differences. This Nicotine Transdermal System has a well-defined pharmacokinetic profile, with sustained plasma nicotine concentrations, and nicotine pharmacokinetics that are independent of the dose of this Nicotine Transdermal System.
The functionality of a once-daily, osmotic dosage form--gastrointestinal therapeutic system (pseudoephedrine HCl) or GITS (PeHCl)--was studied in vitro and in vivo. The in vitro release profiles were close to identical from pH 1 to 7.5 and between USP apparatus 2 and 7, independent of paddle speeds from 50 to 200 rpm; GITS also released drug at the normal rate in aqueous media after incubation in bile salts or fatty media. Both strengths of GITS (PeHCl)--240 and 120 mg--were then compared with a commercially available pseudoephedrine solution given every 6 hours and a timed-release 12-hour pseudoephedrine capsule given every 12 hours in a randomized 4-way crossover study in 24 healthy men. All four formulations were equivalent in total drug absorbed. Both GITS treatments had AUCinf values equivalent to those of PeHCl solution and capsules, and Cmax values equivalent to PeHCl capsules. Cmax for GITS and capsule treatments were each significantly lower than for solution, but the differences were small (14-17%). A one-to-one correlation was shown between rate of absorption and in vitro release profiles for the GITS products, indicating that drug release from GITS controls absorption. Insensitivity to conditions of in vivo release accounts for the close in vitro/in vivo correlation of release rates. In a second randomized crossover trial (12 men), the effect of a high-fat breakfast on GITS performance was evaluated. Mean pseudoephedrine concentrations in plasma were close to identical with or without the breakfast, and the treatments were bioequivalent.(ABSTRACT TRUNCATED AT 250 WORDS)
—The effects of several anaesthetic and hypnotic compounds with well‐defined excitatory side‐effects on glutamate decarboxylase and γ‐aminobutyric acid transaminase activity have been examined. The dissociative anaesthetics ketamine and γ‐hydroxybutyric acid produced competitive inhibition of glutamate decarboxylase with respect to glutamate at concentrations which had no effect on GABA transaminase activity. The inhibitor constant (Ki) values were, ketamine: 13.3 mm, γ‐hydroxybutyric acid; 8.8 mm. The steroid anaesthetic alphaxalone was also a potent competitive inhibitor of glutamate decarboxylase Ki= 4.1 mm). Pentobarbitone, thiopentone and methohexitone non‐competitively inhibited both glutamate decarboxylase and GABA‐transaminase but only at high concentration (> 20 mm). None of the drugs tested produced any significant change in brain GABA or glutamate levels following the injection of an hypnotic or anaesthetic dose. It is proposed that an alteration in the rate of GABA synthesis as a result of the inhibition of glutamate decarboxylase could explain the convulsive properties of the dissociative anaesthetics when given at high doses.
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