Thomas P. Jerussi

Sedative and anxiolytic effects of zopiclone's enantiomers and metabolite

We evaluated racemic zopiclone, its (S)- and (R)-enantiomers and a metabolite, (S)-desmethylzopiclone, for their actions on locomotor activity, rotarod performance, the elevated plus maze and the Vogel conflict test of anxiety, and electroconvulsive shock-induced seizures duration. Zopiclone and its (R)- and (S)-enantiomers reduced locomotor activity, and zopiclone and its (S)-enantiomer disrupted rotarod performance at 10 mg/kg. (S)-desmethylzopiclone did not alter these measures at doses of less than 200 mg/kg. (S)-desmethylzopiclone altered plus maze performance at the lowest dose of all the zopiclone derivatives tested, caused a dose-related effect on the Vogel conflict test and caused a dose-related reduction of electroconvulsive shock-induced seizure durations. The data indicate that (S)-desmethylzopiclone can bring about an anxiolytic effect without a substantial degree of central nervous system depression, and suggest that the agent may be particularly useful clinically in the treatment of anxiety.

Clinical endoscopic evaluation of the gastroduodenal tolerance to (R)- ketoprofen, (R)- flurbiprofen, racemic ketoprofen, and paracetamol: a randomized, single-blind, placebo-controlled trial.

Ketoprofen, a nonsteroidal anti‐inflammatory drug (NSAID) of the 2‐arylpropionic acid class, causes gastroduodenal hemorrhages and erosions in 10–15% of patients. The (S)‐ enantiomer exhibits most of the anti‐inflammatory properties, with concomitant gastrointestinal toxicity. The (R)‐ enantiomer, however, was recently found to have analgesic properties independent of prostaglandin inhibition. Seventy‐two healthy male volunteers not receiving NSAIDs, alcohol, or anti‐ulcer drugs, were enrolled in a randomized, investigator‐blind, placebo‐controlled trial to evaluate the gastroduodenal tolerance of (R)‐ ketoprofen 100 mg b.i.d., (R)‐ flurbiprofen 100 mg b.i.d., racemic ketoprofen 100 mg b.i.d., and paracetamol 1,000 mg b.i.d. Gastroduodenal endoscopies at baseline and after 2.5 days of dosing were used to detect newly occurring hemorrhages and erosions. Adverse events were also recorded. The incidence of submucosal hemorrhages was 4/16 in the (R)‐ ketoprofen group, 5/16 in the (R)‐ flurbiprofen group, 12/16 in the racemic ketoprofen group, 1/16 in the paracetamol group, and 1/8 in the placebo group. The incidence of erosions was 2/16 in the (R)‐ ketoprofen group, 4/16 in the (R)‐ flurbiprofen group, 10/16 in the racemic ketoprofen group, 0/16 in the paracetamol group, and 2/8 in the placebo group. The differences in hemorrhages and erosions among treatments were statistically significant (gastric hemorrhages P = 0.0008; duodenal hemorrhages P = 0.00062; gastric erosions P = 0.0004; duodenal erosions P = 0.0062, Kruskal‐Wallis test). At 100 mg b.i.d., (R)‐ ketoprofen caused fewer gastroduodenal hemorrhages and erosions than racemic ketoprofen (P = 0.019, P = 0.0112, P = 0.0097, P = 0.0139 for gastric, duodenal hemorrhages and gastric, duodenal erosions, respectively). The difference between 100 mg b.i.d. (R)‐ ketoprofen and 100 mg b.i.d (R)‐ flurbiprofen was not statistically significant. The dissociation between analgesic and anti‐inflammatory properties for (R)‐ ketoprofen suggests that it may represent a unique analgesic with a favorable safety profile. J Clin Pharmacol 1998;38:19S‐24S.

In vitro and in vivo evaluation of O-alkyl derivatives of tramadol.

Tramadol is a centrally acting opioid analgesic structurally related to codeine and morphine. O-Alkyl, N-desmethyl, and non-phenol containing derivatives of tramadol were synthesized to probe their effect on metabolic stability and both in vitro and in vivo potency.

A population analysis of nebulized (R)-albuterol in dogs using a novel mixed gut-lung absorption PK-PD model

AbstractPurpose. The objectives of this study were to 1) construct a pharmacokinetic-pharmacodynamic (PK-PD) model, and 2) determine the PKs and PDs of (R)-albuterol when given by nebulization to 8 dogs for 7 consecutive days. Methods. Four doses were evaluated (0.002, 0.02, 0.1, and 0.4 mg/kg/day). Blood samples were obtained after drug administration on days 1 and 7. Heart rates (HR) were obtained during treatment days 1, 4 and 7. All (R)-albuterol plasma concentrations were fitted using a mixed gut-lung absorption 2-compartment PK model. Day-1, 4, and 7 HR data were co-modeled using a direct response model with Hill-type equations, including a necessary tolerance phenomenon. The population PK-PD analysis was performed with an iterative 2-stage methodology (IT2S). Results. No chiral inversion was seen, and double absorption peaks on the plasma concentration versus time curves were observed in the majority of dogs. These were hypothesized to be the result of combined gut and lung absorption of (R)-Albuterol. Results indicated that 67% (range: 57-89%) of (R)-albuterol systemic exposure after nebulized administration is due to gut absorption. Mean population PK parameters were KaGI (10±5.7 h−1), KaLUNG (21±9.5 h−1), CLc/F (0.6±0.2 L/h/kg), CLd/F (1.4±0.5 L/h/kg), Vc/F (1.4±0.9 L/kg), and Vp/F (4.8±2.4 L/kg). (R)-albuterol administration was associated with an increase in the dogs heart rates. A tolerance effect related to the cumulative dose was observed and modeled. Conclusions. The presented PK-PD model appears to differentiate gut from lung absorption when (R)-albuterol is given by 15-minute nebulization to dogs. These results agree with the accepted hypothesis that most of the systemic exposure of (R)-albuterol after nebulized administration is due to gut absorption.