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Du Souich P.,University of Montréal | Fradette C.,Labopharm
Expert Opinion on Drug Metabolism and Toxicology | Year: 2011

Introduction: Chronic pulmonary disease and heart failure reduce drug clearance and consequently enhance adverse drug reactions. The mechanisms of action underlying the regulation of cytochrome P450 (CYP) isoforms and membrane carrier proteins by hypoxia, and the clinical consequences of the regulation of CYP by hypoxia, alone or combined with other conditions have been elucidated in the last decades. Overall, a reduced drug clearance appears to be associated with hypoxemia. Areas covered: In this review, the mechanisms of action underlying hypoxia-induced regulation of CYP enzymes are discussed. The authors also revise the effects of hypoxia on serum mediators, signal transduction pathways, orphan nuclear receptors, transcription factors and post-transcriptional mechanisms regulating CYP and membrane carrier proteins expression. Additionally, the paper also discusses the clinical repercussions of hypoxia-induced changes in CYP and membrane carrier proteins activity. Expert opinion: Acute systemic hypoxia down-regulates selected CYP isoforms and up-regulates CYP3A4 and P-glycoprotein, changing the metabolic clearance of drugs and endogenous compounds biotransformed by these isoforms as well as the kinetics. In patients with acute hypoxia, the dosage of drugs, biotransformed by CYP isoforms, may need to be adjusted. Tissue hypoxia enhances the expression of efflux membrane carrier proteins, increasing the probability of drug resistance. © 2011 Informa UK, Ltd.

Karhu D.,Labopharm | Groenewoud G.,PAREXEL | Potgieter M.A.,PAREXEL | Mould D.R.,Projections Research Inc.
Journal of Clinical Pharmacology | Year: 2010

An extended-release trazodone HCl formulation, Trazodone Contramid OAD (TzCOAD), was developed as scored 150-mg and 300-mg caplets for once-daily administration. Dose proportionality of intact and bisected caplets (dose range, 75-375 mg) was evaluated in a single-dose, randomized, 5-way crossover study. Plasma trazodone and m-chlorophenylpiperazine (mCPP) levels were determined using a validated liquid chromatography-tandem mass spectroscopy method. Dose proportionality was assessed based on confidence intervals for logarithmically transformed, dose-normalized maximum plasma concentration (C max), area under the plasma concentration versus time data pairs (AUC 0-t), and area under the curve from time 0 to infinity (AUC 0-∞) in relation to the acceptance range of 80% to 125% (bioequivalence approach). The power method, combined with confidence interval criteria, was also used to assess proportionality. The conclusion of dose proportionality was generally supported using the bioequivalence approach. Based on the power model, values of the slope and corresponding 90% confidence interval for trazodone C max, AUC 0-t, and AUC 0-∞ were 0.948 (0.899-0.997), 0.920 (0.875-0.964), and 0.913 (0.867-0.958), respectively. All were within the acceptance interval (0.861-1.139). Results for mCPP also fell within the acceptance interval. TzCOAD exhibits linear pharmacokinetics over doses ranging from 75 to 375 mg and maintains its controlled-release properties when the caplets are bisected along the score line. © 2010 The Author(s).

Karhu D.,Labopharm | Gossen E.R.,Labopharm | Mostert A.,PAREXEL | Cronje T.,PAREXEL | Fradette C.,Labopharm
International Journal of Clinical Pharmacology and Therapeutics | Year: 2011

Objective: To characterize the pharmacokinetics, safety, and tolerability of an extended-release formulation of trazodone hydrochloride (HCl), Trazodone Contramid® Once-a-Day (TzCOAD) developed as scored 150-mg and 300-mg caplets for once-daily administration. Methods: Relative bioavailability studies compared the pharmacokinetics of TzCOAD and trazodone immediate-release (TzIR) tablets following single- and multiple-dose administration. In addition, the effect of food on the pharmacokinetics of TzCOAD was assessed. Results: After single-dose administration of 300 mg TzCOAD, trazodone AUC and C max were approximately 20% and 60% lower, respectively, than for TzIR 100-mg tablets administered as 3 doses, 8 h apart. After multiple-dose administration of 300 mg daily for 7 days, TzCOAD given once daily and TzIR given 3 times a day were equivalent with respect to AUC, while C max was 43% lower for TzCOAD. Trazodone AUC following single-dose administration of TzCOAD was similar to AUC at steady state, suggesting that steady-state exposure can be predicted from single-dose data. When TzCOAD was taken shortly after ingestion of a high-fat meal, C max increased 86% compared with fasting conditions. However, AUC and t maxwere not affected by food. Conclusion: Administration of TzCOAD 300 mg once daily provides equivalent steady-state exposure to, with a lower C max than, TzIR 100 mg given 3 times a day. A high-fat meal results in an increase in C max, but there is no substantial effect on AUC. ©2011 Dustri-Verlag Dr. K. Feistle.

Karhu D.,Labopharm | Fradette C.,Labopharm | Potgieter M.A.,PAREXEL | Ferreira M.M.,PAREXEL | Terblanche J.,PAREXEL
Journal of Clinical Pharmacology | Year: 2010

The pharmacokinetics of a once-daily formulation of tramadol (Tramadol Contramid OAD 200-mg tablets) following single-dose and multiple-dose administration was compared with that of an immediate-release product (tramadol IR 50-mg tablets) in 2 separate studies. In both studies, AUC parameters met bioequivalence criteria, whereas Cmax of Tramadol Contramid OAD was lower than that of tramadol IR following a 200-mg daily dosage. After single-dose administration, the mean tramadol concentration at 1 hour postdose was within the range associated with analgesic efficacy (>100 ng/mL), and the mean concentration remained above this level for the remainder of the dosing interval. Steady state was attained within 48 hours following multiple-dose administration. Tramadol Contramid OAD provides a rapid rise in plasma concentrations and an equivalent daily systemic exposure as tramadol IR, with a reduction in peak plasma concentrations. © 2010 the American College of Clinical Pharmacology© 2010 the American College of Clinical Pharmacology.

Paladin Labs and Labopharm | Date: 2011-10-04

Modified starch used in the manufacture of pharmaceutical products as an agent for controlled or sustained release drug delivery for oral and parenteral administration.

Angelini Pharma Inc. and Labopharm | Date: 2011-05-10

Pharmaceutical preparations, namely, an anti-depressant.

Angelini Pharma Inc. and Labopharm | Date: 2011-08-02


There is disclosed a once daily oral pharmaceutical compositon for controlled release of tramadol or a salt thereof, wherein the composition, when ingested orally, provides a clinical effect over 24 hours which is a least as good as the clinical effect over 24 hours of two doses of a twice daily oral pharmaceutical composition for controlled release of tramadol, taken 12 hours apart.

The instant invention provides a two-step polymerization process for preparing amphiphilic poly(N-vinyl-2 pyrrolidone), (PVP)-block-polyester copolymers and other diblock and triblock copolymers consisting of PVP as one block. The block copolymers of the invention can be used as vehicles for drug delivery.

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