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Schoedel K.A.,INC Research | Pope L.E.,Avanir Pharmaceuticals | Sellers E.M.,DL Inc
Clinical Drug Investigation | Year: 2012

Background and Objective: The novel combination of dextromethorphan (DM) and quinidine (Q) [DMQ] has been extensively studied in well controlled clinical trials as treatment for pseudobulbar affect (PBA), and is the first US Food and Drug Administration (FDA)-approved treatment for this indication. The approved dosage of DMQ is DM 20 mg and Q 10mg twice daily. DM is metabolized via cytochrome P450 2D6 (CYP2D6); Q is a CYP2D6 inhibitor used to increaseDMplasma concentrations. Paroxetine is both a substrate and inhibitor of CYP2D6. This trial evaluated the effect of DMQ at a dose of DM 30mg and Q 30mg twice daily on the steady-state pharmacokinetics of paroxetine 20 mg daily and the effects of paroxetine on the steady-state pharmacokinetics of DMQ in healthy volunteers. Methods: This was an open-label, randomized, parallel-group, 20-day trial. Drug plasma concentrations were analysed following monotherapy and concomitant (DMQ+ paroxetine) therapy. Participants were 27 healthy adults who were randomized in a 1 : 1 fashion to one of two groups. Group 1 received paroxetine 20 mg once daily for 12 days to attain steady state, at which point DMQ 30 mg/30mg twice daily was added for 8 days. Group 2 received DMQ 30mg/30 mg twice daily for 8 days to attain steady state, at which point paroxetine 20 mg once daily was added for 12 days. The primary endpoints were the 90% confidence intervals (CIs) for the ratio of the area under the plasma concentration-time curve (AUC) during concomitant therapy versus monotherapy. Safety and tolerability measures including adverse events (AEs) were also assessed. Results: The 90% CIs of the AUCs were outside of the predefined range [0.80, 1.25] for all analytes, indicating a drug-drug interaction. In group 1 (n = 14), addition of DMQ to paroxetine resulted in a 30% increase in mean plasma exposure of paroxetine (AUC up to 24 hours). In group 2 (n = 13), addition of paroxetine to DMQ resulted in increases in mean plasma exposure (AUC up to 12 hours) of 50% for DM and 40% for Q, and a decrease of 12.3% for dextrorphan, the metabolite of DM. The incidence of AEs was higher with paroxetine monotherapy and combination therapy, compared with DMQ given alone (30.8% with DMQ alone vs 83.3% following addition of paroxetine, and 78.6% with paroxetine alone vs 64.3% following addition of DMQ). Three subjects discontinued due to AEs, and no serious AEs were reported. Conclusion: The addition of DMQ 30 mg/30 mg twice daily to paroxetine increased steady-state paroxetine plasma concentrations and addition of paroxetine to DMQ 30 mg/30 mg twice daily increased steady-state plasma concentrations of DM and Q, indicating a potential interaction. Thus, patients should be monitored for AEs and dosage adjustment considered when combining these two agents. © 2012 Adis Data Information BV. All rights reserved.

Romach M.K.,DL Inc | Schoedel K.A.,INC Research | Sellers E.M.,DL Inc | Sellers E.M.,University of Toronto
Drug and Alcohol Dependence | Year: 2013

An expert panel convened in 2005 by the College on Problems of Drug Dependence (CPDD) to consider strategies to reduce the risk of prescription medication abuse concluded that drug formulation plays a significant role in determining risk of abuse. Efforts on the part of the pharmaceutical industry to develop drugs that deter abuse have focused primarily on opioid formulations resistant to common forms of tampering, most notably crushing or dissolving the tablet to accelerate release. Several opioid formulations developed to be tamper resistant have been approved, but the US Food and Drug Administration has not approved explicit label claims of abuse deterrence and has stated that any such claim will require substantial postmarketing data. Drug development efforts in this area raise questions about the relative impact of abuse-deterrent formulations, not only on individuals who might abuse a medication, but also on patients who are compliant with therapy. This review discusses progress since the 2005 CPDD meeting with an emphasis on opioids. Articles cited in the review were identified via a PubMed search covering the period between January 1, 2000, and October 5, 2011. Scientific work presented by the authors and their colleagues at meetings held through May 2012 also was included. Published literature suggests that development of abuse-deterrent products will require broad public health support and continued encouragement from regulatory authorities so that such products will become the expected standard of care for certain drug classes. © 2013 Elsevier Ireland Ltd.

Romach M.K.,University of Toronto | Romach M.K.,DL Inc | Schoedel K.A.,INC Research | Sellers E.M.,University of Toronto | Sellers E.M.,DL Inc
Neuropharmacology | Year: 2014

Psychoactive drugs that increase alertness, attention and concentration and energy, while also elevating mood, heart rate and blood pressure are referred to as stimulants. Despite some overlapping similarities, stimulants cannot be easily categorized by their chemical structure, mechanism of action, receptor binding profile, effects on monoamine uptake, behavioral pharmacology (e.g., effects on locomotion, temperature, and blood pressure), therapeutic indication or efficacy. Because of their abuse liability, a pre-market assessment of abuse potential is required for drugs that show stimulant properties; this review article focuses on the clinical aspects of this evaluation. This includes clinical trial adverse events, evidence of diversion or tampering, overdoses and the results of a human abuse potential study. While there are different types of human experimental studies that can be employed to evaluate stimulant abuse potential (e.g., drug discrimination, self-administration), only the human abuse potential study and clinical trial adverse event data are required for drug approval. The principal advances that have improved human abuse potential studies include using study enrichment strategies (pharmacologic qualification), larger sample sizes, better selection of endpoints and measurement strategies and more carefully considered interpretation of data. Because of the methodological advances, comparisons of newer studies with historical data is problematic and may contribute to a biased regulatory framework for the evaluation of newer stimulant-like drugs, such as A2 antagonists. This article is part of the Special Issue entitled 'CNS Stimulants'. © 2014 Elsevier Ltd. All rights reserved.

Lawrence C.H.,DL Inc | Chen I.Y.,Newcastle Hospitals NHS Trust
Diving and hyperbaric medicine | Year: 2016

BACKGROUND: People with asthma are an under-represented group amongst scuba divers. Many may avoid or are advised against diving due to the potential risks, including bronchoconstriction, pulmonary barotrauma and arterial gas embolism. The aim of this study was to establish whether divers with asthma were more likely to experience reversible airways obstruction following typical scuba diving than divers without asthma.METHOD: All divers with a history of asthma attending Operation Wallacea in Honduras were identified and peak expiratory flow rates (PEF) were measured pre and immediately post dive. All dives were boat dives in tropical sea water. Scuba dives were defined as those lasting between 40 and 55 minutes to a depth of between 10 and 18 metres. Of the 356 divers attending, 22 were identified as having asthma, of whom 19 were suitable for testing. They were classified by treatment regimen: five on no treatment, 11 on salbutamol only and three on regular preventative treatment. Twenty-four divers without a history of asthma acted as a control group.RESULTS: Open-water scuba diving caused a small decrease in PEF in all populations (median decrease 4.4%, P < 0.001). Percentage decrease in PEF was significantly more in divers with asthma on regular preventative medication than in the control group (mean 9.3%, median decrease 6% vs. mean 3.1%, median 4.3% P = 0.039).CONCLUSION: These findings support the view that asthmatics are more susceptible to airway changes following scuba diving. Differences to previous studies are likely due to environmental conditions, including dive depth.

Sellers E.M.,DL Inc | Perrino P.J.,Purdue Pharma | Colucci S.V.,Purdue Pharma | Harris S.C.,Purdue Pharma
Journal of Psychopharmacology | Year: 2013

Reformulated OxyContin® (oxycodone HCl controlled-release or ORF) was developed as a tamper and abuse-deterrent product, to reduce the risk of product abuse, misuse and their consequences. This noninterventional single-session study asked participants who were medically-healthy recreational opioid users, aged 18 years and older, to consider how they would use commonly available supplies to tamper with placebo ORF and placebo original OxyContin (OC) tablets, and how they would assess the attractiveness of tampering and abusing ORF tablets, as compared with other opioid formulations. Participants provided information on past opioid use, and they assessed the properties of five nonhypothetical oxycodone products and two hypothetical oxycodone products. Participants provided feedback on tampering preferences, preferred tamper methods for each product, overall tampering potential and product preferences. We had 30 participants (27 males and 3 females; mean age 35 years, range 18-51) complete both the interview and tampering sessions. Participants judged OC as the most attractive, valuable, desirable and most likely to be tampered with, from among all opioid products studied. By contrast, they rated ORF as the least attractive, least valuable, least desirable, and least likely to be tampered with among all the nonhypothetical opioid products studied. These results suggested that recreational drug abusers view ORF tablets as tamper-deterrent products. © The Author(s) 2013.

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