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High Wycombe, United Kingdom

Vry J.D.,Maastricht University | Martinez-Martinez P.,Maastricht University | Losen M.,Maastricht University | Bode G.H.,Maastricht University | And 6 more authors.
Molecular Therapy | Year: 2010

Viral gene transfer or transgenic animals are commonly used technologies to alter gene expression in the adult brain, although these approaches lack spatial specificity and are time consuming. We delivered plasmid DNA locally into the brain of adult C57BL/6 mice in vivo by voltage-and current-controlled electroporation. The low current-controlled delivery of unipolar square wave pulses of 125νA with microstimulation electrodes at the injection site gave 16 times higher transfection rates than a voltage-controlled electroporation protocol with plate electrodes resulting in currents of about 400mA. Transfection was restricted to the target region and no damage due to the electric pulses was found. Our current-controlled electroporation protocol indicated that the use of very low currents resulting in applied voltages within the physiological range of the membrane potential, allows efficient transfection of nonviral plasmid DNA. In conclusion, low current-controlled electroporation is an excellent approach for electroporation in the adult brain, i.e., gene function can be influenced locally at a high level with no mortality and minimal tissue damage. © The American Society of Gene & Cell Therapy. Source

Turgeon J.,Center Hospitalier Of Luniversit Of Montral | Grning R.,Institute Fr Pharmazeutische Technology und Biopharmazie | Sathyan G.,Adamas India Pharmaceuticals Private Ltd | Sathyan G.,ALZA Corp. | And 2 more authors.
Expert Opinion on Drug Delivery | Year: 2010

Importance of the field: New formulations of opiods can provide round-the-clock pain relief to improve pain management and quality of life for patients with chronic pain. Areas covered in this review: Information and comments on the pharmacokinetic processes associated with a new once-daily formulation of the potent opiod hydromorphone. What the reader will gain: This review presents an overview of data from several small pharmacokinetic studies to gain a better perspective on the pharmacokinetic properties of a new long-acting formulation of hydromorphone. Take home message: The development of advanced oral formulation that deliver analgesic drugs over an extended period provides new solutions to improve pain management and quality of life for patients with chronic pain. © 2010 Informa UK Ltd. Source

Rauck R.,The Carolinas Pain Institute | Rapoport R.,Truesdale Clinic | Thipphawong J.,Johnson and Johnson PRD
Pain Practice | Year: 2013

Objective: Opioids are recommended for patients with moderate to severe pain due to osteoarthritis (OA), who do not receive adequate analgesia from nonopioid treatment. The objective of this study was to evaluate the efficacy and safety of OROS hydromorphone extended-release (ER) compared with placebo in patients with moderate to severe pain associated with OA. Methods: This was a randomized, placebo-controlled, double-blind, fixed-dose study. Patients received placebo or fixed-dose OROS hydromorphone ER (8 or 16mg). The primary efficacy measure was pain intensity score (11-point Numeric Rating Scale) at Maintenance Week 12, analyzed with baseline observation carried forward (BOCF) imputation for missing data. Results: This study did not meet the primary efficacy measure using the BOCF imputation. Study discontinuation was high (52%). When analyzed using last observation carried forward (LOCF) imputation, the prespecified alternate method, OROS hydromorphone ER 16mg provided significantly better analgesia than placebo (P=0.0009). Treatment was associated with significant improvements in patient global assessment (P=0.01), the overall Western Ontario and McMaster Osteoarthritis Index (WOMAC) (P=0.0003), and its subscales: pain (P=0.0001), stiffness (P=0.0023), and physical function (P=0.0006). Gastrointestinal adverse events, such as constipation and nausea, were common among patients receiving OROS hydromorphone ER. Conclusions: OROS hydromorphone ER failed to achieve statistical significance for the primary endpoint using the prespecified imputation method (BOCF), likely due to the high discontinuation rate associated with the fixed-dose design. When data were analyzed according to an alternate method of imputation (LOCF), OROS hydromorphone ER demonstrated statistically significant improvements in pain, stiffness, and physical function. © 2012 The Authors. Pain Practice © 2012 World Institute of Pain. Source

Daly E.J.,Johnson and Johnson PRD | Daly E.J.,University of Texas Southwestern Medical Center | Trivedi M.H.,University of Texas Southwestern Medical Center | Wisniewski S.R.,University of Pittsburgh | And 8 more authors.
Annals of Clinical Psychiatry | Year: 2010

BACKGROUND: Although major depressive disorder (MDD) is associated with significant impairments in health-related quality of life (HRQOL), few studies have evaluated HRQOL dysfunction in multiple domains. This report examined the psychological, physical, and social domains in a large sample of outpatients who entered the Sequenced Treatment Alternatives to Relieve Depression (STAR&z.ast;D) trial. METHODS: The relationship of HRQOL and baseline sociodemographic and clinical features, including depressive severity, was evaluated. We assessed HRQOL with the 12-item Short Form Health Survey, the 5-item Work and Social Adjustment Scale, and the 16-item Quality of Life Enjoyment and Satisfaction Questionnaire. RESULTS: Among 2307 participants, greater depressive symptom severity was associated with poorer HRQOL. After controlling for age and depression severity, lower HRQOL was related independently to being African American or Hispanic, less educated, unemployed, divorced or separated, having public medical insurance, and to having more general medical disorders. We found impairments across all 3 domains, with low correlations between the 3 measures of HRQOL chosen, suggesting that they evaluate different and nonoverlapping aspects of function. CONCLUSION: Sociodemographically disadvantaged patients with greater general medical and depressive illness burden are at greatest risk for poorer quality of life. Distinct impairments are seen in the 3 domains of HRQOL. Source

Steckler T.,Johnson and Johnson PRD
Current Topics in Behavioral Neurosciences | Year: 2010

Neuropeptide systems have been considered a major opportunity for the development of novel treatment approaches for anxiety disorders based on preclinical evidence and neurochemical alterations seen in anxiety disorders. This excitement was further facilitated by the fact that drugs acting at these systems, such as CRF1 antagonists, NK1 antagonists, NK3 antagonists or CCK2 antagonists, may have unique properties not seen with drugs affecting more classical mechanisms involved in anxiety. Consequently, there have been major efforts to develop such smallmolecule, nonpeptide receptor ligands. A number of these molecules have been tested in the clinic, either in trials where levels of anxiety served as a secondary measure, or in a few studies with patients suffering from anxiety disorders. But unfortunately, and despite all the efforts of the field as a whole, we still lack convincing clinical proof-of-concept for any of the neuropeptidergic approaches in patients. It must, therefore, be concluded that neuropeptide targets remain a promising approach for the development of the next generation drugs to treat anxiety disorders, but that they continue to be high-risk targets for drug development. © Springer-Verlag Berlin Heidelberg 2009. Source

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