Publications by authors named "Julia Boyle"

31 Publications

The school-led study: Protocol of a cluster-randomised controlled trial of effectiveness to prevent adolescent alcohol misuse, internalising problems, and externalising problems through a personality-targeted intervention delivered by school staff.

Prev Med Rep 2021 Mar 19;21:101286. Epub 2020 Dec 19.

The Matilda Centre for Research in Mental Health and Substance Use, Sydney Medical School, The University of Sydney, Australia.

Mental disorders and problematic alcohol use are common, co-occurring and cause significant harm to individuals and society. It is critical to intervene early to prevent chronic and debilitating trajectories. Existing prevention programs among adolescents are limited in effectiveness and implementation. This Australian-first study will examine the effectiveness and feasibility of a personality-targeted program called Preventure, in preventing the onset or escalation of alcohol use, internalising problems and externalising problems among young Australians, when delivered by school staff. A cluster randomised controlled trial (RCT) of effectiveness will be conducted from 2020 to 2022 with 12 schools in Sydney, Australia, with students aged 13 years at baseline. Schools will be randomly allocated to the intervention or a control condition who will receive their usual Health Education curriculum. Schools allocated to the intervention will deliver to students scoring one standard deviation above the population mean on one of four personality traits. consists of two 90-minute group sessions that incorporate cognitive-behavioural therapy and motivational interviewing to promote coping skills. Students will be invited to complete surveys at baseline, 6- and 12-months following the intervention. Primary outcomes include student alcohol use, internalising problems, and externalising problems. Implementation fidelity, feasibility and acceptability will also be examined through surveys with school staff and students. Ethical approval has been obtained from the University of Sydney Human Research Ethics Committee, and the State Education Research Applications Process for research in public schools in NSW. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12620000790943).
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http://dx.doi.org/10.1016/j.pmedr.2020.101286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772564PMC
March 2021

CYP2D6 Expression in Veterans Experiencing Opioid Overdose: A Postmortem Review.

Pharmgenomics Pers Med 2020 11;13:289-293. Epub 2020 Aug 11.

Department of Pharmacy, VA Salt Lake City Health Care System, Salt Lake City, UT, USA.

Purpose: The purpose is to characterize the CYP2D6 genotype and predict the phenotype of decedents of opioid overdose to determine if the ultrarapid (UM) phenotype is over-represented in opioid overdose deaths. CYP2D6 is the enzyme responsible for metabolism of various opioids implicated in overdose. The UM group may be at greater risk for overdose due to the rapid metabolism of hydrocodone, oxycodone, or tramadol to more active/potent metabolites than their peers with (poor) PM, (intermediate) IM, or (extensive) EM metabolic phenotypes.

Patients And Methods: Blood samples obtained during autopsy following an opioid overdose from 75 US military veteran decedents prescribed hydrocodone, oxycodone, or tramadol from one VA medical center were analyzed. DNA extraction, CYP2D6 genotyping, and copy number variation (CNV) testing were performed using the iPLEX genotyping assay and MassARRAY. Phenotype prediction was based on Clinical Pharmacogenetics Implementation Consortium (CPIC) recommendations. Toxicology results were obtained from Medical Examiner reports of the deceased. Prescription medication information was extracted from archived medical records.

Results: The majority of the sample had a phenotype of EM metabolizer (75%), with 7% of the total sample having a UM metabolizer phenotype. In addition to hydrocodone, oxycodone, and tramadol (found in 41% of opioid positive samples), other opioids found in toxicology tests included diacetylmorphine, fentanyl, buprenorphine, and methadone. Two or more substances, including alcohol, benzodiazepines, and other potentially sedating medications, were found in nearly half of the opioid positive toxicology samples.

Conclusion: In this study, 7% of veteran decedents of opioid overdose had CYP2D6 UM metabolic phenotype. The small sample size precludes a conclusion that the frequency of UM phenotype is greater than expected in North American Caucasian groups. The findings in this study do not support the hypothesis that the UM phenotype is over-represented in opioid overdose.
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http://dx.doi.org/10.2147/PGPM.S261424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429207PMC
August 2020

Practice Transformation Driven through Academic Partnerships.

Pharmacy (Basel) 2020 Jul 14;8(3). Epub 2020 Jul 14.

Department of Pharmacy Practice and Administrative Sciences, College of Pharmacy, Idaho State University, Pocatello Campus, Pocatello, ID 83209, USA.

Evidence-based interventions have been shown to improve the quality of patient care, reduce costs, and improve overall health outcomes; however, adopting new published research and knowledge into practice has historically been slow, and requires an active, systematic approach to engage clinicians and healthcare administrators in the required change. Pharmacists have been identified as important agents of change and can enhance care delivery in primary care settings through evidence-based interventions. Utilizing the Consolidated Framework for Implementation Research (CFIR) we identify, assess, and share barriers and facilitators to program development, as well as growth and expansion efforts across five discrete, university-subsidized, embedded-pharmacy practices in primary care. We identified two overarching modifiable factors that influence current and future practice delivery and highlight the role of academia as an incubator for practice change and implementation: Data collection and information sharing. Conceptual frameworks such as CFIR help establish a common vernacular that can be used to facilitate systematic practice site implementation and dissemination of information required to support practice transformation.
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http://dx.doi.org/10.3390/pharmacy8030120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558616PMC
July 2020

Rural Community Perceptions and Interests in Pharmacogenomics.

Healthcare (Basel) 2020 Jun 5;8(2). Epub 2020 Jun 5.

College of Pharmacy, Idaho State University, 921 S. 8th Ave., Pocatello, ID 83201, USA.

Pharmacogenomics testing is a rapidly expanding field with increasing importance to individualized patient care. However, it remains unclear whether the general public in rural areas would be willing to engage in this service. The objective of this survey was to determine rural community-dwelling members' perceptions of pharmacogenomics. A questionnaire was developed consisting of five Likert-style questions on knowledge and perceptions of pharmacogenomics, a single multiple-choice question on cost of testing, and a free-response question. Two cohorts received the same questionnaire: attendees at a university-sponsored health fair and patients presenting to two independent community pharmacies in southeastern Idaho. While both showed positive reception to the implementation and value of pharmacogenomics, those at the health fair were more in favor of pharmacogenomics, suggesting a need for greater outreach and education to the general public. The findings suggest that interest of rural community-dwelling individuals may be amenable to the expansion of pharmacogenomics testing.
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http://dx.doi.org/10.3390/healthcare8020159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348789PMC
June 2020

Genetic Influences on the Amount of Cell Death in the Neural Tube of BXD Mice Exposed to Acute Ethanol at Midgestation.

Alcohol Clin Exp Res 2019 03 12;43(3):439-452. Epub 2019 Feb 12.

Department of Anatomy and Neurobiology , University of Tennessee Health Science Center, Memphis, Tennessee.

Background: Fetal alcohol spectrum disorders (FASD) have a strong genetic component although the genes that underlie this are only beginning to be elucidated. In the present study, one of the most common phenotypes of FASD, cell death within the early developing neural tube, was examined across a genetic reference population in a reverse genetics paradigm with the goal of identifying genetic loci that could influence ethanol (EtOH)-induced apoptosis in the early developing neural tube.

Methods: BXD recombinant inbred mice as well as the parental strains were used to evaluate genetic differences in EtOH-induced cell death after exposure on embryonic day 9.5. Dams were given either 5.8 g/kg EtOH or isocaloric maltose-dextrin in 2 doses via intragastric gavage. Embryos were collected 7 hours after the initial exposure and cell death evaluated via TUNEL staining in the brainstem and forebrain. Genetic loci were evaluated using quantitative trait locus (QTL) analysis at GeneNetwork.org.

Results: Significant strain differences were observed in the levels of EtOH-induced cell death that were due to genetic effects and not confounding variables such as differences in developmental maturity or cell death kinetics. Comparisons between the 2 regions of the developing neural tube showed little genetic correlation with the QTL maps exhibiting no overlap. Significant QTLs were found on murine mid-chromosome 4 and mid-chromosome 14 only in the brainstem. Within these chromosomal loci, a number of interesting candidate genes were identified that could mediate this differential sensitivity including Nfia (nuclear factor I/A) and Otx2 (orthodenticle homeobox 2).

Conclusions: These studies demonstrate that the levels of EtOH-induced cell death occur in strain- and region-dependent manners. Novel QTLs on mouse Chr4 and Chr14 were identified that modulate the differential sensitivity to EtOH-induced apoptosis in the embryonic brainstem. The genes underlying these QTLs could identify novel molecular pathways that are critical in this phenotype.
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http://dx.doi.org/10.1111/acer.13947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410727PMC
March 2019

A retrospective chart review of opioid represcribing following nonfatal overdose at a Veterans Affairs hospital.

Ment Health Clin 2017 Nov 23;7(6):276-281. Epub 2018 Mar 23.

Pharmacist/Investigator, VA Salt Lake City Health Care System, Salt Lake City, Utah.

Introduction: Opioid-related overdoses have risen despite extensive media coverage and apparent awareness of this public health crisis. Emergency department visits related to opioid use nearly tripled from 2004 to 2011. Patients with mental illness are more likely to be prescribed opioids and have higher rates of overdose. This retrospective chart review sought to determine if opioid represcribing occurred after patients were treated for a nonfatal opioid overdose (NFO) at a Veterans Affairs hospital.

Methods: Patients who experienced an NFO between 2009 and 2013 were included and charts reviewed until January 1, 2016. Review of the electronic medical record (EMR) was performed to determine if and when opioids were again prescribed after NFO.

Results: Fifty-six veterans met the inclusion criteria. A new opioid prescription was issued to 82% of patients within 3 months following the index NFO date. The average daily morphine equivalent dose prescribed before (122 mg) and after (120 mg) NFO did not differ. A subsequent opioid overdose event occurred in 25% of patients, and there was 1 fatal event. Only 1 patient had medication overdose on the problem list of their EMR.

Discussion: Despite experiencing NFO, veterans continued to be prescribed opioids without significant changes in the drug or dose; some experienced repeated overdose events, possibly due to poor communication and documentation of NFO. Pharmacists can play a key role in clinical interventions and education of patients and prescribers.
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http://dx.doi.org/10.9740/mhc.2017.11.276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007726PMC
November 2017

A cluster randomised feasibility trial of clinically assisted hydration in cancer patients in the last days of life.

Palliat Med 2018 04 18;32(4):733-743. Epub 2018 Jan 18.

2 University of Surrey, Guildford, UK.

Background: The provision of clinically assisted hydration at the end-of-life is one of the most contentious issues in medicine.

Aim: The aim of this feasibility study was to answer the question 'can a definitive (adequately powered) study be done?'

Design: The study was a cluster randomised trial, with sites randomised on a one-to-one basis to intervention 'A' (regular mouth care and usual other care) or intervention 'B' (clinically assisted hydration, mouth care and usual other care). Participants were assessed every 4 h, and data collected on clinical problems, therapeutic interventions and overall survival.

Setting/participants: The study was conducted at 12 sites/'clusters' with specialist palliative care teams (4 cancer centres and 8 hospices), and participants were cancer patients in the last week of life who were unable to maintain sufficient oral fluid intake.

Results: The study achieved its pre-determined criteria for success. Two hundred patients were recruited to the study, and 199 participants completed the study, over a 1-year period. A total of 38.5% participants discontinued clinically assisted hydration due to adverse effects: none of these adverse events were rated as 'severe' or worse in intensity. The primary reasons for discontinuation were site problems ( n = 2), localised oedema ( n = 13), generalised oedema ( n = 5), respiratory secretions ( n = 6) and nausea and vomiting ( n = 1).

Conclusion: The results of this feasibility study suggest that a definitive study can be done, but that minor changes are needed to the protocol to standardise the administration of clinically assisted hydration (which may reduce the incidence of certain adverse effects).
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http://dx.doi.org/10.1177/0269216317741572DOI Listing
April 2018

Sleep Well!: A Pilot Study of an Education Campaign to Improve Sleep of Socioeconomically Disadvantaged Children.

J Clin Sleep Med 2016 12 15;12(12):1593-1599. Epub 2016 Dec 15.

The Children's Hospital of Philadelphia, Philadelphia, PA.

Study Objectives: Socioeconomically disadvantaged children are at risk for poor sleep hygiene and increased sleep problems. This pilot study examined the efficacy of Sleep Well!, a parent-based sleep education endeavor, which supplemented an outreach program that provides beds to socioeconomically disadvantaged children.

Methods: In addition to receiving a bed, 152 children (mean age = 5.95 years, 57.2% boys) were randomly assigned to sleep education (3 messages: bedtime before 21:00; no caffeine; keep electronics out of the bedroom) or control (dental hygiene education) conditions. All education was provided at both the time of scheduling and delivery of a bed to each child. Parent-reported sleep data were collected at baseline and at 4-week follow-up.

Results: Provision of a bed was associated with reduced bedroom electronics and increased parent-reported nighttime sleep duration for all children. However, relative to control children, intervention children showed even greater reductions in electronics (baseline mean = 1.91 items, follow-up mean = 0.85 items) and improvements in sleep duration (baseline mean = 9.75 hours, follow-up mean = 10.19 hours). There was no intervention effect for caffeine consumption or bedtime from baseline to follow-up.

Conclusions: Providing beds to socioeconomically disadvantaged children resulted in increased sleep duration and decreased use of electronics at bedtime, while the combination of a bed and brief parent sleep education conferred additional sleep benefits. Further study of brief child sleep interventions is warranted, particularly among socioeconomically disadvantaged children who are at risk for sleep problems.
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http://dx.doi.org/10.5664/jcsm.6338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155198PMC
December 2016

The Effects of Rhodiola rosea L. Extract on Anxiety, Stress, Cognition and Other Mood Symptoms.

Phytother Res 2015 Dec 27;29(12):1934-9. Epub 2015 Oct 27.

School of Biosciences and Medicine, University of Surrey, Guildford, Surrey, UK.

This trial evaluated the impact of a Rhodiola rosea L. extract on self-reported anxiety, stress, cognition, and other mood symptoms. Eighty mildly anxious participants were randomized into two different groups of either Rhodiola rosea L (2 × 200 mg dose Vitano®, 1 tablet taken before breakfast and 1tablet before lunch) or a control condition (no treatment). Self-report measures and cognitive tests were completed at four testing sessions over a period of 14 days. Relative to the controls, the experimental group demonstrated a significant reduction in self-reported, anxiety, stress, anger, confusion and depression at 14 days and a significant improvements in total mood. No relevant differences in cognitive performance between the groups were observed. Rhodiola rosea L (Vitano®) presented a favourable safety tolerability profile. Although this was a non-placebo controlled trial, it is unlikely that the findings were the result of placebo effects as changes appeared gradual and were specific to certain psychological measures. However, we cannot determine a causal relationship; further investigations are recommended to support the effects of Rhodiola rosea L. extract on stress related symptoms.
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http://dx.doi.org/10.1002/ptr.5486DOI Listing
December 2015

Alternative forms of hydration in patients with cancer in the last days of life: study protocol for a randomised controlled trial.

Trials 2015 Oct 14;16:464. Epub 2015 Oct 14.

Surrey CTU, Surrey Clinical Research Centre, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Egerton Road, Guildford, Surrey, GU2 7XH, UK.

Background: The provision of clinically assisted hydration at the end of life is one of the most contentious issues in medicine, and indeed within the general population. The reasons for contention include: a) the lack of evidence for or against; b) the disparate opinions of healthcare professionals; and c) the generally positive opinions of patients and their carers about clinically assisted hydration.

Methods/design: The study is a cluster randomised trial to assess the feasibility of conducting an adequately powered, randomised controlled trial of clinically assisted hydration in patients with cancer in the last days of life. Twelve sites, four National Health Service (NHS) hospitals and eight NHS/voluntary sector hospices in the United Kingdom, will be randomised to give either standard intervention A: continuance of oral intake and regular mouth care, or standard intervention B: continuance of oral intake, regular mouth care and clinically assisted hydration. Patients will be included if they: i) have a diagnosis of cancer; ii) are aged ≥ 18 yr; iii) have an estimated prognosis of ≤ 1 week and iv) are unable to maintain sufficient oral intake (1 L per day, measured/estimated); and v) are able to give informed consent. Patients will be excluded if they have contra-indications to receiving clinically assisted hydration. The primary endpoint of interest is the frequency of hyperactive delirium ('terminal agitation'), and this will be assessed using the Modified Richmond Agitation and Sedation Scale (administered every four hours). Other data to be collected include the frequency of pain, respiratory secretions ('death rattle'), dyspnoea, nausea and vomiting, adverse effects to clinically assisted hydration and overall survival. In addition, data will be collected on the use of anti-psychotic drugs, sedative drugs, analgesics, anti-secretory drugs and other end-of-life medication. The study has obtained full ethical approval.

Discussion: A randomised controlled trial of clinically assisted hydration in end-of-life care is urgently required. This feasibility study will allow methodological and ethical issues to be understood and addressed to ensure that a robust, adequately powered, randomised controlled trial is designed.

Trial Registration: ClinicalTrials.gov NCT02344927 (registered 4 June 2014).
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http://dx.doi.org/10.1186/s13063-015-0988-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607172PMC
October 2015

Regulatory approval and a first-in-human phase I clinical trial of a monoclonal antibody produced in transgenic tobacco plants.

Plant Biotechnol J 2015 Oct 3;13(8):1106-20. Epub 2015 Jul 3.

Fraunhofer IME, Aachen, Germany.

Although plant biotechnology has been widely investigated for the production of clinical-grade monoclonal antibodies, no antibody products derived from transgenic plants have yet been approved by pharmaceutical regulators for clinical testing. In the Pharma-Planta project, the HIV-neutralizing human monoclonal antibody 2G12 was expressed in transgenic tobacco (Nicotiana tabacum). The scientific, technical and regulatory demands of good manufacturing practice (GMP) were addressed by comprehensive molecular characterization of the transgene locus, confirmation of genetic and phenotypic stability over several generations of transgenic plants, and by establishing standard operating procedures for the creation of a master seed bank, plant cultivation, harvest, initial processing, downstream processing and purification. The project developed specifications for the plant-derived antibody (P2G12) as an active pharmaceutical ingredient (API) based on (i) the guidelines for the manufacture of monoclonal antibodies in cell culture systems; (ii) the draft European Medicines Agency Points to Consider document on quality requirements for APIs produced in transgenic plants; and (iii) de novo guidelines developed with European national regulators. From the resulting process, a GMP manufacturing authorization was issued by the competent authority in Germany for transgenic plant-derived monoclonal antibodies for use in a phase I clinical evaluation. Following preclinical evaluation and ethical approval, a clinical trial application was accepted by the UK national pharmaceutical regulator. A first-in-human, double-blind, placebo-controlled, randomized, dose-escalation phase I safety study of a single vaginal administration of P2G12 was carried out in healthy female subjects. The successful completion of the clinical trial marks a significant milestone in the commercial development of plant-derived pharmaceutical proteins.
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http://dx.doi.org/10.1111/pbi.12416DOI Listing
October 2015

Molecular pathways underpinning ethanol-induced neurodegeneration.

Front Genet 2014 15;5:203. Epub 2014 Jul 15.

Department of Anatomy and Neurobiology, University of Tennessee Health Science Center Memphis, TN, USA.

While genetics impacts the type and severity of damage following developmental ethanol exposure, little is currently known about the molecular pathways that mediate these effects. Traditionally, research in this area has used a candidate gene approach and evaluated effects on a gene-by-gene basis. Recent studies, however, have begun to use unbiased approaches and genetic reference populations to evaluate the roles of genotype and epigenetic modifications in phenotypic changes following developmental ethanol exposure, similar to studies that evaluated numerous alcohol-related phenotypes in adults. Here, we present work assessing the role of genetics and chromatin-based alterations in mediating ethanol-induced apoptosis in the developing nervous system. Utilizing the expanded family of BXD recombinant inbred mice, animals were exposed to ethanol at postnatal day 7 via subcutaneous injection (5.0 g/kg in 2 doses). Tissue was collected 7 h after the initial ethanol treatment and analyzed by activated caspase-3 immunostaining to visualize dying cells in the cerebral cortex and hippocampus. In parallel, the levels of two histone modifications relevant to apoptosis, γH2AX and H3K14 acetylation, were examined in the cerebral cortex using protein blot analysis. Activated caspase-3 staining identified marked differences in cell death across brain regions between different mouse strains. Genetic analysis of ethanol susceptibility in the hippocampus led to the identification of a quantitative trait locus on chromosome 12, which mediates, at least in part, strain-specific differential vulnerability to ethanol-induced apoptosis. Furthermore, analysis of chromatin modifications in the cerebral cortex revealed a global increase in γH2AX levels following ethanol exposure, but did not show any change in H3K14 acetylation levels. Together, these findings provide new insights into the molecular mechanisms and genetic contributions underlying ethanol-induced neurodegeneration.
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http://dx.doi.org/10.3389/fgene.2014.00203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4097813PMC
July 2014

Randomised clinical trial investigating the specificity of a novel skin test (C-Tb) for diagnosis of M. tuberculosis infection.

PLoS One 2013 14;8(5):e64215. Epub 2013 May 14.

Department of Vaccine Development, Statens Serum Institut, Copenhagen, Denmark.

Background: Tuberculin skin testing is simple and relatively inexpensive, but the specificity of PPD is affected by BCG vaccination.

Objective: Determine optimal dose and specificity of recombinant ESAT-6 and CFP-10 (C-Tb) produced in Lactococcus lactis for diagnosis of M. tuberculosis infection.

Methods: In a dose finding phase I trial 0.01 or 0.1 µg preserved and unpreserved C-Tb was injected by Mantoux technique in 38 patients with active tuberculosis and induration responses measured. In a phase II specificity trial in 151 uninfected, BCG vaccinated participants 0.1 µg C-Tb was compared to 2 TU PPD.

Results: 0.1 µg C-Tb gave a median induration of 15 mm after 2 days. Phenol preservation did not affect the response. The specificity of C-Tb was 99.3% (95% CI 96-100%) regarding indurations ≥5 mm as a positive outcome. This was higher than the specificity of PPD (63% using a cut-off of 5 mm or 92% using a cut-off of 15 mm to adjust for non-specific BCG responses). Local adverse reactions following C-Tb injection included transient itching and discomfort as expected components of the immune response.

Conclusion: C-Tb offers a simple and convenient skin test to diagnose M. tuberculosis infection using a single, universal cut-off unaffected by BCG vaccination.

Trial Registration: ClinicalTrials.gov NCT01033929 and NCT01241188.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064215PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653866PMC
December 2013

Randomized, placebo-controlled comparison of amitriptyline, duloxetine, and pregabalin in patients with chronic diabetic peripheral neuropathic pain: impact on pain, polysomnographic sleep, daytime functioning, and quality of life.

Diabetes Care 2012 Dec 18;35(12):2451-8. Epub 2012 Sep 18.

Surrey Clinical Research Centre, Institute of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK.

Objective: Chronic diabetic peripheral neuropathic pain (DPNP) is difficult to treat, with treatment regimens often inadequate at controlling pain and limited by side effects and drug tolerance. Secondary parameters, such as quality of sleep and mood, may also be important for successful DPNP management. The objectives of this study were to compare the analgesic efficacy of pregabalin, amitriptyline, and duloxetine, and their effect on polysomnographic sleep, daytime functioning, and quality of life in patients with DPNP.

Research Design And Methods: This was a double-blind, randomized, parallel group investigation of type 1 and 2 diabetic subjects with DPNP. Each treatment group had a single-blind, 8-day, placebo run-in followed by 14 days of lower-dose and 14 days of higher-dose medication. At the end of each dose titration period, subjective pain, sleep, and daytime functioning were assessed during a 2-day residential period.

Results: All medications reduced pain when compared with placebo, but no one treatment was superior to any other. For sleep, pregabalin improved sleep continuity (P < 0.001), whereas duloxetine increased wake and reduced total sleep time (P < 0.01 and P < 0.001). Despite negative effects on sleep, duloxetine enhanced central nervous system arousal and performance on sensory motor tasks. There were no significant safety findings; however, there was a significantly higher number of adverse events in the pregabalin treatment group.

Conclusions: There was no significant difference in analgesic efficacy between amitriptyline, duloxetine, and pregabalin. However, there were significant differences in the secondary parameters, which may be of relevance when deciding the optimal treatment for DPNP.
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http://dx.doi.org/10.2337/dc12-0656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507552PMC
December 2012

A method to assess the dissipation of the [corrected] residual effects of [corrected] hypnotics: eszopiclone versus zopiclone.

J Clin Psychopharmacol 2012 Oct;32(5):704-9

Surrey Clinical Research Centre, University of Surrey, Guildford, Surrey, UK.

Next-day residual effects of single evening doses of 3 mg of eszopiclone, 7.5 mg of zopiclone, and placebo were assessed in a randomized, double-blind, placebo-controlled, 3-way crossover study that used a mild sleep restriction protocol (sleep duration, 7 hours). During each period, 91 healthy volunteers spent 2 consecutive nights in the laboratory with time in bed restricted to 7 hours. Volunteers completed the Continuous Tracking Test, Critical Flicker Fusion task, Digit Symbol Substitution Test, N-back tasks, and Linear Analogue Rating Scales every half-hour from 7.5 to 11.5 hours after dose, commencing 15 minutes after awakening. Nighttime dosing of both eszopiclone (3 mg) and racemic zopiclone (7.5 mg) was associated with next-day performance impairment, and these residual effects dissipated over time. Eszopiclone did not differ from zopiclone on the primary end point, mean Continuous Tracking Test tracking error averaged from 7.5 to 9.5 hours after dose; however, a prespecified post hoc parametric analysis of reciprocal-transformed data favored eszopiclone over racemic zopiclone (P = 0.026).
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http://dx.doi.org/10.1097/JCP.0b013e3182664eecDOI Listing
October 2012

Acute sleep deprivation: the effects of the AMPAKINE compound CX717 on human cognitive performance, alertness and recovery sleep.

J Psychopharmacol 2012 Aug 22;26(8):1047-57. Epub 2011 Sep 22.

Surrey Clinical Research Centre, Division of Clinical Medicine, Faculty of Health and Medical Sciences University of Surrey, Guildford, Surrey, UK.

AMPA receptor modulation is a potential novel approach to enhance cognitive performance. CX717 is a positive allosteric modulator of the AMPA receptor that has shown efficacy in rodent and primate cognition models. CX717 (100 mg, 300 mg and 1000 mg) and placebo were studied in 16 healthy male volunteers (18-45 years) in a randomized, crossover study. Cognitive function, arousal and recovery sleep (by polysomnography) were assessed during the extended wakefulness protocol. Placebo condition was associated with significant decrements in cognition, particularly at the circadian nadir (between 03:00 and 05:00). Pre-specified primary and secondary analyses (general linear mixed modelling, GLMM) at each separate time point did not reveal consistent improvements in performance or objective alertness with any dose of CX717. Exploratory repeated measures analysis, a method used to take into account the influence of individual differences, demonstrated an improvement in attention-based task performance following the 1000 mg dose. Analysis of the recovery sleep showed that CX717 1000 mg significantly reduced stage 4 and slow-wave sleep (p ≤ 0.05) with evidence of reduced electroencephalogram (EEG) slow-wave and spindle activity. The study suggests that CX717 only at the 1000 mg dose may counteract effects of sleep deprivation on attention-based tasks and that it may interfere with subsequent recovery sleep.
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http://dx.doi.org/10.1177/0269881111405353DOI Listing
August 2012

Effect of a novel histamine subtype-3 receptor inverse agonist and modafinil on EEG power spectra during sleep deprivation and recovery sleep in male volunteers.

Psychopharmacology (Berl) 2011 Jun 8;215(4):643-53. Epub 2011 Feb 8.

Surrey Sleep Research Centre, Faculty of Health and Medical Sciences, University of Surrey, Egerton Road, Guildford, GU2 7XP, UK.

Rationale: Histamine and dopamine contribute to the maintenance of wakefulness.

Objective: This study aims to conduct an exploratory analysis of the effects of 10 and 50 mg of MK-0249, a novel histamine subtype-3 receptor inverse agonist, and 200 mg of modafinil, a presumed dopaminergic compound, on EEG power spectra during sleep deprivation and subsequent recovery sleep.

Methods: A total of 25 healthy men were recruited to a double-blind, placebo-controlled cross-over design. EEG power spectra, an electrophysiological marker of changes in sleepiness and vigilance, were obtained at the beginning of wake maintenance tests at two-hourly intervals throughout a night and day of sleep deprivation, which is an established model of excessive sleepiness.

Results: After placebo, sleep deprivation was associated with enhancements in delta and theta and reductions in alpha and beta activity. Following dosing at 02:00 h, MK-0249 and modafinil reduced delta and theta activity and enhanced alpha and beta activity, compared to placebo. During recovery sleep initiated at 21:00 h, latency to sleep onset and number of awakenings were not different from placebo for any of the active treatments. Wake after sleep onset and stage 1% was increased and total sleep time, SWS% and REM% were reduced after both doses of MK-0249. Compared to placebo, MK-0249, the 50-mg dose in particular, reduced activity in some delta and theta/alpha frequencies and enhanced beta activity during NREM sleep and REM sleep. After modafinil, no changes were observed for power spectra during sleep.

Conclusion: Both MK-0249 and modafinil exert effects on the EEG which are consistent with wake promotion.
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http://dx.doi.org/10.1007/s00213-010-2158-3DOI Listing
June 2011

Human amniocytes regulate serotonin levels by active uptake and express genes suggestive of a wider role in facilitating neurotransmitter regulation in the fetal environment.

Stem Cells Dev 2011 Feb 18;20(2):341-9. Epub 2010 Oct 18.

Laboratory of Developmental Neurobiology, School of Biomolecular and Biomedical Sciences, University College Dublin, Conway Institute, Dublin, Ireland.

Fetal serotonin levels, which mediate multiple developmental processes, are highly regulated. However, an incomplete picture exists on the component parts of such regulation during fetal growth. Serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) are found in the amniotic fluid, also containing significant numbers of amniocytes, previously thought to be the result of cell shedding as a byproduct of growth. The aim of the present study was to examine human amniocytes as a potentially active and dynamic component of serotonin regulation in the fetal environment. Using amniocytes derived from multiple donors of amniocentesis, we found all components necessary for serotonin metabolism. We identified a strong expression of the serotonin transporter and confirmed the high-affinity serotonin transporter-mediated uptake of serotonin (5-HT), along with uptake via the norepinephrine transporter, and an evidence of 5-HT breakdown due to the expression of the degradative enzymes monoamine oxidase A and B. Additionally, wider expression analysis for biogenic amine and cholinergic metabolism suggests a capability for cholinergic synthesis and release and for catecholamine storage. Our results shed new light on amniocytes, consistent with a role in the homeostasis of neurotransmitters during fetal development. Moreover, these results may provide clinical significance for amniocytes as new targets for uptake inhibitors such as tricyclic antidepressants, selective serotonin reuptake inhibitors, and drugs of abuse such as cocaine, with implications on their regulation during pregnancy. This work shows for the first time an inherent in vivo function of amniocytes and more broadly implicates them as a new and active component of the fetal-maternal regulatory system.
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http://dx.doi.org/10.1089/scd.2009.0500DOI Listing
February 2011

Tolerability, pharmacokinetics and night-time effects on postural sway and critical flicker fusion of gaboxadol and zolpidem in elderly subjects.

Br J Clin Pharmacol 2009 Feb 16;67(2):180-90. Epub 2008 Dec 16.

School of Biomedical andMolecular Sciences, Human Psychopharmacology Research Unit, Medical Research Centre, University of Surrey, Egerton Road, Guilford, Surrey, UK.

What Is Already Known About This Subject: Body sway increases in older adults and may lead to an increase in the risk of falling. The problem of impaired stability in the elderly may be compounded by the use of hypnotics, which have been associated with an increased risk of next-day falls as well as drowsiness. The potential adverse effects of hypnotic drugs on steadiness may be exacerbated during the night, in the event that an individual needs to get out of bed.

What This Study Adds: This study examines the effects of gaboxadol (an investigational treatment for insomnia), zolpidem (a current hypnotic included as an active control) and placebo on body sway and attention/information processing ability following bedtime dosing in elderly subjects who were woken during the night for assessments. Zolpidem and gaboxadol increased body sway at various time points during the night relative to placebo; at 1.5 h post dose, the time of peak concentrations of both drugs, gaboxadol produced less impairment than zolpidem. Compared with placebo, neither gaboxadol nor zolpidem impaired attention/information-processing ability as assessed by critical flicker fusion.

Aims: To evaluate tolerability, pharmacokinetics and night-time effects on body sway and critical flicker fusion (CFF) of gaboxadol following bedtime dosing in healthy elderly subjects.

Methods: Subjects (17 women, seven men) aged 65-75 years received gaboxadol 10 mg, zolpidem 5 mg (active control) or placebo at 22.00 h in a three-period, randomized, double-blind crossover study. They were awakened during the night for evaluation of body sway and CFF. Pharmacokinetics of gaboxadol were assessed during a fourth single-blind treatment period. Adverse events were recorded throughout the study.

Results: The number of subjects with adverse events was 14 for gaboxadol 10 mg, seven for zolpidem and nine for placebo; most were mild or moderate in intensity. Two women discontinued the study following gaboxadol; one vomited and one experienced a severe vasovagal syncope after venepuncture. Mean gaboxadol t(max) was 2 h, t((1/2)) was 1.7 h, AUC(0-infinity) was 430 ng.h ml(-1) and C(max) was 139 ng ml(-1). At 1.5 h and 4 h post dose, zolpidem increased body sway relative to placebo (P < 0.01). Gaboxadol increased body sway at 4 h (P < 0.001) and 8 h (P < 0.05) relative to placebo. At 1.5 h, the time point closest to peak drug concentrations, zolpidem increased body sway compared with gaboxadol (P < 0.01). Gaboxadol and zolpidem had no effects on CFF vs. placebo.

Conclusions: A bedtime dose of gaboxadol 10 mg was generally well tolerated. Changes in body sway at 1.5 h after bedtime dosing were smaller with gaboxadol 10 mg than with zolpidem 5 mg, whereas changes were similar at 4 h for both treatments and returned to near baseline at 8 h.
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http://dx.doi.org/10.1111/j.1365-2125.2008.03331.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670375PMC
February 2009

Efficacy of a nicotine (4 mg)-containing lozenge on the cognitive impairment of nicotine withdrawal.

J Clin Psychopharmacol 2008 Dec;28(6):667-74

CRC, Faculty of Medical & Health Sciences, University of Surrey, Guildford, Surrey, UK.

Objective: Controversy exists over the effect of tobacco deprivation in nicotine-dependent individuals and the efficacy of nicotine in reversing performance decrements. This study's aim was to assess the efficacy of nicotine (4-mg lozenge) versus placebo on aspects of cognitive and psychomotor performance, mood, and withdrawal symptoms in male and female established smokers.

Methods: Male and female smokers (N = 22; mean age, 28.8 years), with a smoking history of more than 1 year and time to first cigarette of less than 30 minutes upon waking, were enrolled. Baseline measures were obtained at 17 hours of abstinence. At 18-hour abstinence, nicotine or placebo was administered every 2 hours over an 8-hour period. Cognitive and psychomotor performance measurements were taken 30 minutes after dose. Cognitive test battery included Rapid Visual Information Processing, Continuous Tracking Task, Critical Flicker Fusion, Choice Reaction Time, Stroop Test, and Sternberg's Short-term Memory Scanning Task. Withdrawal (Modified Minnesota Withdrawal Scale) and mood (Positive and Negative Affect Schedule) were also assessed. A mixed-models analysis of covariance was performed.

Results: Compared with placebo nicotine (4 mg) significantly improved vigilance, divided attention, executive functioning, working memory, and sensorimotor performance in abstinent volunteers (P < or = 0.05). Withdrawal symptoms including craving, difficulty concentrating, irritability, and restlessness were also attenuated, and affective state was improved after nicotine 4 mg administration.

Conclusions: Compared with placebo, nicotine (4 mg) improved measures of vigilance, memory, and attention; improved mood; and reduced withdrawal symptoms. These findings suggest that repeated nicotine replacement therapy over a period of 8 hours can improve cognitive deficits associated with nicotine withdrawal.
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http://dx.doi.org/10.1097/JCP.0b013e31818c9bb8DOI Listing
December 2008

Next-day residual effects of gaboxadol and flurazepam administered at bedtime: a randomized double-blind study in healthy elderly subjects.

Hum Psychopharmacol 2009 Jan;24(1):61-71

Human Psychopharmacology Research Unit, University of Surrey, Guildford, Surrey, UK.

Objective: To evaluate the next-day residual effects of the novel hypnotic, gaboxadol, following bedtime dosing in healthy elderly subjects.

Methods: Healthy women (N = 15) and men (N = 10) aged 65-79 years received a single bedtime (22:00 h) dose of gaboxadol 10 mg, flurazepam 30 mg (positive control), and placebo in a randomized, double-blind, crossover study. Measures of information processing and psychomotor performance (choice reaction time, critical flicker fusion, digit symbol substitution, compensatory tracking, body sway), memory (immediate and delayed word recall), and daytime sleepiness (Multiple Sleep Latency Test), as well as subjective ratings (line analog rating scales, Leeds Sleep Evaluation Questionnaire), were obtained starting at 07:00 h the following morning. Adverse events were recorded.

Results: Gaboxadol did not show next-day impairments versus placebo on any pharmacodynamic measures whereas the positive control, flurazepam, did show impairments versus placebo on most measures. Gaboxadol showed improvements versus placebo on some measures including subjective rating of next-day alertness/clumsiness on the Leeds Sleep Evaluation Questionnaire. Gaboxadol was generally well-tolerated; there were no serious adverse experiences and no subjects discontinued due to an adverse experience.

Conclusions: A single oral bedtime dose of gaboxadol 10 mg did not have next-day residual effects in healthy elderly subjects, as measured by a range of pharmacodynamic assessments, in contrast to the clear impairments produced by flurazepam 30 mg.
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http://dx.doi.org/10.1002/hup.986DOI Listing
January 2009

Sedation and antihistamines: an update. Review of inter-drug differences using proportional impairment ratios.

Hum Psychopharmacol 2008 Oct;23(7):555-70

Surrey Clinical Research Centre, University of Surrey, Egerton Road, Guildford, Surrey, UK.

Background: The use of antihistamines (AHs) has been associated with cognitive and psychomotor impairments, largely caused by the sedative properties of many of these drugs. Due to the ambulant nature of the population using AHs, it is important to evaluate these effects using standardised methodology and psychometric tests. A previous extensive review of the literature collated the results of studies of H(1) receptor antagonists to determine the extent to which a particular AH produced impairments on a battery of psychometric tests by calculating a proportional impairment ratio for each AH.

Objective: In light of a number of major studies published following the previous review, and the development of the second and new-generation AHs, the present review aims to add to the database and update the review, using the same methodology.

Results And Conclusion: The newer generation AHs appear to be the least impairing, and the first generation, as expected, appear to be the most impairing. There are also differences within the AH drug generations. The review highlights the necessity to consider the sedating potential of AHs, along with other factors such as efficacy, when prescribing AHs to ambulant patients.
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http://dx.doi.org/10.1002/hup.962DOI Listing
October 2008

Benzodiazepine-induced reduction in activity mirrors decrements in cognitive and psychomotor performance.

Hum Psychopharmacol 2008 Oct;23(7):605-13

Faculty of Health and Medical Sciences, HPRU Medical Research Centre, University of Surrey, Guildford, UK.

Objective: To assess whether actigraphy is sensitive to benzodiazepine-induced changes in cognitive and psychomotor performance and sleep.

Methods: Healthy young volunteers (n = 23; 11 males), were randomised to a double-blind, placebo-controlled, crossover trial. Actigraphy was used to record motor activity continuously. Following dosing at 18.00 h with 2.5 mg lorazepam (LZP), psychomotor and cognitive assessments were made at hourly intervals post-dose for 4 h and after sleep at 14.5 h post-dose.

Results: Activity levels were significantly reduced after LZP for 5 h post-dose (p = 0.0104), during sleep (5-13 h) (p < 0.02) and the following morning, 13-14.5 h post-dose (p < 0.02). At the same time cognitive and psychomotor performance was also significantly impaired (p < 0.05). LZP also significantly increased actigraphic sleep efficiency and sleep per cent (p < 0.02).

Conclusion: This study showed that activity levels were significantly reduced following dosing with a benzodiazepine and these changes coincided with impairment of cognitive and psychomotor performance. Actigraphy, therefore, appears to be able to reflect the psychopharmacological effects of a benzodiazepine in changes in daytime function and nocturnal behaviour, which, without waking the subject, is beyond the power of conventional psychometrics.
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http://dx.doi.org/10.1002/hup.961DOI Listing
October 2008

Next-day cognition, psychomotor function, and driving-related skills following nighttime administration of eszopiclone.

Hum Psychopharmacol 2008 Jul;23(5):385-97

Clinical Research Centre, University of Surrey, Guildford, Surrey, UK.

Objective: To evaluate next-day driving ability, as assessed by brake reaction time (BRT), and cognitive/psychomotor function following nighttime administration of 3 mg eszopiclone.

Methods: Two randomized, double-blind, placebo-controlled, cross-over studies were performed in healthy volunteers (n = 32) and patients with primary insomnia (n = 32). Study participants received nighttime dosing of 3 mg eszopiclone or placebo. BRT and a psychometric test battery were used to assess the next-day effects of eszopiclone treatment.

Results: In both studies, driving ability and measures of cognitive and psychomotor function were not impaired the morning after eszopiclone, as compared to placebo. All eszopiclone subjects reported improved ease in getting to sleep and quality of sleep with no significant changes in behavior upon awakening. A significant increase in next-day feelings of sedation was reported in healthy volunteers, but not in patients with primary insomnia, following eszopiclone treatment relative to placebo. Sleep induction, maintenance, duration, and efficiency, as assessed by PSG, were significantly improved following eszopiclone treatment in patients with insomnia.

Conclusions: Nighttime administration of 3 mg eszopiclone improved objective and subjective sleep measures in patients with insomnia (and subjective sleep measures in healthy patients) and did not impair next-day driving-related skills or measures of cognition in either study population relative to placebo.
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http://dx.doi.org/10.1002/hup.936DOI Listing
July 2008

Allergy medication in Japanese volunteers: treatment effect of single doses on nocturnal sleep architecture and next day residual effects.

Curr Med Res Opin 2006 Jul;22(7):1343-51

HPRU Medical Research Centre, University of Surrey, Guildford, UK.

Objectives: To evaluate the acute effects of two histamine H(1)-receptor antagonists on nocturnal sleep architecture and on next day cognitive function and psychomotor performance.

Methods: This was a single-site, randomized, double-blind, 3-way crossover study, comparing the effects of a single dose of chlorpheniramine (6 mg), fexofenadine (120 mg) and placebo in 18 healthy (male and female) Japanese volunteers aged 20-55 years. Volunteers were resident for 3 days and each period was separated by a minimum 5-day washout period. The three treatments were administered at 23.00 h. Overnight sleep was measured from 23.00 h to 07.00 h using polysomnography. Residual effects were studied at 07.00 h and 9.00 h the next morning, with the latency to sleep (sleep latency test) measured at 09.30 h.

Results: Compared with placebo, chlorpheniramine increased the latencies to sleep onset and rapid eye movement (REM) sleep (p < or = 0.05 for both), and reduced the duration of REM sleep (p
Conclusion: These findings suggest that a single nocturnal dose of fexofenadine has advantages over the first-generation antihistamine chlorpheniramine, being free of disruption of night-time sleep and detrimental effects on cognitive performance the next day. It is likely that this advantage will remain with chronic ingestion, but this would need to be confirmed.
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http://dx.doi.org/10.1185/030079906X112660DOI Listing
July 2006

Development of a portable psychometric testing device for use in the field: an alcohol investigation.

Percept Mot Skills 2005 Oct;101(2):383-92

HPRU Medical Research Centre, School of Biomedical and Molecular Sciences, University of Surrey, Egerton Road, Guildford GU2 7XP, United Kingdom

Cognitive and psychomotor performance have traditionally been assessed in the laboratory. There is a need for an objective portable assessment tool to assess cognitive and psychomotor performance. This study investigated the viability of a portable psychometric test battery, in a controlled laboratory environment, possibly leading to use in the field. A randomised, double-blind placebo controlled, three-way crossover design was employed. 16 subjects received 50 mg/100 ml and 80 mg/100 ml of alcohol and alcohol placebo. Performance was assessed with a tracking task, and an attention task presented on a small ruggedised handheld computer. The attention task showed no significant training effects; however, an element of the tracking task did. Statistical significance, effect size, and test-retest reliability analyses are presented indicating sensitivity of the portable psychometric test battery to the impairing effects of two separate doses of alcohol. Ability to undertake wide-scale impairment testing in the field with meaningful results in the absence of baseline data collection may have wide reaching implications, particularly in relation to the assessment of drivers impaired by drug use.
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http://dx.doi.org/10.2466/pms.101.2.383-392DOI Listing
October 2005

Suppression of the histamine-induced wheal and flare response by fexofenadine HCl 60 mg twice daily, loratadine 10 mg once daily and placebo in healthy Japanese volunteers.

Curr Med Res Opin 2005 Sep;21(9):1495-503

HPRU Medical Research Centre, University of Surrey, Egerton Road, Guildford, GU2 7XP, UK.

Background: The effects of the selective H1-receptor antagonist fexofenadine have been widely demonstrated in Western populations; however, to date, limited data comparing the effects of fexofenadine with other antihistamines have been reported in Japanese subjects.

Objective: To investigate the effect of fexofenadine and loratadine on the histamine-induced cutaneous wheal and flare response in healthy Japanese volunteers.

Methods: Eighteen healthy male and female Japanese volunteers aged 20-53 years were randomized to receive fexofenadine HCl 60 mg twice daily, loratadine 10 mg once daily or placebo in a 1-day, three-period, double-blind, crossover study. For each treatment, the wheal and flare response to 100 mg/mL histamine was assessed at baseline and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 8, 12 and 24 hours post-dose. Blood samples were taken for pharmacokinetic analysis.

Results: Fexofenadine produced significantly greater percentage suppression of the overall wheal response compared with placebo and loratadine (43.1% versus 10.0% and 15.2%, respectively; p < 0.001). Similarly, fexofenadine significantly suppressed the overall flare response compared with placebo and loratadine (43.0% versus 3.5% and -8.9%, respectively; p < 0.01). Loratadine was statistically no different from placebo in terms of both overall wheal and flare suppression. Area under the curve analysis for wheal and flare reduction (0-12 hours post-dose) confirmed these findings. For wheal inhibition, fexofenadine had a significantly faster onset of action (defined as time to > or = 35% inhibition) compared with placebo (p < 0.001) and loratadine (p < 0.01); for flare, fexofenadine had a significantly faster onset of action than loratadine (p < 0.01). Mean maximum inhibition (the mean of the greatest inhibition achieved from baseline for each treatment) for wheal was achieved significantly faster with fexofenadine than loratadine (p < 0.01), and fexofenadine had a significantly longer duration of effect on suppressing wheal and flare compared with placebo and loratadine (p < 0.05 for all). The antihistamine effects of fexofenadine correlated significantly with its Cmax, while loratadine activity did not correlate significantly with its plasma levels.

Conclusions: Fexofenadine is a potent suppressor of the histamine-induced wheal and flare response in healthy Japanese volunteers. These results support findings in Caucasian subjects, and confirm that fexofenadine has greater antihistaminergic activity than loratadine in this human model.
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http://dx.doi.org/10.1185/030079905X59175DOI Listing
September 2005

Timing of the retinoid-signalling pathway determines the expression of neuronal markers in neural progenitor cells.

Dev Biol 2005 Feb;278(1):60-70

Stem Cell Laboratory, The Wolfson Centre for Age Related Diseases, London SE1 1UL, UK.

By culturing neural progenitor cells in the presence of retinoid receptor agonists, we have defined the components of the retinoid-signalling pathway that are important for the birth and maintenance of neuronal cells. We provide evidence that depending on the order and combination of retinoid receptors activated, different neuronal cells are obtained. Astrocytes and oligodendrocytes are predominantly formed in the presence of activated retinoic acid receptor (RAR) alpha, whereas motoneurons are formed when RARbeta is activated. We have looked at the regulation of two transcription factors islet-1/2 which are involved in neuronal development. We find that activated RARbeta up-regulates islet-1 expression, whereas activation of RARalpha can either act in combination with RARbeta signalling to maintain islet-1 expression or induce islet-2 expression in the absence of activated RARbeta. RARgamma cannot directly regulate islet-1/2 but can down-regulate RARbeta expression, which results in loss of islet-1 expression. We finally show that activated RARalpha is one of the final steps required for a mature motoneuron phenotype.
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http://dx.doi.org/10.1016/j.ydbio.2004.10.015DOI Listing
February 2005

Children's sleep: problems and solutions.

J Fam Health Care 2004 ;14(3):61-3

Human Psychopharmacology Research Unit, University of Surrey.

It is now believed that up to 43% of children can experience a sleep problem at some stage during their development. Reduced quality of sleep can have important implications for the developing child as it can impair growth, learning and emotional development. It is important for health professionals to understand the significance of sleep and the ways to alleviate problems so that these can be tackled at an early age. By educating people in how to get a good night's sleep we shall hopefully move towards a more happy, healthy and capable child population.
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September 2004

The effects of Ginkgo biloba extract (LI 1370) supplementation and discontinuation on activities of daily living and mood in free living older volunteers.

Phytother Res 2004 Jul;18(7):531-7

HPRU Medical Research Centre, University of Surrey, Egerton Road, Guildford GU2 7XP, UK.

The aim of the study was to investigate the effects of continuing treatment with Ginkgo biloba extract (GBE) 120 mg/day on the activities of daily living (ADLs) and mood in healthy older volunteers who had immediately previously participated in a survey of the effects of a 4 month treatment with the drug. Following a prior postal survey investigating the effects of 4 months supplementation with GBE on ADLs and various aspects of mood and sleep, 1570 volunteers continued onto a 6 month follow-up postal survey. Subjects selected their own treatment option for the follow-up survey, which effectively created four groups: a continuation group who received GBE in the initial 4 month study and during the 6 month follow-up (GBE-GBE), a discontinuation group who received GBE in the initial study but not during the follow-up (GBE-NT), a new treatment group who did not receive GBE in the initial 4 month study but who did receive GBE during the 6 month follow-up (NT-GBE), and a no treatment group who received no treatment in either survey (NT-NT). At the end of the 6 month follow-up period each subject completed a line analogue rating scale (LARS) and a self-rating activities of daily living scale (SR-ADL). There were signi fi cant differences in the mean overall LARS and SR-ADL scores between the four treatment combination groups at the end of the follow-up period. A factor analysis of the LARS revealed two factors, 'mood' and 'alertness'. When scores from each of the treatment groups were examined over the whole 10 month period it was evident that the ratings of overall competence in the SR-ADL and both factors of the LARS were diminished on cessation of treatment with GBE, and improved when GBE treatment was initiated. The magnitude of the improvements on all scales was related to the overall duration of GBE supplementation.Signi fi cant differences between the groups of subjects treated with GBE for different periods of time (4-10 months) suggests that the extract has a demonstrable effect in improving mood and the self-assessed performance of the tasks of everyday living.
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http://dx.doi.org/10.1002/ptr.1479DOI Listing
July 2004