Publications by authors named "Mary Corcoran"

50 Publications

Changes in the incidence of invasive disease due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis during the COVID-19 pandemic in 26 countries and territories in the Invasive Respiratory Infection Surveillance Initiative: a prospective analysis of surveillance data.

Lancet Digit Health 2021 06;3(6):e360-e370

Irish Meningitis and Sepsis Reference Laboratory, Children's Health Ireland at Temple Street, Dublin, Ireland; Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.

Background: Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are typically transmitted via respiratory droplets, are leading causes of invasive diseases, including bacteraemic pneumonia and meningitis, and of secondary infections subsequent to post-viral respiratory disease. The aim of this study was to investigate the incidence of invasive disease due to these pathogens during the early months of the COVID-19 pandemic.

Methods: In this prospective analysis of surveillance data, laboratories in 26 countries and territories across six continents submitted data on cases of invasive disease due to S pneumoniae, H influenzae, and N meningitidis from Jan 1, 2018, to May, 31, 2020, as part of the Invasive Respiratory Infection Surveillance (IRIS) Initiative. Numbers of weekly cases in 2020 were compared with corresponding data for 2018 and 2019. Data for invasive disease due to Streptococcus agalactiae, a non-respiratory pathogen, were collected from nine laboratories for comparison. The stringency of COVID-19 containment measures was quantified using the Oxford COVID-19 Government Response Tracker. Changes in population movements were assessed using Google COVID-19 Community Mobility Reports. Interrupted time-series modelling quantified changes in the incidence of invasive disease due to S pneumoniae, H influenzae, and N meningitidis in 2020 relative to when containment measures were imposed.

Findings: 27 laboratories from 26 countries and territories submitted data to the IRIS Initiative for S pneumoniae (62 837 total cases), 24 laboratories from 24 countries submitted data for H influenzae (7796 total cases), and 21 laboratories from 21 countries submitted data for N meningitidis (5877 total cases). All countries and territories had experienced a significant and sustained reduction in invasive diseases due to S pneumoniae, H influenzae, and N meningitidis in early 2020 (Jan 1 to May 31, 2020), coinciding with the introduction of COVID-19 containment measures in each country. By contrast, no significant changes in the incidence of invasive S agalactiae infections were observed. Similar trends were observed across most countries and territories despite differing stringency in COVID-19 control policies. The incidence of reported S pneumoniae infections decreased by 68% at 4 weeks (incidence rate ratio 0·32 [95% CI 0·27-0·37]) and 82% at 8 weeks (0·18 [0·14-0·23]) following the week in which significant changes in population movements were recorded.

Interpretation: The introduction of COVID-19 containment policies and public information campaigns likely reduced transmission of S pneumoniae, H influenzae, and N meningitidis, leading to a significant reduction in life-threatening invasive diseases in many countries worldwide.

Funding: Wellcome Trust (UK), Robert Koch Institute (Germany), Federal Ministry of Health (Germany), Pfizer, Merck, Health Protection Surveillance Centre (Ireland), SpID-Net project (Ireland), European Centre for Disease Prevention and Control (European Union), Horizon 2020 (European Commission), Ministry of Health (Poland), National Programme of Antibiotic Protection (Poland), Ministry of Science and Higher Education (Poland), Agencia de Salut Pública de Catalunya (Spain), Sant Joan de Deu Foundation (Spain), Knut and Alice Wallenberg Foundation (Sweden), Swedish Research Council (Sweden), Region Stockholm (Sweden), Federal Office of Public Health of Switzerland (Switzerland), and French Public Health Agency (France).
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http://dx.doi.org/10.1016/S2589-7500(21)00077-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166576PMC
June 2021

Global Landscape Review of Serotype-Specific Invasive Pneumococcal Disease Surveillance among Countries Using PCV10/13: The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) Project.

Microorganisms 2021 Apr 2;9(4). Epub 2021 Apr 2.

National Public Health Organisation, 15123 Athens, Greece.

Serotype-specific surveillance for invasive pneumococcal disease (IPD) is essential for assessing the impact of 10- and 13-valent pneumococcal conjugate vaccines (PCV10/13). The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) project aimed to evaluate the global evidence to estimate the impact of PCV10/13 by age, product, schedule, and syndrome. Here we systematically characterize and summarize the global landscape of routine serotype-specific IPD surveillance in PCV10/13-using countries and describe the subset that are included in PSERENADE. Of 138 countries using PCV10/13 as of 2018, we identified 109 with IPD surveillance systems, 76 of which met PSERENADE data collection eligibility criteria. PSERENADE received data from most (n = 63, 82.9%), yielding 240,639 post-PCV10/13 introduction IPD cases. Pediatric and adult surveillance was represented from all geographic regions but was limited from lower income and high-burden countries. In PSERENADE, 18 sites evaluated PCV10, 42 PCV13, and 17 both; 17 sites used a 3 + 0 schedule, 38 used 2 + 1, 13 used 3 + 1, and 9 used mixed schedules. With such a sizeable and generally representative dataset, PSERENADE will be able to conduct robust analyses to estimate PCV impact and inform policy at national and global levels regarding adult immunization, schedule, and product choice, including for higher valency PCVs on the horizon.
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http://dx.doi.org/10.3390/microorganisms9040742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066045PMC
April 2021

Serotype Distribution of Remaining Pneumococcal Meningitis in the Mature PCV10/13 Period: Findings from the PSERENADE Project.

Microorganisms 2021 Apr 1;9(4). Epub 2021 Apr 1.

Department of Clinical Microbiology, Landspitali-The National University Hospital, Hringbraut, 101 Reykjavik, Iceland.

Pneumococcal conjugate vaccine (PCV) introduction has reduced pneumococcal meningitis incidence. The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) project described the serotype distribution of remaining pneumococcal meningitis in countries using PCV10/13 for least 5-7 years with primary series uptake above 70%. The distribution was estimated using a multinomial Dirichlet regression model, stratified by PCV product and age. In PCV10-using sites ( = 8; cases = 1141), PCV10 types caused 5% of cases <5 years of age and 15% among ≥5 years; the top serotypes were 19A, 6C, and 3, together causing 42% of cases <5 years and 37% ≥5 years. In PCV13-using sites ( = 32; cases = 4503), PCV13 types caused 14% in <5 and 26% in ≥5 years; 4% and 13%, respectively, were serotype 3. Among the top serotypes are five (15BC, 8, 12F, 10A, and 22F) included in higher-valency PCVs under evaluation. Other top serotypes (24F, 23B, and 23A) are not in any known investigational product. In countries with mature vaccination programs, the proportion of pneumococcal meningitis caused by vaccine-in-use serotypes is lower (≤26% across all ages) than pre-PCV (≥70% in children). Higher-valency PCVs under evaluation target over half of remaining pneumococcal meningitis cases, but questions remain regarding generalizability to the African meningitis belt where additional data are needed.
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http://dx.doi.org/10.3390/microorganisms9040738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066874PMC
April 2021

Learning health systems from an academic perspective: establishing a collaboratory within a school of medicine and health sciences.

Med Educ Online 2021 Dec;26(1):1917038

Department of Clinical Research & Leadership, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.

Learning Health Systems (LHSs) seek continuous improvement through the translation and integration of internally and externally generated knowledge across stakeholders within and external to the organization, yet current approaches are primarily described from the healthcare delivery perspective, leaving teaching and research responsibilities underexposed. Academic medical centers offer a unique perspective on LHSs because their mission includes teaching, research, and healthcare. This introduces an opportunity to enact, educate, and study processes and outcomes of LHSs within a single system. Little information is available to describe these processes and outcomes, resulting in a knowledge gap regarding the role of education and research in the quality improvement cycles and learning of LHSs. To close this knowledge gap, The George Washington University School of Medicine and Health Sciences initiated the Health Research and Education Collaboratory (GW Collaboratory) in 2017. The GW Collaboratory was established to study mechanisms supporting continuous quality improvement and learning in health systems within an academic medical center. We envision the GW Collaboratory as interconnected knowledge nodes facilitating collaboration among clinicians, patients, researchers, and educators to study the knowledge generation, dissemination, application, and evaluation required for continuous quality improvement and learning. We employ a project-based approach to foster communities of learning focused on exploring specific health problems of interest. We propose the GW Collaboratory as one model by which academic medical centers can contribute to the science of LHS.
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http://dx.doi.org/10.1080/10872981.2021.1917038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079055PMC
December 2021

Youth Soccer Parents' Perceptions of Long-Term Effects of Concussion .

Dev Neuropsychol 2020 Apr-Jun;45(3):110-117. Epub 2020 May 18.

Department of Health, Human Performance and Recreation, University of Arkansas , Fayetteville, AR, USA.

Increased focus on sports-related concussion (SRC) in football in the media, and mandatory concussion education for parents of youth sport athletes, may result in parental concern that youth athletes will experience long-term effects from concussion. We sought to identify beliefs about long-term effects of concussion in parents of youth soccer athletes. Four hundred and eleven parents from soccer leagues in three states completed a survey assessing parents' perceptions and knowledge of long-term effects of SRC. Nearly all youth soccer parents surveyed (96.5%) believe there are long-term effects from SRCs, 76% reported concern their child would sustain a concussion, and 71% had talked with their child about concussion symptoms/reporting. Parents ranked tackle football as having the highest risk for concussion, followed by soccer, ice hockey, cheerleading, and lacrosse. Parents of children that had previously sustained a concussion were 8.3x more likely to be concerned their child would sustain a concussion, and parents with a personal history of concussion were 2x more likely to consider not allowing their child to participate in youth sports. There are wide-spread beliefs among youth soccer parents regarding long-term effects of SRCs, and concerns their children will sustain concussions while participating in youth sports.
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http://dx.doi.org/10.1080/87565641.2020.1766464DOI Listing
October 2020

Invasive Streptococcus pneumoniae Infections and Vaccine Failures in Children in Ireland From the Postvaccine Era From 2007 to 2018.

Pediatr Infect Dis J 2020 04;39(4):339-344

Department of Clinical Microbiology, the Royal College of Surgeons in Ireland, Dublin, Ireland.

Background: Invasive pneumococcal disease (IPD) causes life-threatening illnesses including meningitis and bloodstream infection. Here, we report the impact of 7- and 13-valent pneumococcal conjugate vaccines (PCV7/PCV13) after introduction into the Irish pediatric immunization schedule in 2008 and 2010, respectively, and the clinical details surrounding suspected PCV vaccine failures.

Methods: Serotyping and antimicrobial susceptibility testing of all culture-confirmed cases referred from children <16 years of age from July 2007 to June 2018 were assessed. Surveillance data were assessed to identify any potential vaccine failures.

Results: The number of IPD cases has decreased by >50% since the introduction of PCVs. The most significant decline PCV serotypes in children <2 years of age, with a 97% decline in PCV7 serotypes, incidence rate ratio (IRR) 0.03, 95% confidence interval (CI): 0.00-0.21; and a 78% decline PCV13-only (PCV13-7) serotypes, IRR 0.22, 95% CI: 0.05-1.04, respectively. However, there has been an increase in non-PCV13 serotypes in children <2 years during the same period (IRR: 2.82, 95% CI: 1.02-7.84; P = 0.0463), with similar serotype trends observed for those 2-4 and 5-15 years of age. There were no clear vaccine replacement serotypes, instead a number of different serotypes emerged. Sixteen vaccine failures were identified, 10 of which were postbooster vaccine failures. Most failures were serotype 19A and resistant to antimicrobials.

Conclusions: Further reducing the incidence of IPD is more challenging as the number of non-PCV13 serotypes has expanded and is now less susceptible to antimicrobials. Consequently, higher valency or broader target vaccines are now required to further prevent IPD in children.
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http://dx.doi.org/10.1097/INF.0000000000002549DOI Listing
April 2020

A phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of single and multiple doses of lisdexamfetamine dimesylate in Japanese and Caucasian healthy adult subjects.

Neuropsychopharmacol Rep 2020 03 25;40(1):16-29. Epub 2019 Nov 25.

Shionogi & Co., Ltd, Osaka, Japan.

Aim: To assess safety, tolerability, and pharmacokinetics of lisdexamfetamine dimesylate in Japanese and Caucasian healthy adults.

Methods: A phase 1, double-blind, randomized, placebo-controlled, single- and multiple-dose study in Japanese and Caucasian subjects. Subjects received lisdexamfetamine 20 mg or placebo on Day 1, then lisdexamfetamine 20 mg/d (Days 4-8), 50 mg/d (Days 9-13), 70 mg/d (Days 14-18), or matching placebo. Pharmacokinetic parameters for lisdexamfetamine and d-amphetamine were estimated by noncompartmental analysis.

Results: Fifteen Japanese and 19 Caucasian subjects were enrolled and randomized. The lisdexamfetamine and d-amphetamine plasma concentration-time curves were similar for both ethnic groups following single and multiple doses. Mean area under the concentration-time curves for d-amphetamine were higher (by 11%-15%) in Japanese than Caucasian subjects following multiple dosing of lisdexamfetamine. Mean bodyweight was 17% lower in Japanese than Caucasian subjects. Weight-corrected means for oral clearance were similar in both ethnic groups, with no unexpected accumulation of d-amphetamine. Lisdexamfetamine was generally well tolerated by both ethnic groups, with no serious adverse events reported. The 10/12 Japanese and 11/16 Caucasian subjects who received lisdexamfetamine completed the study; two Japanese and three Caucasian subjects discontinued due to adverse events. Most adverse events were of mild severity.

Conclusion: Pharmacokinetics were generally similar for Japanese and Caucasian subjects; the minor differences observed were likely due to bodyweight differences in the two ethnic groups. Lisdexamfetamine was generally well tolerated. Adverse events were consistent with the established safety profile of lisdexamfetamine and were similar in both ethnic groups.
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http://dx.doi.org/10.1002/npr2.12082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292221PMC
March 2020

Group Gardening in a Native American Community: A Collaborative Approach.

Health Promot Pract 2020 07 20;21(4):611-623. Epub 2019 Feb 20.

Chippewa Cree Tribal Health Center, Box Elder, MT, USA.

. There is increasing awareness of the potential health benefits derived from gardening activities. Gardening practices are gaining momentum in Native American (NA) communities, yet no efforts have applied a community-based participatory research approach within a social-ecological model to understand opportunities and barriers for group gardening on an American Indian reservation. . The primary objective of this study was to identify influences across social-ecological levels that promote or hinder the implementation of community gardens and use of locally grown foods on the reservation; a secondary objective was to assess the feasibility of implementing a group gardening program for NA adults and potential of collecting health outcome measures. . Community members and academicians collaborated to develop and implement this study. The study (1) conducted interviews with key stakeholders to identify influences across social-ecological levels that promote or hinder the implementation of community gardens and using locally produced food and (2) assessed the physical and psychological well-being of NA adults participating in a group gardening feasibility study. . Major factors influencing using locally grown food and community gardens that emerged from nine interviews included knowledge/experience, self-efficacy, Elders, traditional ways, community values, generational gaps, and local tribal policies. Twenty NA adults with prediabetes or diabetes participated in the feasibility study. The Profile of Mood States Inventory showed consistently positive change in score for participants in the group gardening program versus the comparison group. . This study identified key influences for growing locally grown food, and approaches for implementing group gardening programs for NA adults.
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http://dx.doi.org/10.1177/1524839919830930DOI Listing
July 2020

Effect of childhood pneumococcal conjugate vaccination on invasive disease in older adults of 10 European countries: implications for adult vaccination.

Thorax 2019 05 24;74(5):473-482. Epub 2018 Oct 24.

EpiConcept, Paris, France.

Background: Pneumococcal conjugate vaccines (PCVs) have the potential to prevent pneumococcal disease through direct and indirect protection. This multicentre European study estimated the indirect effects of 5-year childhood PCV10 and/or PCV13 programmes on invasive pneumococcal disease (IPD) in older adults across 13 sites in 10 European countries, to support decision-making on pneumococcal vaccination policies.

Methods: For each site we calculated IPD incidence rate ratios (IRR) in people aged ≥65 years by serotype for each PCV10/13 year (2011-2015) compared with 2009 (pre-PCV10/13). We calculated pooled IRR and 95% CI using random-effects meta-analysis and PCV10/13 effect as (1 - IRR)*100.

Results: After five PCV10/13 years, the incidence of IPD caused by all types, PCV7 and additional PCV13 serotypes declined 9% (95% CI -4% to 19%), 77% (95% CI 67% to 84%) and 38% (95% CI 19% to 53%), respectively, while the incidence of non-PCV13 serotypes increased 63% (95% CI 39% to 91%). The incidence of serotypes included in PCV13 and not in PCV10 decreased 37% (95% CI 22% to 50%) in six PCV13 sites and increased by 50% (95% CI -8% to 146%) in the four sites using PCV10 (alone or with PCV13). In 2015, PCV13 serotypes represented 20-29% and 32-53% of IPD cases in PCV13 and PCV10 sites, respectively.

Conclusion: Overall IPD incidence in older adults decreased moderately after five childhood PCV10/13 years in 13 European sites. Large declines in PCV10/13 serotype IPD, due to the indirect effect of childhood vaccination, were countered by increases in non-PCV13 IPD, but these declines varied according to the childhood vaccine used. Decision-making on pneumococcal vaccination for older adults must consider the indirect effects of childhood PCV programmes. Sustained monitoring of IPD epidemiology is imperative.
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http://dx.doi.org/10.1136/thoraxjnl-2018-211767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484683PMC
May 2019

Encountering offenders in community palliative care settings: challenges for care provision.

Int J Palliat Nurs 2018 Aug;24(8):368-375

Professor of Learning Disability Nursing, School of Nursing and Midwifery, Keele University, Staffordshire, UK.

Background: There is very little research into the way that offender management strategies impinge on the practices and decision-making of palliative care personnel in community settings.

Aims: To improve understanding of the challenges that community palliative care service providers encounter when caring for people who have been sentenced to custody and are under the supervision of the prison or probation services.

Methods: This paper discusses one part of a larger multidisciplinary study on bereavement, loss and grief in the criminal justice system. It reports the findings from a focus group with 10 health professionals working within specialist community palliative care services. Thematic analysis was undertaken to identify and explicate the most significant themes arising from the transcript data.

Results: There were situations where the participants were able to identify that patients were under the jurisdiction of the criminal justice system or had relatives in custody. Three themes emerged that highlighted distinctive aspects of providing care to this patient group. These themes were: patients under prison, probation or police supervision altered the dynamics of care provision; prisoners were restricted from supporting or contacting their dying relatives in the community; and participants (professionals) were obstructed from supporting patients at home because of criminal or antisocial behaviour by relatives of the dying.

Conclusions: Health professionals face multiple challenges that curtail them from fully realising the aims of palliative care for patients and relatives under criminal justice supervision, in ways that merit further consideration and research.
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http://dx.doi.org/10.12968/ijpn.2018.24.8.368DOI Listing
August 2018

Evaluation of the Clinical Utility of a Real-time PCR Assay for the Diagnosis of Streptococcus pneumoniae Bacteremia in Children: A Retrospective Diagnostic Accuracy Study.

Pediatr Infect Dis J 2018 02;37(2):153-156

Background: The widespread uptake of pneumococcal vaccines has substantially reduced the incidence of invasive pneumococcal disease, such that pneumococcal bacteremia in children is now considered a relatively rare event. The objective of this study was to ascertain the clinical utility of a Streptococcus pneumoniae real-time polymerase chain reaction (PCR) assay compared with standard blood culture for the diagnosis of pneumococcal bacteremia in children in the post-vaccine era.

Methods: A systematic retrospective review of laboratory and patient records from Children's University Hospital, Temple Street, during a 6-year period was performed. Paired blood PCR and blood culture specimens from children younger than 16 years of age were investigated. Statistical analysis was performed to measure the diagnostic accuracy of PCR versus routine bacterial culture techniques.

Results: More than 1900 PCR test requests were examined from 2010 to 2015, of which 1561 paired PCR and blood culture specimens met criteria for inclusion in the statistical analysis. The PCR assay demonstrated high specificity (99%, confidence interval 95%: 98.81%-99.69%); however, the sensitivity was low compared with that of blood culture (47%, confidence interval 95%: 21.27%-73.41%). Investigation of 10 PCR-positive/culture-negative cases revealed that these cases ranged from definite, probable, and possible significance, indicating a low false positivity rate associated with the assay.

Conclusion: This study demonstrates the limited utility of blood PCR testing for S. pneumoniae in pediatric patients without radiographic evidence pneumonia or empyema. Moreover, we report that PCR may be a useful diagnostic tool when blood cultures are negative because of antimicrobial therapy before sampling. Given that the incidence of pneumococcal disease has decreased considerably in recent years, justification of S. pneumoniae PCR requisition is necessary. Hence, new guidelines for pediatric pneumococcal blood PCR testing have been introduced at the Irish Meningitis and Sepsis Reference Laboratory.
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http://dx.doi.org/10.1097/INF.0000000000001772DOI Listing
February 2018

Colonisation of Irish patients with chronic obstructive pulmonary disease by and analysis of the pneumococcal vaccine coverage: a non-interventional, observational, prospective cohort study.

BMJ Open 2017 Jul 9;7(7):e013944. Epub 2017 Jul 9.

Department of Clinical Microbiology, Royal College of Surgeons in Ireland, RCSI Education and Research Centre, Beaumont Hospital, Beaumont, Dublin, Republic of Ireland.

Objectives: To characterise the pattern of colonisation and serotypes of among patients with chronic obstructive pulmonary disease (COPD) who currently receive the 23-valent pneumococcal polysaccharide vaccine (PPV-23) according to vaccination status, use of antibiotics and steroids. To investigate the prevalence of PPV-23 and 13-valent pneumococcal conjugate vaccine (PCV-13) serotypes within the study cohort.

Design: A non-interventional, observational, prospective cohort study with a 12 -month follow-up period inclusive of quarterly study visits.

Setting: Beaumont Hospital and The Royal College of Surgeons in Ireland Clinical Research Centre, Dublin, Ireland.

Participants: Patients with an established diagnosis of COPD attending a tertiary medical centre.

Primary Outcome Measure: Colonisation rate of in patients with COPD and characterisation of serotypes of with correlation to currently available pneumococcal vaccines. Sputum and oropharyngeal swab samples were collected for the isolation of .

Secondary Outcome Measure: Seasonality of colonisation of and its relationship with the incidence of exacerbations of COPD.

Results: was detected in 16 of 417 samples, a colonisation incident rate of 3.8% and in 11 of 133 (8%) patients at least once during the study. The majority of isolates were identified in spring and were non-vaccine serotypes for either the PPV-23 or PCV-13 (63%). The colonisation incident rate of fluctuated over the four seasons with a peak of 6.6% in spring and the lowest rate of 2.2% occurring during winter. Antibiotic use was highest during periods of low colonisation.

Conclusions: There is seasonal variation in colonisation among patients with COPD which may reflect antibiotic use in autumn and winter. The predominance of non-vaccine types suggests that PCV-13 may have limited impact among patients with COPD in Ireland who currently receive PPV-23.

Trial Registration Number: NCT02535546; post-results.
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http://dx.doi.org/10.1136/bmjopen-2016-013944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541633PMC
July 2017

Clinical Utility of Polymerase Chain Reaction Testing for Streptococcus pneumoniae in Pediatric Cerebrospinal Fluid Samples: A Diagnostic Accuracy Study of More Than 2000 Samples From 2004 to 2015.

Pediatr Infect Dis J 2017 Sep;36(9):833-836

From the *Department of Paediatric Infectious Diseases, and †Department of Clinical Microbiology, Temple Street Children's University Hospital, Dublin 1, Ireland; ‡Irish Meningitis and Sepsis Reference Laboratory, and §Irish Pneumococcal Reference Laboratory, Temple Street Children's University Hospital, Dublin 7, Ireland; ¶Department of Paediatric Infectious Diseases, Our Lady's Childrens' Hospital Crumlin, Dublin 12, Ireland; ‖UCD School of Medicine and Medical Science, University College Dublin, Dublin, Ireland; **Department of Clinical Microbiology, Rotunda Hospital, Dublin 1, Ireland; and ††Department of Clinical Microbiology, Royal College of Surgeons in Ireland, Dublin 2, Ireland.

The aim of this retrospective study was to review the diagnostic accuracy of real-time polymerase chain reaction (PCR) testing of cerebrospinal fluid (CSF) samples for Streptococcus pneumoniae DNA in comparison with traditional bacterial culture. The hypothesis was that PCR is more sensitive than culture and would detect more cases of pneumococcal meningitis, particularly in children treated with antimicrobials before CSF sampling occurred. Patients younger than 16 years of age who had a CSF sample tested for S. pneumoniae DNA by PCR between 2004 and 2015 were included. A total of 2025 samples were included, and the PCR had a sensitivity of 100% and specificity of 98% for the detection of S. pneumoniae DNA in comparison with culture. Of the 28 culture negative/PCR positive cases, 25 (89%) were probable meningitis cases and only 3 (11%) were suspected false positive results. Nineteen (76%) of the 25 probable cases required ICU admission, and 3 died (12%). Six different serotypes were found in the culture positive patients (18C, 6B, 14, 22F, 7F and 33F). This study demonstrates that PCR testing of CSF samples for S. pneumoniae is sensitive and specific when compared with culture. PCR is particularly useful in detecting those cases where culture is negative, perhaps relating to pre-CSF sampling administration of antimicrobials.
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http://dx.doi.org/10.1097/INF.0000000000001608DOI Listing
September 2017

Relative Bioavailabilities of Lisdexamfetamine Dimesylate and D-Amphetamine in Healthy Adults in an Open-Label, Randomized, Crossover Study After Mixing Lisdexamfetamine Dimesylate With Food or Drink.

Ther Drug Monit 2016 12;38(6):769-776

*Formerly of Shire; †Shire, Lexington, Massachusetts; and ‡Clinical Pharmacology of Miami, Miami, Florida.

Background: This open-label, crossover study examined lisdexamfetamine dimesylate (LDX) and D-amphetamine pharmacokinetics in healthy adults after administration of an intact LDX capsule or after the capsule was emptied into orange juice or yogurt and the contents consumed.

Methods: Healthy adult volunteers (N = 30) were administered a 70-mg LDX capsule or the contents of a 70-mg capsule mixed with yogurt or orange juice using a 3-way crossover design. Blood samples were collected serially for up to 96 hours after dose. Pharmacokinetic endpoints included maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve from zero to infinity (AUC0-∞) or to last assessment (AUClast). Relative LDX and D-amphetamine bioavailabilities from the contents of a 70-mg LDX capsule mixed with orange juice or yogurt were compared with those from the intact LDX capsule using bioequivalence-testing procedures.

Results: Geometric least squares mean ratios (90% confidence intervals [CIs]) for D-amphetamine (active moiety) were within the prespecified bioequivalence range (0.80-1.25) when the contents of a 70-mg LDX capsule were mixed with orange juice [Cmax: 0.971 (0.945, 0.998); AUC0-∞: 0.986 (0.955, 1.019); AUClast: 0.970 (0.937, 1.004)] or yogurt [Cmax: 0.970 (0.944, 0.997); AUC0-∞: 0.945 (0.915, 0.976); AUClast: 0.944 (0.912, 0.977)]. Geometric least squares mean ratios (90% CIs) for LDX (inactive prodrug) were below the accepted range when the contents of a 70-mg LDX capsule were mixed with orange juice [Cmax: 0.641 (0.582, 0.707); AUC0-∞: 0.716 (0.647, 0.792); AUClast: 0.708 (0.655, 0.766)]; the lower 90% CI for Cmax [0.828 (0.752, 0.912)] was below the accepted range when the contents of a 70-mg LDX capsule were mixed with yogurt.

Conclusions: Relative bioavailability of D-amphetamine (the active moiety) did not differ across administrations, which suggests that emptying an LDX capsule into orange juice or yogurt and consuming it is an alternative to intact capsules.
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http://dx.doi.org/10.1097/FTD.0000000000000343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5158093PMC
December 2016

A Single-Dose, Open-Label Study of the Pharmacokinetics, Safety, and Tolerability of Lisdexamfetamine Dimesylate in Individuals With Normal and Impaired Renal Function.

Ther Drug Monit 2016 08;38(4):546-55

*Department of Clinical Pharmacology & Pharmacokinetics; †Departments of Clinical Pharmacology & Pharmacokinetics, and Biostatistics, Shire, Lexington, Massachusetts; ‡Clinical Pharmacology of Miami, Inc.; and §Orlando Clinical Research Center, Florida.

Background: Lisdexamfetamine (LDX) and D-amphetamine pharmacokinetics were assessed in individuals with normal and impaired renal function after a single LDX dose; LDX and D-amphetamine dialyzability was also examined.

Methods: Adults (N = 40; 8/group) were enrolled in 1 of 5 renal function groups [normal function, mild impairment, moderate impairment, severe impairment/end-stage renal disease (ESRD) not requiring hemodialysis, and ESRD requiring hemodialysis] as estimated by glomerular filtration rate (GFR). Participants with normal and mild to severe renal impairment received 30 mg LDX; blood samples were collected predose and serially for 96 hours. Participants with ESRD requiring hemodialysis received 30 mg LDX predialysis and postdialysis separated by a washout period of 7-14 days. Predialysis blood samples were collected predose, serially for 72 hours, and from the dialyzer during hemodialysis; postdialysis blood samples were collected predose and serially for 48 hours. Pharmacokinetic end points included maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve from time 0 to infinity (AUC0-∞) or to last assessment (AUClast).

Results: Mean LDX Cmax, AUClast, and AUC0-∞ in participants with mild to severe renal impairment did not differ from those with normal renal function; participants with ESRD had higher mean Cmax and AUClast than those with normal renal function. D-amphetamine exposure (AUClast and AUC0-∞) increased and Cmax decreased as renal impairment increased. Almost no LDX and little D-amphetamine were recovered in the dialyzate.

Conclusions: There seems to be prolonged D-amphetamine exposure after 30 mg LDX as renal impairment increases. In individuals with severe renal impairment (GFR: 15 ≤ 30 mL·min·1.73 m), the maximum LDX dose is 50 mg/d; in patients with ESRD (GFR: <15 mL·min·1.73 m), the maximum LDX dose is 30 mg/d. Neither LDX nor D-amphetamine is dialyzable.
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http://dx.doi.org/10.1097/FTD.0000000000000296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949011PMC
August 2016

Lisdexamfetamine Dimesylate Effects on the Pharmacokinetics of Cytochrome P450 Substrates in Healthy Adults in an Open-Label, Randomized, Crossover Study.

Drugs R D 2015 Jun;15(2):175-85

Shire, 725 Chesterbrook Blvd, Wayne, PA, 19087, USA,

Introduction: This open-label, randomized, two-period drug interaction study assessed lisdexamfetamine dimesylate (LDX) effects on cytochrome P450 (CYP) enzyme (CYP1A2, CYP2D6, CYP2C19, and CYP3A) activity.

Methods: Thirty healthy volunteers were administered the Cooperstown cocktail (CYP1A2 [caffeine 200 mg], CYP2D6 [dextromethorphan 30 mg], CYP2C19 [omeprazole 40 mg], and CYP3A [midazolam 0.025 mg/kg] substrates) or Cooperstown cocktail + oral LDX 70 mg. Blood samples for pharmacokinetic analysis were collected pre-dose and serially for 72 h post-dose. Treatment differences in the primary endpoints, maximum plasma concentration (C max) and area under the plasma concentration versus time curve from 0 to infinity (AUC0-∞), were assessed using geometric mean ratios with 90 % CIs.

Results: Geometric least squares (LS) means (without versus with LDX) for C max (ng/mL) were 5370 versus 5246 for caffeine, 2.43 versus 2.87 for dextromethorphan, 35.23 versus 35.11 for midazolam, and 677.9 versus 466.9 for omeprazole; and for AUC0-∞ (ng · h/mL) were 56,207 versus 56,688 for caffeine, 34.85 versus 37.27 for dextromethorphan, 92.07 versus 93.04 for midazolam, and 1428 versus 1499 for omeprazole. Geometric LS mean ratios were within the standard bioequivalence testing range, except for omeprazole and dextromethorphan C max. Parent/metabolite C max and AUC0-∞ ratios were similar between treatments except for dextromethorphan/dextrorphan AUC0-∞ ratio, which was lower with LDX. No serious or severe treatment-emergent adverse events were reported.

Conclusions: LDX did not alter CYP1A2, CYP2D6, or CYP3A activity. A small C max reduction for omeprazole and its metabolite was observed, possibly reflecting an effect either on the activity of CYP2C19 or omeprazole absorption.
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http://dx.doi.org/10.1007/s40268-015-0090-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488187PMC
June 2015

A phase 1 randomized study evaluating the effect of omeprazole on the pharmacokinetics of a novel 5-hydroxytryptamine receptor 4 agonist, revexepride (SSP-002358), in healthy adults.

Drug Des Devel Ther 2015 27;9:1257-68. Epub 2015 Feb 27.

Shire, Wayne, PA, USA.

Background: About 30% of patients with gastroesophageal reflux disease continue to experience symptoms despite treatment with proton pump inhibitors. The 5-hydroxytryptamine 4 receptor agonist revexepride (SSP-002358) is a novel prokinetic that stimulates gastrointestinal motility, which has been suggested as a continued cause of symptoms in these patients. The aim of this study was to assess whether revexepride pharmacokinetics were affected by co-administration of omeprazole, in preparation for a proof-of-concept evaluation of revexepride added to proton pump inhibitor treatment.

Methods: In this phase 1, open-label, randomized, two-period crossover study, healthy adults aged 18-55 years were given a single dose of revexepride 1 mg or revexepride 1 mg + omeprazole 40 mg. Pharmacokinetic parameters were assessed for up to 48 hours after administration of the investigational product. Adverse events, clinical chemistry and hematology parameters, electrocardiograms, and vital signs were monitored.

Results: In total, 42 participants were enrolled and 40 completed the study. The median age was 24 years (18-54 years), 55% were women and 93% were white. The pharmacokinetic parameters of revexepride were similar without or with omeprazole co-administration. The mean area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) was 23.3 ng · h/mL (standard deviation [SD]: 6.33 ng · h/mL) versus 24.6 ng · h/mL (SD: 6.31 ng · h/mL), and maximum plasma concentrations (Cmax) were 3.89 ng/mL (SD: 1.30 ng/mL) and 4.12 ng/mL (SD: 1.29 ng/mL) in participants without and with omeprazole, respectively. For AUC0-∞ and Cmax, the 90% confidence intervals for the ratios of geometric least-squares means (with:without omeprazole) were fully contained within the pre-defined equivalence limits of 0.80-1.25. Mean apparent terminal phase half-life was 9.95 hours (SD: 2.06 hours) without omeprazole, and 11.0 hours (SD: 3.25 hours) with omeprazole.

Conclusion: Co-administration of the 5-hydroxytryptamine receptor 4 agonist revexepride with omeprazole did not affect the pharmacokinetics of revexepride in healthy adults.
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http://dx.doi.org/10.2147/DDDT.S64621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354395PMC
August 2016

Population Pharmacokinetic Modeling of Guanfacine in Pediatric Patients.

Clin Pharmacokinet 2015 Aug;54(8):875-83

Metrum Research Group LLC, 2 Tunxis Road, Suite 112, Tariffville, CT, 06081, USA,

Introduction: The population pharmacokinetics of guanfacine extended release were characterized in pediatric patients aged 6-17 years using NONMEM and evaluated by predictive check and bootstrap.

Methods: Data were described using a one-compartment model. A covariate modeling approach that emphasized parameter estimation rather than stepwise hypothesis testing was implemented. A nonparametric bootstrap procedure and a predictive check method were used to evaluate the final model and parameter estimates.

Results: Typical population pharmacokinetic parameters (95 % confidence interval), given the reference covariates (Caucasian, male, age 12 years, weight 50 kg), were 33.1 (30.2-36.4) L/h for apparent clearance (CL/F), 804 (703-900) L for apparent volume of distribution, 0.552 (0.437-0.670) h(-1) for the absorption rate constant, and 0.651 (0.608-0.697) h for absorption lag time.

Discussion: The pharmacokinetics of guanfacine are similar in pediatric patients compared with adults when appropriately scaled by patient weight. The main predictor of guanfacine exposure, as determined by a change in CL/F, was weight. Effects of the other covariates (age, sex, and race) on CL/F were estimated with reasonable precision; however, the additional effects of age, sex, and race can be considered to have little to no clinical relevance.
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http://dx.doi.org/10.1007/s40262-015-0245-7DOI Listing
August 2015

Safety and pharmacokinetics of lisdexamfetamine dimesylate in adults with clinically stable schizophrenia: a randomized, double-blind, placebo-controlled trial of ascending multiple doses.

J Clin Psychopharmacol 2014 Dec;34(6):682-9

From the *Shire Development LLC, Wayne, PA; †California Clinical Trials Medical Group, Glendale; and ‡Collaborative Neuroscience Network, Garden Grove, CA.

To assess the safety and pharmacokinetics of lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug, this double-blind study enrolled adults with clinically stable schizophrenia who were adherent (≥12 weeks) to antipsychotic pharmacotherapy. The participants received placebo or ascending LDX doses (50, 70, 100, 150, 200, and 250 mg) daily for 5 days at each dose (dose periods, 1-6; days, 1-5). Of the 31 enrolled participants, 27 completed the study (placebo, n = 6; LDX, n = 21). Treatment-emergent adverse events (AEs) were reported by 4 participants receiving placebo and by 23 participants receiving LDX (all doses) with no serious AEs while on active treatment. For all periods, the mean postdose change on day 5 (up to 12 hours postdose) in systolic and diastolic blood pressure and pulse, respectively, ranged from -4.62 to 8.05 mm Hg, -3.67 to 4.43 mm Hg, and -3.57 to 14.43 beats per minute for placebo and -3.83 to 11.25 mm Hg, -1.55 to 5.80 mm Hg, and -0.36 to 21.26 beats per minute for LDX. With ascending LDX dose, the mean (SD) maximum plasma concentration for LDX-derived d-amphetamine ranged from 51.68 (10.28) to 266.27 (56.55) ng/mL. The area under the plasma concentration-time curve for 24 hours ranged from 801.8 (170.2) to 4397.9 (1085.9) ng[BULLET OPERATOR]h/mL. The d-amphetamine maximum plasma concentration and area under the plasma concentration-time curve increased linearly with ascending LDX dose. Antipsychotic agents did not markedly affect d-amphetamine pharmacokinetics. Over a wide range of ascending doses, LDX safety profile in adults with schizophrenia was consistent with previous findings with no unexpected treatment-emergent AEs. Pulse tended to increase with LDX dose; overall, blood pressure did not increase with LDX dose. Consistent with previous studies, pharmacokinetic parameters increased linearly with increasing LDX dose.
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http://dx.doi.org/10.1097/JCP.0000000000000205DOI Listing
December 2014

A thorough QT study of guanfacine.

Int J Clin Pharmacol Ther 2015 Apr;53(4):301-16

Objectives: Guanfacine extended- release (GXR) is approved for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. As part of the clinical development of GXR, and to further explore the effect of guanfacine on QT intervals, a thorough QT study of guanfacine was conducted (ClinicalTrials. gov identifier: NCT00672984).

Methods: In this double-blind, 3-period, crossover trial, healthy adults (n = 83) received immediaterelease guanfacine (at therapeutic (4 mg) and supra-therapeutic (8 mg) doses), placebo, and 400 mg moxifloxacin (positive control) in 1 of 6 randomly assigned sequences. Continuous 12-lead electrocardiograms were extracted, and guanfacine plasma concentrations were assessed pre-dose and at intervals up to 24 hours post-dose. QT intervals were corrected using 2 methods: subject-specific (QTcNi) and Fridericia (QTcF). Time-matched analyses examined the largest, baseline-adjusted, drug-placebo difference in QTc intervals.

Results: In the QTcNi analysis, the largest 1-sided 95% upper confidence bound (UCB) through hour 12 was 1.94 ms (12 hours postdose). For the 12-hour QTcF analysis, the largest 1-sided 95% UCB was 10.34 ms (12 hours post-supratherapeutic dose), representing the only 1-sided 95% UCB > 10 ms. Following the supra-therapeutic dose, maximum guanfacine plasma concentration was attained at 5.0 hours (median) post-dose. Assay sensitivity was confirmed by moxifloxacin results. Among guanfacine-treated subjects, most treatment-emergent adverse events were mild (78.9%); dry mouth (65.8%) and dizziness (61.8%) were most common.

Conclusions: Neither therapeutic nor supra-therapeutic doses of guanfacine prolonged QT interval after adjusting for heart rate using individualized correction, QTcNi, through 12 hours postdose. Guanfacine does not appear to interfere with cardiac repolarization of the form associated with pro-arrhythmic drugs.
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http://dx.doi.org/10.5414/CP202065DOI Listing
April 2015

Pharmacokinetics and pharmacodynamics of guanfacine extended release in adolescents aged 13-17 years with attention-deficit/hyperactivity disorder.

Clin Pharmacol Drug Dev 2014 07 17;3(4):252-61. Epub 2014 May 17.

Shire Development LLC, Wayne, PA.

The safety and efficacy of guanfacine extended release (up to 4 mg/day) for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents aged 6-17 years is well documented. Data suggest that weight-adjusted doses of guanfacine extended release >0.08 mg/kg but ≤0.12 mg/kg, if tolerated, may provide additional clinical benefits. For many adolescents, such dosing would exceed 4 mg/day, the highest approved dose. This open-label multicenter study evaluated the safety, tolerability, and steady-state pharmacokinetics of guanfacine extended release at escalated forced doses ≤9 mg/day in adolescents (N = 31) aged 13-17 years with ADHD. Following doses of approximately 0.12 mg/kg, the highest weight group (>70-90 kg) exhibited lower mean clearance at steady-state than the lowest weight group (≥30-50 kg). Consistent with its known antihypertensive effects, guanfacine extended release was associated with dose-dependent decreases in blood pressure (BP) and heart rate (HR). The physiologic response of increased BP upon standing was blunted in a dose-related manner while the physiologic response of increased HR upon standing was not substantively affected. The most common treatment-emergent adverse events were somnolence, dizziness, and sinus bradycardia. These results, and those from prior studies, support further examination of the efficacy and safety of higher weight-adjusted doses of guanfacine extended release for ADHD.
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http://dx.doi.org/10.1002/cpdd.124DOI Listing
July 2014

Effect of MMX® mesalamine coadministration on the pharmacokinetics of amoxicillin, ciprofloxacin XR, metronidazole, and sulfamethoxazole: results from four randomized clinical trials.

Drug Des Devel Ther 2014 14;8:529-43. Epub 2014 May 14.

PRA International, Lenexa, KS, USA.

Background: MMX(®) mesalamine is a once daily oral 5-aminosalicylic acid formulation, effective in induction and maintenance of ulcerative colitis remission. Patients on long-term mesalamine maintenance may occasionally require concomitant antibiotic treatment for unrelated infections.

Aim: To evaluate the potential for pharmacokinetic interactions between MMX mesalamine and amoxicillin, ciprofloxacin extended release (XR), metronidazole, or sulfamethoxazole in four open-label, randomized, placebo-controlled, two-period crossover studies.

Methods: In all four studies, healthy adults received placebo once daily or MMX mesalamine 4.8 g once daily on days 1-4 in one of two treatment sequences. In studies 1 and 2, subjects also received a single dose of amoxicillin 500 mg (N=62) or ciprofloxacin XR 500 mg (N=30) on day 4. In studies 3 and 4, subjects received metronidazole 750 mg twice daily on days 1-3 and once on day 4 (N=30); or sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily on days 1-3 and once on day 4 (N=44).

Results: MMX mesalamine had no significant effects on systemic exposure to amoxicillin, ciprofloxacin, or metronidazole; the 90% confidence intervals (CIs) around the geometric mean ratios (antibiotic + MMX mesalamine: antibiotic + placebo) for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) fell within the predefined equivalence range (0.80-1.25). Sulfamethoxazole exposure increased by a statistically significant amount when coadministered with MMX mesalamine; however, increased exposure (by 12% in Cmax at steady state; by 15% in AUC at steady state) was not considered clinically significant, as the 90% CIs for each point estimate fell entirely within the predefined equivalence range. Adverse events in all studies were generally mild.

Conclusion: MMX mesalamine may be coadministered with amoxicillin, ciprofloxacin, metronidazole, or sulfamethoxazole, without affecting pharmacokinetics or safety of these antibiotics.

Clinicaltrialsgov Identifiers: NCT01442688, NCT01402947, NCT01418365, and NCT01469637.
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http://dx.doi.org/10.2147/DDDT.S55373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4029757PMC
November 2014

Randomized, double-blind, placebo-controlled, crossover study of the effects of lisdexamfetamine dimesylate and mixed amphetamine salts on cognition throughout the day in adults with attention-deficit/hyperactivity disorder.

Clin Drug Investig 2014 Feb;34(2):147-57

Shire Development LLC, 725 Chesterbrook Blvd, Wayne, PA, 19087-5637, USA,

Background: Understanding the nature and time course of the pharmacodynamic effects of attention-deficit/hyperactivity disorder (ADHD) medications is useful. The Cognitive Drug Research Computerized Battery of Tests (CDR-CBT) is a 20-min battery of ten standardized, validated neuropsychometric tasks.

Objective: This pilot study examined the sensitivity and responsiveness of the CDR-CBT for assessing cognitive function in adults with ADHD prior to and up to 16 h postdose during treatment with lisdexamfetamine dimesylate (LDX) or mixed amphetamine salts immediate release (MAS-IR; various generics available).

Methods: This was a double-blind three-period crossover study. Participants received LDX 50 mg/day, MAS-IR 20 mg/day, and placebo (~7 a.m.) for 7 days each in randomized order. CDR-CBT was administered on day 1 of period 1 and day 7 of each period at scheduled times between -0.5 (predose) and 16 h postdose. Composite power of attention (PoA) score (sum of simple reaction time, choice reaction time, and digit vigilance speed) was the primary outcome measure. The Conners' Adult ADHD Rating Scales-Self-Report: Short Version (CAARS-S:S) was administered at baseline and on day 1 of period 1, and days 6 and 7 of each treatment period. Tertiary outcomes included CDR-CBT composite continuity of attention scores, its component task scores, cognitive reaction time, and response variability scores. No inferential statistical comparisons were conducted. Safety assessments included adverse events (AEs) and vital signs.

Results: This analysis included 18 participants (mean age 30.8 years); one withdrew because of AEs. Mean pretreatment PoA scores were 1175.9-1361.2 ms, scores commensurate with a normative age of >40 years. Maximum reductions in PoA scores with LDX and MAS-IR occurred at 5 h postdose at day 7 (least squares mean difference [95% CI] of -150.0 [-235.41 to -64.50] and -79.8 [-165.72 to 6.21] ms vs. placebo, respectively). CAARS-S:S scores were unchanged with LDX and MAS-IR (vs. placebo) at all postdose timepoints. Tertiary attention-related CDR-CBT outcomes were sensitive to LDX and MAS-IR (vs. placebo). Treatment-emergent AEs and vital signs were consistent with previous studies in adult ADHD.

Conclusion: In adults with ADHD, PoA scores indicated impaired attention at baseline and response to treatment with LDX and MAS-IR (vs. placebo), demonstrating value for measuring the time course of pharmacologic treatment effects.
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http://dx.doi.org/10.1007/s40261-013-0156-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899471PMC
February 2014

Pharmacokinetics of coadministered guanfacine extended release and lisdexamfetamine dimesylate.

Drugs R D 2013 Jun;13(2):119-28

Advanced Biomedical Research, Inc., 241 Main Street, 3rd Floor, Hackensack, NJ 07601, USA.

Background: In clinical practice, α₂-adrenoceptor agonists have been adjunctively administered with psychostimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD). Two studies have examined the adjunctive use of guanfacine extended release (GXR, Intuniv®; Shire Development LLC, Wayne, PA, USA) with psychostimulants in children and adolescents with a suboptimal response to psychostimulant treatment. However, the potential for pharmacokinetic drug-drug interactions (DDIs) between GXR and lisdexamfetamine dimesylate (LDX, Vyvanse®; Shire US LLC, Wayne, PA, USA) has not been thoroughly evaluated.

Objective: The primary objective of this study was to examine the pharmacokinetics of GXR 4 mg and LDX 50 mg given as single doses alone and in combination.

Study Design: This was an open-label, randomized, three-period crossover, DDI study.

Setting: The study was conducted in a single clinical research center.

Participants: Forty-two healthy adults were randomized in this study.

Interventions: Subjects were administered single oral doses of GXR 4 mg, LDX 50 mg, or GXR and LDX in combination.

Main Outcome Measures: Blood samples collected predose and up to 72 h postdose assessed guanfacine, LDX, and d-amphetamine levels. Bioequivalence was defined as the 90% confidence intervals (CIs) of the geometric mean ratios of the area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞) and maximum plasma concentration (Cmax) falling within the bioequivalence reference interval (0.80-1.25). Safety measures included adverse events, vital signs, and electrocardiograms (ECGs).

Results: Forty subjects completed the study. Following administration of LDX alone or in combination with GXR, the statistical comparisons of the AUC0-∞ and Cmax of d-amphetamine fell entirely within the reference interval. For guanfacine, the 90% CI of the geometric mean ratio of AUC∞ for the two treatments was within the bioequivalence criteria, but for Cmax the upper bound of the 90% CI exceeded the standard range for bioequivalence by 7%. This relatively small change is unlikely to be clinically meaningful. Treatment-emergent adverse events (TEAEs) were reported by 42.9% of subjects; the most commonly reported TEAEs included dizziness (5.0, 7.3, and 7.3%) and headache (7.5, 4.9, and 7.3%) following administration of GXR, LDX, and GXR and LDX in combination, respectively. Clinically significant ECG abnormalities occurred in one subject following administration of LDX and in one subject following coadministration of GXR and LDX.

Conclusions: In healthy adults, coadministration of GXR and LDX did not result in a clinically meaningful pharmacokinetic DDI compared with either treatment alone. No unique TEAEs were observed with coadministration of GXR and LDX compared with either treatment alone.
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http://dx.doi.org/10.1007/s40268-013-0014-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689918PMC
June 2013

Pharmacokinetics of coadministration of guanfacine extended release and methylphenidate extended release.

Drugs R D 2013 Mar;13(1):53-61

Advanced Biomedical Research Inc., 241 Main Street, 3rd Floor, Hackensack, NJ 07601, USA.

Background: α2-Adrenoceptor agonists are used adjunctively to psychostimulants in treating attention-deficit/hyperactivity disorder (ADHD) when psychostimulants alone do not sufficiently reduce symptoms. However, data on the pharmacokinetic profiles and safety of combination treatments in ADHD are needed.

Objective: The primary objective of this study was to evaluate the pharmacokinetic profiles of guanfacine extended release (GXR) and methylphenidate hydrochloride (MPH) extended release, alone and in combination.

Study Design: This was an open-label, randomized, three-period crossover, drug-drug interaction study.

Setting: The study was conducted at a single clinical research center.

Participants: Thirty-eight healthy adults were randomized in this study.

Interventions: Subjects were administered single oral doses of GXR (Intuniv(®); Shire Development LLC, Wayne, PA, USA) 4 mg, MPH (Concerta(®); McNeil Pediatrics, Titusville, NJ, USA) 36 mg, or GXR and MPH combined.

Main Outcome Measures: Guanfacine, dexmethylphenidate (d-MPH), and l-methylphenidate (l-MPH) levels were measured with blood samples collected predose and up to 72 h postdose. Safety evaluations included treatment-emergent adverse events (TEAEs), vital signs, and electrocardiograms (ECGs).

Results: Thirty-five subjects completed the study. Analyses of the 90 % confidence intervals (CIs) for the geometric mean ratios of the maximum plasma concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUC∞) values for guanfacine and d-MPH following administration of GXR or MPH alone or combined met strict bioequivalence criteria (90 % CIs within the interval of 0.80-1.25). Overall, combining GXR and MPH did not alter the pharmacokinetic parameters of either medication. Sixteen subjects (42.1 %) had at least one TEAE. The most commonly reported TEAEs included headache and dizziness following GXR, MPH, and GXR and MPH combined. Two subjects had clinically significant abnormalities in ECG results following coadministration: both events were mild and resolved the same day.

Conclusions: In this short-term, open-label study of healthy adults, coadministration of GXR and MPH did not result in significant pharmacokinetic drug-drug interactions. No unique TEAEs were observed with coadministration of GXR and MPH compared with either treatment alone.
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http://dx.doi.org/10.1007/s40268-013-0009-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627016PMC
March 2013

An open-label investigation of the pharmacokinetic profiles of lisdexamfetamine dimesylate and venlafaxine extended-release, administered alone and in combination, in healthy adults.

Clin Drug Investig 2013 Apr;33(4):243-54

Shire Development LLC, 725 Chesterbrook Blvd, Wayne, PA 19087, USA.

Background: Lisdexamfetamine dimesylate (LDX), a prodrug consisting of d-amphetamine and l-lysine, is being studied in clinical trials of major depressive disorder. Additional drug-drug interaction studies were warranted.

Objective: This study aimed to describe the pharmacokinetics and safety of LDX and venlafaxine extended-release (VXR), alone or combined.

Study Design: The study was an open-label, two-arm, single-sequence crossover investigation with randomization to treatment sequence.

Setting And Participants: The study was conducted at two clinical study centres and included healthy adult males and females (18-45 years of age).

Intervention: The study included two single-sequence crossover designs: LDX alone followed by LDX + VXR (Treatment Arm A); and VXR alone followed by VXR + LDX (Treatment Arm B). Drug treatment was initiated on day 1 with once-daily LDX or VXR alone with 15 days' titration to final dose (LDX 30, 50 and 70 mg for 5 days each; VXR 75, 150 and 225 mg for 5 days each). On days 16-30, VXR, titrated to a final dose of 225 mg, or LDX, titrated to a final dose of 70 mg, was coadministered for participants in Treatment Arm A or B, respectively. On days 31-38, VXR doses were tapered.

Main Outcome Measures: On days 1-2, 15-16 and 30-31, safety evaluations and blood samples were obtained pre-dose through 24 h post-dose for analysis of LDX, d-amphetamine, venlafaxine (VEN), and O-desmethylvenlafaxine (ODV). Combination treatment was considered bioequivalent to single treatment if 90 % confidence intervals (CIs) for geometric mean ratios (GMRs) of analytes fell within the interval 0.80-1.25 based on maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) from time zero to time of last measurable concentration (AUCτ). Safety assessments included treatment-emergent adverse events (TEAEs), pulse rate and blood pressure (BP), clinical laboratory assessments, and 12-lead electrocardiograms (ECG).

Results: Among 80 enrolled subjects, 77 were included in pharmacokinetic and safety analyses. Combination LDX + VXR was bioequivalent to LDX alone, based on exposure to d-amphetamine (GMR [95 % CI], Cmax (ng/mL): 0.97 [0.82, 1.14], AUCτ: 0.95 [0.81, 1.12]). Exposure to VEN with LDX + VXR (vs. VXR alone) was increased (Cmax: 1.10 [0.88, 1.38], AUCτ: 1.13 [0.88, 1.45]) and ODV decreased (Cmax: 0.91 [0.77, 1.06], AUCτ: 0.83 [0.71, 0.96]), whereas composite VEN + ODV was bioequivalent to VXR alone (Cmax: 0.96 [0.84, 1.09], AUCτ: 0.98 [0.85, 1.13]). TEAEs with LDX or LDX + VXR were similar. Maximum mean increases from baseline were: pulse rate, +8.73 to 12.76 beats/min with either treatment alone and +17.67 to 20.85 beats/min with LDX + VXR; systolic BP, +4.32 to 6.56 mmHg with either treatment alone and +12.96 to 13.78 mmHg with LDX + VXR; diastolic BP, +5.39 to 5.74 mmHg with either treatment alone and +12.09 to 12.46 mmHg with LDX + VXR. One participant was withdrawn due to a serious TEAE (presyncope). No unexpected, clinically meaningful trends or changes from baseline in mean laboratory or ECG parameters were observed during the trial.

Conclusion: In healthy adults, combination LDX + VXR (vs. LDX alone) did not alter exposure to d-amphetamine. Although small changes in exposure to VEN (increased) and ODV (decreased) were seen with combination treatment, total VEN + ODV exposure showed no change (vs. VEN alone). LDX + VXR led to increases in BP and pulse rate, supporting existing recommendations for vital sign monitoring when using these medications.
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http://dx.doi.org/10.1007/s40261-013-0073-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608883PMC
April 2013

Double-blind, placebo-controlled, two-period, crossover trial to examine the pharmacokinetics of lisdexamfetamine dimesylate in healthy older adults.

Neuropsychiatr Dis Treat 2013 12;9:219-29. Epub 2013 Feb 12.

Shire Development LLC, Wayne, PA.

Background: Pharmacokinetic and safety data on stimulants in older adults are limited. The objective of this study was to characterize the pharmacokinetics of lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug, in older adults.

Methods: In this two-period crossover trial, healthy adults (n = 47) stratified by age (55-64, 65-74, and ≥ 75 years) and gender received randomized, double-blind, single doses of LDX 50 mg or placebo. Baseline creatinine clearance, d-amphetamine and intact LDX pharmacokinetics, and safety were assessed.

Results: Mean (±standard deviation) baseline creatinine clearance in participants aged 55-64, 65-74, and ≥ 75 years was 102.5 ± 26.1, 105.3 ± 23.1, and 94.9 ± 27.3 mL per minute, respectively. In the groups aged 55-64, 65-74, and ≥ 75 years, the mean maximum plasma d-amphetamine concentration in men was 44.2 ± 11.1, 47.7 ± 7.0, and 53.4 ± 19.4 ng/mL, respectively; area under the concentration time curve from time 0 extrapolated to infinity (AUC(0-inf)) was 915.0 ± 164.9, 1123.0 ± 227.0, and 1325.0 ± 464.4 nghour/mL; median time to reach peak plasma concentration was 4.5, 3.5, and 5.5 hours; in women, mean maximum plasma d-amphetamine concentration was 51.0 ± 6.7, 50.2 ± 6.8, and 64.3 ± 12.1 ng/mL, AUC(0-inf) was 1034.5 ± 154.6, 988.4 ± 80.5, and 1347.8 ± 198.9 ng hour/mL, and median time to reach peak plasma concentration was 3.5, 4.1, and 5.5 hours, respectively. d-Amphetamine clearance was unrelated to baseline creatinine clearance. Five participants aged 55-64 years reported treatment-emergent adverse events (versus one each aged 65-74 and ≥ 75 years), and as did six women (versus one man). No trends in blood pressure or pulse changes were seen with LDX according to age. In participants aged 55-64, 65-74, and ≥ 75 years, the mean change from time-matched baseline pulse ranged from -5.0 to 14.7, -4.3 to 9.5, and -3.0 to 14.7 beats per minute; for systolic blood pressure, from -3.9 to 18.5 mmHg, -2.1 to 14.5 mmHg, and -5.9 to 16.0 mmHg; for diastolic blood pressure from -2.5 to 8.3 mmHg, from -0.8 to 9.4 mmHg, and -0.6 to 9.5 mmHg. Vital sign changes were similar between men and women.

Conclusion: Clearance of d-amphetamine decreased with age and was unrelated to creatinine clearance. No trends in pulse or blood pressure changes with LDX were seen according to age. The safety profile of LDX was consistent with prior observations in younger adult study participants.
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http://dx.doi.org/10.2147/NDT.S38377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575217PMC
July 2013

Pharmacokinetics of lisdexamfetamine dimesylate after targeted gastrointestinal release or oral administration in healthy adults.

Drug Metab Dispos 2012 Feb 28;40(2):290-7. Epub 2011 Oct 28.

Clinical Pharmacology, Shire Development Inc., Wayne, Pennsylvania, USA.

The purpose of this work was to assess the pharmacokinetics and safety of lisdexamfetamine dimesylate (LDX) delivered and released regionally in the gastrointestinal (GI) tract. In this open-label, randomized, crossover study, oral capsules and InteliSite delivery capsules containing LDX (50 mg) with radioactive marker were delivered to the proximal small bowel (PSB), distal SB (DSB), and ascending colon (AC) during separate periods. Gamma scintigraphy evaluated regional delivery and GI transit. LDX and d-amphetamine in blood were measured postdose (≤72 h). Treatment-emergent adverse events (TEAEs) were assessed. Healthy males (n = 18; 18-48 years) were enrolled. Mean (S.D.) maximal plasma concentration (C(max)) was 37.6 (4.54), 40.5 (4.95), 38.7 (6.46), and 25.7 (9.07) ng/ml; area under the concentration-time curve to the last measurable time point was 719.1 (157.05), 771.2 (152.88), 752.4 (163.38), and 574.3 (220.65) ng · h · ml⁻¹, respectively, for d-amphetamine after oral, PSB, DSB, and AC delivery of LDX. Median time to C(max) was 5, 4, 5, and 8 h, respectively. Most TEAEs were mild to moderate. No clinically meaningful changes were observed (laboratory, physical examination, or electrocardiogram). LDX oral administration or targeted delivery to small intestine had similar d-amphetamine systemic exposure, indicating good absorption, and had reduced absorption after colonic delivery. The safety profile was consistent with other LDX studies.
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http://dx.doi.org/10.1124/dmd.111.040691DOI Listing
February 2012

Caregiving styles: a cognitive and behavioral typology associated with dementia family caregiving.

Authors:
Mary A Corcoran

Gerontologist 2011 Aug 18;51(4):463-72. Epub 2011 Feb 18.

The George Washington University, Washington, DC 20037, USA.

Purpose: An increasing number of elderly individuals are diagnosed with Alzheimer's disease and related disorders (ADRD), many of whom receive daily caregiving from spouse or adult child. Caregiving is a "cultural activity," and as such it is strongly influenced by sociocultural beliefs about caregiving and how it should be enacted. Understanding this thinking-action process has important implications for future research and service. Reasoned action theory provides empirical evidence that attitudes and beliefs, as they are influenced by the social environment, predict intentions to act. In turn, behavioral intentions can reliably predict behaviors. This grounded theory study describes a typology of caregiving styles relevant to family members of an individual with ADRD, where caregiving style is defined as a culturally based pattern in thinking and action. The goal of this study was to characterize the relationship between caregiver intentions and care strategies.

Methods: Study participants included 97 individuals residing in the Washington, DC, area, who provide daily care for a family member with ADRD. Narrative data were collected from each caregiver during three 1-hr interview sessions. A subset of 30 caregiver-care recipient (CR) dyads was videotaped during typical interactions.

Results: Four caregiving styles were identified (facilitating, balancing, advocating, and directing), which differ primarily in the intended focus of care and preferred interactions with the CR.

Implications: The results provide a foundation for future studies of the relationships between sociocultural context, caregiving styles and strategies, and ensuing outcomes for caregiver-CR dyads.
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http://dx.doi.org/10.1093/geront/gnr002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146804PMC
August 2011

"God's Golden Acre for Children": pastoralism and sense of place in new suburban communities.

Authors:
Mary P Corcoran

Urban Stud 2010 ;47(12):2537-554

Department of Sociology and National Institute for Regional and Spatial Analysis (NIRSA), National University of Ireland Maynooth.

This paper is based on an empirical case study of four suburbs in the Dublin city hinterland. It is argued that pastoral ideology plays an active role in constituting these new suburbs and helps to inculcate a sense of place. This sense of place in turn helps to cement social embeddedness which acts as a bulwark against isolation and alienation. Pastoral ideology is invoked by suburbanites even when the pastoral dimension of the suburb is under threat or has disappeared. The village or ‘main street’ acts as an important anchor for new suburban residents as does the surrounding ‘rural’ landscape and their own collective memories. However, the study reveals a gap between how some newer suburbs are represented and imagined, and how they are experienced in everyday life. This raises questions about the long-term viability of suburbs that lack a sense of place.
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http://dx.doi.org/10.1177/0042098009359031DOI Listing
December 2010