Potentially harmful drug-drug interactions in the therapeutic regimens of persons with spinal cord injury.

OBJECTIVES: Individuals with spinal cord injury deal with multiple health complications that require them to use many medications. The purpose of this paper was to find the most common potentially harmful drug-drug interactions (DDIs) in therapeutic regimens of persons with spinal cord injury, and the risk factors associated with it. We further highlight the relevance of each of the DDIs specific to spinal cord injury population. DESIGN: Observational design and cross-sectional analysis. SETTING: Community; Canada. PARTICIPANTS: Individuals with spinal cord injury (n = 108). MAIN OUTCOME MEASURES/ANALYSIS: The main outcome was the presence of one or more potential DDIs that can lead to an adverse outcome. All the reported drugs were classified as per the World Health Organization's Anatomical Therapeutic Chemical Classification system. Twenty potential DDIs were selected for the analysis based on the most common medications prescribed to people with spinal cord injury and severity of clinical consequences. The medication lists of study participants were analyzed for selected DDIs. RESULTS: Among the 20 potential DDIs analyzed in our sample, the top 3 prevalent DDIs were Opioids + Skeletal Muscle Relaxants, Opioids + Gabapentinoids, and Benzodiazepines + ≥ 2 other central nervous system (CNS)-active drugs. Of the total sample of 108 respondents, 31 participants (29%) were identified with having at least one potential DDI. The risk of having a potential DDI was highly associated with polypharmacy, though no associations were found between the presence of a drug interaction and age, sex, level of injury, time since injury, or cause of injury among the study sample. CONCLUSION: Almost three out of ten individuals with spinal cord injury were at risk of having a potentially harmful drug interaction. Clinical and communication tools are needed that facilitate identification and elimination of harmful drug combinations in the therapeutic regimens of patients with spinal cord injury.

Prescribing patterns for treating common complications of spinal cord injury.

OBJECTIVE: The purpose of this study was to find the most and least commonly prescribed medications for treating secondary health complications associated with spinal cord injury (SCI); and determine overall polypharmacy rates and risk factors associated with it. DESIGN: Observational design, cross-sectional analysis. SETTING: Community; Canada. PARTICIPANTS: Individuals with spinal cord injury (n = 108). RESULTS: A total of 515 prescriptions were issued to the sample comprising 213 different medications to treat 10 SCI-related complications. Forty-five (45%) participants were prescribed >5 medications concurrently. No associations were found between the number of drugs taken and age, sex, level of injury, completeness of injury, time since injury, or cause of injury. The most commonly treated complications included pain (56.5%), muscle spasms (54%) and urinary tract infections (43%). Anti-convulsants (pregabalin, gabapentin), anti-spasmodics (baclofen, diazepam) and nitrofurantoins (Macrobid) were the most commonly prescribed medications to treat each of the three conditions, respectively. Thirty five percent of the total sample received a combination of two or more analgesics including fourth-line agents in the opiate class (hydromorphone, hydrocodone and morphine). Similarly, some participants were prescribed general muscle relaxants and cephalosporins for treatment of muscle spasms and urinary tract infections, respectively, that are generally not recommended in SCI patients. We compare these prescribing patterns with the available clinical practice guidelines and highlight areas where the prescriptions fall outside the recommended clinical practice while considering the complexity of medication management in SCI. CONCLUSION: Medication management in SCI is complex. Tools are required that enable prescribers to choose evidence-based medical regimens and deprescribe potentially inappropriate medications for their patients with SCI.

Prescribing for common complications of spinal cord injury.

OBJECTIVE: To describe prescribing patterns for 3 common complications associated with spinal cord injury (SCI) and to provide family doctors with strategies for optimizing the care of patients with SCI. SOURCES OF INFORMATION: Results of a nationwide survey of prescription medication use among people with SCI in Canada and a longitudinal study of secondary complications associated with SCI. MAIN MESSAGE: Altered neurologic and cardiometabolic function in patients with SCI make it difficult for family physicians to predict optimal medication regimens for these patients. Three common problems seen in primary care among patients with SCI that require pharmacologic treatment are pain (treated in 57% of survey respondents), muscle spasms (54%), and recurrent urinary tract infections (43%). Pain management may require multiple medications, depending on the source or nature of the pain. Some prescription medications recommended for treating pain may be underused in this population, such as amitriptyline, while others may be overused in this population, such as antibiotics for urinary tract infections. Spasticity is often related to an underlying problem such as pain, and treatment of concomitant conditions may also reduce spasticity. Short-acting benzodiazepines were found to have been prescribed for spasticity outside the recommended treatment paradigm at a surprisingly high rate. The longitudinal study of secondary complications associated with SCI led to the development of Actionable Nuggets, an innovative knowledge translation tool for primary care providers. CONCLUSION: To provide optimal treatment to patients with SCI, family doctors are encouraged to engage in open communication with them about prescription medications, including aspects of cost, polypharmacy, and therapeutic substitutions. Family physicians should also explore interprofessional collaboration with SCI specialists and allied health providers to provide patients with nonpharmacologic strategies tailored to their activity levels and nutritional needs. The Actionable Nuggets mobile app provides family doctors with brief, actionable, evidence-based information on the top 20 health concerns associated with SCI.

Prescriptions pour les complications courantes des lésions de la moelle épinière.

OBJECTIF: Décrire les modèles de prescriptions dans le cas de 3 complications communes associées à une lésion de la moelle épinière (LME) et proposer aux médecins de famille des stratégies pour optimiser les soins aux patients atteints d'une LME. SOURCES DE L'INFORMATION: Les résultats d'une enquête nationale sur l'utilisation des médicaments d'ordonnance par des personnes atteintes d'une LME au Canada et d'une étude longitudinale des complications secondaires liées aux LME. MESSAGE PRINCIPAL: Les fonctions neurologiques et cardiométaboliques altérées chez les patients atteints d'une LME compliquent le choix des régimes pharmacologiques optimaux chez de tels patients. Trois problèmes courants observés en soins primaires chez des patients atteints d'une LME exigent une pharmacothérapie, soit la douleur (traitée chez 57 % des répondants à l'enquête), les spasmes musculaires (54 %) et les infections des voies urinaires récurrentes (43 %). Le contrôle de la douleur peut nécessiter plusieurs médicaments, selon la source ou la nature de la douleur. Certains médicaments d'ordonnance recommandés pour le traitement de la douleur pourraient être sous-utilisés dans cette population, comme l'amitriptyline, tandis que d'autres pourraient être surutilisés chez de tels patients, comme les antibiotiques pour les infections des voies urinaires. La spasticité est souvent liée à un problème sous-jacent, comme la douleur, et le traitement des problèmes concomitants peut donc aussi réduire la spasticité. Il a été observé que des benzodiazépines à courte durée d'action ont été prescrites pour la spasticité à des taux étonnamment élevés, même si elles ne font pas partie du paradigme thérapeutique recommandé. L'étude longitudinale sur les complications secondaires associées aux LME a mené à l'élaboration de pépites exploitables, un outil novateur de transmission des connaissances à l'intention des professionnels des soins primaires. CONCLUSION: Dans le but de prodiguer un traitement optimal des patients souffrant d'une LME, les médecins de famille sont encouragés à entamer des communications franches au sujet des médicaments d'ordonnance, y compris sur les aspects liés aux coûts, à la polypharmacie et aux substituts thérapeutiques. Les médecins de famille devraient aussi explorer l'établissement d'une collaboration interprofessionnelle avec des spécialistes des LME et d'autres professionnels de la santé afin d'offrir aux patients des stratégies non pharmacologiques adaptées à leur degré d'activité et à leurs besoins nutritionnels. L'application mobile des pépites exploitables fournit aux médecins de famille des renseignements concis, pratiques et fondés sur des données probantes portant sur les 20 principales préoccupations liées à la santé causées par une LME.

Use and Costs of Nonprescription Medications Among People With Spinal Cord Injury.

OBJECTIVES: The study objectives were to assess the prevalence of, and factors associated with the use and costs of nonprescription medications among people with spinal cord injury. DESIGN: Observational design; a cross-sectional online survey. SETTING: Community in Canada. PARTICIPANTS: Individuals with spinal cord injury (N=160). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Not applicable. RESULTS: A total of 160 individuals participated in this study. Of all study participants, 83% reported that they used at least 1 nonprescription medication over the last 12 months. On average, participants spent $52 per month on nonprescription medications. The average use and monthly expenditure did not differ significantly by age, sex, or injury parameters. Vitamins and minerals were most commonly used and constituted 62% of all nonprescription medications listed by the participants. Musculoskeletal issues were the most common health problems for which nonprescription medications were used. CONCLUSION: Nonprescription medications are a common part of therapeutic drug regimens for people with spinal cord injuries and are purchased as an out-of-pocket expense. These products may or may not have established benefits. Knowledge about the use of nonprescription medications may help prescribers to improve drug safety, medication affordability, and quality of pharmacotherapy for patients with spinal cord injury.

Are we getting any better? A study on repair integrity in 1600 consecutive arthroscopic rotator cuff repairs.

BACKGROUND: Postoperative retear is the most common surgical complication after rotator cuff repair. This study aimed to determine whether there had been any improvements in rotator cuff repair integrity in our center and to identify any changes in the management of rotator cuff tears that may have impacted postoperative retear rate. METHODS: This retrospective observational single cohort study used running average analysis to examine 1600 consecutive patients over 8 years, who underwent primary arthroscopic rotator cuff repair by a single surgeon, and had cuff integrity assessed by ultrasound 6 months after operation. RESULTS: Retear rates ranged from 3% to 34%, with a mean of 15%. Over our study retear rates decreased from 18% to 5%. Reductions in retear rates were associated with less aggressive rehabilitation, postoperative abduction sling use, and increased surgical experience. Increases in retear rates were associated with increased false positives with a more sensitive ultrasound machine and learning curves with new equipment for a surgeon and sonographer. CONCLUSION: A decrease in retear rate after arthroscopic rotator cuff repair occurred during our study. Although the study design prevents us from directly attributing changes in retear rate to changes in management, our results suggest that rehabilitation optimization and increased surgeon experience decrease postoperative retear.

Promoting Long-Term Health among People with Spinal Cord Injury: What's New?

A key ingredient to successful health promotion is a primary care provider who can offer an informed first response to lifestyle issues, emerging problems and chronic challenges. This article aims to assist family physicians to play their role in promoting the health of people with SCI, by summarizing the latest evidence in the management of spinal cord injury in primary care. This study used a scoping review methodology to survey peer-reviewed journal articles and clinical guidelines published between January 2012 to June 2016. This search strategy identified 153 articles across 20 topics. A prevention framework is used to identify five primary, nine secondary, four tertiary, and two quaternary prevention issues about which family physicians require current information. Major changes in the management of SCI in primary care were noted for 8 of the 20 topics, specifically in the areas of pharmacological management of neuropathic pain and urinary tract infection; screening for bowel and bladder cancer; improvements in wound care; and clarification of dietary fibre recommendations. All of these changes are represented in the 3rd edition of Actionable Nuggets-an innovative tool to assist family physicians to be aware of the best practices in primary care for spinal cord injury.

A new framing approach in guideline development to manage different sources of knowledge.

RATIONALE: Contemporary guideline methodology struggles to consider context and information from different sources of knowledge besides quantitative research. Return to work programmes involve multiple components and stakeholders. If the guideline is to be relevant and practical for a complex intervention such as return to work, it is essential to use broad sources of knowledge. AIMS AND OBJECTIVE: This paper reports on a new method in guideline development to manage different sources of knowledge. METHODS: The method used framing for the return-to-work guidance within the Clinical Practice Guidelines for the Management of Rotator Cuff Syndrome in the Workplace. The development involved was a multi-disciplinary working party of experts including consumers. The researchers considered a broad range of research, expert (practice and experience) knowledge, the individual's and workplace contexts, and used framing with the International Classification of Functioning, Disability and Health. Following a systematic database search on four clinical questions, there were seven stages of knowledge management to extract, unpack, map and pack information to the ICF domains framework. Companion graded recommendations were developed. RESULTS: The results include practical examples, user and consumer guides, flow charts and six graded or consensus recommendations on best practice for return to work intervention. CONCLUSIONS: Our findings suggest using framing in guideline methodology with internationally accepted frames such as the ICF is a reliable and transparent framework to manage different sources of knowledge. Future research might examine other examples and methods for managing complexity and using different sources of knowledge in guideline development.

Actionable nuggets: knowledge translation tool for the needs of patients with spinal cord injury.

OBJECTIVE: To present the results of a pilot study of an innovative methodology for translating best evidence about spinal cord injury (SCI) for family practice. DESIGN: Review of Canadian and international peer-reviewed literature to develop SCI Actionable Nuggets, and a mixed qualitative-quantitative evaluation to determine Nuggets' effect on physician knowledge of and attitudes toward patients with SCI, as well as practice accessibility. SETTING: Ontario, Newfoundland, and Australia. PARTICIPANTS: Forty-nine primary care physicians. METHODS: Twenty Actionable Nuggets (pertaining to key health issues associated with long-term SCI) were developed. Nugget postcards were mailed weekly for 20 weeks to participating physicians. Prior knowledge of SCI was self-rated by participants; they also completed an online posttest to assess the information they gained from the Nugget postcards. Participants' opinions about practice accessibility and accommodations for patients with SCI, as well as the acceptability and usefulness of Nuggets, were assessed in interviews. MAIN FINDINGS: With Actionable Nuggets, participants' knowledge of the health needs of patients with SCI improved, as knowledge increased from a self-rating of fair (58%) to very good (75%) based on posttest quiz results. The mean overall score for accessibility and accommodations in physicians' practices was 72%. Participants' awareness of the need for screening and disease prevention among this population also increased. The usefulness and acceptability of SCI Nugget postcards were rated as excellent. CONCLUSION: Actionable Nuggets are a knowledge translation tool designed to provide family physicians with concise, practical information about the most prevalent and pressing primary care needs of patients with SCI. This evidence-based resource has been shown to be an excellent fit with information consumption processes in primary care. They were updated and adapted for distribution by the Canadian Medical Association to approximately 50,000 primary care physicians in Canada, in both English and French.

Primary care of people with spinal cord injury: scoping review.

OBJECTIVE: To perform a scoping review of the empirical evidence between 1980 and 2009 regarding primary care for adults with spinal cord injury (SCI). DATA SOURCES: Peer-reviewed journals were searched from 1980 to 2009 using CINAHL, PubMed-MEDLINE, EMBASE, PsycINFO, Social Sciences Abstracts, and Social Work Abstracts. STUDY SELECTION: The key word-driven electronic search identified 42 articles on primary care and SCI. Inclusion criteria narrowed the set to 21 articles that were published in English, that had a sample size of greater than 3, and that offered empirical analysis. SYNTHESIS: Approximately 90% of people with SCI identify family physicians as their regular doctors; 63% have SCI specialists. People with long-term SCI develop complex rubrics for navigating their personal health care systems. There is conflicting evidence about the effectiveness of outreach programs for maintaining health and preventing complications following SCI. Regular follow-up by specialized teams and annual comprehensive health examination are supported by the evidence. The research shows a high level of consistency in identifying the most common issues raised by people with SCI in primary care, most of which are related to disability-specifically, secondary complications such as bowel or bladder dysfunction and pain. There is also good evidence that many general health issues require attention in this population, such as bone density problems, depression, and sexual and reproductive health issues. There is level 4 and 5 evidence for unmet health needs among individuals living with SCI in the community. Despite patients with SCI being high users of primary care and health services in general, the evidence suggests that the information needs of these patients in particular are poorly met. CONCLUSION: A robust system of primary care is the best assurance of good health outcomes and reasonable health service use for people with SCI, including annual comprehensive examination, appropriate specialist use, and attention to accessibility and unmet needs.

Discovery and optimization of a novel spiropyrrolidine inhibitor of ß-secretase (BACE1) through fragment-based drug design.

The aspartyl protease ß-secretase, or BACE, has been demonstrated to be a key factor in the proteolytic formation of Aß-peptide, a major component of plaques in the brains of Alzheimer's disease (AD) patients, and inhibition of this enzyme has emerged as a major strategy for pharmacologic intervention in AD. An X-ray-based fragment screen of Pfizer's proprietary fragment collection has resulted in the identification of a novel BACE binder featuring spiropyrrolidine framework. Although exhibiting only weak inhibitory activity against the BACE enzyme, the small compound was verified by biophysical and NMR-based methods as a bona fide BACE inhibitor. Subsequent optimization of the lead compound, relying heavily on structure-based drug design and computational prediction of physiochemical properties, resulted in a nearly 1000-fold improvement in potency while maintaining ligand efficiency and properties predictive of good permeability and low P-gp liability.

Glycomimetic ligands for the human asialoglycoprotein receptor.

The asialoglycoprotein receptor (ASGPR) is a high-capacity galactose-binding receptor expressed on hepatocytes that binds its native substrates with low affinity. More potent ligands are of interest for hepatic delivery of therapeutic agents. We report several classes of galactosyl analogues with varied substitution at the anomeric, C2-, C5-, and C6-positions. Significant increases in binding affinity were noted for several trifluoromethylacetamide derivatives without covalent attachment to the protein. A variety of new ligands were obtained with affinity for ASGPR as good as or better than that of the parent N-acetylgalactosamine, showing that modification on either side of the key C3,C4-diol moiety is well tolerated, consistent with previous models of a shallow binding pocket. The galactosyl pyranose motif therefore offers many opportunities for the attachment of other functional units or payloads while retaining low-micromolar or better affinity for the ASGPR.

A multi-university study of which factors medical students consider when deciding to attend a rural clinical school in Australia.

INTRODUCTION: As in many developed nations, there is a shortage in the rural medical workforce in Australia. Research indicates that a strong relationship exists between rural educational exposure and an increased interest in pursuing a rural career or selecting a rural internship. Accordingly, in 2000 the Australian Commonwealth Government established the Rural Clinical Schools (RCS) program. Under this program, 25% of parent medical schools' Commonwealth Supported Place (CSP) medical students must spend at least 1 year of their clinical medical education in a rural setting. Research indicates that positive experiences are of vital importance in determining future rural practice. Arguably, if students are conscripted to a RCS, they may view their overall experience negatively. Thus, the development and sustainability of an adequate future rural medical workforce depends on medical schools understanding and fostering the factors that encourage voluntary student recruitment to the RCSs. The aim of the present study was to determine which factors Australian medical students consider in their decision to attend RCSs. METHODS: This study employed survey research. The questionnaire, which used a 6 point Likert scale, addressed factors influencing students' decision to attend an RCS, including whether these factors were viewed as positive or negative. Open-ended questions provided students with an opportunity to make comments about their decision-making. The setting was the RCSs of six participating Australian universities. The participants were medical students enrolled at one of six Australian universities in 2006 (n=166) who had completed their RCS term; 125 students responded (75% response rate). RESULTS: At least three-quarters of the respondents considered the following when deciding whether to attend an RCS: patient access, academic reputation, their friends, the availability of subsidized accommodation provided by the clinical school, extra-curricular activities, social opportunities and transport costs. The majority of students considered the following as positive considerations: 'patient access', 'academic reputation', and 'subsidized accommodation'. However, for other students these same factors were negative considerations. CONCLUSION: Students consider both clinical and non-clinical factors in their decision to attend an RCS. The primary positive factor in the present study was patient access with 97% students (n=119) considering this to be important, and 84% students (n=81) stating that this was a positive factor in their decision-making. The other major factors, friends and academic reputation, appear equally considered. However, they differed in the degree to which they were regarded as a positive or negative consideration. Identifying and promoting positive factors is essential if the future rural medical workforce is to be enhanced. This study supports the importance of RCSs not being over-crowded and, thus, maintaining patient access, and also the importance of institutions having sufficient resources to support an excellent academic reputation. Interestingly, and perhaps somewhat contrary to expectations, students of metropolitan origin appear to be increasingly attracted to RCSs. Although numerous studies show that rural origin is a strong predictor of rural medical workforce membership, urban students who attend an RCS and have a positive experience may also be open to future rural practice.

A nuclear magnetic resonance-based functional assay for nicotinamide adenine dinucleotide synthetase.

Nicotinamide adenine dinucleotide synthetase (NadE) is an essential enzyme for bacterial pathogens and is thus a promising antibacterial target. It catalyzes the conversion of nicotinic acid adenine dinucleotide to nicotinamide adenine dinucleotide. Changes in chemical shifts that occur in the nicotinic acid ring as it is converted to nicotinamide can be used for monitoring the reaction. A robust nuclear magnetic resonance-based activity assay was developed using robotically controlled reaction initiation and quenching. The single-enzyme assay has less potential for false positives compared to a coupled activity assay and is especially well suited to the high concentration of compounds in fragment screens. The assay has been used to screen fragment libraries for NadE inhibitors.