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1.  Canadian Society of Allergy and Clinical Immunology annual scientific meeting 2016 
Alsayegh, Mohammad A. | Alshamali, Hanan | Khadada, Mousa | Ciccolini, Amanda | Ellis, Anne K. | Quint, Diana | Powley, William | Lee, Laurie | Fiteih, Yahya | Baksh, Shairaz | Vliagoftis, Harissios | Gerega, Sebastien K. | Millson, Brad | Charland, Katia | Barakat, Stephane | Sun, Xichun | Jimenez, Ricardo | Waserman, Susan | FitzGerald, Mark J. | Hébert, Jacques | Cognet-Sicé, Josiane | Renahan, Kevin E. | Huq, Saiful | Chooniedass, Rishma | Sawyer, Scott | Pasterkamp, Hans | Becker, Allan | Smith, Steven G. | Zhang, Shiyuan | Jayasundara, Kavisha | Tacon, Claire | Simidchiev, Alex | Nadeau, Gilbert | Gunsoy, Necdet | Mullerova, Hana | Albers, Frank | Kim, Young Woong | Shannon, Casey P. | Singh, Amrit | Neighbour, Helen | Larché, Mark | Tebbutt, Scott J. | Klopp, Annika | Vehling, Lorena | Becker, Allan B. | Subbarao, Padmaja | Mandhane, Piushkumar J. | Turvey, Stuart E. | Sears, Malcolm R. | Azad, Meghan B. | Loewen, Keely | Monchka, Barret | Mahmud, Salaheddin M. | Jong, Geert ‘t | Longo, Cristina | Bartlett, Gillian | Ducharme, Francine M. | Schuster, Tibor | MacGibbon, Brenda | Barnett, Tracie | North, Michelle L. | Brook, Jeff | Lee, Elizabeth | Omana, Vanessa | Thiele, Jenny | Steacy, Lisa M. | Evans, Greg | Diamond, Miriam | Sussman, Gordon L. | Amistani, Yann | Abiteboul, Kathy | Tenn, Mark W. | Yang, ChenXi | Carlsten, Christopher | Conway, Edward M. | Mack, Douglas | Othman, Yasmin | Barber, Colin M. | Kalicinsky, Chrystyna | Burke, Andrea E. | Messieh, Mary | Nair, Parameswaran | Che, Chun T. | Douglas, Lindsay | Liem, Joel | Duan, Lucy | Miller, Charlotte | Dupuis, Pascale | Connors, Lori A. | Fein, Michael N. | Shuster, Joseph | Hadi, Hani | Polk, Brooke | Raje, Nikita | Labrosse, Roxane | Bégin, Philippe | Paradis, Louis | Roches, Anne Des | Lacombe-Barrios, Jonathan | Mishra, Sanju | Lacuesta, Gina | Chiasson, Meredith | Haroon, Babar | Robertson, Kara | Issekutz, Thomas | Leddin, Desmond | Couban, Stephen | Connors, Lori | Roos, Adrienne | Kanani, Amin | Chan, Edmond S. | Schellenberg, Robert | Rosenfield, Lana | Cvetkovic, Anna | Woodward, Kevin | Quirt, Jaclyn | Watson, Wade T. A. | Castilho, Edson | Sullivan, Jennifer A. | Temple, Beverley | Martin, Donna | Cook, Victoria E. | Mills, Christopher | Portales-Casamar, Elodie | Fu, Lisa W. | Ho, Alexander | Zaltzman, Jeffrey | Chen, Lucy | Vadas, Peter | Gabrielli, Sofianne | Clarke, Ann | Eisman, Harley | Morris, Judy | Joseph, Lawrence | LaVieille, Sebastien | Ben-Shoshan, Moshe | Graham, François | Barnes, Charles | Portnoy, Jay | Stagg, Vincent | Simons, Elinor | Lefebvre, Diana | Dai, David | Mandhane, Piushkumar | Sears, Malcolm | Tam, Herman | Simons, F. Estelle R. | Alotaibi, Dhaifallah | Dawod, Bassel | Tunis, Matthew C. | Marshall, Jean | Desjardins, Marylin | Béland, Marianne | Lejtenyi, Duncan | Drolet, Jean-Phillipe | Lemire, Martine | Tsoukas, Christos | Noya, Francisco J.D. | Alizadehfar, Reza | McCusker, Christine T. | Mazer, Bruce D. | Maestre-Batlle, Danay | Gunawan, Evelyn | Rider, Christopher F. | Bølling, Anette K. | Pena, Olga M. | Suez, Daniel | Melamed, Isaac | Hussain, Iftikhar | Stein, Mark | Gupta, Sudhir | Paris, Kenneth | Fritsch, Sandor | Bourgeois, Christelle | Leibl, Heinz | McCoy, Barbara | Noel, Martin | Yel, Leman | Scott, Ori | Reid, Brenda | Atkinson, Adelle | Kim, Vy Hong-Diep | Roifman, Chaim M. | Grunebaum, Eyal | AlSelahi, Eiman | Aleman, Fernando | Oberle, Amber | Trus, Mike | Sussman, Gordon | Kanani, Amin S. | Chambenoi, Olivier | Chiva-Razavi, Sima | Grodecki, Savannah | Joshi, Nikhil | Menikefs, Peter | Holt, David | Pun, Teresa | Tworek, Damian | Hanna, Raphael | Heroux, Delia | Rosenberg, Elli | Stiemsma, Leah | Turvey, Stuart | Denburg, Judah | Mill, Christopher | Teoh, Timothy | Zimmer, Preeti | Avinashi, Vishal | Paina, Mihaela | Darwish Hassan, Ahmed A. | Oliveria, John Paul | Olesovsky, Chris | Gauvreau, Gail | Pedder, Linda | Keith, Paul K. | Plunkett, Greg | Bolner, Michelle | Pourshahnazari, Persia | Stark, Donald | Vostretsova, Kateryna | Moses, Andrew | Wakeman, Andrew | Singer, Alexander | Gerstner, Thomas | Abrams, Elissa | Johnson, Sara F. | Woodgate, Roberta L.
doi:10.1186/s13223-017-0192-y
PMCID: PMC5390240
2.  Antibiotic-Induced Liver Injury in Paediatric Outpatients: A Case-Control Study in Primary Care Databases 
Drug Safety  2016;40(4):305-315.
Introduction
Antibiotics are the most commonly prescribed drug class in children. Real-world data mining on the paediatric population showed potential associations between antibiotic use and acute liver injury.
Objective
We assessed risk estimates of liver injury associated with antibiotic use in children and adolescent outpatients.
Methods
A large, multi-database, population-based, case-control study was performed in people <18 years of age from two European countries (Italy and The Netherlands) during the period 2000–2008. All potential cases of liver injury were automatically extracted from three databases and then manually validated based on Council for International Organizations of Medical Sciences (CIOMS) criteria and by exclusion of all competing causes for liver injury. Up to 100 control participants were sampled for each case and were matched on index date of the event, age, sex and database. Based on prescription data, antibiotic exposure was categorized as current, recent or past use by calculating the time period between the end of prescription and the index date. Multivariate conditional logistic regression analyses were applied to calculate odds ratios (ORs) as a measure of the association (with 95% confidence interval [CI]).
Results
We identified 938 cases of liver injury and matched to 93,665 controls. Current use of overall antibiotics is associated with a threefold increased risk of liver injury compared with past use (adjusted OR [ORadj] 3.22, 95% CI 2.57–4.03). With regard to individual antibiotics, the risk is significantly increased for current use of each antibiotic (p < 0.005), except for azithromycin. Risk estimates vary from the lowest ORadj of 1.86 (95% CI 1.08–3.21) for amoxicillin to the highest ORadj of 24.16 (95% CI 11.78–49.54) for cotrimoxazole (i.e. sulphamethoxazole/trimethoprim) and 26.70 (95% CI 12.09–58.96) for ceftriaxone. Sensitivity analyses confirm the associations for ceftriaxone, cotrimoxazole, and clarithromycin.
Conclusion
Antibiotic-induced liver injury in children is heterogeneous across the use of individual antibiotics. When prescribing ceftriaxone, cotrimoxazole and clarithromycin in children, paediatricians should definitely be aware of their potential risk of liver injury, even if for short periods.
Electronic supplementary material
The online version of this article (doi:10.1007/s40264-016-0493-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s40264-016-0493-y
PMCID: PMC5362651  PMID: 28025733
3.  Time-trends in the prescribing of gastroprotective agents to primary care patients initiating low-dose aspirin or non-steroidal anti-inflammatory drugs: a population-based cohort study 
Aims
Low-dose aspirin (LDA) and non-steroidal-anti-inflammatory drugs (NSAIDs) both increase the risk of upper gastrointestinal events (UGIEs). In the Netherlands, recommendations regarding the prescription of gastroprotective agents (GPAs) in LDA users were first issued in 2009 in the HARM-Wrestling consensus. National guidelines on gastroprotective strategies (GPSs) in NSAID users were issued in the first part of the preceding. The aim of the present study was to examine time-trends in GPSs in patients initiating LDA and those initiating NSAIDs between 2000 and 2012.
Methods
Within a large electronic primary healthcare database, two cohorts were selected: (i) patients newly prescribed LDA and (ii) patients newly prescribed NSAIDs between 2000 and 2012. Patients who had been prescribed a GPA in the previous six months were excluded. For both cohorts, patients’ risk of a UGIE was classified as low, moderate or high, based on the HARM-Wrestling consensus, and the presence of an adequate GPSwas determined.
Results
A total of 37 578 patients were included in the LDA cohort and 352 025 patients in the NSAID cohort. In both cohorts, an increase in GPSs was observed over time, but prescription of GPAs was lower in the LDA cohort. By 2012, an adequate GPS was present in 31.8% of high-risk LDA initiators, vs. 48.0% of high-risk NSAID initiators.
Conclusions
Despite a comparable risk of UGIEs, GPSs are prescribed less in high-risk LDA initiators than in high-risk NSAID initiators. For both groups of patients, there is still room for improvement in guideline adherence.
doi:10.1111/bcp.12626
PMCID: PMC4574843  PMID: 25777983
gastrointestinal hemorrhages; gastroprotective agents; low-dose aspirin; NSAIDs; pharmacoepidemiology
4.  Adverse drug reactions in a primary care population prescribed non-steroidal anti-inflammatory drugs 
Objective. To determine how often patients with musculoskeletal (MSK) complaints prescribed a non-steroidal anti-inflammatory drug (NSAID) subsequently consult their general practitioner (GP) with a non-serious adverse drug reaction (ADR). Design. Cohort study. Setting. A healthcare database containing the electronic GP medical records of over 1.5 million patients throughout the Netherlands. Patients. A total of 16 626 adult patients with MSK complaints prescribed an NSAID. Main outcome measures. The patients’ medical records were manually assessed for the duration of NSAID use for a maximum of two months, and consultations for complaints predefined as potential ADRs were identified. Subsequently, the likelihood of an association with the NSAID use was assessed and these potential ADRs were categorized as likely, possible, or unlikely ADRs. Results. In total, 961 patients (6%) consulted their GP with 1227 non-serious potential ADRs. In 174 patients (1%) at least one of these was categorized as a likely ADR, and in a further 408 patients (2.5%) at least one was categorized as a possible ADR. Dyspepsia was the most frequent likely ADR, followed by diarrhoea and dyspnoea (respectively 34%, 8%, and 8% of all likely ADRs). Conclusion. Of the patients with MSK complaints prescribed an NSAID, almost one in 30 patients re-consulted their GP with a complaint likely or possibly associated with the use of this drug. The burden of such consultations for non-serious ADRs should be taken into account by GPs when deciding whether treatment with an NSAID is appropriate.
doi:10.3109/02813432.2015.1067513
PMCID: PMC4750719  PMID: 26198810
Anti-inflammatory agents; drug toxicity; general practice; musculoskeletal/connective tissue; non-steroidal; pharmacoepidemiology; primary health care; The Netherlands
5.  High-risk use of over-the-counter non-steroidal anti-inflammatory drugs: a population-based cross-sectional study 
The British Journal of General Practice  2014;64(621):e191-e198.
Background
The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with serious adverse drug events (ADEs).
Aim
To determine the prevalence of over-the-counter (OTC) NSAID use in the general population and in patients with a high risk of developing a serious NSAID-related ADE.
Design and setting
Cross-sectional study in four general practices in the Netherlands.
Method
Two patient samples were selected: a random sample of adults (general population sample); and adult patients with a high risk of developing a serious ADE in case of NSAID use (high-risk sample). All included patients were sent a questionnaire regarding their use of OTC NSAIDs in the 4 weeks prior to participation.
Results
In the general population sample, 118 of 456 (26%) invited patients completed the questionnaire. Of these, 35 (30%) had used an OTC NSAID. In the high-risk sample, 264 of 713 (37%) invited patients completed the questionnaire, and of these high-risk patients 33 (13%) had used an OTC NSAID. Over 20% of OTC NSAID users in the general population sample and over 30% in the high-risk sample had used the OTC NSAID for >7 days. OTC NSAIDs were used in a dosage exceeding the recommended daily maximum by 9% and 3% of OTC NSAID users in the general population and the high-risk sample respectively.
Conclusion
OTC NSAIDs are used by almost one-third of the general population. In the high-risk patients selected, one in eight patients used an OTC NSAID. Continued efforts by health authorities and healthcare professionals to inform patients of the risks of these drugs are warranted.
doi:10.3399/bjgp14X677815
PMCID: PMC3964463  PMID: 24686883
anti-inflammatory agents, non-steroidal; general practice; over-the-counter drugs; primary care
6.  Pediatric Drug Safety Signal Detection: A New Drug–Event Reference Set for Performance Testing of Data-Mining Methods and Systems 
Drug Safety  2015;38(2):207-217.
Background
Better evidence regarding drug safety in the pediatric population might be generated from existing data sources such as spontaneous reporting systems and electronic healthcare records. The Global Research in Paediatrics (GRiP)–Network of Excellence aims to develop pediatric-specific methods that can be applied to these data sources. A reference set of positive and negative drug–event associations is required.
Objective
The aim of this study was to develop a pediatric-specific reference set of positive and negative drug–event associations.
Methods
Considering user patterns and expert opinion, 16 drugs that are used in individuals aged 0–18 years were selected and evaluated against 16 events, regarded as important safety outcomes. A cross-table of unique drug–event pairs was created. Each pair was classified as potential positive or negative control based on information from the drug’s Summary of Product Characteristics and Micromedex. If both information sources consistently listed the event as an adverse event, the combination was reviewed as potential positive control. If both did not, the combination was evaluated as potential negative control. Further evaluation was based on published literature.
Results
Selected drugs include ibuprofen, flucloxacillin, domperidone, methylphenidate, montelukast, quinine, and cyproterone/ethinylestradiol. Selected events include bullous eruption, aplastic anemia, ventricular arrhythmia, sudden death, acute kidney injury, psychosis, and seizure. Altogether, 256 unique combinations were reviewed, yielding 37 positive (17 with evidence from the pediatric population and 20 with evidence from adults only) and 90 negative control pairs, with the remainder being unclassifiable.
Conclusion
We propose a drug–event reference set that can be used to compare different signal detection methods in the pediatric population.
Electronic supplementary material
The online version of this article (doi:10.1007/s40264-015-0265-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s40264-015-0265-0
PMCID: PMC4328124  PMID: 25663078
8.  Ischaemic cardiovascular risk and prescription of non-steroidal anti-inflammatory drugs for musculoskeletal complaints 
Abstract
Objective. To determine the influence of ischaemic cardiovascular (CV) risk on prescription of non-steroidal anti-inflammatory drugs (NSAIDs) by general practitioners (GPs) in patients with musculoskeletal complaints. Design. Cohort study. Setting. A healthcare database containing the electronic GP medical records of over one million patients throughout the Netherlands. Patients. A total of 474 201 adults consulting their GP with a new musculoskeletal complaint between 2000 and 2010. Patients were considered at high CV risk if they had a history of myocardial infarction, angina pectoris, stroke, transient ischaemic attack, or peripheral arterial disease, and at low CV risk if they had no CV risk factors. Main outcome measures. Frequency of prescription of non-selective (ns)NSAIDs and selective cyclooxygenase-2 inhibitors (coxibs). Results. Overall, 24.4% of patients were prescribed an nsNSAID and 1.4% a coxib. Of the 41,483 patients with a high CV risk, 19.9% received an nsNSAID and 2.2% a coxib. These patients were more likely to be prescribed a coxib than patients with a low CV risk (OR 1.9, 95% CI 1.8–2.0). Prescription of nsNSAIDs decreased over time in all risk groups and was lower in patients with a high CV risk than in patients with a low CV risk (OR 0.8, 95% CI 0.7–0.8). Conclusion. Overall, patients with a high CV risk were less likely to be prescribed an NSAID for musculoskeletal complaints than patients with a low CV risk. Nevertheless, one in five high CV risk patients received an NSAID, indicating that there is still room for improvement.
doi:10.3109/02813432.2014.929810
PMCID: PMC4075023  PMID: 24931511
Cardiovascular diseases; general practice; musculoskeletal diseases; non-steroidal anti-inflammatory agents; pharmacoepidemiology; The Netherlands
9.  Population-based analysis of non-steroidal anti-inflammatory drug use among children in four European countries in the SOS project: what size of data platforms and which study designs do we need to assess safety issues? 
BMC Pediatrics  2013;13:192.
Background
Data on utilization patterns and safety of non-steroidal anti-inflammatory drugs (NSAIDs) in children are scarce. The purpose of this study was to investigate the utilization of NSAIDs among children in four European countries as part of the Safety Of non-Steroidal anti-inflammatory drugs (SOS) project.
Methods
We used longitudinal patient data from seven databases (GePaRD, IPCI, OSSIFF, Pedianet, PHARMO, SISR, and THIN) to calculate prevalence rates of NSAID use among children (0–18 years of age) from Germany, Italy, Netherlands, and United Kingdom. All databases contained a representative population sample and recorded demographics, diagnoses, and drug prescriptions. Prevalence rates of NSAID use were stratified by age, sex, and calendar time. The person-time of NSAID exposure was calculated by using the duration of the prescription supply. We calculated incidence rates for serious adverse events of interest. For these adverse events of interest, sample size calculations were conducted (alpha = 0.05; 1-beta = 0.8) to determine the amount of NSAID exposure time that would be required for safety studies in children.
Results
The source population comprised 7.7 million children with a total of 29.6 million person-years of observation. Of those, 1.3 million children were exposed to at least one of 45 NSAIDs during observation time. Overall prevalence rates of NSAID use in children differed across countries, ranging from 4.4 (Italy) to 197 (Germany) per 1000 person-years in 2007. For Germany, United Kingdom, and Italian pediatricians, we observed high rates of NSAID use among children aged one to four years. For all four countries, NSAID use increased with older age categories for children older than 11. In this analysis, only for ibuprofen (the most frequently used NSAID), enough exposure was available to detect a weak association (relative risk of 2) between exposure and asthma exacerbation (the most common serious adverse event of interest).
Conclusions
Patterns of NSAID use in children were heterogeneous across four European countries. The SOS project platform captures data on more than 1.3 million children who were exposed to NSAIDs. Even larger data platforms and the use of advanced versions of case-only study designs may be needed to conclusively assess the safety of these drugs in children.
doi:10.1186/1471-2431-13-192
PMCID: PMC4225575  PMID: 24252465
Pharmacoepidemiology; Database; Drug utilization; Health resource utilization; Drug safety; Sample size; Asthma exacerbation; Self-controlled case series design; Case-crossover design
10.  A Clinical Tool for Reducing Central Nervous System Depression among Neonates Exposed to Codeine through Breast Milk 
PLoS ONE  2013;8(7):e70073.
Background
Neonates are commonly exposed to maternal codeine through breast milk. Central Nervous System (CNS) depression has been reported in up to 24% of nurslings following codeine exposure. In 2009, we developed guidelines to improve the safety of codeine use during breastfeeding based on previously established pharmacogenetic and clinical risk factors. The primary objective of this study was to prospectively evaluate the effectiveness of these guidelines in ensuring neonatal safety.
Methods and Findings
Women taking codeine for pain following caesarean section were given safety guidelines, including advice to use the lowest codeine dose for no longer than four days and to switch to a non-opioid when possible. Mothers provided a saliva sample for analysis of genes involved in opioid disposition, metabolism and response. A total of 238 consenting women participated. Neonatal sedation was reported in 2.1% (5/238) of breastfeeding women taking codeine according to our safety guidelines. This rate was eight fold lower than that reported in previous prospective studies. Women reporting sedated infants were taking codeine for a significantly longer period of time (4.80±2.59 days vs. 2.52±1.58 days, p = 0.0018). While following the codeine safety guidelines, mothers were less likely to supplement with formula, reported lower rates of sedation in themselves and breastfed more frequently throughout the day when compared to previously reported rates. Genotyping analysis of cytochrome p450 2D6 (CYP2D6), uridine-diphosphate glucuronosyltransferase (UGT) 2B7, p-glycoprotein (ABCB1), the mu-opioid receptor (OPRM1) and catechol-o-demethyltransferase (COMT) did not predict codeine response in breastfeeding mother/infant pairs when following the safety guidelines.
Conclusions
The only cases of CNS depression occurred when the length of codeine use exceeded the guideline recommendations. Neonatal safety of codeine can be improved using evidence-based guidelines, even in those deemed by genetics to be at high risk for toxicity.
doi:10.1371/journal.pone.0070073
PMCID: PMC3726489  PMID: 23922910
11.  Adverse drug reaction-related admissions in paediatrics, a prospective single-centre study 
BMJ Open  2012;2(4):e000934.
Objective
To investigate the incidence and characteristics of hospital admissions related to adverse drug events in the paediatric setting.
Design
Prospective single-centre study.
Setting
A secondary and tertiary paediatric care centre.
Participants
A total of 683 acutely admitted patients, aged 0–18 year. All acutely admitted patients, using medication before admission, were prospectively screened for possible Adverse Drug Reactions (ADR)-related admission with a trigger list. Included cases were analysed with the Naranjo score for the assessment of causality.
Main outcome measures
This research explored the incidence of ADR-related admissions and investigated the relation between ADR and the licensing status of the medicines, as well as the severity and potential to prevent the ADRs.
Results
A total of 683 patients were admitted acutely during the study period, 47 of them were exposed to cancer chemotherapy. Fifteen patients not exposed to chemotherapy (2.4%) were admitted due to an ADR. Five of these 15 ADRs (33%) were caused by unlicensed or off-label used drugs. Thirty-two patients exposed to chemotherapy (68.1%) were admitted due to an ADR; 27 of these (84%) were caused by unlicensed or off-label used drugs.
Conclusions
In conclusion, this study shows that ADR-related hospital admissions occur more frequently in the paediatric population compared with adults, and more frequently in patients exposed to cancer chemotherapy. No relation was found between the unlicensed and off-label used drugs and the incidence of ADRs.
doi:10.1136/bmjopen-2012-000934
PMCID: PMC3432848  PMID: 22923623
Paediatrics; Clinical Pharmacology; Therapeutics; Adverse events
12.  Effects of safety warnings on prescription rates of cough and cold medicines in children below 2 years of age 
AIM
The aim of the study was to assess the influence of national and international warnings on the prescription rates of cough and cold medicines (CCMs) in the youngest children (<2 years) in the Netherlands and Italy.
METHODS
Analysis of outpatient electronic medical records of children <2 years in Italy and the Netherlands was carried out. Age and country specific prescription prevalence rates were calculated for the period 2005–08. Comparisons of prescription rates in 2005 (pre) and 2008 (post) warnings were done by means of a chi-square test.
RESULTS
The cohort consisted of 99 176 children <2 years of age. After international warnings, overall prescription rates for CCMs decreased slightly from 83 to 77/1000 person years (P = 0.05) in Italy and increased in the Netherlands from 74 to 92/1000 children per year. Despite the international warnings, prescription rates for nasal sympathomimetics and opium alkaloids increased in the Netherlands (P < 0.01). In Italy a significant decrease in the prescription rates of opium alkaloids and other cough suppressants (P < 0.01) was observed, and also a significant reduction in use of combinations of nasal sympathomimetics.
CONCLUSION
Despite the international safety warnings and negative benefit-risk profiles, prescription rates of cough and cold medicines remain substantial and were hardly affected by the warnings, especially in the Netherlands where no warning was issued. The hazards of use of these medicines in young children should be explicitly stipulated by the European Medicines Agency and all national agencies, in order to increase awareness amongst physicians and caretakers and reduce heterogeneity across the EU.
doi:10.1111/j.1365-2125.2010.03860.x
PMCID: PMC3099382  PMID: 21564162
cough and cold medicines; drug utilization; regulatory warnings
13.  Assessment of Pediatric asthma drug use in three European countries; a TEDDY study 
European Journal of Pediatrics  2010;170(1):81-92.
Asthma drugs are amongst the most frequently used drugs in childhood, but international comparisons on type and indication of use are lacking. The aim of this study was to describe asthma drug use in children with and without asthma in the Netherlands (NL), Italy (IT), and the United Kingdom (UK). We conducted a retrospective analysis of outpatient medical records of children 0–18 years from 1 January 2000 until 31 December 2005. For all children, prescription rates of asthma drugs were studied by country, age, asthma diagnosis, and off-label status. One-year prevalence rates were calculated per 100 children per patient-year (PY). The cohort consisted of 671,831 children of whom 49,442 had been diagnosed with asthma at any time during follow-up. ß2-mimetics and inhaled steroids were the most frequently prescribed asthma drug classes in NL (4.9 and 4.1/100 PY), the UK (8.7 and 5.3/100 PY) and IT (7.2 and 16.2/100 PY), respectively. Xanthines, anticholinergics, leukotriene receptor antagonists, and anti-allergics were prescribed in less than one child per 100 per year. In patients without asthma, ß2-mimetics were used most frequently. Country differences were highest for steroids, (Italy highest), and for ß2-mimetics (the UK highest). Off-label use was low, and most pronounced for ß2-mimetics in children <18 months (IT) and combined ß2-mimetics + anticholinergics in children <6 years (NL). Conclusion: This study shows that among all asthma drugs, ß2-mimetics and inhaled steroids are most often used, also in children without asthma, and with large variability between countries. Linking multi-country databases allows us to study country specific pediatric drug use in a systematic manner without being hampered by methodological differences. This study underlines the potency of healthcare databases in rapidly providing data on pediatric drug use and possibly safety.
doi:10.1007/s00431-010-1275-7
PMCID: PMC3016194  PMID: 20811908
Pediatric asthma; Drug utilization
14.  Inappropriate drug prescribing in older adults: the updated 2002 Beers criteria – a population-based cohort study 
Background
In 1997, Beers and colleagues developed explicit criteria for potentially inappropriate drug prescribing in ambulatory older adults aged 65 years and over. Several studies have been performed to estimate the prevalence of inappropriate drug prescribing based on these criteria. In 2002, the criteria were updated.
Aims
To examine the extent and trend of inappropriate drug prescribing to ambulatory older adults in the Netherlands between 1997 and 2001, according to the 1997 and the updated Beers criteria.
Methods
Data were retrieved from the Integrated Primary Care Information (IPCI) project, a general practice research database with data from computer-based patient records of a group of 150 general practitioners in the Netherlands. All subjects aged 65 and over were included. Prescriptions were classified as inappropriate if they fulfilled the Beers criteria of prescriptions that generally should be avoided in older adults because of a high risk of adverse effects, while also considering dose and comorbidity.
Results
Between 1997 and 2001, the 1-year risk of receiving at least one inappropriate drug prescription for older adults ranged between 16.8% (95% CI: 16.3–17.3%) and 18.5% (18.3–18.7%) according to the 1997 criteria and between 19.1% (18.6–19.6%) and 20.0% (19.5–20.5%) according to the updated Beers criteria. According to the updated criteria, the most frequently prescribed inappropriate drugs were nitrofurantoin, long-acting benzodiazepines, amitriptyline, promethazine and cimetidine. Temazepam and zolpidem were mostly prescribed in supratherapeutic dose. Conventional NSAIDs in persons with a history of gastric/duodenal ulcer were the most frequently prescribed contra-indicated drugs.
Conclusions
Prescribing potentially inappropriate prescriptions to ambulatory older people in the Netherlands is substantial. Compared with other studies using the 1997 Beers criteria, inappropriate prescribing to the elderly is lower than in the USA but similar to Finland. Despite a restrictive medication policy and a growing attention for medication surveillance in Europe, inappropriate drug prescribing is still a substantial problem.
doi:10.1111/j.1365-2125.2005.02391.x
PMCID: PMC1884923  PMID: 16042666
inappropriate prescribing; elderly; Beers criteria; population-based
15.  Age at retirement and long term survival of an industrial population: prospective cohort study 
BMJ : British Medical Journal  2005;331(7523):995.
Objective To assess whether early retirement is associated with better survival.
Design Long term prospective cohort study.
Setting Petroleum and petrochemical industry, United States.
Subjects Past employees of Shell Oil who retired at ages 55, 60, and 65 between 1 January 1973 and 31 December 2003.
Main outcome measure Hazard ratio of death adjusted for sex, year of entry to study, and socioeconomic status.
Results Subjects who retired early at 55 and who were still alive at 65 had a significantly higher mortality than those who retired at 65 (hazard ratio 1.37, 95% confidence interval 1.09 to 1.73). Mortality was also significantly higher for subjects in the first 10 years after retirement at 55 compared with those who continued working (1.89, 1.58 to 2.27). After adjustment, mortality was similar between those who retired at 60 and those who retired at 65 (1.06, 0.92 to 1.22). Mortality did not differ for the first five years after retirement at 60 compared with continuing work at 60 (1.04, 0.82 to 1.31).
Conclusions Retiring early at 55 or 60 was not associated with better survival than retiring at 65 in a cohort of past employees of the petrochemical industry. Mortality was higher in employees who retired at 55 than in those who continued working.
doi:10.1136/bmj.38586.448704.E0
PMCID: PMC1273451  PMID: 16243848
18.  Survey of unlicensed and off label drug use in paediatric wards in European countries 
BMJ : British Medical Journal  2000;320(7227):79-82.
Objective
To determine the extent of use of unlicensed and off label drugs in children in hospital in five European countries.
Design
Prospective study of drugs administered to children in general paediatric medical wards over four weeks.
Setting
Children’s wards in five hospitals (one each in the United Kingdom, Sweden, Germany, Italy, and the Netherlands).
Subjects
Children aged 4 days to 16 years admitted to general paediatric medical wards.
Main outcome measure
Proportion of drugs that were used in an unlicensed or off label manner.
Results
2262 drug prescriptions were administered to 624 children in the five hospitals. Almost half of all drug prescriptions (1036; 46%) were either unlicensed or off label. Of these 1036, 872 were off label and 164 were unlicensed. Over half of the patients (421; 67%) received an unlicensed or off label drug prescription.
Conclusions
Use of off label or unlicensed drugs to treat children is widespread. This problem is likely to affect children throughout Europe and requires European action.
Key messagesMany drugs are not tested in children, which means that they are not specifically licensed for use in childrenLicensed drugs are often prescribed outside the terms of the product license (off label) in relation to age, indication, dose of frequency, route of administration, or formulationOver two thirds (67%) of 624 children admitted to wards in five European hospitals received drugs prescribed in an unlicensed or off label manner39% of the 2262 drug prescriptions given to children were off labelThe problem of off label and unlicensed drug prescribing in children is a European problem that requires European action
PMCID: PMC27251  PMID: 10625257

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