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Commonly prescribed drugs associated with cognition: a cross-sectional study in UK Biobank
ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2016-012177
Article Type: Research
Date Submitted by the Author: 06-Apr-2016
Complete List of Authors: Nevado-Holgado, Alejo; University of Oxford, Psychiatry Kim, Chi-Hun; University of Oxford, Psychiatry Winchester, Laura; University of Oxford, Psychiatry Gallacher, John; University of Oxford, Psychiatry Lovestone, Simon; University of Oxford, Psychiatry
Primary Subject Public health Heading:
Secondary Subject Heading: Mental health, Pharmacology and therapeutics, Neurology
Keywords: PUBLIC HEALTH, MENTAL HEALTH, Cognition, UK biobank
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1 2 3 Commonly prescribed drugs associate with cognition: a cross-sectional study 4 in UK Biobank 5 6 7 8 Authors 9 10 Alejo J Nevado Holgado*, Chi Hun Kim*, Laura Winchester, John Gallacher, Simon Lovestone 11 12 13 14 15 Address For peer review only 16 17 Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK 18 19 20 21 22 23 Authors’ names and positions 24 25 Alejo J Nevado Holgado*: Postdoctoral researcher 26 27 Chi Hun Kim*: Postdoctoral researcher 28 29 Laura Winchester: Postdoctoral researcher 30 31 John Gallacher: Professor 32 33 Simon Lovestone: Professor
34 http://bmjopen.bmj.com/ 35 *These authors contributed equally to this work. 36
37 38
39 40 Correspondence to: S Lovestone [email protected] 41 42 on September 26, 2021 by guest. Protected copyright. 43 44
45 46
47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 For peer review only − http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 16 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from Abstract 1 2 Objective To investigate medications associated with cognitive function 3 4 Design Population based cross sectional cohort study 5 6 Setting UK Biobank 7 8 Participants UK Biobank participants aged 37 73 years who completed cognitive tests at the baseline visit 9 in 2006 2010 10 11 Main outcome measures Cognitive test outcomes on verbal numerical reasoning test (n=165493), 12 memory test (n=482766) and reaction time test (n=496813). 13 14 Results Most drugs were not associated with significant changes in any of the cognitive tests (262 of 368) 15 For peer review only 16 after adjusting for age, gender, education, household income, ethnicity, assessment centre and concurrent 17 diagnoses and other medications. Among those that were, the majority were associated with poorer 18 cognitive performance. Drugs used for nervous system disorders showed the largest effect size with a 19 direction of effect associated with poorer cognition (effect size ± 95% confidence interval) for reasoning (as 20 assessed by number of corrects), memory (assessed by number of errors) and reaction time (ms) 21 respectively: antipsychotics e.g. risperidone 0.55±0.40/0.36±0.41/37±1, antiepileptics e.g. topiramate 22 23 0.75±0.41/1.47±0.38/7± 2. Other drugs used for non nervous system conditions also showed significant 24 negative association with cognitive score, including those where such an effect might have been predicted 25 (antidiabetics e.g. insulin 0.05±0.11/0.11±0.11/14±1, antihypertensive e.g. amlodipine 26 0.13±0.05/0.10±0.05/5±1) and others where such an association was a surprising observation (proton 27 pump inhibitors e.g. omeprazole 0.15±0.04/0.10±0.04/7±1, calcium 0.12±0.08/ 0.01±0.08/6±1). Finally, 28 only a few medications and health supplements showed association towards a positive effect on cognition 29 30 (anti inflammatory agents e.g. ibuprofen 0.07±0.03/ 0.05±0.03/ 5±0, glucosamine 0.12±0.05/ 0.08±0.05/ 31 6±0). 32 33 Conclusions In this large volunteer study, some commonly prescribed medications in the UK were
34 associated with poor cognitive performance. Some associations may reflect underlying diseases for which http://bmjopen.bmj.com/ 35 the medications were prescribed, although the analysis controlled for the possible effect of diagnosis. 36 Other drugs, whose association cannot be linked to the effect of any disease, may need vigilance for their 37 implications in clinical practice. 38 39
40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 For peer review only − http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 16 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from Strengths and limitations of this study 1 2 • Using a very large UK population cohort, this study was sufficiently powered to perform a systematic 3 investigation for a range of medications and its association with cognition. 4 5 • We report multiple associations between commonly prescribed medications and poorer or better 6 cognitive performance, which may have implications for clinicians and patients. 7 • Due to the cross sectional design, it is difficult to make causal inferences between medication and 8 cognition. 9 • Although trained nurses interviewed participants to obtain medications and diagnoses, this self 10 11 reported nature may limit the accuracy of information. 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3 For peer review only − http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 16 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from Introduction 1 2 A significant number of drugs are used for therapeutic indications other than those they were either 3 designed, or first used for. Well known examples include Viagra, developed for cardiac indications but used 4 for erectile failure, and aspirin, used in an increasingly wide range of indications. This phenomenon has 5 6 prompted systematic efforts to repurpose compounds already in clinical practice.[1,2] In the field of 7 cognitive disorders, repurposing approaches have included consensus building using understanding from 8 epidemiology to molecular sciences,[3] and informatics driven approaches using platforms such as the 9 connectivity map,[1] which derives gene expression signatures from in vitro cells exposed to drugs and 10 matches these to disease associated signatures. As part of a process seeking drugs to promote healthy 11 brain ageing, and potentially counter disorders of cognitive decline, as well as to identify compounds that 12 13 might have a detrimental effect on cognition, we have used the UK Biobank [4] dataset to identify drugs 14 associated with cognitive performance. 15 For peer review only 16 17 18 Methods 19 20 UK Biobank is a prospective study of a half million participants across the UK with extensive data from 21 questionnaires, interviews, physical measures, biological samples and imaging.[4] This study used baseline 22 data from 502647 subjects aged between 37 and 73 years collected at 21 assessment centres in 2006 23 2010. 24 25 Outcome and other measures 26 27 Three cognitive tests, which have been described previously [5], were used as outcome variables. In brief, 28 29 cognitive tests were administered using a touch screen device with trained researchers present for 30 assistance. Memory was assessed using the pairs matching test in which subjects had to remember 6 pairs 31 of shapes and their locations displayed for 5 seconds on the screen. Performance was assessed as the 32 total number of errors made in matching all 6 pairs. For verbal numerical reasoning, subjects were asked to 33 solve as many multiple choice questions as possible (maximum 13) within two minutes. Performance was
34 http://bmjopen.bmj.com/ assessed as the total number of correct responses. Reaction time (RT) was measured by pressing a button 35 36 as quickly as possible when two identical shapes were presented on the screen. Performance was 37 assessed as the mean RT for correctly identified matching pairs. Participants completed each cognitive test 38 were included for the analysis of that cognitive test: verbal numerical reasoning test (n=165493), memory 39 test (n=482766) and RT test (n=496813). The verbal numeric reasoning test was introduced later to the 40 study and the numbers available for analysis are lower. 41 42 Trained nurses interviewed subjects to obtain diagnoses given by doctors and medications. Only on September 26, 2021 by guest. Protected copyright. 43 regular medications and health supplements taken weekly, monthly or three monthly were recorded. 44 45 Medications were recorded using 6745 categories adapted from Read code version 3 (CTV3) used in the 46 general practice in the UK. Of these, 1192 medications were taken by 30 or more participants, and were 47 classified using the Anatomical Therapeutic Chemical (ATC) classification [6] as a backbone. For example, 48 brand names with different doses were allocated into their chemical substance (e.g. Lipitor and atorvastatin 49 were treated as atorvastatin), chemical subgroup (e.g. HMG CoA reductase), therapeutic subgroup (e.g. 50 51 lipid modifying agents) and anatomical group (e.g. cardiovascular system). Compound medications were 52 divided into single chemical substances (e.g. CoAprovel into irbesartan and hydrochlorothiazide). In UK 53 Biobank, diagnosis was recorded according to hierarchical tree systems. For analysis, Level 2 diagnosis 54 was used for non cancer illness (UK Biobank data coding 6: e.g. Top level = cardiovascular, Level 1 = 55 cerebrovascular disease, Level 2 = stroke); top level diagnosis was used for cancer (UK Biobank data 56 coding 3: e.g. breast cancer, skin cancer). Further details of the UK Biobank procedures are available at 57 58 the official website (http://www.ukbiobank.ac.uk). Demographic variables beyond age and gender included 59 household income, education and ethnicity. UK Biobank assessment centre was also recorded. 60 4 For peer review only − http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 16 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from Statistical analyses 1 2 Analyses were conducted using linear modelling for each cognitive test and medication combination 3 separately. For each cognitive test medication combination, the study group identified for analysis was all 4 participants with complete cognitive and covariate data. The modelling strategy was to relate cognitive 5 6 performance to medication with adjustment for confounding by co morbidity (diagnosis), other medications, 7 relevant demographics and assessment centre. To simplify the problem, for each medication of interest, the 8 10 diagnoses and the 10 medications which were most strongly co occurring (largest odds ratios) with the 9 medication of interest, were identified and added as co variants in the linear model.t. 10 11 Cognitive outcomes and age were modelled as continuous variables. Sex, medication and 12 diagnosis were modelled as two level factors. Education was modelled as a 5 level factor (A levels and 13 above, O levels or equivalent, professional qualifications only, none of the above, prefer not to answer), 14 15 and annual householdFor income aspeer a 7 level factor review (£<18K, 18 30.9K, 31K 51.9K,only 52 100K, >100K, do not 16 know, prefer not to answer).Full adjustment was made in all models. Analyses were conducted at three 17 medication classification levels (chemical substance, chemical subgroup and therapeutic subgroup) 18 separately and are presented according to functional system (e.g. nervous, cardiovascular, gastrointestinal 19 and metabolism, immune, others). Results are presented as effect sizes with 95% confidence intervals. 20 21 To detect an effect size of 0.25 SD with 80% power at a significance level of 0.05, chemical 22 substance or its subgroups taken by 125 or more participants were required. This criterion was met for 368 23 24 chemical substances, 165 chemical subgroups and 68 therapeutic subgroups. The statistical power of a 25 medication used by ‘n’ UK Biobank participants was approximated as the power of a binomial test with two 26 samples of unequal size – one sample of size ‘n’ and the other of size equal to the total number of 27 participants minus ‘n’.[7] False Discovery Rate was used to correct for multiple comparisons. 28 29 30 31 Results 32 33 Table 1 presents demographic characteristics of UK BioBank participants at baseline assessment that were
34 included into the statistical analyses. Figure 1 show the effect size for the 71 medicines that show some http://bmjopen.bmj.com/ 35 evidence of independent association with cognitive performance. Results for all 368 medicines may be 36 37 found in supplementary materials Appendix 1. Most drugs were not associated with significant changes in 38 any of the cognitive tests (262 of 368) after adjusting for potential confounding factors. Among those that 39 were, the majority associated with poorer cognitive performance i.e. fewer correct answers on the 40 reasoning test, more errors on the memory test, and longer RT. 41 42 Medications prescribed for nervous system disorders showed the strongest associations with on September 26, 2021 by guest. Protected copyright. 43 cognitive performance relative to the other systems. For example, users of users of levetiracetam, 44 toparimates and dopamine derivates had one more error on the memory test, and users of risperidone, 45 46 benzamides and primidone had a 50ms slower mean RT when compared to non users. Conversely 47 dopamine agonists, often prescribed for early Parkinson’s disease, were associated with faster RT (effect 48 size ± 95% confidence interval: 0.02±0.28/ 0.30±0.29/ 35±0, for reasoning, memory and RT, 49 respectively).Among antipsychotics, risperidone were associated with slower RT (effect size ± 95% 50 confidence interval: 0.55±0.40/0.36±0.41/37±1, for reasoning, memory and RT, respectively). Among 51 anti epileptics, topiramate was associated with poor cognitive scores ( 0.75±0.41/1.47±0.38/7± 2) as was 52 53 levetiracetam ( 0.09±0.35/0.81±0.38/34±1). 54 55 Among cardiovascular medications, first line antihypertensives such as ACE inhibitors were 56 associated with more correct responses in the reasoning test (e.g. perindopril, 0.17±0.08). However, beta 57 blocking agents, calcium blocking channels (e.g. amlodipine, 0.13±0.05/0.10±0.05/5±1) and some diuretics 58 (e.g. furosemide, 0.13±0.11/ 0.07±0.10/10±1) were associated with poorer cognitive function. 59 60 5 For peer review only − http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 16 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from In the gastroinstestinal (GI) tract and metabolism system, drugs for diabetes were adversely 1 associated with cognitive performance. Insulin was related to slower RT ( 0.06±0.11/0.11±0.11/15±1). 2 Proton pump inhibitors (PPI) were adversely related to reasoning, memory and RT (e.g. omeprazole, 3 4 0.15±0.04/0.10±0.04/7±1). But these effects were not found in H2 receptor antagonists. Laxatives 5 (including contact and osmotic but not bulk form laxatives) were associated with slower RT. 6 7 Immunomodulating medications were among the very few drugs that showed beneficial cognitive 8 associations. For example, ibuprofen was related to significantly better reasoning test and RT (0.07±0.03/ 9 0.05±0.03/ 5±0), as were some cancer medications when tested at the subgroup level (e.g. aromatase 10 inhibitors in reasoning, 0.30±0.15). Similar but non significant beneficial trends were found in anti 11 inflammatory/antineoplastic medication such as meloxicam, methotrexate and TNF alpha inhibitors. 12 13 However these effects were not found in other anti inflammatory medications e.g. diclofenac and 14 corticosteroids, and were reversed in some non inflammatory analgesics (e.g. paracetamol, 15 0.20±0.03/0.10±0.03/6±1).For peer review only 16 17 Some health supplements (e.g. glucosamine, 0.12±0.05/ 0.08±0.05/ 6±0) showed beneficial 18 cognitive association. But supplements used for anaemia (e.g. iron 0.24±0.16/0.12±0.16/0.93±5.27) or 19 osteoporosis (e.g. calcium in reasoning and RT, 0.05±0.12/ 0.10±0.11/2± 2) were related to poor cognitive 20 function. 21 22 23 24 Discussion 25 26 This analysis of a very large volunteer cohort finds considerable evidence for an association between 27 28 commonly prescribed medications and cognition within the normal range. Of interest is whether these 29 associations reflect an effect of the medication on cognition or reflect a wider causal context, such as an 30 effect of the underlying disorder, comorbidity or socioeconomic context. 31 32 Examples of associations where there is an a priori reason to suspect a primary relationship with an 33 underlying disease includes antipychotics, drugs used to treat Parkinson’s disease and antiepileptics. In
34 each case these classs of compound are most commonly used for diseases known to have an element of http://bmjopen.bmj.com/ 35 cognitive impairment as part of the core syndrome [8–10] although, in addition, antipsychotics and 36 37 antiepileptics are known to have independent effects on cognition.[11–14] 38 39 In other cases we report an association with medications where there is a plausible association with 40 a cognitive component of the underlying disease but where cognition is not a necessary or well established 41 part of the underlying syndrome. Examples include anti diabetes medications (e.g. insulin and 42 sulfonylurea), antihypertensives (e.g. calcium channel blockers and diuretics) and anaemia medications. on September 26, 2021 by guest. Protected copyright. 43 Both diabetes and hypertension are associated with cognitive impairment.[15,16]The fact that we find an 44 association between drugs used to treat anaemia iron and thiamine and poor cognition does lend weight 45 46 to those studies that do suggest that poor cognition is associated with anaemia.[17] It is noteworthy 47 however, that most of these studies reported such an association in the elderly and the majority of 48 participants analysed in the current study are between 40 and 70 years old. These findings suggest that 49 disorders known to have a relationship with pathological cognitive impairment and dementia in the elderly 50 might also have a relationship with poor cognitive performance within the normal range and in middle aged 51 people. 52 53 However some of the associations between poor cognition and medication we find do not have a 54 55 clear link with underlying diagnosis and have not received much attention until recently. Examples here 56 include PPIs, calcium/vitamin D3 and laxatives. Recent studies have found that PPIs were associated with 57 an increased risk of dementia.[18,19] Low blood vitamin D level and osteoporosis, the most common 58 indication for calcium and vitamin D3, were also correlated with an increased risk of dementia.[20–23] In 59 60 6 For peer review only − http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 16 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from the present study, participants in their middle age taking PPIs, calcium or vitamin D3 showed poorer 1 cognitive performance compared to non takers. Additionally many laxatives showed a strong association 2 with increased RT. It is unclear whether these associations were due to the side effects of medications or 3 4 underlying syndromes for which they were prescribed. However clinicians may need to consider having a 5 careful discussion with their patients about the potential ‘cognitive’ side effects of these medications. 6 7 Perhaps not surprisingly, we find very few associations between drugs and better cognitive 8 performance. However, it is interesting that there is a small but significant effect of Ibuprofen and 9 comparable but non significant trends with other anti inflammatories including meloxicam and 10 11 methotrexate. There is an important role of inflammation in Alzheimer’s disease and other dementias [24] 12 and these data might be in line with the known effect of anti inflammatory medication including nonsteroidal 13 anti inflammatory medication in reducing incidence of dementia [25,26]. Nonetheless, if this is an 14 explanation of the association we observe, then it is remarkable that the effect is detectable within the 15 normal range of cognitionFor and inpeer people in mid life review and before the onset only of dementia. Alternatively, it might 16 be that these anti inflammatory medications have a dementia independent beneficial effect on cognition 17 18 and that the previous epidemiological evidence suggesting a protective effect in relation to dementia was a 19 reflection of such an effect. This is clearly a critical important distinction as is the observation that the effect 20 we observe is not present in all anti inflammatory medications including, for example acetic acid derivatives 21 and fenamates. 22 23 In terms of the broader causal environment, attempts were made to control for the effects of 24 25 underlying disorder, comorbidity and socioeconomic context. That consistent patterns of association were 26 not always found within chemical or therapeutic subgroups argues against all the associations detected 27 being confounded. Nevertheless, residual confounding cannot be discounted and more detailed analyses 28 using diverse datasets are required for specific causal pathways to be identified. Of particular interest 29 would be longitudinal data demonstrating an impact of medication on cognitive change. Nevertheless, 30 these data illustrate the opportunity and the challenges provided by real world data to investigate the 31 32 broader impact of medicines. 33 In summary, using a very large volunteer cohort, we find multiple associations between a range of 34 http://bmjopen.bmj.com/ 35 medications and poorer cognition, albeit within the normal range. Many of these associations are likely to 36 reflect the underlying disease or syndrome for which the medication is prescribed. Nonetheless it is 37 remarkable that this is apparent in relatively young and relatively healthy volunteers. In other cases the link 38 to underlying disease is less obvious and even where there is a putative link to the underlying disease we 39 40 do not find association with cognition with all drugs used to treat that disease. These findings raise the 41 possibility that some drugs may have hitherto unsuspected negative effects on cognition and a very few 42 compounds, most especially anti inflammatory agents, might even have a positive effect. Further replication on September 26, 2021 by guest. Protected copyright. 43 and extension studies are warranted and will become increasingly possible as large cohort data and 44 routine, real world data from clinical records become more widely available. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 7 For peer review only − http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 16 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from This research has been conducted using the UK Biobank resource. 1 2 3 4 Contributors: ANH, CHK, LW, JG and SL contributed to study design and wrote the manuscript; ANH, 5 CHK and LW contributed to data acquisition; ANH and CHK conducted data processing and statistical 6 analyses; SL is the guarantor. 7 8 9 10 Funding: We received funding for this analysis through the Medical Research Council Dementias Platform 11 UK (MR/L015382/1) and the Wellcome Trust Consortium for Neuroimmunology for Mood Disorders and 12 13 Alzheimer’s Disease (104025/Z/14/Z). The funders had no influence on study design, data collection and 14 analysis, decision to publish, or preparation of the manuscript. 15 For peer review only 16 17 18 Competing interests: All authors have completed the ICMJE uniform disclosure form at 19 www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work ; 20 no financial relationships with any organisations that might have an interest in the submitted work in the 21 previous three years; no other relationships or activities that could appear to have influenced the submitted 22 work. 23 24
25 26 Ethical approval: This study has been conducted using UK Biobank data. UK Biobank has received ethics 27 28 approval from the UK Biobank Research Ethics Committee (ref 11/NW/0382). 29 30 31 32 Transparency statement: The lead author (the manuscript’s guarantor) affirms that this manuscript is an 33 honest, accurate, and transparent account of the study being reported; that no important aspects of the
34 study have been omitted; and that any discrepancies from the study as planned (and, if relevant, http://bmjopen.bmj.com/ 35 registered) have been explained. 36 37 38 39 Data sharing: No additional data are available.. 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 Copyright The Corresponding Author has the right to grant on behalf of all authors and does grant on 44 behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all forms, 45 formats and media (whether known now or created in the future), to i) publish, reproduce, distribute, display 46 and store the Contribution, ii) translate the Contribution into other languages, create adaptations, reprints, 47 48 include within collections and create summaries, extracts and/or, abstracts of the Contribution, iii) create 49 any other derivative work(s) based on the Contribution, iv) to exploit all subsidiary rights in the Contribution, 50 v) the inclusion of electronic links from the Contribution to third party material where ever it may be located; 51 and, vi) licence any third party to do any or all of the above. All research articles will be made available on 52 an Open Access basis (with authors being asked to pay an open access fee. The terms of such Open 53 Access shall be governed by a Creative Commons licence—details as to which Creative Commons licence 54 55 will apply to the research article are set out in our worldwide licence referred to above. 56 57 58 59 60 8 For peer review only − http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 16 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from References 1 2 1 Chung F H, Chiang Y R, Tseng A L, et al. Functional Module Connectivity Map (FMCM): a framework 3 for searching repurposed drug compounds for systems treatment of cancer and an application to 4 colorectal adenocarcinoma. PloS One 2014;9:e86299. doi:10.1371/journal.pone.0086299 5 6 2 Corbett A, Pickett J, Burns A, et al. Drug repositioning for Alzheimer’s disease. Nat Rev Drug Discov 7 2012;11:833–46. doi:10.1038/nrd3869 8 9 3 Corbett A, Williams G, Ballard C. Drug repositioning in Alzheimer’s disease. Front Biosci Sch Ed 10 2015;7:184–8. 11 12 4 Sudlow C, Gallacher J, Allen N, et al. UK Biobank: An Open Access Resource for Identifying the 13 Causes of a Wide Range of Complex Diseases of Middle and Old Age. PLoS Med 2015;12:e1001779. 14 doi:10.1371/journal.pmed.1001779 15 For peer review only 16 5 Hagenaars SP, Harris SE, Davies G, et al. Shared genetic aetiology between cognitive functions and 17 physical and mental health in UK Biobank (N=112 151) and 24 GWAS consortia. Mol Psychiatry 18 Published Online First: 26 January 2016. doi:10.1038/mp.2015.225 19 20 6 WHO Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC classification and DDD 21 assignment 2016. Oslo: 2016. http://www.whocc.no/atc_ddd_publications/guidelines/ 22 23 7 Cohen J. Statistical Power Analysis for the Behavioral Sciences. L. Erlbaum Associates 1988. 24 25 8 Barch DM, Ceaser A. Cognition in schizophrenia: core psychological and neural mechanisms. Trends 26 Cogn Sci 2012;16:27–34. doi:10.1016/j.tics.2011.11.015 27 28 9 Svenningsson P, Westman E, Ballard C, et al. Cognitive impairment in patients with Parkinson’s 29 disease: diagnosis, biomarkers, and treatment. Lancet Neurol 2012;11:697–707. doi:10.1016/S1474 30 4422(12)70152 7 31 32 10 Berg AT. Epilepsy, cognition, and behavior: The clinical picture. Epilepsia 2011;52 Suppl 1:7–12. 33 doi:10.1111/j.1528 1167.2010.02905.x
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34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 10 For peer review only − http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 16 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
Participants completed cognitive test 1 All
2 participants Verbal-numerical reasoning Memory Reaction time 3 (n = 502647) (n = 165493) (n = 482766) (n = 496813) 4 5.98 ± 2.16 4.25 ± 3.36 559 ± 118 Cognitive test score 5 (max. correct of 13) (no. of errors) (ms) 6 Age (years) 57.03 ± 8.09 57.20 ± 8.14 56.96 ± 8.08 57.02 ± 8.09 7 Gender (women) 55.0% 54.5% 54.5% 54.4% 8 Education 9 A levels and above 43.6% 45.7% 44.0% 43.4% 10 Other educational qualifications 33.2% 33.9% 33.4% 33.0% 11 Professional qualifications only 5.2% 5.2% 5.2% 5.1% 12 None of the above 17.2% 14.3% 16.4% 16.7% 13 Prefer not to answer 0.9% 0.9% 0.9% 1.7% Household income (GBP/year) 14 < 18,000 19.6% 18.8% 19.2% 19.2% 15 18,000 30,999 For peer21.8% review22.0% only21.9% 22.2% 16 31,000 51,999 22.3% 22.6% 22.6% 22.2% 17 52,000 100,000 17.4% 17.9% 17.7% 17.4% 18 > 100,000 4.6% 5.1% 4.7% 4.6% 19 Do not know 4.3% 3.9% 4.0% 4.1% 20 Prefer not to answer 10.0% 9.4% 9.7% 9.9% 21 22 Table 1. Baseline characteristics of participants The table shows summary statistics of all UK Biobank 23 participants (first column) and the participants who completed each cognitive test during their baseline visit 24 25 (second to fourth columns). Values indicate mean ± standard deviation for cognitive test score and age, or 26 percentages for education and household income. 27 28 29 30 31 32 33
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 Figure 1. Medication use and cognitive performance according to anatomical system A summary of 49 selected medications are presented here (for all medications see Appendix 1). As analyses were conducted 50 at three medication classification levels (see Methods), numbers in parenthesis next to a medication name 51 52 on the left indicate the classification level of the medication: (1) chemical substance, (2) chemical subgroup 53 and (3) therapeutic subgroup. Relationship between medication and each cognitive test are represented by 54 effect size and 95% confidence intervals across three columns: verbal reasoning test (number of correct 55 responses), memory test (number of errors) and reaction time test (ms). The corresponding p values after 56 False Discovery Rate correction for multiple comparisons were indicated by filled circles with red line (p < 57 .005), empty circle (p < .05) and ‘x’ with black line (p > .05) *Abbreviations: ACE = angiotensin converting 58 59 enzyme, TNF = tumour necrosis factor, GI = gastroinstestinal. 60 12 For peer review only − http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 16 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 Legend for Appendix 1 3 4 All medications are presented according to the three classification levels used for analysis (i.e. chemical 5 substance, chemical subgroup and therapeutic subgroup) and aggregated by their anatomical groups (see 6 Methods). Numbers in parenthesis next to a medication name on the left indicate the classification level of 7 the medication: (1) chemical substance, (2) chemical subgroup, (3) therapeutic subgroup and (4) 8 9 anatomical group. Some extra formatting is included in the Y axis to ease visual inspection of the drug 10 classification tree. First, all labels are sorted such that, for any given category, the descendants in the 11 classification tree appear below. Secondly, an arrow is included besides each label such that its length 12 represents how deep the drug or drug group is in the classification tree. Namely, no arrow for the 13 anatomical group, “< “ for therapeutic subgroup, “< “ for chemical subgroup and “< “ for chemical 14 15 substance. For peer review only 16 17 Relationship between medication and each cognitive test are represented by effect size and 95% 18 confidence intervals across three columns: verbal reasoning test (number of correct responses), memory 19 test (number of errors) and reaction time test (ms). The corresponding p values after False Discovery Rate 20 correction for multiple comparisons were indicated by filled circles with red line (p < .005), empty circle (p < 21 .05) and ‘x’ with black line (p > .05). *Abbreviations: ACE = angiotensin converting enzyme, TNF = tumour 22 necrosis factor, RTI = reverse transcriptase inhibitor, GI = gastroinstestinal. 23 24 25 26 27 28 29 30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 13 For peer review only − http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 16
p−value >0.05 ● <0.05 ● <0.005 1 2 Verbal−numerical reasoning Memory Reaction time 3 cardiovascular (4) ● 4 renin−angiotensin agents<−(3) ● 5 ACE inhibitors<−−(2) ● 6 captopril<−−−(1) 7 enalapril<−−−(1) fosinopril<−−−(1) 8 lisinopril<−−−(1) 9 perindopril<−−−(1) ● 10 quinapril<−−−(1) ramipril<−−−(1) 11 trandolapril<−−−(1) 12 angiotensin II antagonists<−−(2) 13 candesartan<−−−(1) 14 eprosartan<−−−(1) irbesartan<−−−(1) 15 losartan<−−−(1) 16 olmesartan medoxomil<−−−(1) 17 telmisartan<−−−(1) valsartan<−−−(1) 18 beta blocking agents<−(3) ● 19 alpha and beta blocking agents<−−(2) 20 carvedilol<−−−(1) ● 21 beta blocking agents, selective<−−(2) atenolol<−−−(1) 22 bisoprolol<−−−(1) 23 metoprolol<−−−(1) 24 nebivolol<−−−(1) peripherial antiadrenergic<−(3) 25 antiarrhythmics<−(3) 26 antiarrhythmics<−−(2) 27 amiodarone<−−−(1) 28 flecainide<−−−(1) ● calcium channel blockers<−(3) ● ● ● 29 benzothiazepine derivatives<−−(2) 30 diltiazem<−−−(1) 31 dihydropyridine derivatives<−−(2) ● ● ● amlodipine<−−−(1) ● ● ● 32 felodipine<−−−(1) 33 lacidipine<−−−(1) 34 lercanidipine<−−−(1) 35 nifedipine<−−−(1) ● ● phenylalkylamine derivatives<−−(2) 36
verapamil<−−−(1) cardiovascular 37 lipid modifying agents<−(3) ● 38 bile acid sequestrants<−−(2) colestyramine<−−−(1) 39 fibrates<−−(2) 40 bezafibrate<−−−(1) 41 fenofibrate<−−−(1) 42 hmg coa reductase inhibitors<−−(2) atorvastatin<−−−(1) 43 fluvastatin<−−−(1) 44 pravastatin<−−−(1) 45 rosuvastatin<−−−(1) 46 simvastatin<−−−(1) other lipid modifying agents<−−(2) 47 ezetimibe<−−−(1) 48 antiadrenergic agents, centrally acting<−(3) 49 vasodilators used in cardiac diseases<−(3) organic nitrates<−−(2) 50 glyceryl trinitrate<−−−(1) 51 isosorbide mononitrate<−−−(1) 52 other vasodilators<−−(2) 53 nicorandil<−−−(1) peripheral vasodilators<−(3) 54 other peripheral vasodilators<−−(2) 55 diuretics<−(3) ● 56 potassium−sparing diuretics<−−(2) amiloride<−−−(1) 57 spironolactone<−−−(1) 58 sulfonamides<−−(2) ● ● 59 bumetanide<−−−(1) 60 chlortalidone<−−−(1) furosemide<−−−(1) ● indapamide<−−−(1) thiazides<−−(2) bendroflumethiazide<−−−(1) hydrochlorothiazide<−−−(1) cinnarizine<−−−(1) imidazoline receptor agonists<−−(2) clonidine<−−−(1) moxonidine<−−−(1) alpha−adrenoreceptor antagonists<−−(2) doxazosin<−−−(1) alfuzosin<−−−(1) tamsulosin<−−−(1) terazosin<−−−(1) beta blocking agents<−−(2) levobunolol<−−−(1) beta blocking agents, non−selective<−−(2) propranolol<−−−(1) ● sotalol<−−−(1) timolol<−−−(1) immune/cancer (4) ● ● ● antiinflammatory agents<−(3) ● ● ● acetic acid and related<−−(2) diclofenac<−−−(1) etodolac<−−−(1) indometacin<−−−(1) aminosalicylic acid and similar agents<−−(2) ● balsalazide<−−−(1) mesalazine<−−−(1) sulfasalazine<−−−(1) ● corticosteroids<−−(2) beclometasone<−−−(1) betamethasone<−−−(1) budesonide<−−−(1) clobetasol<−−−(1) clobetasone<−−−(1) dexamethasone<−−−(1) fluocinolone acetonide<−−−(1) fluticasone<−−−(1) hydrocortisone<−−−(1) mometasone<−−−(1) ● prednisolone<−−−(1) prednisone<−−−(1) triamcinolone<−−−(1) coxibs<−−(2) celecoxib<−−−(1) etoricoxib<−−−(1) fenamates<−−(2) mefenamic acid<−−−(1) immune/cancer other NSAIDs<−−(2) nabumetone<−−−(1) oxicams<−−(2) meloxicam<−−−(1) piroxicam<−−−(1) propionic acid derivatives<−−(2) ● ● ● ibuprofen<−−−(1) ● ● ketoprofen<−−−(1) naproxen<−−−(1) antineoplastic agents<−(3) antimetabolites<−−(2) ● methotrexate<−−−(1) other antineoplastic agents<−−(2) hydroxycarbamide<−−−(1) antineoplastic endocrine therapy<−(3) ● ● anti−estrogens<−−(2) tamoxifen<−−−(1) aromatase inhibitors<−−(2) ● anastrozole<−−−(1) exemestane<−−−(1) letrozole<−−−(1) gonadotropin releasing hormone analogues<−−(2) goserelin<−−−(1) immunosuppressants<−(3) calcineurin inhibitors<−−(2) tacrolimus<−−−(1) other immunosuppressants<−−(2) azathioprine<−−−(1) selective immunosuppressants<−−(2) leflunomide<−−−(1) mycophenolic acid<−−−(1) TNF alpha inhibitors<−−(2) adalimumab<−−−(1) anti−androgens<−−(2) bicalutamide<−−−(1) blood organs (4) antihemorrhagics<−(3) amino acids<−−(2)
tranexamic acid<−−−(1) blood organs antithrombotic agents<−(3) platelet aggregation inhibitors excl. heparin<−−(2) ● acetylsalicylic acid<−−−(1) clopidogrel<−−−(1) dipyridamole<−−−(1) vitamin k antagonists<−−(2) ● warfarin<−−−(1) blood substitutes and perfusion solutions<−(3) salt solutions<−−(2) sodium bicarbonate<−−−(1) antiinfectives (4) ● antibacterials<−(3) beta−lactam antibacterials, penicillins<−−(2) amoxicillin<−−−(1) benzathine benzylpenicillin<−−−(1) flucloxacillin<−−−(1) phenoxymethylpenicillin<−−−(1) first−generation cephalosporins<−−(2) cefalexin<−−−(1) fluoroquinolones<−−(2) ciprofloxacin<−−−(1) macrolides<−−(2) azithromycin<−−−(1) erythromycin<−−−(1) nitrofuran derivatives<−−(2) ● nitrofurantoin<−−−(1) sulfonamides and trimethoprim<−−(2) tetracyclines<−−(2) doxycycline<−−−(1) lymecycline<−−−(1) minocycline<−−−(1)
oxytetracycline<−−−(1) antiinfectives tetracycline<−−−(1) trimethoprim and derivatives<−−(2) trimethoprim<−−−(1) antiprotozoals<−(3) aminoquinolines<−−(2) hydroxychloroquine<−−−(1) methanolquinolines<−−(2) quinine<−−−(1) ● antifungals<−(3) antifungals<−−(2) terbinafine<−−−(1) imidazole derivatives<−−(2) clotrimazole<−−−(1) ketoconazole<−−−(1) metronidazole<−−−(1) miconazole<−−−(1) vaccines<−(3) influenza vaccines<−−(2) influenza vaccines<−−−(1) antivirals<−(3) non−nucleoside RTIs<−−(2) ● ● nucleoside and nucleotide RTIs<−−(2) ● ● ● tenofovir disoproxil<−−−(1) nucleosides and nucleotides excl. RTIs<−−(2) aciclovir<−−−(1) antibiotics<−(3) other antibiotics for topical use<−−(2) fusidic acid<−−−(1) respiratory system (4) ● antihistamines, 2nd generation<−(3) ● alkylamines<−−(2) acrivastine<−−−(1) other antihistamines for systemic use<−−(2) azelastine<−−−(1) piperidines<−−(2) ● desloratadine<−−−(1) fexofenadine<−−−(1) loratadine<−−−(1) ● terfenadine<−−−(1) antihistamines, 1st generation<−(3) ● aminoalkyl ethers<−−(2) diphenhydramine<−−−(1) phenothiazine derivatives<−−(2) promethazine<−−−(1) piperazine derivatives<−−(2) cyclizine<−−−(1) ● cetirizine<−−−(1) levocetirizine<−−−(1)
substituted alkylamines<−−(2) system respiratory chlorphenamine<−−−(1) drugs for obstructive airway diseases<−(3) ● ● antiallergic agents, excl. corticosteroids<−−(2) cromoglicic acid<−−−(1) leukotriene receptor antagonists<−−(2) montelukast<−−−(1) other antiallergics<−−(2) nedocromil<−−−(1) selective beta−2−adrenoreceptor agonists<−−(2) ● formoterol<−−−(1) salbutamol<−−−(1) ● ● salmeterol<−−−(1) terbutaline<−−−(1) xanthines<−−(2) aminophylline<−−−(1) theophylline<−−−(1) expectorants<−(3) mucolytics<−−(2) carbocisteine<−−−(1) nasal preparations<−(3) anticholinergics<−−(2) ● oxybutynin<−−−(1) ● solifenacin<−−−(1) tolterodine<−−−(1) ● trospium<−−−(1) ipratropium bromide<−−−(1) ● tiotropium bromide<−−−(1) sympathomimetics<−−(2) brimonidine<−−−(1) pseudoephedrine<−−−(1) nervous system (4) ● ● ● anti−parkinson drugs<−(3) ● adamantane derivatives<−−(2) amantadine<−−−(1) comt inhibitor<−−(2) decarboxylase inhibitor<−−(2) ● ● benserazide<−−−(1) carbidopa<−−−(1) dopa and dopa derivatives<−−(2) ● ● levodopa<−−−(1) dopamine agonists<−−(2) ● pramipexole<−−−(1) ● ● ropinirole<−−−(1) For peer review only tertiary amines<−−(2) ● ● procyclidine<−−−(1) analgesics<−(3) ● ● ● anilides<−−(2) ● ● ● paracetamol<−−−(1) ● ● ● opioids<−−(2) ● buprenorphine<−−−(1) codeine<−−−(1) ● dextropropoxyphene<−−−(1) dihydrocodeine<−−−(1) ● ● fentanyl<−−−(1) morphine<−−−(1) oxycodone<−−−(1) tramadol<−−−(1) ● ● other analgesics and antipyretics<−−(2) nefopam<−−−(1) antivertigo preparations<−(3) antivertigo preparations<−−(2) betahistine<−−−(1) anxiolytics and hypnotics<−(3) ● ● ● benzodiazepine related drugs<−−(2) ● ● zolpidem<−−−(1) zopiclone<−−−(1) ● diphenylmethane derivatives<−−(2) hydroxyzine<−−−(1) antiepileptics<−(3) ● ● ● barbiturates and derivatives<−−(2) ● primidone<−−−(1) ● benzodiazepine derivatives<−−(2) ● ● ● clonazepam<−−−(1) diazepam<−−−(1) ● ● ● lorazepam<−−−(1) nitrazepam<−−−(1) temazepam<−−−(1) carboxamide derivatives<−−(2) ● carbamazepine<−−−(1) ●
fatty acid derivatives<−−(2) ● system nervous valproic acid<−−−(1) ● hydantoin derivatives<−−(2) ● phenytoin<−−−(1) other antiepileptics<−−(2) ● ● ● gabapentin<−−−(1) ● lamotrigine<−−−(1) ● levetiracetam<−−−(1) ● ● pregabalin<−−−(1) ● topiramate<−−−(1) ● ● antipsychotics<−(3) ● ● ● benzamides<−−(2) ● ● diaz−, oxaz−, thiaz− and ox−epines<−−(2) ● ● olanzapine<−−−(1) ● ● quetiapine<−−−(1) ● lithium<−−(2) ● lithium<−−−(1) other antipsychotics<−−(2) ● ● ● risperidone<−−−(1) ● phenothiazines with aliphatic side−chain<−−(2) ● ● chlorpromazine<−−−(1) phenothiazines with piperazine structure<−−(2) ● prochlorperazine<−−−(1) trifluoperazine<−−−(1) thioxanthene derivatives<−−(2) ● flupentixol<−−−(1) psychostimulants<−(3) xanthine derivatives<−−(2) caffeine<−−−(1) drugs used in addictive disorders<−(3) ● antimigraine preparations<−(3) other antimigraine preparations<−−(2) pizotifen<−−−(1) selective serotonin (5ht1) agonists<−−(2) almotriptan<−−−(1) naratriptan<−−−(1) rizatriptan<−−−(1) sumatriptan<−−−(1) zolmitriptan<−−−(1) antidepressants<−(3) ● monoamine reuptake inhibitors<−−(2) ● ● amitriptyline<−−−(1) ● ● ● clomipramine<−−−(1) dosulepin<−−−(1) imipramine<−−−(1) lofepramine<−−−(1) nortriptyline<−−−(1) other antidepressants<−−(2) ● duloxetine<−−−(1) mirtazapine<−−−(1) ● trazodone<−−−(1) ● venlafaxine<−−−(1) SSRI<−−(2) ● citalopram<−−−(1) escitalopram<−−−(1) fluoxetine<−−−(1) ● paroxetine<−−−(1) sertraline<−−−(1) ● supplements (4) ● ● mineral supplements<−(3) magnesium<−−(2) magnesium<−−−(1) magnesium carbonate<−−−(1) magnesium citrate<−−−(1) minerals<−−(2) minerals<−−−(1) potassium<−−(2) potassium<−−−(1) potassium citrate<−−−(1) selenium<−−(2) ● selenium<−−−(1) ● zinc<−−(2) zinc<−−−(1) general nutrients<−(3) antianemic preparations<−(3) ● ● iron<−−(2) ● ● ferrous fumarate<−−−(1) ferrous sulfate<−−−(1) ● iron<−−−(1) vitamins<−(3) ● ● multivitamins, plain<−−(2) multivitamins<−−−(1) vitamin a, plain<−−(2) retinol (vit a)<−−−(1) vitamin b, plain<−−(2) ● ● cyanocobalamin (vit b12)<−−−(1) folic acid<−−−(1) ● hydroxocobalamin (vit b12)<−−−(1) vitamin b12<−−−(1) pyridoxine (vit b6)<−−−(1) vitamin B1<−−−(1) ●
vitamin b<−−−(1) supplements vitamin c, plain<−−(2) ascorbic acid (vit c)<−−−(1) vitamin e, plain<−−(2) tocopherol (vit e)<−−−(1) supplements<−(3) ● ● supplements<−−(2) ● ● aloe vera<−−−(1) cod liver oil<−−−(1) co−enzyme q10/ubiquinone/bio−quinone<−−−(1) flax oil<−−−(1) food supplement/plant/herbal extract<−−−(1) garlic<−−−(1) ginkgo folium<−−−(1) ginseng<−−−(1) glucosamine<−−−(1) ● ● kaolin<−−−(1) kelp<−−−(1) lecithin<−−−(1) omega−3−triglycerides<−−−(1) ● peppermint oil<−−−(1) saw palmetto<−−−(1) st john's wort/hypericum<−−−(1) starflower oil<−−−(1) drugs for treatment of bone diseases<−(3) ● ● ● bisphosphonates<−−(2) alendronic acid<−−−(1) etidronic acid<−−−(1) ibandronic acid<−−−(1) risedronic acid<−−−(1) calcium<−−(2) ● ● calcium<−−−(1) calcium carbonate<−−−(1) other drugs affecting bone<−−(2) strontium ranelate<−−−(1) vitamin d and analogues<−−(2) calcipotriol<−−−(1) alfacalcidol<−−−(1) vitamin D3<−−−(1) ● ergocalciferol (vit d2)<−−−(1) vitamin d<−−−(1) GI & metabolism (4) ● ● drugs used in diabetes<−(3) ● ● insulin<−−(2) ● insulin<−−−(1) ● other blood glucose lowering drugs<−−(2) sulfonylureas<−−(2) ● glibenclamide<−−−(1) gliclazide<−−−(1) glimepiride<−−−(1) thiazolidinediones<−−(2) pioglitazone<−−−(1) rosiglitazone<−−−(1) drugs for ulcer and reflux<−(3) ● ● ● other drugs for ulcer and reflux<−−(2) alginic acid<−−−(1) ● h2−receptor antagonists<−−(2) cimetidine<−−−(1) ranitidine<−−−(1) ● prostaglandins<−−(2) misoprostol<−−−(1) proton pump inhibitors<−−(2) ● ● ● esomeprazole<−−−(1) lansoprazole<−−−(1) ● ● omeprazole<−−−(1) ● ● ● pantoprazole<−−−(1) rabeprazole<−−−(1) stomatological preparations<−(3) other agents for local oral treatment<−−(2)
intestinal antiinflammatory/antiinfective<−(3) GI & metabolism antipropulsives<−−(2) loperamide<−−−(1) drugs for functional gastrointestinal disorders<−(3) ● belladonna alkaloids<−−(2) butylscopolamine<−−−(1) other gastrointestinal drugs<−−(2) alverine<−−−(1) propulsives<−−(2) domperidone<−−−(1) ● metoclopramide<−−−(1) synthetic anticholinergics<−−(2) dicycloverine<−−−(1) mebeverine<−−−(1) bile therapy<−(3) bile acid preparations<−−(2) ursodeoxycholic acid<−−−(1) drugs for constipation<−(3) ● ● bulk−forming laxatives<−−(2) ispaghula (psylla seeds)<−−−(1) sterculia<−−−(1) contact laxatives<−−(2) ● bisacodyl<−−−(1) senna glycosides<−−−(1) ● osmotically acting laxatives<−−(2) ● lactulose<−−−(1) ● softeners, emollients<−−(2) ● docusate sodium<−−−(1) ● antiobesity preparations, excl. diet products<−(3) centrally acting antiobesity products<−−(2) sibutramine<−−−(1) peripherally acting antiobesity products<−−(2) orlistat<−−−(1) digestives, incl. enzymes<−(3) enzyme preparations<−−(2) multienzymes (lipase, protease etc.)<−−−(1) biguanides<−−(2) metformin<−−−(1) musculo−skeletal (4) ● ● topical products for joint and muscular pain<−(3) musculo−skeletal preparations with salicylic acid derivatives<−−(2) ● heparinoid<−−−(1) ● central muscle relaxants<−(3) ● other centrally acting agents<−−(2) ● baclofen<−−−(1) ● antigout preparations<−(3) preparations inhibiting uric acid production<−−(2) allopurinol<−−−(1) preparations with no effect on uric acid metabolism<−−(2) colchicine<−−−(1) hormones and modulators (4) ● ● sex hormones and modulators of the genital system<−(3) ● ● androgens<−−(2)
testosterone<−−−(1) BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from estrogens<−−(2) conjugated estrogens<−−−(1) estradiol<−−−(1) estriol<−−−(1) estrogen<−−−(1) estrone<−−−(1) ethinylestradiol<−−−(1) and modulators hormones mestranol<−−−(1) tibolone<−−−(1) progestogens<−−(2) ● ● desogestrel<−−−(1) dydrogesterone<−−−(1) etonogestrel<−−−(1) levonorgestrel<−−−(1) medroxyprogesterone<−−−(1) norethisterone<−−−(1) ● norgestimate<−−−(1) progesterone<−−−(1) progestogen<−−−(1) selective estrogen receptor modulators<−−(2) raloxifene<−−−(1) mineralocorticoids<−(3) mineralocorticoids<−−(2) fludrocortisone<−−−(1) pituitary and hypothalamic hormones and analogues<−(3) ● thyroid therapy<−(3) sulfur−containing imidazole derivatives<−−(2) carbimazole<−−−(1) thyroid hormones<−−(2) levothyroxine sodium<−−−(1) ophthalmologicals (4) ● ophthalmologicals<−(3) ● artificial tears and other<−−(2) ● carbomers<−−−(1)
carmellose<−−−(1) ophthalmologicals celluvisc<−−−(1) hypromellose<−−−(1) lacri−lube<−−−(1) liquifilm tears<−−−(1) tears naturale<−−−(1) viscotears<−−−(1) antiglaucoma preparations and miotics<−(3) carbonic anhydrase inhibitors<−−(2) brinzolamide<−−−(1)
dorzolamide<−−−(1) http://bmjopen.bmj.com/ prostaglandin analogues<−−(2) bimatoprost<−−−(1) latanoprost<−−−(1) travoprost<−−−(1) dermatologicals (4) emollients and protectives<−(3) ● ● other emollients and protectives<−−(2) ● ● aqueous bp<−−−(1)
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dermol<−−−(1) on September 26, 2021 by guest. Protected copyright. diprobase<−−−(1) ● doublebase<−−−(1) e45 cream<−−−(1) ● epaderm<−−−(1) oilatum<−−−(1) other dermatological preparations<−(3) other dermatologicals<−−(2) gamolenic acid<−−−(1) antipsoriatics<−(3) tars<−−(2) coal tar<−−−(1) urinary (4) ● drugs used in benign prostatic hypertrophy<−(3) testosterone−5−alpha reductase inhibitors<−−(2)
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Commonly prescribed drugs associate with cognitive function: a cross-sectional study in UK Biobank
ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2016-012177.R1
Article Type: Research
Date Submitted by the Author: 23-Jun-2016
Complete List of Authors: Nevado-Holgado, Alejo; University of Oxford, Psychiatry Kim, Chi-Hun; University of Oxford, Psychiatry Winchester, Laura; University of Oxford, Psychiatry Gallacher, John; University of Oxford, Psychiatry Lovestone, Simon; University of Oxford, Psychiatry
Primary Subject Public health Heading:
Secondary Subject Heading: Mental health, Pharmacology and therapeutics, Neurology
Keywords: PUBLIC HEALTH, MENTAL HEALTH, Cognition, UK biobank
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1 2 3 Commonly prescribed drugs associate with cognitive function: a cross- 4 sectional study in UK Biobank 5 6 7 8 Authors 9 10 Alejo J Nevado Holgado*, Chi Hun Kim*, Laura Winchester, John Gallacher, Simon Lovestone 11 12 13 14 15 Address For peer review only 16 17 Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK 18 19 20 21 22 23 Authors’ names and positions 24 25 Alejo J Nevado Holgado*: Postdoctoral researcher 26 27 Chi Hun Kim*: Postdoctoral researcher 28 29 Laura Winchester: Postdoctoral researcher 30 31 John Gallacher: Professor 32 33 Simon Lovestone: Professor
34 http://bmjopen.bmj.com/ 35 *These authors contributed equally to this work. 36
37 38
39 40 Correspondence to: S Lovestone [email protected] 41 42 on September 26, 2021 by guest. Protected copyright. 43 44
45 46
47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from Abstract 1 2 Objective To investigate medications associated with cognitive function 3 4 Design Population based cross sectional cohort study 5 6 Setting UK Biobank 7 8 Participants UK Biobank participants aged 37 73 years who completed cognitive tests at the baseline visit 9 in 2006 2010 10 11 Main outcome measures Cognitive test outcomes on verbal numerical reasoning test (n=165493), 12 memory test (n=482766) and reaction time test (n=496813). 13 14 Results Most drugs (262 of 368) were not associated with any cognitive tests after adjusting for age, 15 For peer review only 16 gender, education, household income, smoking, alcohol status, psychostimulant/nootropic medication use, 17 assessment centre and concurrent diagnoses and medications. Drugs used for nervous system disorders 18 were associated with poorer cognitive performance (antiepileptics e.g. topiramate breasoning 0.65 [95%CI:
19 1.05, 0.24], bmemory 1.41[ 1.79, 1.04]; antipsychotics e.g. risperidone breaction time 33[ 46, 20], negative 20 values indicate poor cognitive performance and vice versa). Drugs used for non nervous system conditions 21 also showed significant negative association with cognitive score, including those where such an 22 23 association might have been predicted (antihypertensives e.g. amlodipine breasoning 0.1[ 0.15, 0.06], bmemory 24 0.08[ 0.13, 0.03], breaction time 3[ 5, 2]; antidiabetics e.g. insulin breaction time 13[ 17, 10]) and others where 25 such an association was a surprising observation (proton pump inhibitors e.g. omeprazole breasoning 0.11[
26 0.15, 0.06], bmemory 0.08[ 0.12, 0.04], breaction time 5[ 6, 3]; laxatives e.g. contact laxatives breaction time 13[ 27 19, 8]). Finally, only a few medications and health supplements showed association towards a positive 28 effect on cognitive function (anti inflammatory agents e.g. ibuprofen b 0.05[0.02, 0.08], b 4[3, 29 reasoning reaction time 30 5]; glucosamine breasoning 0.09[0.03, 0.14], breaction time 5[3, 6]). 31 32 Conclusions In this large volunteer study, some commonly prescribed medications were associated with 33 poor cognitive performance. Some associations may reflect underlying diseases for which the medications
34 were prescribed, although the analysis controlled for the possible effect of diagnosis. Other drugs, whose http://bmjopen.bmj.com/ 35 association cannot be linked to the effect of any disease, may need vigilance for their implications in clinical 36 practice. 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from Strengths and limitations of this study 1 2 • Using a very large UK population cohort, this study was sufficiently powered to perform a systematic 3 investigation for a range of medications and its association with cognitive function. 4 5 • We report multiple associations between commonly prescribed medications and poorer or better 6 cognitive performance, which may have implications for clinicians and patients. 7 • Due to the cross sectional design, it is difficult to make causal inferences between medication and 8 cognitive function. 9 • Although trained nurses interviewed participants to obtain medications and diagnoses, this self 10 11 reported nature may limit the accuracy of information. 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from Introduction 1 2 A significant number of drugs are used for therapeutic indications other than those they were either 3 designed, or first used for. Well known examples include Viagra, developed for cardiac indications but used 4 for erectile failure, and aspirin, used in an increasingly wide range of indications. This phenomenon has 5 6 prompted systematic efforts to repurpose compounds already in clinical practice.[1,2] In the field of 7 cognitive performance, repurposing approaches have included consensus building using understanding 8 from epidemiology to molecular sciences,[3] and informatics driven approaches using platforms such as the 9 connectivity map,[1] which derives gene expression signatures from in vitro cells exposed to drugs and 10 matches these to disease associated signatures. In this paper we adopt a real world evidence approach, 11 analysing data from UK Biobank, a large scale population based cohort study to identify compounds that 12 13 are associated with cognitive performance. 14 15 For peer review only 16 17 Methods 18 19 UK Biobank is a prospective study of a half million participants across the UK with extensive data from 20 questionnaires, interviews, physical measures, biological samples and imaging.[4] This study used baseline 21 data from 502647 subjects aged between 37 and 73 years collected at 21 assessment centres in 2006 22 2010. 23 24 Outcome and other measures 25 26 Three cognitive tests (verbal numeric reasoning, memory and reaction time), were administered using a 27 touch screen.[5–7] These tests cover domains that have been shown to be sensitive to change over time 28 29 and are widely used in studies of ageing and brain disorders.[8–10] For verbal numerical reasoning, 30 subjects were asked to solve as many multiple choice questions as possible (maximum 13) within two 31 minutes. Performance was assessed as the total number of correct responses. Memory was assessed 32 using the pairs matching test in which subjects had to remember 6 pairs of shapes and their locations 33 displayed for 5 seconds. Performance was assessed as the total number of errors made in matching all 6
34 http://bmjopen.bmj.com/ pairs. Reaction time was measured by pressing a button as quickly as possible when two identical shapes 35 36 were presented. Performance was assessed as the mean reaction time (ms) of eight trials for correctly 37 identified matching pairs. 38 39 Medications and diagnoses were obtained by nurse led interview. Only regular medications and health 40 supplements taken weekly, monthly or three monthly were recorded. Medications were recorded using 41 6745 categories adapted from Read code version 3 (CTV3) used in the general practice in the UK. Of 42 these, 1192 medications were taken by 30 or more participants, and were classified using the Anatomical on September 26, 2021 by guest. Protected copyright. 43 Therapeutic Chemical (ATC) classification [11] as a backbone. For example, brand names with different 44 45 doses were allocated into their chemical substance (e.g. Lipitor and atorvastatin were treated as 46 atorvastatin), chemical subgroup (e.g. HMG CoA reductase), therapeutic subgroup (e.g. lipid modifying 47 agents) and anatomical group (e.g. cardiovascular system). Compound medications were divided into 48 single chemical substances (e.g. CoAprovel into irbesartan and hydrochlorothiazide), 49 50 Demographic and lifestyle variables included in the model were age, gender, education, household income, 51 smoking, alcohol status, psychostimulant/nootropic medication use and assessment centre. 52 53 Statistical analyses 54 55 For each cognitive test, performance was regressed on each medication, adjusting for other medication 56 use, comorbidity (diagnosis), and a range demographic variables using multivariable linear regression on 57 58 all participants with complete data. Medications and comorbidities were modelled as binary variables. Due 59 to the large number of medications, the problem was simplified by identifying for each the 10 medications 60 that were most strongly associated with use of the target medication as indicated by the odds ratio. The For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from number of potential comorbidities was reduced to 10 using the same method (see Supplementary tables for 1 top 10 odds ratio tables). Education was modelled as a 5 level factor (A levels and above, O levels or 2 equivalent, professional qualifications only, none of the above, prefer not to answer), annual household 3 4 income as a 7 level factor (£<18K, 18 30.9K, 31K 51.9K, 52 100K, >100K, do not know, prefer not to 5 answer), and smoking and alcohol status as 4 level factors (current, previous, never, prefer not to answer). 6 Nominal scales were due to non ordinal options such as the ‘prefer not to answer’ option. Gender and use 7 of psychostimulants or nootropics were each modelled as binary variables. 8 9 Full adjustment was made in all models. Analyses were conducted at three medication classification levels 10 (chemical substance, chemical subgroup and therapeutic subgroup) separately and are presented 11 according to functional system (e.g. nervous, cardiovascular, gastrointestinal and metabolism, immune, 12 13 others). Results are presented as regression coefficients (b, unstandardised) with 95% confidence 14 intervals. 15 For peer review only 16 Statistical power was estimated on the basis of a binomial test with unequal group sizes. To detect an 17 effect size of b=0.25 SD with 80% power at a significance level of 0.05, 125 reported users were required. 18 This criterion was met for 368 chemical substances, 165 chemical subgroups and 68 therapeutic 19 subgroups. If the criterion was not met the medication was omitted from the analysis. False discovery rate 20 was used to correct for multiple comparisons. 21 22 23 24 25 Results 26 27 Table 1 gives the distributions of the cognitive and demographic variables (see Supplementary tables for 28 further details). The numbers available to the analysis varied as the cognitive tests were introduced at 29 different times during the baseline assessment. Verbal and numeric reasoning was normally distributed 30 with a test retest correlation of 0.62. The memory score was positively skew with a test retest correlation of 31 0.15. Reaction time was log normally distributed with a test retest correlation of 0.85. 32 33 Most drugs were not associated with significant difference in any of the cognitive tests after adjustment for 34 confounding. Figure 1 shows the effect sizes for the 32 medications and 31 higher medication classification http://bmjopen.bmj.com/ 35 36 categories (e.g. amlodipine as a medication and calcium channel blockers as a higher category). Results 37 for all 368 medications and their higher categories can be found in Supplementary Figure 1. In Figure 1 38 most drugs were associated with poorer cognitive performance i.e. fewer correct answers on the reasoning 39 test, more errors on the memory test, and longer reaction time. The scores are presented such that 40 negative values correspond to poor cognitive performance and vice versa. 41 42 Medications prescribed for nervous system disorders showed the strongest associations with cognitive on September 26, 2021 by guest. Protected copyright. 43 performance relative to the other systems. For example, users of levetiracetam and toparimate had one 44 45 more error on the memory test, and users of benzamides and primidone had a 50ms slower mean reaction 46 time when compared to non users. Among anti epileptics, topiramate was associated with poor cognitive 47 scores (breasoning 0.65[ 1.05, 0.24], bmemory 1.41[ 1.79, 1.04]) as was levetiracetam (bmemory 0.75[ 1.12,
48 0.37], breaction time 32[ 44, 20]). Among antipsychotics, risperidone were associated with slower reaction time 49 ( 33[ 46, 20]). 50 51 Among cardiovascular medications, first line antihypertensives such as ACE inhibitors were associated with 52 more correct responses in the reasoning test (e.g. perindopril 0.17[0.08, 0.25]). However calcium blocking 53 54 channels (e.g. amlodipine breasoning 0.1[ 0.15, 0.06], bmemory 0.08[ 0.13, 0.03], breaction time 3[ 5, 2]) and 55 some diuretics (e.g. furosemide breaction time 9[ 12, 5]) were associated with poorer cognitive function. 56 57 In the gastroinstestinal (GI) tract and metabolism system, drugs for diabetes were adversely associated 58 with cognitive performance. Insulin was related to slower reaction time ( 13[ 17, 10]). Proton pump
59 inhibitors (PPI) were adversely related to reasoning, memory and reaction time (e.g. omeprazole breasoning 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
0.11[ 0.15, 0.06], bmemory 0.08[ 0.12, 0.04], breaction time 5[ 6, 3]). Laxatives (including contact and osmotic 1 but not bulk form laxatives) were associated with slower reaction time. 2 3 Immunomodulating medications were among the very few drugs that showed beneficial cognitive 4 associations. For example, ibuprofen was related to significantly better reasoning test and reaction time 5 6 (breasoning 0.05[0.02, 0.08], breaction time 4[3, 5]), as were some cancer medications when tested at the 7 subgroup level (e.g. aromatase inhibitors, breasoning 0.28[0.13, 0.43]). Similar but non significant beneficial 8 trends were found in anti inflammatory/antineoplastic medication such as meloxicam, methotrexate and 9 TNF alpha inhibitors. However these associations were not found in other anti inflammatory medications 10 e.g. diclofenac and corticosteroids, and were reversed in some non inflammatory analgesics (e.g. 11 paracetamol b 0.19[ 0.21, 0.16], b 0.11[ 0.13, 0.08], b 5[ 6, 4]). 12 reasoning memory reaction time 13 Some health supplements (e.g. glucosamine b 0.09[0.03, 0.14], b 5[3, 6]) showed beneficial 14 reasoning reaction time 15 cognitive association.For But supplements peer used for review anaemia (e.g. iron b reasoningonly 0.16[ 0.27, 0.06]) or 16 osteoporosis (e.g. calcium breaction time 4[ 7, 2]) were related to poor cognitive function. 17 18 19 20 Discussion 21 22 This analysis of a large and diverse population based cohort has shown considerable evidence for an 23 association between commonly prescribed medications and cognitive performance. Of interest is the extent 24 to which these associations reflect an effect of the medication on cognitive performance or a wider context, 25 such as an effect of the underlying disorder, comorbidity or socioeconomic context. 26 27 Examples of associations where there is an a priori reason to suspect a primary relationship with an 28 underlying disease includes antipsychotics, drugs used to treat Parkinson’s disease and antiepileptics. In 29 30 each case these classes of compound are most commonly used for diseases known to have an element of 31 cognitive impairment as part of the core syndrome [9,12,13] although, in addition, antipsychotics and 32 antiepileptics are known to have independent effects on cognitive performance.[14–17] 33
34 We also find associations with medications for which there is a plausible association with a cognitive http://bmjopen.bmj.com/ 35 component of the underlying disease but where cognitive ability is not a necessary or well established part 36 of the underlying syndrome. Examples include anti diabetes medications (e.g. insulin and sulfonylurea), 37 antihypertensives (e.g. calcium channel blockers and diuretics) and anaemia medications. Both diabetes 38 39 and hypertension are associated with cognitive impairment.[18,19] That we find an association between 40 drugs used to treat anaemia iron and thiamine (i.e. vitamin B1) and poor cognitive performance lends 41 weight to those studies that suggest poor cognitive function is associated with anaemia.[20] Our findings 42 show that this association is not limited to elderly or frail populations. on September 26, 2021 by guest. Protected copyright. 43 44 For several medications however, associations with cognitive performance might not be expected. 45 Examples include PPIs, calcium and laxatives. Recent studies have found PPIs to be associated with an 46 increased risk of dementia.[21,22] Osteoporosis, one of the most common indications for calcium, has also 47 48 been associated with increased risk of dementia.[23,24] In the present study, participants in their middle 49 age taking PPIs or calcium showed poorer cognitive performance compared to non takers. Additionally 50 many laxatives showed a strong association with increased reaction time. It is unclear whether these 51 associations were due to the side effects of medications or underlying syndromes for which they were 52 prescribed. 53
54 55 For a small number of medications, use was associated with better cognitive performance. It is interesting 56 that there is a small but significant association with ibuprofen and comparable but non significant trends 57 with other anti inflammatories including meloxicam, methotrexate and TNF alpha inhibitors. The importance 58 of inflammation in Alzheimer’s disease and other dementias is increasingly recognised [25] and these 59 findings are consistent with the known effect of anti inflammatory medication including nonsteroidal anti 60 inflammatory medication in reducing incidence of dementia [26,27]. These data suggest that an effect of For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from anti inflammatory medication may be detectable within the normal range of cognitive function. Alternatively, 1 it might be that anti inflammatory medications have a dementia independent beneficial effect on cognitive 2 function and that previous evidence suggesting a protective effect in relation to dementia reflects this. This 3 4 is clearly a critical important distinction as is the observation that the association we observe is not present 5 in all anti inflammatory medications including, for example acetic acid derivatives and fenamates. 6 7 The limitations of the study suggest these findings should be interpreted cautiously. The data are cross 8 sectional, and medications and diagnoses are self reported. Residual confounding cannot be discounted. 9 The cognitive battery is not exhaustive and the tests are indicative of cognitive function rather than 10 11 definitive. Also, the tests are of variable psychometric quality. Nevertheless, that associations were 12 detected using relatively coarse cognitive measures does not suggest that the associations are spurious, 13 but that more detailed testing would be informative. As with all real world data, these findings require 14 replication in other cohort and clinical datasets. Moreover, although in a cross sectional study such as this 15 we cannot concludeFor that the associations peer we observe review are due to change only in cognition for a given individual, 16 clearly that is a possibility and if medications do influence change then any decline is likely to be of 17 18 importance to that person. Limitations notwithstanding, that associations have been detected at a 19 population level and within the normal distribution of cognitive performance is consistent with 20 neurodegeneration being an incremental process that begins many decades before clinical presentation, 21 and which might be amenable to prophylaxis. 22 23 In summary, in a large and diverse population cohort, associations between medication and cognitive 24 performance have been found. Causal inferences cannot be drawn from these data, but the findings 25 illustrate the opportunities and challenges of real world data. 26 27
28 29
30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from This research has been conducted using the UK Biobank resource. 1 2 3 4 Contributors: ANH, CHK, LW, JG and SL contributed to study design and wrote the manuscript; ANH, 5 CHK and LW contributed to data acquisition; ANH and CHK conducted data processing and statistical 6 analyses; SL is the guarantor. 7 8 9 10 Funding: We received funding for this analysis through the Medical Research Council Dementias Platform 11 UK (MR/L015382/1) and the Wellcome Trust Consortium for Neuroimmunology for Mood Disorders and 12 13 Alzheimer’s Disease (104025/Z/14/Z). The funders had no influence on study design, data collection and 14 analysis, decision to publish, or preparation of the manuscript. 15 For peer review only 16 17 18 Competing interests: All authors have completed the ICMJE uniform disclosure form at 19 www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work ; 20 no financial relationships with any organisations that might have an interest in the submitted work in the 21 previous three years; no other relationships or activities that could appear to have influenced the submitted 22 work. 23 24
25 26 Ethical approval: This study has been conducted using UK Biobank data. UK Biobank has received ethics 27 28 approval from the UK Biobank Research Ethics Committee (ref 11/NW/0382). 29 30 31 32 Transparency statement: The lead author (the manuscript’s guarantor) affirms that this manuscript is an 33 honest, accurate, and transparent account of the study being reported; that no important aspects of the
34 study have been omitted; and that any discrepancies from the study as planned (and, if relevant, http://bmjopen.bmj.com/ 35 registered) have been explained. 36 37 38 39 Data sharing: No additional data are available.. 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 Copyright The Corresponding Author has the right to grant on behalf of all authors and does grant on 44 behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all forms, 45 formats and media (whether known now or created in the future), to i) publish, reproduce, distribute, display 46 and store the Contribution, ii) translate the Contribution into other languages, create adaptations, reprints, 47 48 include within collections and create summaries, extracts and/or, abstracts of the Contribution, iii) create 49 any other derivative work(s) based on the Contribution, iv) to exploit all subsidiary rights in the Contribution, 50 v) the inclusion of electronic links from the Contribution to third party material where ever it may be located; 51 and, vi) licence any third party to do any or all of the above. All research articles will be made available on 52 an Open Access basis (with authors being asked to pay an open access fee. The terms of such Open 53 Access shall be governed by a Creative Commons licence—details as to which Creative Commons licence 54 55 will apply to the research article are set out in our worldwide licence referred to above. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from References 1 2 1 Chung F H, Chiang Y R, Tseng A L, et al. Functional Module Connectivity Map (FMCM): a framework 3 for searching repurposed drug compounds for systems treatment of cancer and an application to 4 colorectal adenocarcinoma. PloS One 2014;9:e86299. doi:10.1371/journal.pone.0086299 5 6 2 Corbett A, Pickett J, Burns A, et al. Drug repositioning for Alzheimer’s disease. Nat Rev Drug Discov 7 2012;11:833–46. doi:10.1038/nrd3869 8 9 3 Corbett A, Williams G, Ballard C. Drug repositioning in Alzheimer’s disease. Front Biosci Sch Ed 10 2015;7:184–8. 11 12 4 Sudlow C, Gallacher J, Allen N, et al. UK Biobank: An Open Access Resource for Identifying the 13 Causes of a Wide Range of Complex Diseases of Middle and Old Age. PLoS Med 2015;12:e1001779. 14 doi:10.1371/journal.pmed.1001779 15 For peer review only 16 5 Hagenaars SP, Harris SE, Davies G, et al. Shared genetic aetiology between cognitive functions and 17 physical and mental health in UK Biobank (N=112 151) and 24 GWAS consortia. Mol Psychiatry 18 Published Online First: 26 January 2016. doi:10.1038/mp.2015.225 19 20 6 Davies G, Marioni RE, Liewald DC, et al. Genome wide association study of cognitive functions and 21 educational attainment in UK Biobank (N=112 151). Mol Psychiatry 2016;21:758–67. 22 doi:10.1038/mp.2016.45 23 24 7 Lyall DM, Cullen B, Allerhand M, et al. Cognitive Test Scores in UK Biobank: Data Reduction in 25 480,416 Participants and Longitudinal Stability in 20,346 Participants. PLOS ONE 2016;11:e0154222. 26 doi:10.1371/journal.pone.0154222 27 28 8 Harada CN, Natelson Love MC, Triebel KL. Normal cognitive aging. Clin Geriatr Med 2013;29:737–52. 29 doi:10.1016/j.cger.2013.07.002 30 31 9 Svenningsson P, Westman E, Ballard C, et al. Cognitive impairment in patients with Parkinson’s 32 disease: diagnosis, biomarkers, and treatment. Lancet Neurol 2012;11:697–707. doi:10.1016/S1474 33 4422(12)70152 7
34 http://bmjopen.bmj.com/ 35 10 Weintraub S, Wicklund AH, Salmon DP. The Neuropsychological Profile of Alzheimer Disease. Cold 36 Spring Harb Perspect Med 2012;2. doi:10.1101/cshperspect.a006171 37 38 11 WHO Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC classification and DDD 39 assignment 2016. Oslo: 2016. http://www.whocc.no/atc_ddd_publications/guidelines/ 40 41 12 Barch DM, Ceaser A. Cognition in schizophrenia: core psychological and neural mechanisms. Trends 42 Cogn Sci 2012;16:27–34. doi:10.1016/j.tics.2011.11.015 on September 26, 2021 by guest. Protected copyright. 43 44 13 Berg AT. Epilepsy, cognition, and behavior: The clinical picture. Epilepsia 2011;52 Suppl 1:7–12. 45 doi:10.1111/j.1528 1167.2010.02905.x 46 47 14 Bédard MA, Schérer H, Stip E, et al. Procedural learning in schizophrenia: further consideration on the 48 deleterious effect of neuroleptics. Brain Cogn 2000;43:31–9. 49 50 15 Reilly JL, Harris MSH, Keshavan MS, et al. Adverse effects of risperidone on spatial working memory in 51 first episode schizophrenia. Arch Gen Psychiatry 2006;63:1189–97. doi:10.1001/archpsyc.63.11.1189 52 53 16 Mula M, Trimble MR. Antiepileptic drug induced cognitive adverse effects: potential mechanisms and 54 contributing factors. CNS Drugs 2009;23:121–37. 55 56 17 Park S P, Kwon S H. Cognitive Effects of Antiepileptic Drugs. J Clin Neurol Seoul Korea 2008;4:99– 57 106. doi:10.3988/jcn.2008.4.3.99 58 59 18 Sadanand S, Balachandar R, Bharath S. Memory and executive functions in persons with type 2 60 diabetes: a meta analysis. Diabetes Metab Res Rev 2016;32:132–42. doi:10.1002/dmrr.2664 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from 19 Elias MF, Goodell AL, Dore GA. Hypertension and Cognitive Functioning A Perspective in Historical 1 Context. Hypertension 2012;60:260–8. doi:10.1161/HYPERTENSIONAHA.111.186429 2 3 20 Andro M, Le Squere P, Estivin S, et al. Anaemia and cognitive performances in the elderly: a 4 systematic review. Eur J Neurol 2013;20:1234–40. doi:10.1111/ene.12175 5 6 21 Gomm W, von Holt K, Thomé F, et al. Association of proton pump inhibitors with risk of dementia: A 7 pharmacoepidemiological claims data analysis. JAMA Neurol Published Online First: 15 February 2016. 8 doi:10.1001/jamaneurol.2015.4791 9 10 22 Haenisch B, Holt K von, Wiese B, et al. Risk of dementia in elderly patients with the use of proton pump 11 inhibitors. Eur Arch Psychiatry Clin Neurosci 2014;265:419–28. doi:10.1007/s00406 014 0554 0 12 13 23 Chang K H, Chung C J, Lin C L, et al. Increased risk of dementia in patients with osteoporosis: a 14 population based retrospective cohort analysis. AGE 2013;36:967–75. doi:10.1007/s11357 013 9608 x 15 For peer review only 16 24 Zhou R, Zhou H, Rui L, et al. Bone loss and osteoporosis are associated with conversion from mild 17 cognitive impairment to Alzheimer’s disease. Curr Alzheimer Res 2014;11:706–13. 18 19 25 Heneka MT, Carson MJ, Khoury JE, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 20 2015;14:388–405. doi:10.1016/S1474 4422(15)70016 5 21 22 26 Zandi PP, Anthony JC, Hayden KM, et al. Reduced incidence of AD with NSAID but not H2 receptor 23 antagonists: the Cache County Study. Neurology 2002;59:880–6. 24 25 27 Szekely CA, Breitner JCS, Fitzpatrick AL, et al. NSAID use and dementia risk in the Cardiovascular 26 Health Study: role of APOE and NSAID type. Neurology 2008;70:17–24. 27 doi:10.1212/01.wnl.0000284596.95156.48 28 29 30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
Participants completed cognitive test 1 All
2 participants Verbal-numerical reasoning Memory Reaction time 3 (n = 502647) (n = 165493) (n = 482766) (n = 496813) 4 5.98 ± 2.16 4.25 ± 3.36 559 ± 118 Cognitive test score 5 (max. correct of 13) (no. of errors) (ms) 6 Age (years) 57.03 ± 8.09 57.20 ± 8.14 56.96 ± 8.08 57.02 ± 8.09 7 Gender (women) 55.0% 54.5% 54.5% 54.4% 8 Education 9 A levels and above 43.6% 45.7% 44.0% 43.4% 10 Other educational qualifications 33.2% 33.9% 33.4% 33.0% 11 Professional qualifications only 5.2% 5.2% 5.2% 5.1% 12 None of the above 17.2% 14.3% 16.4% 16.7% 13 Prefer not to answer 2.0% 2.0% 2.0% 1.7% Household income (GBP/year) 14 < 18,000 19.6% 18.8% 19.2% 19.2% 15 18,000 30,999 For peer21.8% review22.0% only21.9% 22.2% 16 31,000 51,999 22.3% 22.6% 22.6% 22.2% 17 52,000 100,000 17.4% 17.9% 17.7% 17.4% 18 > 100,000 4.6% 5.1% 4.7% 4.6% 19 Do not know 4.3% 3.9% 4.0% 4.1% 20 Prefer not to answer 10.0% 9.4% 9.7% 9.9% 21 22 Table 1. Baseline characteristics of participants The table shows summary statistics of all UK Biobank 23 participants (first column) and the participants who completed each cognitive test during their baseline visit 24 25 (second to fourth columns). Values indicate mean ± standard deviation for cognitive test score and age, or 26 percentages for gender, education and household income. 27 28 29 30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 Figure legend 3 4 5 6 Figure 1. Medication use and cognitive performance according to anatomical system A summary of 7 selected medications are presented here (for all medications see Appendix 1). As analyses were conducted 8 at three medication classification levels (see Methods), numbers in parenthesis next to a medication name 9 on the left indicate the classification level of the medication: (1) chemical substance, (2) chemical subgroup 10 11 and (3) therapeutic subgroup. Relationship between medication and each cognitive test are represented by 12 effect size and 95% confidence intervals across three columns: verbal numerical reasoning test (score), 13 memory test (score) and reaction time test (ms). For all three tests, negative values correspond to poor 14 cognitive performance and vice versa. The corresponding p values after false discovery rate correction for 15 multiple comparisonsFor were indicated peer by filled circles review with red line (p < .005),only empty circle (p < .05) and ‘x’ 16 with black line (p > .05) *Abbreviations: ACE = angiotensin converting enzyme, TNF = tumour necrosis 17 18 factor, GI = gastroinstestinal 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 Figure 1. Medication use and cognitive performance according to anatomical system A summary of selected medications are presented here (for all medications see Appendix 1). As analyses were conducted at three 48 medication classification levels (see Methods), numbers in parenthesis next to a medication name on the left 49 indicate the classification level of the medication: (1) chemical substance, (2) chemical subgroup and (3) 50 therapeutic subgroup. Relationship between medication and each cognitive test are represented by effect 51 size and 95% confidence intervals across three columns: verbal-numerical reasoning test (score), memory 52 test (score) and reaction time test (ms). For all three tests, negative values correspond to poor cognitive 53 performance and vice versa. The corresponding p-values after false discovery rate correction for multiple 54 comparisons were indicated by filled circles with red line (p < .005), empty circle (p < .05) and ‘x’ with 55 black line (p > .05) *Abbreviations: ACE = angiotensin converting enzyme, TNF = tumour necrosis factor, GI = gastroinstestinal 56 Figure 1 57 304x365mm (300 x 300 DPI) 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 V1 V2 V3 V4 3 captopril nifedipine furosemide doxazosin warfarin 4 enalapril hydrochlorothiazidedoxazosin moxonidine bendroflumethiazide 5 6 fosinopril doxazosin pravastatin bendroflumethiaziderosuvastatin 7 lisinopril glibenclamide glimepiride pioglitazone rosiglitazone 8 perindopril indapamide dipyridamole carvedilol lercanidipine 9 quinapril felodipine bendroflumethiazidedoxazosin furosemide 10 11 ramipril carvedilol clopidogrel bisoprolol glyceryl trinitrate 12 trandolapril lercanidipine furosemide rosuvastatin doxazosin 13 diclofenac misoprostol tramadol leflunomide dihydrocodeine 14 etodolac hydroxychloroquinesulfasalazine methotrexate folic acid 15 For peer review only 16 indometacin allopurinol sulfasalazine methotrexate dihydrocodeine 17 amantadine benserazide carbidopa levodopa pramipexole 18 acrivastine pseudoephedrine cromoglicic acid fluticasone salbutamol 19 carvedilol spironolactone bumetanide furosemide amiodarone 20 21 doxazosin moxonidine sodium bicarbonatebumetanide fosinopril 22 alfuzosin dutasteride finasteride saw palmetto tolterodine 23 tamsulosin dutasteride finasteride bicalutamide saw palmetto 24 terazosin finasteride furosemide acetylsalicylic acid metformin 25 26 tranexamic acid mefenamic acid ferrous sulfate iron norethisterone 27 diphenhydramine citalopram multivitamins codeine beclometasone 28 hydroxychloroquinemethotrexate leflunomide folic acid sulfasalazine 29 balsalazide azathioprine mesalazine prednisolone calcium carbonate 30 31 mesalazine azathioprine colestyramine balsalazide ursodeoxycholic acid 32 sulfasalazine methotrexate hydroxychloroquinefolic acid leflunomide 33 testosterone hydrocortisone estrogen sildenafil tadalafil
34 candesartan carvedilol moxonidine spironolactone amiodarone http://bmjopen.bmj.com/ 35 eprosartan bendroflumethiazideindapamide rosuvastatin doxazosin 36 37 irbesartan sodium bicarbonatehydrochlorothiazidemoxonidine alfacalcidol 38 losartan hydrochlorothiazidemoxonidine doxazosin carvedilol 39 olmesartan medoxomilnebivolol rosuvastatin lercanidipine indapamide 40 telmisartan hydrochlorothiazidemoxonidine glimepiride lacidipine 41 42 valsartan hydrochlorothiazidemoxonidine doxazosin piroxicam on September 26, 2021 by guest. Protected copyright. 43 paracetamol dextropropoxyphenecodeine dihydrocodeine caffeine 44 alginic acid domperidone heparinoid esomeprazole clotrimazole 45 cromoglicic acid fexofenadine loratadine acrivastine desloratadine 46 47 bicalutamide goserelin tamsulosin atorvastatin atenolol 48 amiodarone warfarin spironolactone carvedilol furosemide 49 flecainide warfarin verapamil bisoprolol metoprolol 50 oxybutynin amantadine baclofen cefalexin nitrofurantoin 51 52 solifenacin nitrofurantoin baclofen carbidopa cefalexin 53 tolterodine baclofen nitrofurantoin carbidopa docusate sodium 54 trospium senna glycosides lactulose mebeverine quinine 55 ipratropium bromidetheophylline aminophylline salbutamol carbocisteine 56 57 tiotropium bromideazithromycin carbocisteine aminophylline theophylline 58 tamoxifen goserelin escitalopram quinine anastrozole 59 terbinafine oxybutynin selenium betamethasone hydrocortisone 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 methotrexate adalimumab folic acid leflunomide hydroxychloroquine 3 loperamide colestyramine kaolin tenofovir disoproxilmultienzymes (lipase, protease etc.) 4 betahistine cinnarizine prochlorperazine cyclizine alverine 5 6 cinnarizine betahistine prochlorperazine domperidone hypromellose 7 anastrozole goserelin colecalciferol (vit d3)calcium ibandronic acid 8 exemestane colecalciferol (vit d3)calcium alendronic acid fluoxetine 9 letrozole ibandronic acid colecalciferol (vit d3)calcium alendronic acid 10 11 carbomers lacri-lube hypromellose dexamethasone dorzolamide 12 carmellose lacri-lube hypromellose ispaghula (psylla seeds)prednisolone 13 celluvisc lacri-lube viscotears bimatoprost dexamethasone 14 hypromellose dexamethasone lacri-lube carbomers carmellose 15 For peer review only 16 lacri-lube carmellose celluvisc liquifilm tears viscotears 17 liquifilm tears lacri-lube viscotears lactulose colecalciferol (vit d3) 18 tears naturale tramadol amitriptyline colecalciferol (vit d3)codeine 19 viscotears lacri-lube liquifilm tears celluvisc hypromellose 20 21 primidone phenytoin valproic acid propranolol colecalciferol (vit d3) 22 butylscopolamine peppermint oil docusate sodium domperidone loperamide 23 clonazepam carbidopa levodopa pramipexole baclofen 24 diazepam oxycodone quetiapine temazepam nitrazepam 25 26 lorazepam mirtazapine zopiclone venlafaxine propranolol 27 nitrazepam diazepam senna glycosides dihydrocodeine lactulose 28 temazepam diazepam morphine baclofen quetiapine 29 zolpidem escitalopram venlafaxine mirtazapine diazepam 30 31 zopiclone chlorpromazine procyclidine diazepam quetiapine 32 diltiazem nicorandil isosorbide mononitrateglyceryl trinitrate moxonidine 33 levobunolol latanoprost acetylsalicylic acid bendroflumethiazideomeprazole
34 propranolol naratriptan almotriptan zolmitriptan sumatriptan http://bmjopen.bmj.com/ 35 sotalol warfarin hydrochlorothiazidenicorandil spironolactone 36 37 timolol dorzolamide bimatoprost latanoprost brimonidine 38 atenolol chlortalidone isosorbide mononitrateglyceryl trinitrate nicorandil 39 bisoprolol clopidogrel spironolactone amiodarone nicorandil 40 metoprolol glyceryl trinitrate isosorbide mononitrateacetylsalicylic acid warfarin 41 42 nebivolol olmesartan medoxomilindapamide spironolactone rosuvastatin on September 26, 2021 by guest. Protected copyright. 43 amoxicillin ciprofloxacin carbocisteine nitrofurantoin metronidazole 44 benzathine benzylpenicillinfolic acid bisoprolol lansoprazole omeprazole 45 flucloxacillin metronidazole dihydrocodeine diclofenac codeine 46 47 phenoxymethylpenicillinfolic acid warfarin prednisolone furosemide 48 metformin glibenclamide gliclazide glimepiride pioglitazone 49 ursodeoxycholic acidazathioprine mesalazine prednisolone colecalciferol (vit d3) 50 colestyramine loperamide vitamin b12 mesalazine hydroxocobalamin (vit b12) 51 52 alendronic acid colecalciferol (vit d3)calcium calcium carbonate prednisone 53 etidronic acid prednisolone amitriptyline codeine fluticasone 54 ibandronic acid letrozole colecalciferol (vit d3)calcium calcium carbonate 55 risedronic acid colecalciferol (vit d3)calcium prednisone prednisolone 56 57 ispaghula (psylla seeds)bisacodyl alverine lactulose peppermint oil 58 sterculia alverine mebeverine esomeprazole alginic acid 59 tacrolimus sodium bicarbonatemycophenolic acid alfacalcidol prednisolone 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 calcium colecalciferol (vit d3)ergocalciferol (vit d2)vitamin d alendronic acid 3 calcium carbonate alendronic acid risedronic acid ibandronic acid strontium ranelate 4 brinzolamide bimatoprost latanoprost travoprost brimonidine 5 6 dorzolamide timolol bimatoprost latanoprost travoprost 7 carbamazepine levetiracetam topiramate lamotrigine phenytoin 8 sibutramine metformin furosemide tramadol codeine 9 bisacodyl baclofen lactulose senna glycosides ispaghula (psylla seeds) 10 11 senna glycosides docusate sodium lactulose morphine bisacodyl 12 beclometasone salbutamol salmeterol cromoglicic acid nedocromil 13 betamethasone fusidic acid calcipotriol coal tar epaderm 14 budesonide formoterol terbutaline montelukast theophylline 15 For peer review only 16 clobetasol cetraben dermol diprobase epaderm 17 clobetasone coal tar dermol diprobase epaderm 18 dexamethasone hypromellose celluvisc dorzolamide lacri-lube 19 fluocinolone acetonidecalcipotriol betamethasone fluticasone beclometasone 20 21 fluticasone salbutamol theophylline aminophylline tiotropium bromide 22 hydrocortisone miconazole fludrocortisone clotrimazole testosterone 23 mometasone azithromycin nedocromil diprobase cetraben 24 prednisolone mycophenolic acid azathioprine tacrolimus azithromycin 25 26 prednisone mycophenolic acid tacrolimus azathioprine alendronic acid 27 triamcinolone desloratadine terbutaline formoterol cetirizine 28 celecoxib adalimumab leflunomide methotrexate dextropropoxyphene 29 etoricoxib buprenorphine morphine methotrexate sulfasalazine 30 31 benserazide amantadine carbidopa levodopa pramipexole 32 carbidopa amantadine benserazide levodopa pramipexole 33 olanzapine lithium procyclidine valproic acid lamotrigine
34 quetiapine lithium lamotrigine duloxetine valproic acid http://bmjopen.bmj.com/ 35 amlodipine moxonidine doxazosin tacrolimus nicorandil 36 37 felodipine quinapril fosinopril moxonidine trandolapril 38 lacidipine moxonidine telmisartan doxazosin indapamide 39 lercanidipine moxonidine trandolapril indapamide doxazosin 40 nifedipine captopril tacrolimus mycophenolic acid fluvastatin 41 42 hydroxyzine epaderm diprobase clobetasol betamethasone on September 26, 2021 by guest. Protected copyright. 43 levodopa amantadine benserazide carbidopa pramipexole 44 pramipexole amantadine benserazide carbidopa levodopa 45 ropinirole amantadine benserazide carbidopa levodopa 46 47 multienzymes (lipase,thiamine protease (vit etc.) b1) insulin loperamide gabapentin 48 conjugated estrogensmedroxyprogesteronedextropropoxyphenelevocetirizine zolmitriptan 49 estradiol estrone dydrogesterone norethisterone estriol 50 estriol estrone trimethoprim estradiol clobetasol 51 52 estrogen progesterone testosterone levothyroxine sodiummultivitamins 53 estrone estradiol estriol levothyroxine sodiummultivitamins 54 ethinylestradiol levonorgestrel norgestimate desogestrel norethisterone 55 mestranol progestogen iron gamolenic acid dosulepin 56 57 tibolone escitalopram cromoglicic acid tocopherol (vit e) sumatriptan 58 valproic acid quetiapine lamotrigine levetiracetam olanzapine 59 mefenamic acid tranexamic acid ferrous sulfate norethisterone ibuprofen 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 bezafibrate glyceryl trinitrate isosorbide mononitrategliclazide nicorandil 3 fenofibrate pioglitazone metformin insulin glimepiride 4 cefalexin nitrofurantoin trimethoprim amoxicillin oxybutynin 5 6 ciprofloxacin carbocisteine amoxicillin trimethoprim prednisolone 7 goserelin bicalutamide tamoxifen anastrozole selenium 8 cimetidine alginic acid ranitidine cetirizine naproxen 9 ranitidine sodium bicarbonatealginic acid bisacodyl domperidone 10 11 atorvastatin clopidogrel nicorandil glyceryl trinitrate isosorbide mononitrate 12 fluvastatin ezetimibe isosorbide mononitratebisoprolol prednisolone 13 pravastatin mycophenolic acid tacrolimus amiodarone carvedilol 14 rosuvastatin ezetimibe fenofibrate nebivolol trandolapril 15 For peer review only 16 simvastatin dipyridamole metformin gliclazide pioglitazone 17 phenytoin primidone carbamazepine valproic acid warfarin 18 clotrimazole hydrocortisone betamethasone alginic acid quinine 19 ketoconazole miconazole clobetasone hydrocortisone diprobase 20 21 metronidazole flucloxacillin amoxicillin lymecycline oxytetracycline 22 miconazole hydrocortisone ketoconazole oilatum fusidic acid 23 clonidine naratriptan peppermint oil gabapentin prochlorperazine 24 moxonidine doxazosin lacidipine lercanidipine furosemide 25 26 influenza vaccines salbutamol metformin beclometasone fluticasone 27 insulin metformin multienzymes (lipase,sodium protease bicarbonate etc.) bumetanide 28 ferrous fumarate vitamin b12 prednisolone folic acid colecalciferol (vit d3) 29 ferrous sulfate sodium bicarbonatetranexamic acid cyanocobalamin (vithydroxocobalamin b12) (vit b12) 30 31 iron folic acid methotrexate multivitamins vitamin b12 32 montelukast theophylline aminophylline azithromycin carbocisteine 33 lithium quetiapine chlorpromazine olanzapine risperidone
34 azithromycin tiotropium bromidecarbocisteine montelukast prednisolone http://bmjopen.bmj.com/ 35 erythromycin zinc prednisolone furosemide mometasone 36 37 magnesium zinc tocopherol (vit e) vitamin d vitamin b 38 magnesium carbonatezinc tocopherol (vit e) calcium selenium 39 magnesium citrate zinc tocopherol (vit e) pyridoxine (vit b6) flax oil 40 quinine e45 cream buprenorphine senna glycosides alfacalcidol 41 42 fludrocortisone hydrocortisone levodopa alendronic acid levothyroxine sodium on September 26, 2021 by guest. Protected copyright. 43 minerals multivitamins ginseng food supplement/plant/herbalco-enzyme extractq10/ubiquinone/bio-quinone 44 carbocisteine tiotropium bromideazithromycin aminophylline theophylline 45 multivitamins minerals ginseng iron co-enzyme q10/ubiquinone/bio-quinone 46 47 nitrofurantoin cefalexin trimethoprim amoxicillin baclofen 48 amitriptyline oxycodone morphine fentanyl baclofen 49 clomipramine lithium olanzapine diazepam propranolol 50 dosulepin cinnarizine baclofen temazepam diazepam 51 52 imipramine diazepam lactulose nifedipine glyceryl trinitrate 53 lofepramine olanzapine diazepam lactulose zopiclone 54 nortriptyline pregabalin gabapentin senna glycosides tramadol 55 tenofovir disoproxilaciclovir loperamide zopiclone citalopram 56 57 aciclovir tenofovir disoproxildexamethasone prednisolone hypromellose 58 buprenorphine cyclizine pregabalin morphine gabapentin 59 codeine kaolin paracetamol caffeine heparinoid 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 dextropropoxypheneparacetamol celecoxib meloxicam methotrexate 3 dihydrocodeine paracetamol nitrazepam ketoprofen buprenorphine 4 fentanyl morphine pregabalin gabapentin senna glycosides 5 6 morphine fentanyl cyclizine docusate sodium pregabalin 7 oxycodone pregabalin gabapentin docusate sodium lactulose 8 tramadol pregabalin gabapentin buprenorphine fentanyl 9 glyceryl trinitrate isosorbide mononitratenicorandil acetylsalicylic acid clopidogrel 10 11 isosorbide mononitrateglyceryl trinitrate nicorandil diltiazem acetylsalicylic acid 12 lactulose senna glycosides bisacodyl docusate sodium oxycodone 13 nefopam gabapentin amitriptyline tramadol isosorbide mononitrate 14 nedocromil desloratadine loratadine cetirizine fexofenadine 15 For peer review only 16 fusidic acid betamethasone epaderm diprobase hydrocortisone 17 duloxetine quetiapine lithium lamotrigine pregabalin 18 mirtazapine quetiapine lithium chlorpromazine fentanyl 19 trazodone quetiapine lithium lamotrigine duloxetine 20 21 venlafaxine lithium quetiapine chlorpromazine olanzapine 22 gabapentin oxycodone baclofen morphine fentanyl 23 lamotrigine levetiracetam quetiapine valproic acid topiramate 24 levetiracetam carbamazepine lamotrigine topiramate valproic acid 25 26 pregabalin oxycodone fentanyl buprenorphine morphine 27 topiramate levetiracetam lamotrigine carbamazepine rizatriptan 28 azelastine fexofenadine cetirizine fluticasone loratadine 29 nabumetone methotrexate sulfasalazine hydroxychloroquinefolic acid 30 31 pizotifen rizatriptan sumatriptan naratriptan zolmitriptan 32 hydroxycarbamide acetylsalicylic acid allopurinol warfarin lansoprazole 33 risperidone procyclidine lithium valproic acid venlafaxine
34 baclofen amantadine gabapentin bisacodyl pregabalin http://bmjopen.bmj.com/ 35 gamolenic acid pyridoxine (vit b6) starflower oil potassium citrate kelp 36 37 strontium ranelate colecalciferol (vit d3)calcium calcium carbonate prednisolone 38 alverine sterculia peppermint oil ispaghula (psylla seeds)domperidone 39 aqueous bp oilatum doublebase epaderm dermol 40 cetraben clobetasol clobetasone betamethasone calcipotriol 41 42 dermol doublebase epaderm oilatum aqueous bp on September 26, 2021 by guest. Protected copyright. 43 diprobase oilatum epaderm dermol clobetasone 44 doublebase dermol epaderm oilatum aqueous bp 45 e45 cream oilatum coal tar miconazole hydrocortisone 46 47 epaderm dermol oilatum doublebase hydroxyzine 48 oilatum diprobase dermol epaderm coal tar 49 azathioprine balsalazide prednisolone mesalazine prednisone 50 ezetimibe fluvastatin rosuvastatin clopidogrel nicorandil 51 52 nicorandil glyceryl trinitrate isosorbide mononitrateacetylsalicylic acid clopidogrel 53 meloxicam methotrexate heparinoid dextropropoxyphenesulfasalazine 54 piroxicam dihydrocodeine tramadol methotrexate quinine 55 sildenafil testosterone carbidopa pioglitazone ropinirole 56 57 tadalafil rosiglitazone testosterone insulin metformin 58 vardenafil insulin metformin gliclazide irbesartan 59 orlistat bumetanide pioglitazone pregabalin glimepiride 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 promethazine quinine tramadol glyceryl trinitrate dihydrocodeine 3 chlorpromazine lithium procyclidine zopiclone venlafaxine 4 prochlorperazine betahistine cinnarizine cyclizine buprenorphine 5 6 trifluoperazine procyclidine lithium sertraline citalopram 7 verapamil warfarin carbocisteine moxonidine nicorandil 8 cyclizine caffeine morphine buprenorphine docusate sodium 9 cetirizine nedocromil cromoglicic acid azelastine montelukast 10 11 levocetirizine montelukast cromoglicic acid mometasone fluticasone 12 desloratadine nedocromil cromoglicic acid montelukast triamcinolone 13 fexofenadine cromoglicic acid nedocromil azelastine hydroxyzine 14 loratadine nedocromil cromoglicic acid azelastine mometasone 15 For peer review only 16 terfenadine beclometasone gamolenic acid multivitamins salbutamol 17 acetylsalicylic acid dipyridamole nicorandil glyceryl trinitrate isosorbide mononitrate 18 clopidogrel nicorandil glyceryl trinitrate isosorbide mononitratebisoprolol 19 dipyridamole acetylsalicylic acid simvastatin indapamide perindopril 20 21 potassium bendroflumethiazidehydrochlorothiazidevalsartan nifedipine 22 potassium citrate selenium garlic chondroitin sulfate gamolenic acid 23 amiloride furosemide hydrochlorothiazideamiodarone theophylline 24 spironolactone carvedilol bumetanide furosemide amiodarone 25 26 allopurinol colchicine sodium bicarbonateindometacin bumetanide 27 colchicine allopurinol furosemide warfarin doxazosin 28 heparinoid diprobase alginic acid pregabalin meloxicam 29 desogestrel ethinylestradiol fexofenadine zinc ibuprofen 30 31 dydrogesterone estradiol gamolenic acid mometasone loratadine 32 etonogestrel ibuprofen paracetamol salbutamol NA 33 etynodiol loratadine gamolenic acid beclometasone ibuprofen
34 levonorgestrel ethinylestradiol cromoglicic acid ibuprofen chlorphenamine http://bmjopen.bmj.com/ 35 medroxyprogesteroneconjugated estrogensestradiol vitamin b12 dosulepin 36 37 norethisterone estradiol ethinylestradiol tranexamic acid mefenamic acid 38 norgestimate ethinylestradiol ibuprofen multivitamins paracetamol 39 progesterone estrogen co-enzyme q10/ubiquinone/bio-quinoneselenium tocopherol (vit e) 40 progestogen mestranol iron gamolenic acid dosulepin 41 42 ibuprofen paracetamol pseudoephedrine mefenamic acid almotriptan on September 26, 2021 by guest. Protected copyright. 43 ketoprofen lactulose dihydrocodeine tramadol quinine 44 naproxen nefopam leflunomide sulfasalazine methotrexate 45 domperidone amantadine benserazide levodopa ropinirole 46 47 metoclopramide morphine docusate sodium dexamethasone senna glycosides 48 bimatoprost timolol brinzolamide dorzolamide brimonidine 49 latanoprost timolol brinzolamide dorzolamide brimonidine 50 travoprost brinzolamide dorzolamide brimonidine timolol 51 52 misoprostol diclofenac dextropropoxyphenemethotrexate tramadol 53 esomeprazole domperidone metoclopramide alginic acid heparinoid 54 lansoprazole mycophenolic acid domperidone metoclopramide tacrolimus 55 omeprazole domperidone metoclopramide multienzymes (lipase,heparinoid protease etc.) 56 57 pantoprazole domperidone alginic acid metoclopramide clopidogrel 58 rabeprazole domperidone alginic acid viscotears metoclopramide 59 sodium bicarbonatetacrolimus mycophenolic acid alfacalcidol allopurinol 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 formoterol budesonide terbutaline montelukast theophylline 3 salbutamol aminophylline theophylline tiotropium bromidefluticasone 4 salmeterol salbutamol azithromycin beclometasone theophylline 5 6 terbutaline budesonide formoterol montelukast theophylline 7 raloxifene colecalciferol (vit d3)calcium calcium carbonate hydrocortisone 8 leflunomide methotrexate hydroxychloroquinefolic acid sulfasalazine 9 mycophenolic acid tacrolimus prednisolone prednisone sodium bicarbonate 10 11 almotriptan propranolol amitriptyline paracetamol estradiol 12 naratriptan pizotifen caffeine propranolol clonidine 13 rizatriptan pizotifen topiramate metoclopramide prochlorperazine 14 sumatriptan pizotifen topiramate propranolol caffeine 15 For peer review only 16 zolmitriptan pizotifen topiramate propranolol caffeine 17 citalopram zolpidem quetiapine zopiclone lorazepam 18 escitalopram zolpidem quetiapine zopiclone diazepam 19 fluoxetine chlorpromazine fentanyl buprenorphine docusate sodium 20 21 paroxetine risperidone diazepam olanzapine quetiapine 22 sertraline trifluoperazine risperidone olanzapine zolpidem 23 selenium retinol (vit a) saw palmetto zinc tocopherol (vit e) 24 docusate sodium senna glycosides morphine oxycodone cyclizine 25 26 chlorphenamine aqueous bp fusidic acid diprobase cromoglicic acid 27 bumetanide spironolactone carvedilol amiodarone alfacalcidol 28 chlortalidone atenolol nifedipine enalapril finasteride 29 furosemide amiloride spironolactone carvedilol amiodarone 30 31 indapamide perindopril moxonidine nebivolol lercanidipine 32 glibenclamide metformin rosiglitazone lisinopril allopurinol 33 gliclazide metformin pioglitazone rosiglitazone fenofibrate
34 glimepiride metformin rosiglitazone pioglitazone fenofibrate http://bmjopen.bmj.com/ 35 carbimazole propranolol warfarin levothyroxine sodiumcalcium 36 37 aloe vera ginkgo folium ginseng selenium magnesium 38 chondroitin sulfate glucosamine potassium citrate ginseng ginkgo folium 39 cod liver oil garlic glucosamine retinol (vit a) gamolenic acid 40 co-enzyme q10/ubiquinone/bio-quinonemagnesium citrate selenium lecithin kelp 41 42 flax oil magnesium citrate lecithin starflower oil kelp on September 26, 2021 by guest. Protected copyright. 43 food supplement/plant/herbalmagnesium extract kelp lecithin co-enzyme q10/ubiquinone/bio-quinone 44 garlic kelp lecithin ginseng ginkgo folium 45 ginkgo folium ginseng kelp saw palmetto aloe vera 46 47 ginseng ginkgo folium saw palmetto st john's wort/hypericumaloe vera 48 glucosamine chondroitin sulfate ginkgo folium omega-3-triglyceridescod liver oil 49 kaolin codeine loperamide amitriptyline paracetamol 50 kelp garlic lecithin pyridoxine (vit b6) ginkgo folium 51 52 lecithin kelp flax oil garlic co-enzyme q10/ubiquinone/bio-quinone 53 omega-3-triglyceridesglucosamine ginkgo folium tocopherol (vit e) magnesium citrate 54 peppermint oil butylscopolamine dicycloverine alverine mebeverine 55 saw palmetto selenium ginseng ginkgo folium co-enzyme q10/ubiquinone/bio-quinone 56 57 st john's wort/hypericumginseng pyridoxine (vit b6) ginkgo folium starflower oil 58 starflower oil flax oil pyridoxine (vit b6) tocopherol (vit e) magnesium 59 brimonidine timolol brinzolamide dorzolamide bimatoprost 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 pseudoephedrine acrivastine loratadine fluticasone cetirizine 3 dicycloverine peppermint oil domperidone ispaghula (psylla seeds)alginic acid 4 mebeverine peppermint oil ispaghula (psylla seeds)butylscopolamine loperamide 5 6 coal tar calcipotriol oilatum betamethasone clobetasone 7 procyclidine risperidone chlorpromazine trifluoperazine flupentixol 8 dutasteride alfuzosin tamsulosin sildenafil clopidogrel 9 finasteride tamsulosin alfuzosin terazosin miconazole 10 11 doxycycline carbocisteine amoxicillin lacri-lube tiotropium bromide 12 lymecycline metronidazole cetirizine loratadine tramadol 13 minocycline estradiol ibuprofen paracetamol glucosamine 14 oxytetracycline metronidazole amoxicillin terbutaline lactulose 15 For peer review only 16 tetracycline omeprazole salbutamol ibuprofen acetylsalicylic acid 17 bendroflumethiazidepotassium eprosartan quinapril fosinopril 18 hydrochlorothiazideamiloride losartan telmisartan irbesartan 19 pioglitazone metformin gliclazide glimepiride fenofibrate 20 21 rosiglitazone metformin glimepiride glibenclamide gliclazide 22 flupentixol procyclidine tramadol codeine metformin 23 levothyroxine sodiumfludrocortisone alfacalcidol testosterone hydroxocobalamin (vit b12) 24 trimethoprim nitrofurantoin cefalexin ciprofloxacin amoxicillin 25 26 adalimumab methotrexate folic acid celecoxib sulfasalazine 27 retinol (vit a) vitamin d tocopherol (vit e) selenium ascorbic acid (vit c) 28 cyanocobalamin (vitferrous b12) sulfate azathioprine loperamide folic acid 29 folic acid methotrexate adalimumab leflunomide hydroxychloroquine 30 31 hydroxocobalamin (vitcolestyramine b12) ferrous sulfate loperamide folic acid 32 vitamin b12 colestyramine pyridoxine (vit b6) ferrous fumarate folic acid 33 pyridoxine (vit b6) magnesium citrate kelp starflower oil magnesium
34 thiamine (vit b1) vitamin b spironolactone multienzymes (lipase,folic protease acid etc.) http://bmjopen.bmj.com/ 35 vitamin b thiamine (vit b1) tocopherol (vit e) magnesium retinol (vit a) 36 37 ascorbic acid (vit c) retinol (vit a) zinc tocopherol (vit e) vitamin b 38 calcipotriol betamethasone coal tar fluocinolone acetonideclobetasone 39 alfacalcidol tacrolimus sodium bicarbonatemycophenolic acid bumetanide 40 colecalciferol (vit d3)calcium alendronic acid risedronic acid strontium ranelate 41 42 ergocalciferol (vit d2)calcium alendronic acid risedronic acid ginkgo folium on September 26, 2021 by guest. Protected copyright. 43 vitamin d retinol (vit a) calcium tocopherol (vit e) magnesium 44 tocopherol (vit e) retinol (vit a) magnesium citrate magnesium carbonateascorbic acid (vit c) 45 warfarin amiodarone carvedilol sotalol flecainide 46 47 caffeine cyclizine codeine naratriptan zolmitriptan 48 aminophylline tiotropium bromidecarbocisteine salbutamol ipratropium bromide 49 theophylline tiotropium bromidemontelukast carbocisteine salbutamol 50 zinc magnesium magnesium citrate magnesium carbonateselenium 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 V5 V6 V7 V8 V9 3 atenolol gliclazide glyceryl trinitrate bendroflumethiazidesimvastatin 4 carvedilol nifedipine furosemide bumetanide gliclazide 5 6 felodipine metformin diltiazem furosemide allopurinol 7 hydrochlorothiazideinsulin bendroflumethiazidemetformin gliclazide 8 spironolactone bisoprolol moxonidine nicorandil clopidogrel 9 metformin amlodipine allopurinol bisoprolol atorvastatin 10 11 nicorandil isosorbide mononitratemetoprolol metformin pioglitazone 12 gliclazide nifedipine bendroflumethiazideinsulin metformin 13 sulfasalazine methotrexate codeine hydroxychloroquinefentanyl 14 dihydrocodeine tramadol viscotears codeine amitriptyline 15 For peer review only 16 dosulepin folic acid salmeterol tramadol nifedipine 17 ropinirole baclofen oxybutynin domperidone gabapentin 18 beclometasone mometasone budesonide ranitidine codeine 19 warfarin isosorbide mononitratenicorandil glyceryl trinitrate clopidogrel 20 21 mycophenolic acid tacrolimus alfacalcidol lercanidipine furosemide 22 nicorandil tadalafil glyceryl trinitrate pregabalin sildenafil 23 vardenafil sildenafil goserelin solifenacin tolterodine 24 simvastatin atenolol lisinopril ramipril lansoprazole 25 26 fexofenadine gamolenic acid ibuprofen paracetamol loratadine 27 paracetamol salbutamol omega-3-triglyceridesomeprazole cod liver oil 28 etodolac nabumetone prednisone prednisolone mycophenolic acid 29 colecalciferol (vit d3)calcium bisoprolol codeine amitriptyline 30 31 prednisolone prednisone hydroxocobalamin (vitvitamin b12) b12 loperamide 32 nabumetone adalimumab etodolac indometacin celecoxib 33 gabapentin levothyroxine sodiumalendronic acid insulin carbamazepine
34 nebivolol bumetanide furosemide bendroflumethiazidedoxazosin http://bmjopen.bmj.com/ 35 felodipine diltiazem gliclazide furosemide formoterol 36 37 mycophenolic acid glimepiride vardenafil doxazosin insulin 38 bumetanide bendroflumethiazidediltiazem furosemide spironolactone 39 pioglitazone felodipine doxazosin bendroflumethiazidegliclazide 40 indapamide lercanidipine doxazosin etoricoxib diltiazem 41 42 carvedilol spironolactone indapamide lercanidipine amiodarone on September 26, 2021 by guest. Protected copyright. 43 heparinoid metoclopramide morphine tramadol buprenorphine 44 aqueous bp pantoprazole dicycloverine e45 cream metoclopramide 45 levocetirizine cetirizine oilatum beclometasone montelukast 46 47 lansoprazole simvastatin acetylsalicylic acid amlodipine bendroflumethiazide 48 bumetanide bisoprolol amiloride nicorandil pravastatin 49 acetylsalicylic acid diltiazem irbesartan clopidogrel hydrochlorothiazide 50 carbidopa levodopa docusate sodium senna glycosides domperidone 51 52 levodopa trimethoprim estriol butylscopolamine prochlorperazine 53 levodopa cefalexin ropinirole senna glycosides glimepiride 54 gabapentin warfarin lansoprazole amitriptyline dihydrocodeine 55 azithromycin montelukast salmeterol fluticasone formoterol 56 57 salbutamol fluticasone montelukast formoterol budesonide 58 zopiclone gamolenic acid venlafaxine sertraline calcium 59 quinine ginkgo folium minerals prednisolone doxazosin 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 sulfasalazine nabumetone prednisolone etodolac celecoxib 3 butylscopolamine cyclizine hydroxocobalamin (vitalverine b12) cyanocobalamin (vit b12) 4 amiloride lactulose senna glycosides quinine pizotifen 5 6 dosulepin alginic acid dihydrocodeine mebeverine gabapentin 7 calcium carbonate alendronic acid risedronic acid vitamin d clonidine 8 amitriptyline levothyroxine sodiumgamolenic acid omeprazole fluticasone 9 calcium carbonate vitamin d quinine gamolenic acid codeine 10 11 hydroxychloroquineispaghula (psylla seeds)senna glycosides lactulose gabapentin 12 alginic acid gliclazide colecalciferol (vit d3)furosemide cetirizine 13 hydroxychloroquinehypromellose timolol sulfasalazine prednisolone 14 viscotears e45 cream oilatum hydroxychloroquinecelluvisc 15 For peer review only 16 carbomers hypromellose dexamethasone hydroxychloroquinedoxycycline 17 fluticasone calcium alendronic acid omeprazole codeine 18 calcium beclometasone levothyroxine sodiumparacetamol bendroflumethiazide 19 hydroxychloroquinecromoglicic acid dexamethasone lactulose etodolac 20 21 calcium ramipril levothyroxine sodiumsimvastatin acetylsalicylic acid 22 morphine alverine mebeverine diazepam tramadol 23 valproic acid lamotrigine pregabalin temazepam gabapentin 24 procyclidine mirtazapine zopiclone morphine baclofen 25 26 citalopram omeprazole codeine lansoprazole atorvastatin 27 venlafaxine alginic acid furosemide glyceryl trinitrate tramadol 28 clonazepam trazodone olanzapine mirtazapine senna glycosides 29 tramadol sertraline citalopram dosulepin lactulose 30 31 mirtazapine tenofovir disoproxillorazepam olanzapine risperidone 32 clopidogrel acetylsalicylic acid furosemide tiotropium bromidehydrochlorothiazide 33 simvastatin paracetamol NA NA NA
34 primidone lorazepam carbimazole rizatriptan clonazepam http://bmjopen.bmj.com/ 35 acetylsalicylic acid clopidogrel isosorbide mononitrateindapamide furosemide 36 37 travoprost brinzolamide dexamethasone celluvisc carbomers 38 acetylsalicylic acid clopidogrel moxonidine captopril nifedipine 39 glyceryl trinitrate bumetanide isosorbide mononitratewarfarin furosemide 40 clopidogrel nicorandil flecainide spironolactone furosemide 41 42 nicorandil glyceryl trinitrate furosemide doxazosin clopidogrel on September 26, 2021 by guest. Protected copyright. 43 doxycycline cefalexin trimethoprim tiotropium bromideprednisolone 44 codeine calcium colecalciferol (vit d3)simvastatin multivitamins 45 paracetamol metformin lansoprazole amlodipine omeprazole 46 47 ferrous sulfate dihydrocodeine insulin colecalciferol (vit d3)allopurinol 48 rosiglitazone insulin fenofibrate vardenafil sildenafil 49 calcium carbonate calcium alendronic acid furosemide insulin 50 folic acid codeine colecalciferol (vit d3)fluoxetine omeprazole 51 52 prednisolone mycophenolic acid azathioprine azithromycin ergocalciferol (vit d2) 53 lansoprazole salbutamol omeprazole atorvastatin paracetamol 54 anastrozole prednisolone methotrexate tiotropium bromidevitamin d 55 calcium carbonate mycophenolic acid azathioprine leflunomide ergocalciferol (vit d2) 56 57 senna glycosides carmellose carbomers mebeverine heparinoid 58 lactulose fluoxetine fluticasone codeine citalopram 59 prednisone azathioprine clobetasone clobetasol diprobase 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 strontium ranelate risedronic acid magnesium carbonateibandronic acid magnesium 3 prednisone alfacalcidol mycophenolic acid prednisolone azathioprine 4 timolol prednisolone tamsulosin gliclazide doxazosin 5 6 brimonidine dexamethasone carbomers hypromellose viscotears 7 valproic acid risperidone baclofen olanzapine quetiapine 8 lisinopril atorvastatin diclofenac lansoprazole omeprazole 9 pregabalin quinine tramadol gabapentin dihydrocodeine 10 11 baclofen fentanyl oxycodone cyclizine nitrofurantoin 12 ipratropium bromideloratadine azelastine aminophylline cetirizine 13 oilatum diprobase dermol clobetasone cetraben 14 carbocisteine aminophylline tiotropium bromideipratropium bromideazithromycin 15 For peer review only 16 doublebase aqueous bp hydroxyzine fusidic acid tacrolimus 17 oilatum ketoconazole cetraben doublebase aqueous bp 18 carbomers aciclovir metoclopramide domperidone timolol 19 salbutamol multivitamins simvastatin omeprazole paracetamol 20 21 montelukast carbocisteine azithromycin ipratropium bromideazelastine 22 fusidic acid oilatum ketoconazole epaderm diprobase 23 doublebase montelukast epaderm oilatum levocetirizine 24 alendronic acid leflunomide adalimumab risedronic acid hydroxychloroquine 25 26 risedronic acid hydroxychloroquinecalcium carbonate montelukast colecalciferol (vit d3) 27 loratadine budesonide ispaghula (psylla seeds)salmeterol hydrocortisone 28 buprenorphine hydroxychloroquinesulfasalazine folic acid tramadol 29 hydroxychloroquinetramadol montelukast pregabalin orlistat 30 31 ropinirole domperidone lactulose amitriptyline omeprazole 32 ropinirole clonazepam domperidone oxybutynin sildenafil 33 venlafaxine lofepramine clomipramine mirtazapine zopiclone
34 venlafaxine mirtazapine diazepam trazodone zopiclone http://bmjopen.bmj.com/ 35 bendroflumethiazidefosinopril perindopril indapamide isosorbide mononitrate 36 37 bendroflumethiazideeprosartan indapamide doxazosin potassium 38 valsartan bendroflumethiazideallopurinol gliclazide candesartan 39 olmesartan medoxomiltelmisartan irbesartan valsartan bendroflumethiazide 40 trandolapril moxonidine imipramine doxazosin alfacalcidol 41 42 fexofenadine hydrocortisone prednisolone cetirizine quinine on September 26, 2021 by guest. Protected copyright. 43 ropinirole fludrocortisone clonazepam domperidone lactulose 44 clonazepam domperidone lactulose quinine amitriptyline 45 domperidone sildenafil tolterodine lactulose isosorbide mononitrate 46 47 clopidogrel vitamin b alginic acid ferrous sulfate omeprazole 48 butylscopolamine rizatriptan naratriptan duloxetine etodolac 49 medroxyprogesteronenedocromil potassium citrate nitrofurantoin almotriptan 50 solifenacin peppermint oil hypromellose zolmitriptan viscotears 51 52 ibuprofen paracetamol salbutamol omega-3-triglyceridesbeclometasone 53 paracetamol omeprazole salbutamol omega-3-triglyceridesbendroflumethiazide 54 iron cromoglicic acid loratadine chlorphenamine ibuprofen 55 food supplement/plant/herbalvitamin d extract ascorbic acid (vit c) amitriptyline omega-3-triglycerides 56 57 magnesium pregabalin zopiclone solifenacin meloxicam 58 risperidone primidone topiramate procyclidine clonazepam 59 propranolol loratadine gamolenic acid paracetamol codeine 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 ezetimibe metformin pioglitazone insulin rosiglitazone 3 gliclazide rosuvastatin ezetimibe nicorandil irbesartan 4 solifenacin tolterodine prednisolone alginic acid furosemide 5 6 gabapentin lactulose tramadol fluticasone furosemide 7 tamsulosin colecalciferol (vit d3)calcium alendronic acid diclofenac 8 dihydrocodeine amitriptyline glyceryl trinitrate mebeverine codeine 9 cimetidine fentanyl multienzymes (lipase,mycophenolic protease etc.) acid morphine 10 11 sodium bicarbonaterosiglitazone glimepiride ezetimibe carvedilol 12 nifedipine warfarin diltiazem doxazosin acetylsalicylic acid 13 ezetimibe fosinopril isosorbide mononitratewarfarin glimepiride 14 olmesartan medoxomilpioglitazone nicorandil fosinopril eprosartan 15 For peer review only 16 isosorbide mononitrateacetylsalicylic acid glyceryl trinitrate glibenclamide nicorandil 17 folic acid colecalciferol (vit d3)alendronic acid calcium codeine 18 ispaghula (psylla seeds)lactulose tramadol prednisolone dihydrocodeine 19 betamethasone calcipotriol mometasone alginic acid clopidogrel 20 21 betamethasone prednisolone mebeverine glyceryl trinitrate cetirizine 22 e45 cream coal tar clobetasone diprobase calcipotriol 23 ispaghula (psylla seeds)domperidone pregabalin celecoxib quinine 24 irbesartan pioglitazone spironolactone diltiazem indapamide 25 26 acetylsalicylic acid calcium atenolol paracetamol atorvastatin 27 vardenafil fenofibrate glimepiride alfacalcidol furosemide 28 insulin calcium tramadol metformin lansoprazole 29 leflunomide alfacalcidol adalimumab mycophenolic acid vitamin b12 30 31 magnesium zinc ascorbic acid (vit c) tranexamic acid alfacalcidol 32 salbutamol formoterol fluticasone budesonide tiotropium bromide 33 procyclidine trifluoperazine clomipramine venlafaxine lamotrigine
34 salmeterol ipratropium bromidefluticasone salbutamol formoterol http://bmjopen.bmj.com/ 35 fluticasone norethisterone cetirizine estradiol ranitidine 36 37 pyridoxine (vit b6) lecithin co-enzyme q10/ubiquinone/bio-quinonecalcium selenium 38 co-enzyme q10/ubiquinone/bio-quinonevitamin d ginkgo folium vitamin b ascorbic acid (vit c) 39 co-enzyme q10/ubiquinone/bio-quinoneselenium vitamin b ascorbic acid (vit c) vitamin d 40 oxycodone heparinoid docusate sodium bisacodyl morphine 41 42 colecalciferol (vit d3)calcium estradiol fluticasone codeine on September 26, 2021 by guest. Protected copyright. 43 st john's wort/hypericumkelp ginkgo folium omega-3-triglyceridesaloe vera 44 ciprofloxacin montelukast amoxicillin salbutamol ipratropium bromide 45 omega-3-triglyceridesmagnesium citrate ginkgo folium lecithin st john's wort/hypericum 46 47 oxybutynin senna glycosides tolterodine solifenacin lactulose 48 nefopam buprenorphine gabapentin pregabalin tramadol 49 colecalciferol (vit d3)ranitidine calcium lansoprazole codeine 50 zolpidem naratriptan zopiclone senna glycosides butylscopolamine 51 52 insulin dihydrocodeine tramadol doxazosin metformin 53 propranolol ferrous sulfate codeine estradiol tramadol 54 lactulose mebeverine quinine dihydrocodeine propranolol 55 atorvastatin multivitamins salbutamol omeprazole ibuprofen 56 57 loperamide dihydrocodeine tramadol formoterol norethisterone 58 etoricoxib prochlorperazine tramadol amitriptyline lactulose 59 piroxicam e45 cream etodolac nefopam ketoconazole 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 misoprostol folic acid zopiclone amitriptyline diclofenac 3 nabumetone fentanyl etodolac adalimumab senna glycosides 4 mirtazapine lactulose amitriptyline tramadol prednisolone 5 6 senna glycosides gabapentin buprenorphine metoclopramide lactulose 7 diazepam senna glycosides amitriptyline glyceryl trinitrate clopidogrel 8 nabumetone nefopam amitriptyline morphine senna glycosides 9 diltiazem bisoprolol metoprolol bumetanide carvedilol 10 11 clopidogrel bumetanide carvedilol furosemide bisoprolol 12 morphine fentanyl amantadine ispaghula (psylla seeds)baclofen 13 furosemide naproxen clopidogrel folic acid codeine 14 mometasone fluticasone beclometasone budesonide salbutamol 15 For peer review only 16 miconazole clobetasone clobetasol montelukast chlorphenamine 17 trazodone zopiclone diazepam mirtazapine valproic acid 18 olanzapine lorazepam diazepam zopiclone venlafaxine 19 venlafaxine temazepam zopiclone senna glycosides sertraline 20 21 risperidone mirtazapine lorazepam zolpidem trazodone 22 buprenorphine nortriptyline amantadine nefopam docusate sodium 23 lithium olanzapine duloxetine carbamazepine clonazepam 24 pregabalin gabapentin folic acid alendronic acid warfarin 25 26 baclofen nortriptyline clonazepam cyclizine tramadol 27 valproic acid sumatriptan zolmitriptan gabapentin propranolol 28 mometasone beclometasone salbutamol lansoprazole omeprazole 29 tramadol dihydrocodeine prednisolone ferrous sulfate amitriptyline 30 31 cyclizine prochlorperazine alverine caffeine propranolol 32 ranitidine amlodipine atenolol omeprazole simvastatin 33 diazepam sertraline carbamazepine zopiclone mirtazapine
34 oxybutynin clonazepam nitrofurantoin docusate sodium senna glycosides http://bmjopen.bmj.com/ 35 tocopherol (vit e) st john's wort/hypericummagnesium carbonatemagnesium cod liver oil 36 37 esomeprazole vitamin d folic acid ranitidine fluticasone 38 butylscopolamine loperamide esomeprazole pizotifen lactulose 39 coal tar clobetasone diprobase clobetasol betamethasone 40 hydrocortisone mometasone prednisolone alginic acid tramadol 41 42 clobetasone diprobase clobetasol betamethasone hydrocortisone on September 26, 2021 by guest. Protected copyright. 43 clobetasol coal tar fusidic acid betamethasone aqueous bp 44 clobetasone clobetasol diprobase betamethasone hydrocortisone 45 clobetasone betamethasone diprobase hypromellose calcipotriol 46 47 diprobase fusidic acid aqueous bp clobetasone betamethasone 48 doublebase aqueous bp e45 cream clobetasone betamethasone 49 tacrolimus alfacalcidol ursodeoxycholic acidrisedronic acid hydroxychloroquine 50 fenofibrate glyceryl trinitrate isosorbide mononitratepravastatin atorvastatin 51 52 diltiazem bumetanide bisoprolol carvedilol furosemide 53 buprenorphine hydroxychloroquinefolic acid tramadol dihydrocodeine 54 amitriptyline valsartan codeine alginic acid glyceryl trinitrate 55 e45 cream levodopa rosiglitazone metformin gliclazide 56 57 pioglitazone gliclazide indapamide alfuzosin sildenafil 58 tamsulosin perindopril losartan atorvastatin amlodipine 59 rosiglitazone metformin furosemide etoricoxib insulin 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 29 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 citalopram ranitidine lansoprazole amitriptyline codeine 3 mirtazapine fluoxetine propranolol amitriptyline citalopram 4 naratriptan morphine diazepam rizatriptan pizotifen 5 6 simvastatin metformin amlodipine atenolol atorvastatin 7 flecainide furosemide glyceryl trinitrate isosorbide mononitratetiotropium bromide 8 pizotifen domperidone senna glycosides pregabalin prochlorperazine 9 oilatum dermol hydroxyzine diprobase theophylline 10 11 formoterol esomeprazole salbutamol budesonide quinine 12 mometasone fluticasone alverine hypromellose formoterol 13 montelukast dermol doublebase mometasone oilatum 14 triamcinolone montelukast dermol pseudoephedrine beclometasone 15 For peer review only 16 ascorbic acid (vit c) fluticasone minerals estradiol ibuprofen 17 hydroxycarbamide bisoprolol metoprolol diltiazem glimepiride 18 carvedilol atorvastatin oxycodone diltiazem ezetimibe 19 nicorandil baclofen glimepiride isosorbide mononitratethiamine (vit b1) 20 21 felodipine enalapril doxazosin warfarin atenolol 22 zinc omega-3-triglyceridesglucosamine multivitamins ascorbic acid (vit c) 23 warfarin temazepam verapamil ipratropium bromidebetahistine 24 thiamine (vit b1) warfarin bisoprolol isosorbide mononitratemoxonidine 25 26 mycophenolic acid hydroxycarbamide alfacalcidol moxonidine carvedilol 27 bisoprolol naproxen glyceryl trinitrate clopidogrel ezetimibe 28 ispaghula (psylla seeds)tramadol lactulose quinine esomeprazole 29 citalopram propranolol mebeverine fluoxetine cetirizine 30 31 ibuprofen citalopram formoterol vitamin d minerals 32 NA NA NA NA NA 33 salbutamol paracetamol multivitamins omega-3-triglyceridescodeine
34 escitalopram caffeine iron estradiol gamolenic acid http://bmjopen.bmj.com/ 35 mesalazine fexofenadine fluoxetine meloxicam sumatriptan 36 37 rizatriptan erythromycin aciclovir peppermint oil caffeine 38 NA NA NA NA NA 39 ginkgo folium magnesium zinc vitamin b minerals 40 food supplement/plant/herbalvitamin d extract ascorbic acid (vit c) amitriptyline omega-3-triglycerides 41 42 rizatriptan sumatriptan tranexamic acid naratriptan zolmitriptan on September 26, 2021 by guest. Protected copyright. 43 mometasone amitriptyline glyceryl trinitrate codeine folic acid 44 adalimumab colchicine dihydrocodeine tramadol morphine 45 carbidopa esomeprazole cyclizine docusate sodium morphine 46 47 rizatriptan esomeprazole loperamide alginic acid pantoprazole 48 celluvisc viscotears doxazosin prednisolone candesartan 49 levobunolol celluvisc carbomers viscotears e45 cream 50 diltiazem clopidogrel glyceryl trinitrate doxazosin felodipine 51 52 baclofen dihydrocodeine quinine codeine hydroxychloroquine 53 strontium ranelate alverine sterculia morphine butylscopolamine 54 nefopam adalimumab morphine docusate sodium prednisone 55 alginic acid buprenorphine morphine nabumetone nicorandil 56 57 alverine nicorandil celecoxib hydroxychloroquinepeppermint oil 58 senna glycosides ipratropium bromideoxybutynin betahistine montelukast 59 ferrous sulfate prednisolone irbesartan doxazosin furosemide 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 30 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 carbocisteine aminophylline tiotropium bromideazithromycin ipratropium bromide 3 ipratropium bromidemontelukast carbocisteine salmeterol beclometasone 4 montelukast ipratropium bromideaminophylline tiotropium bromidecarbocisteine 5 6 aminophylline tiotropium bromidecarbocisteine salmeterol amoxicillin 7 alginic acid prednisolone alendronic acid quinine vitamin d 8 prednisolone celecoxib risedronic acid ferrous sulfate naproxen 9 alfacalcidol hydroxychloroquinerisedronic acid calcium carbonate alendronic acid 10 11 diclofenac ibuprofen codeine omeprazole salbutamol 12 prochlorperazine domperidone dosulepin amitriptyline lactulose 13 propranolol valproic acid amitriptyline sumatriptan codeine 14 metoclopramide prochlorperazine amitriptyline domperidone zolmitriptan 15 For peer review only 16 domperidone amitriptyline prochlorperazine estriol sumatriptan 17 olanzapine chlorpromazine diazepam risperidone thiamine (vit b1) 18 thiamine (vit b1) propranolol pregabalin mirtazapine etoricoxib 19 olanzapine diazepam nitrazepam risperidone oxycodone 20 21 lithium zopiclone temazepam trazodone propranolol 22 trazodone quetiapine diazepam temazepam domperidone 23 magnesium carbonateco-enzyme q10/ubiquinone/bio-quinonemagnesium citrate kelp magnesium 24 lactulose baclofen alfacalcidol metoclopramide butylscopolamine 25 26 clobetasol clobetasone montelukast betamethasone prochlorperazine 27 warfarin isosorbide mononitratenicorandil bisoprolol glyceryl trinitrate 28 gliclazide metformin simvastatin doxazosin felodipine 29 warfarin isosorbide mononitratesodium bicarbonatemoxonidine nicorandil 30 31 dipyridamole eprosartan doxazosin telmisartan olmesartan medoxomil 32 simvastatin acetylsalicylic acid ramipril atorvastatin amlodipine 33 sildenafil vardenafil simvastatin bezafibrate acetylsalicylic acid
34 insulin orlistat atorvastatin acetylsalicylic acid irbesartan http://bmjopen.bmj.com/ 35 furosemide colecalciferol (vit d3)alendronic acid bisoprolol omeprazole 36 37 co-enzyme q10/ubiquinone/bio-quinonetocopherol (vit e) peppermint oil garlic zinc 38 omega-3-triglyceridesco-enzyme q10/ubiquinone/bio-quinonemagnesium saw palmetto selenium 39 ascorbic acid (vit c) multivitamins tocopherol (vit e) ginseng kelp 40 magnesium carbonatemagnesium tocopherol (vit e) saw palmetto ginkgo folium 41 42 tocopherol (vit e) co-enzyme q10/ubiquinone/bio-quinoneginkgo folium magnesium ginseng on September 26, 2021 by guest. Protected copyright. 43 ginseng saw palmetto ginkgo folium pyridoxine (vit b6) flax oil 44 potassium citrate cod liver oil selenium saw palmetto aloe vera 45 selenium co-enzyme q10/ubiquinone/bio-quinonelecithin flax oil magnesium carbonate 46 47 selenium co-enzyme q10/ubiquinone/bio-quinonetocopherol (vit e) garlic food supplement/plant/herbal extract 48 ginseng selenium saw palmetto kelp co-enzyme q10/ubiquinone/bio-quinone 49 lansoprazole diclofenac beclometasone omeprazole salbutamol 50 zinc co-enzyme q10/ubiquinone/bio-quinoneflax oil selenium magnesium 51 52 magnesium zinc tocopherol (vit e) ginkgo folium vitamin b 53 lecithin selenium co-enzyme q10/ubiquinone/bio-quinonegarlic aloe vera 54 ispaghula (psylla seeds)aloe vera docusate sodium senna glycosides domperidone 55 zinc garlic food supplement/plant/herbalalfuzosin extract tocopherol (vit e) 56 57 flax oil co-enzyme q10/ubiquinone/bio-quinonegamolenic acid zinc food supplement/plant/herbal extract 58 gamolenic acid ginseng st john's wort/hypericumco-enzyme q10/ubiquinone/bio-quinoneginkgo folium 59 latanoprost travoprost prednisolone insulin fluticasone 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 31 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 paracetamol beclometasone ibuprofen minerals salbutamol 3 loperamide tramadol dihydrocodeine amitriptyline glyceryl trinitrate 4 trospium domperidone sterculia docusate sodium lactulose 5 6 aqueous bp diprobase e45 cream miconazole clobetasol 7 olanzapine lithium valproic acid zopiclone diazepam 8 doxazosin ezetimibe warfarin bisoprolol irbesartan 9 doxazosin clopidogrel glyceryl trinitrate nicorandil isosorbide mononitrate 10 11 prednisolone zopiclone mometasone fluticasone furosemide 12 budesonide losartan candesartan colecalciferol (vit d3)diclofenac 13 salbutamol atenolol multivitamins levothyroxine sodiumacetylsalicylic acid 14 finasteride norethisterone sumatriptan felodipine ispaghula (psylla seeds) 15 For peer review only 16 paracetamol simvastatin NA NA NA 17 moxonidine enalapril lercanidipine doxazosin trandolapril 18 sotalol valsartan bisoprolol enalapril potassium 19 moxonidine sildenafil orlistat acetylsalicylic acid simvastatin 20 21 tadalafil sildenafil atorvastatin hydroxocobalamin (vitacetylsalicylic b12) acid 22 simvastatin omeprazole ramipril paracetamol levothyroxine sodium 23 amiodarone lithium cyanocobalamin (vittears b12) naturale hydrocortisone 24 estriol solifenacin lactulose gabapentin mebeverine 25 26 prednisolone ferrous sulfate alendronic acid dihydrocodeine colecalciferol (vit d3) 27 zinc vitamin b cod liver oil omega-3-triglyceridesginkgo folium 28 iron mesalazine calcium carbonate irbesartan quinine 29 sulfasalazine iron nabumetone prednisolone etodolac 30 31 rosiglitazone azathioprine mesalazine lacri-lube sulfasalazine 32 iron ferrous sulfate azathioprine loperamide mesalazine 33 tocopherol (vit e) vitamin b12 gamolenic acid st john's wort/hypericumzinc
34 tiotropium bromidediazepam furosemide tocopherol (vit e) zopiclone http://bmjopen.bmj.com/ 35 magnesium citrate ascorbic acid (vit c) zinc lecithin magnesium carbonate 36 37 magnesium citrate magnesium magnesium carbonatelecithin kelp 38 oilatum cetraben ketoconazole diprobase epaderm 39 azathioprine docusate sodium prednisolone calcium carbonate senna glycosides 40 ibandronic acid prednisolone prednisone letrozole raloxifene 41 42 ferrous sulfate folic acid prednisolone ezetimibe irbesartan on September 26, 2021 by guest. Protected copyright. 43 magnesium carbonatemagnesium citrate kelp zinc ascorbic acid (vit c) 44 selenium vitamin d magnesium vitamin b zinc 45 spironolactone bumetanide furosemide verapamil bisoprolol 46 47 sumatriptan paracetamol prochlorperazine pizotifen flax oil 48 montelukast fluticasone formoterol salmeterol budesonide 49 ipratropium bromidefluticasone formoterol salmeterol budesonide 50 ascorbic acid (vit c) kelp retinol (vit a) tocopherol (vit e) lecithin 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 32 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 V10 3 amlodipine 4 mycophenolic acid 5 6 amlodipine 7 doxazosin 8 doxazosin 9 acetylsalicylic acid 10 11 acetylsalicylic acid 12 felodipine 13 morphine 14 gabapentin 15 For peer review only 16 codeine 17 lactulose 18 paracetamol 19 ramipril 20 21 trandolapril 22 clopidogrel 23 amiodarone 24 codeine 25 26 fluoxetine 27 ibuprofen 28 celluvisc 29 amlodipine 30 31 cyanocobalamin (vit b12) 32 meloxicam 33 calcium carbonate
34 lercanidipine http://bmjopen.bmj.com/ 35 nifedipine 36 37 pioglitazone 38 amiodarone 39 amlodipine 40 rosiglitazone 41 42 bumetanide on September 26, 2021 by guest. Protected copyright. 43 docusate sodium 44 oilatum 45 viscotears 46 47 omeprazole 48 isosorbide mononitrate 49 esomeprazole 50 gabapentin 51 52 lactulose 53 quinine 54 glyceryl trinitrate 55 bumetanide 56 57 salmeterol 58 colecalciferol (vit d3) 59 diclofenac 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 33 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 prednisone 3 metoclopramide 4 orlistat 5 6 glyceryl trinitrate 7 venlafaxine 8 metformin 9 levothyroxine sodium 10 11 timolol 12 lansoprazole 13 methotrexate 14 cinnarizine 15 For peer review only 16 senna glycosides 17 salbutamol 18 omeprazole 19 bimatoprost 20 21 salbutamol 22 ispaghula (psylla seeds) 23 venlafaxine 24 risperidone 25 26 paracetamol 27 amitriptyline 28 lithium 29 alginic acid 30 31 duloxetine 32 theophylline 33 NA
34 chlorpromazine http://bmjopen.bmj.com/ 35 glyceryl trinitrate 36 37 viscotears 38 atorvastatin 39 acetylsalicylic acid 40 atorvastatin 41 42 candesartan on September 26, 2021 by guest. Protected copyright. 43 montelukast 44 metformin 45 acetylsalicylic acid 46 47 tramadol 48 simvastatin 49 omeprazole 50 calcium 51 52 letrozole 53 atenolol 54 lactulose 55 theophylline 56 57 docusate sodium 58 cetirizine 59 nifedipine 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 34 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 magnesium citrate 3 raloxifene 4 budesonide 5 6 prednisolone 7 clonazepam 8 paracetamol 9 amitriptyline 10 11 alfacalcidol 12 desloratadine 13 ketoconazole 14 salbutamol 15 For peer review only 16 coal tar 17 calcipotriol 18 viscotears 19 acetylsalicylic acid 20 21 nedocromil 22 e45 cream 23 cromoglicic acid 24 methotrexate 25 26 methotrexate 27 fluticasone 28 pregabalin 29 folic acid 30 31 codeine 32 lactulose 33 diazepam
34 temazepam http://bmjopen.bmj.com/ 35 enalapril 36 37 olmesartan medoxomil 38 furosemide 39 perindopril 40 enalapril 41 42 lactulose on September 26, 2021 by guest. Protected copyright. 43 sildenafil 44 propranolol 45 quinine 46 47 lansoprazole 48 peppermint oil 49 fludrocortisone 50 meloxicam 51 52 glucosamine 53 ibuprofen 54 fluoxetine 55 mometasone 56 57 ispaghula (psylla seeds) 58 phenytoin 59 dihydrocodeine 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 35 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 allopurinol 3 rosiglitazone 4 lactulose 5 6 colecalciferol (vit d3) 7 codeine 8 losartan 9 butylscopolamine 10 11 acetylsalicylic acid 12 glyceryl trinitrate 13 glyceryl trinitrate 14 rosiglitazone 15 For peer review only 16 rosiglitazone 17 lansoprazole 18 methotrexate 19 furosemide 20 21 omeprazole 22 betamethasone 23 orlistat 24 verapamil 25 26 ramipril 27 spironolactone 28 amitriptyline 29 bumetanide 30 31 vitamin d 32 ipratropium bromide 33 mirtazapine
34 mometasone http://bmjopen.bmj.com/ 35 beclometasone 36 37 kelp 38 omega-3-triglycerides 39 calcium 40 clotrimazole 41 42 salbutamol on September 26, 2021 by guest. Protected copyright. 43 starflower oil 44 fluticasone 45 flax oil 46 47 gabapentin 48 docusate sodium 49 garlic 50 pregabalin 51 52 omeprazole 53 lansoprazole 54 alginic acid 55 acetylsalicylic acid 56 57 folic acid 58 celecoxib 59 celecoxib 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 36 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 esomeprazole 3 piroxicam 4 alginic acid 5 6 domperidone 7 isosorbide mononitrate 8 heparinoid 9 furosemide 10 11 metoprolol 12 benserazide 13 glyceryl trinitrate 14 colecalciferol (vit d3) 15 For peer review only 16 calcipotriol 17 senna glycosides 18 morphine 19 gabapentin 20 21 procyclidine 22 tramadol 23 trazodone 24 citalopram 25 26 heparinoid 27 amitriptyline 28 codeine 29 codeine 30 31 domperidone 32 ramipril 33 paroxetine
34 tolterodine http://bmjopen.bmj.com/ 35 aloe vera 36 37 codeine 38 alginic acid 39 hydrocortisone 40 insulin 41 42 calcipotriol on September 26, 2021 by guest. Protected copyright. 43 ketoconazole 44 calcipotriol 45 senna glycosides 46 47 clobetasol 48 hydrocortisone 49 alendronic acid 50 bezafibrate 51 52 morphine 53 codeine 54 folic acid 55 insulin 56 57 tamsulosin 58 acetylsalicylic acid 59 montelukast 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 37 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 omeprazole 3 ranitidine 4 caffeine 5 6 levothyroxine sodium 7 amiloride 8 gabapentin 9 triamcinolone 10 11 betamethasone 12 prochlorperazine 13 theophylline 14 oilatum 15 For peer review only 16 cod liver oil 17 rosiglitazone 18 metoprolol 19 atorvastatin 20 21 candesartan 22 calcium 23 senna glycosides 24 nicorandil 25 26 glibenclamide 27 tramadol 28 codeine 29 vitamin b 30 31 beclometasone 32 NA 33 levothyroxine sodium
34 fluoxetine http://bmjopen.bmj.com/ 35 loperamide 36 37 lofepramine 38 NA 39 chondroitin sulfate 40 mometasone 41 42 caffeine on September 26, 2021 by guest. Protected copyright. 43 gliclazide 44 nitrofurantoin 45 butylscopolamine 46 47 lactulose 48 allopurinol 49 hypromellose 50 dihydrocodeine 51 52 pregabalin 53 cyclizine 54 nicorandil 55 butylscopolamine 56 57 isosorbide mononitrate 58 ispaghula (psylla seeds) 59 insulin 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 38 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 salbutamol 3 azithromycin 4 fluticasone 5 6 triamcinolone 7 folic acid 8 alendronic acid 9 pravastatin 10 11 glucosamine 12 paracetamol 13 conjugated estrogens 14 rizatriptan 15 For peer review only 16 zopiclone 17 promethazine 18 valproic acid 19 trazodone 20 21 hydroxocobalamin (vit b12) 22 pregabalin 23 ginkgo folium 24 domperidone 25 26 hydrocortisone 27 ipratropium bromide 28 pravastatin 29 alfacalcidol 30 31 valsartan 32 omeprazole 33 trandolapril
34 telmisartan http://bmjopen.bmj.com/ 35 codeine 36 37 omega-3-triglycerides 38 magnesium carbonate 39 zinc 40 flax oil 41 42 selenium on September 26, 2021 by guest. Protected copyright. 43 minerals 44 omega-3-triglycerides 45 glucosamine 46 47 flax oil 48 garlic 49 lisinopril 50 food supplement/plant/herbal extract 51 52 selenium 53 magnesium carbonate 54 clonidine 55 glucosamine 56 57 minerals 58 selenium 59 metformin 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 39 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 multivitamins 3 codeine 4 alginic acid 5 6 hydrocortisone 7 venlafaxine 8 furosemide 9 spironolactone 10 11 calcium carbonate 12 calcium 13 omeprazole 14 estradiol 15 For peer review only 16 NA 17 losartan 18 diltiazem 19 rosuvastatin 20 21 moxonidine 22 salbutamol 23 chlorpromazine 24 prednisolone 25 26 tramadol 27 garlic 28 colecalciferol (vit d3) 29 hydroxocobalamin (vit b12) 30 31 hydroxychloroquine 32 magnesium 33 food supplement/plant/herbal extract
34 mirtazapine http://bmjopen.bmj.com/ 35 selenium 36 37 selenium 38 miconazole 39 furosemide 40 anastrozole 41 42 codeine on September 26, 2021 by guest. Protected copyright. 43 vitamin b 44 pyridoxine (vit b6) 45 colchicine 46 47 peppermint oil 48 prednisolone 49 prednisolone 50 vitamin b 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 40 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 V1 V2 3 captopril disease_hypertension disease_heart attack/myocardial infarction 4 enalapril disease_hypertension disease_diabetic eye disease 5 6 fosinopril disease_hypertension disease_diabetes 7 lisinopril disease_hypertension disease_diabetes 8 perindopril disease_hypertension disease_cardiomyopathy 9 quinapril disease_hypertension disease_type 2 diabetes 10 11 ramipril disease_hypertension disease_heart attack/myocardial infarction 12 trandolapril disease_hypertension disease_type 2 diabetes 13 diclofenac disease_osteoarthritis disease_rheumatoid arthritis 14 etodolac disease_psoriatic arthropathy disease_rheumatoid arthritis 15 For peer review only 16 indometacin disease_gout disease_ankylosing spondylitis 17 amantadine disease_chronic/degenerative neurologicaldisease_depression problem 18 acrivastine disease_hayfever/allergic rhinitisdisease_allergy/hypersensitivity/anaphylaxis 19 carvedilol disease_heart failure/pulmonarydisease_cardiomyopathy odema 20 21 doxazosin disease_hypertension disease_renal failure requiring dialysis 22 alfuzosin disease_prostate problem (not cancer)disease_bladder problem (not cancer) 23 tamsulosin disease_prostate problem (not cancer)disease_urinary frequency / incontinence 24 terazosin disease_prostate problem (not cancer)disease_angina 25 26 tranexamic acid disease_dysmenorrhoea / dysmenorrheadisease_menorrhagia (unknown cause) 27 diphenhydramine disease_depression disease_asthma 28 hydroxychloroquine disease_systemic lupus erythematosis/sledisease_sjogren's syndrome/sicca syndrome 29 balsalazide disease_inflammatory bowel diseasedisease_colitis/not crohns or ulcerative colitis 30 31 mesalazine disease_colitis/not crohns or ulcerativedisease_inflammatory colitis bowel disease 32 sulfasalazine disease_rheumatoid arthritis disease_psoriatic arthropathy 33 testosterone disease_pituitary adenoma/tumourdisease_hypopituitarism
34 candesartan disease_hypertension disease_heart failure/pulmonary odema http://bmjopen.bmj.com/ 35 eprosartan disease_hypertension disease_type 2 diabetes 36 37 irbesartan disease_hypertension disease_renal failure requiring dialysis 38 losartan disease_hypertension disease_scleroderma/systemic sclerosis 39 olmesartan medoxomil disease_hypertension disease_essential hypertension 40 telmisartan disease_hypertension disease_high cholesterol 41 42 valsartan disease_hypertension disease_renal failure not requiring dialysis on September 26, 2021 by guest. Protected copyright. 43 paracetamol disease_fibromyalgia disease_cervical spondylosis 44 alginic acid disease_gastro-oesophageal refluxdisease_dyspepsia (gord) / gastric reflux / indigestion 45 cromoglicic acid disease_hayfever/allergic rhinitisdisease_dry eyes 46 47 bicalutamide disease_angina disease_high cholesterol 48 amiodarone disease_cardiomyopathy disease_heart arrhythmia 49 flecainide disease_heart arrhythmia disease_heart/cardiac problem 50 oxybutynin disease_bladder problem (not cancer)disease_urinary frequency / incontinence 51 52 solifenacin disease_urinary frequency / incontinencedisease_bladder problem (not cancer) 53 tolterodine disease_bladder problem (not cancer)disease_urinary frequency / incontinence 54 trospium disease_bladder problem (not cancer)disease_urinary frequency / incontinence 55 ipratropium bromide disease_chronic obstructive airwaysdisease_emphysema disease/copd 56 57 tiotropium bromide disease_chronic obstructive airwaysdisease_emphysema disease/copd 58 tamoxifen disease_ovarian problem disease_osteoporosis 59 terbinafine disease_infection of nervous systemdisease_type 2 diabetes 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 41 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 methotrexate disease_rheumatoid arthritis disease_psoriatic arthropathy 3 loperamide disease_irritable bowel syndromedisease_inflammatory bowel disease 4 betahistine disease_ear/vestibular disorder disease_sjogren's syndrome/sicca syndrome 5 6 cinnarizine disease_ear/vestibular disorder disease_chronic/degenerative neurological problem 7 anastrozole disease_lymphoedema disease_osteopenia 8 exemestane disease_ovarian problem disease_gall bladder disease 9 letrozole disease_osteoporosis disease_ovarian problem 10 11 carbomers disease_dry eyes disease_sjogren's syndrome/sicca syndrome 12 carmellose disease_dry eyes disease_sjogren's syndrome/sicca syndrome 13 celluvisc disease_sjogren's syndrome/siccadisease_dry syndrome eyes 14 hypromellose disease_dry eyes disease_sjogren's syndrome/sicca syndrome 15 For peer review only 16 lacri-lube disease_sjogren's syndrome/siccadisease_dry syndrome eyes 17 liquifilm tears disease_dry eyes disease_eye/eyelid problem 18 tears naturale disease_sjogren's syndrome/siccadisease_dry syndrome eyes 19 viscotears disease_dry eyes disease_sjogren's syndrome/sicca syndrome 20 21 primidone disease_epilepsy disease_other neurological problem 22 butylscopolamine disease_irritable bowel syndromedisease_diverticular disease/diverticulitis 23 clonazepam disease_chronic/degenerative neurologicaldisease_epilepsy problem 24 diazepam disease_deliberate self-harm/suicidedisease_anxiety/panic attempt attacks 25 26 lorazepam disease_anxiety/panic attacks disease_depression 27 nitrazepam disease_insomnia disease_depression 28 temazepam disease_insomnia disease_liver failure/cirrhosis 29 zolpidem disease_insomnia disease_mania/bipolar disorder/manic depression 30 31 zopiclone disease_insomnia disease_deliberate self-harm/suicide attempt 32 diltiazem disease_angina disease_heart attack/myocardial infarction 33 levobunolol disease_glaucoma disease_eye/eyelid problem
34 propranolol disease_anxiety/panic attacks disease_liver failure/cirrhosis http://bmjopen.bmj.com/ 35 sotalol disease_heart arrhythmia disease_cardiomyopathy 36 37 timolol disease_glaucoma disease_cataract 38 atenolol disease_hypertension disease_angina 39 bisoprolol disease_heart failure/pulmonarydisease_cardiomyopathy odema 40 metoprolol disease_heart attack/myocardialdisease_cardiomyopathy infarction 41 42 nebivolol disease_hypertension disease_angina on September 26, 2021 by guest. Protected copyright. 43 amoxicillin disease_bronchiectasis disease_chronic obstructive airways disease/copd 44 benzathine benzylpenicillin disease_hereditary/genetic haematologicaldisease_clotting disorder disorder/excessive bleeding 45 flucloxacillin disease_stroke disease_deep venous thrombosis (dvt) 46 47 phenoxymethylpenicillin disease_clotting disorder/excessivedisease_hereditary/genetic bleeding haematological disorder 48 metformin disease_diabetes disease_type 2 diabetes 49 ursodeoxycholic acid disease_liver/biliary/pancreas problemdisease_liver failure/cirrhosis 50 colestyramine disease_inflammatory bowel diseasedisease_malabsorption/coeliac disease 51 52 alendronic acid disease_osteoporosis disease_osteopenia 53 etidronic acid disease_osteoporosis disease_osteoarthritis 54 ibandronic acid disease_osteoporosis disease_osteopenia 55 risedronic acid disease_osteoporosis disease_vasculitis 56 57 ispaghula (psylla seeds) disease_constipation disease_diverticular disease/diverticulitis 58 sterculia disease_constipation disease_irritable bowel syndrome 59 tacrolimus disease_renal failure requiring dialysisdisease_polycystic kidney 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 42 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 calcium disease_osteopenia disease_osteoporosis 3 calcium carbonate disease_osteoporosis disease_osteopenia 4 brinzolamide disease_glaucoma disease_cataract 5 6 dorzolamide disease_glaucoma disease_cataract 7 carbamazepine disease_epilepsy disease_cranial nerve problem/palsy 8 sibutramine disease_diabetes disease_gall bladder disease 9 bisacodyl disease_constipation disease_chronic/degenerative neurological problem 10 11 senna glycosides disease_constipation disease_renal failure requiring dialysis 12 beclometasone disease_asthma disease_allergy to house dust mite 13 betamethasone disease_psoriasis disease_eczema/dermatitis 14 budesonide disease_asthma disease_chronic obstructive airways disease/copd 15 For peer review only 16 clobetasol disease_lichen planus disease_lichen sclerosis 17 clobetasone disease_lichen sclerosis disease_eczema/dermatitis 18 dexamethasone disease_dry eyes disease_eye/eyelid problem 19 fluocinolone acetonide disease_eczema/dermatitis disease_psoriasis 20 21 fluticasone disease_asthma disease_chronic obstructive airways disease/copd 22 hydrocortisone disease_adrenocortical insufficiency/addison'sdisease_hypopituitarism disease 23 mometasone disease_nasal/sinus disorder disease_hayfever/allergic rhinitis 24 prednisolone disease_vasculitis disease_renal failure requiring dialysis 25 26 prednisone disease_vasculitis disease_systemic lupus erythematosis/sle 27 triamcinolone disease_nasal/sinus disorder disease_hayfever/allergic rhinitis 28 celecoxib disease_psoriatic arthropathy disease_rheumatoid arthritis 29 etoricoxib disease_ankylosing spondylitis disease_psoriatic arthropathy 30 31 benserazide disease_chronic/degenerative neurologicaldisease_gastro-oesophageal problem reflux (gord) / gastric reflux 32 carbidopa disease_chronic/degenerative neurologicaldisease_prostate problem problem (not cancer) 33 olanzapine disease_schizophrenia disease_mania/bipolar disorder/manic depression
34 quetiapine disease_schizophrenia disease_mania/bipolar disorder/manic depression http://bmjopen.bmj.com/ 35 amlodipine disease_hypertension disease_diabetic eye disease 36 37 felodipine disease_hypertension disease_leg claudication/ intermittent claudication 38 lacidipine disease_hypertension disease_type 2 diabetes 39 lercanidipine disease_hypertension disease_essential hypertension 40 nifedipine disease_scleroderma/systemic sclerosisdisease_raynaud's phenomenon/disease 41 42 hydroxyzine disease_eczema/dermatitis disease_allergy/hypersensitivity/anaphylaxis on September 26, 2021 by guest. Protected copyright. 43 levodopa disease_chronic/degenerative neurologicaldisease_prostate problem problem (not cancer) 44 pramipexole disease_chronic/degenerative neurologicaldisease_other problem neurological problem 45 ropinirole disease_chronic/degenerative neurologicaldisease_other problem neurological problem 46 47 multienzymes (lipase, protease etc.)disease_pancreatic disease disease_liver/biliary/pancreas problem 48 conjugated estrogens disease_menopausal symptoms /disease_uterine menopause problem 49 estradiol disease_menopausal symptoms /disease_adrenocortical menopause insufficiency/addison's disease 50 estriol disease_gynaecological disorder disease_bladder(not cancer) problem (not cancer) 51 52 estrogen disease_uterine problem disease_migraine 53 estrone disease_uterine problem disease_gall bladder disease 54 ethinylestradiol disease_cervical problem disease_allergy or anaphylactic reaction to food 55 mestranol disease_ovarian problem disease_hyperthyroidism/thyrotoxicosis 56 57 tibolone disease_menopausal symptoms /disease_osteopenia menopause 58 valproic acid disease_epilepsy disease_mania/bipolar disorder/manic depression 59 mefenamic acid disease_dysmenorrhoea / dysmenorrheadisease_menorrhagia (unknown cause) 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 43 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 bezafibrate disease_diabetic eye disease disease_high cholesterol 3 fenofibrate disease_high cholesterol disease_diabetes 4 cefalexin disease_urinary tract infection/kidneydisease_cystitis infection 5 6 ciprofloxacin disease_bronchiectasis disease_urinary tract infection/kidney infection 7 goserelin disease_stroke disease_heart attack/myocardial infarction 8 cimetidine disease_duodenal ulcer disease_gastric/stomach ulcers 9 ranitidine disease_dyspepsia / indigestion disease_gastro-oesophageal reflux (gord) / gastric reflux 10 11 atorvastatin disease_high cholesterol disease_heart attack/myocardial infarction 12 fluvastatin disease_angina disease_high cholesterol 13 pravastatin disease_renal failure requiring dialysisdisease_hiv/aids 14 rosuvastatin disease_high cholesterol disease_angina 15 For peer review only 16 simvastatin disease_high cholesterol disease_diabetes 17 phenytoin disease_epilepsy disease_stroke 18 clotrimazole disease_eczema/dermatitis disease_psoriasis 19 ketoconazole disease_eczema/dermatitis disease_psoriasis 20 21 metronidazole disease_rosacea disease_blistering/desquamating skin disorder 22 miconazole disease_blistering/desquamatingdisease_eczema/dermatitis skin disorder 23 clonidine disease_menopausal symptoms /disease_migraine menopause 24 moxonidine disease_hypertension disease_diabetes 25 26 influenza vaccines disease_heart attack/myocardialdisease_diabetes infarction 27 insulin disease_diabetes disease_type 1 diabetes 28 ferrous fumarate disease_anaemia disease_inflammatory bowel disease 29 ferrous sulfate disease_anaemia disease_renal/kidney failure 30 31 iron disease_anaemia disease_renal failure requiring dialysis 32 montelukast disease_asthma disease_bronchiectasis 33 lithium disease_mania/bipolar disorder/manicdisease_schizophrenia depression
34 azithromycin disease_bronchiectasis disease_emphysema/chronic bronchitis http://bmjopen.bmj.com/ 35 erythromycin disease_acne/acne vulgaris disease_rosacea 36 37 magnesium disease_chronic fatigue syndromedisease_allergy or anaphylactic reaction to food 38 magnesium carbonate disease_irritable bowel syndromedisease_migraine 39 magnesium citrate disease_migraine disease_irritable bowel syndrome 40 quinine disease_leg claudication/ intermittentdisease_spinal claudication stenosis 41 42 fludrocortisone disease_adrenocortical insufficiency/addison'sdisease_chronic/degenerative disease neurological problem on September 26, 2021 by guest. Protected copyright. 43 minerals disease_anorexia/bulimia/other disease_allergyeating disorder or anaphylactic reaction to food 44 carbocisteine disease_bronchiectasis disease_chronic obstructive airways disease/copd 45 multivitamins disease_anorexia/bulimia/other disease_chroniceating disorder fatigue syndrome 46 47 nitrofurantoin disease_urinary tract infection/kidneydisease_cystitis infection 48 amitriptyline disease_fibromyalgia disease_insomnia 49 clomipramine disease_psychological/psychiatricdisease_depression problem 50 dosulepin disease_insomnia disease_depression 51 52 imipramine disease_depression disease_chronic/degenerative neurological problem 53 lofepramine disease_depression disease_mania/bipolar disorder/manic depression 54 nortriptyline disease_peripheral nerve disorderdisease_muscle/soft tissue problem 55 tenofovir disoproxil disease_hiv/aids disease_hepatitis 56 57 aciclovir disease_hiv/aids disease_herpes simplex 58 buprenorphine disease_fibromyalgia disease_spinal injury 59 codeine disease_fibromyalgia disease_spine arthritis/spondylitis 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 44 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 dextropropoxyphene disease_chronic fatigue syndromedisease_rheumatoid arthritis 3 dihydrocodeine disease_spinal stenosis disease_chronic skin ulcers 4 fentanyl disease_peripheral nerve disorderdisease_pulmonary embolism +/- dvt 5 6 morphine disease_spinal injury disease_fibromyalgia 7 oxycodone disease_spine arthritis/spondylitisdisease_peripheral nerve disorder 8 tramadol disease_fibromyalgia disease_spinal injury 9 glyceryl trinitrate disease_angina disease_heart attack/myocardial infarction 10 11 isosorbide mononitrate disease_angina disease_heart attack/myocardial infarction 12 lactulose disease_constipation disease_rectal prolapse 13 nefopam disease_spine arthritis/spondylitisdisease_arthritis (nos) 14 nedocromil disease_hayfever/allergic rhinitisdisease_asthma 15 For peer review only 16 fusidic acid disease_eczema/dermatitis disease_blistering/desquamating skin disorder 17 duloxetine disease_depression disease_bladder problem (not cancer) 18 mirtazapine disease_depression disease_deliberate self-harm/suicide attempt 19 trazodone disease_depression disease_insomnia 20 21 venlafaxine disease_depression disease_mania/bipolar disorder/manic depression 22 gabapentin disease_peripheral nerve injury disease_peripheral nerve disorder 23 lamotrigine disease_epilepsy disease_mania/bipolar disorder/manic depression 24 levetiracetam disease_epilepsy disease_head injury 25 26 pregabalin disease_peripheral nerve disorderdisease_peripheral nerve injury 27 topiramate disease_epilepsy disease_migraine 28 azelastine disease_nasal/sinus disorder disease_hayfever/allergic rhinitis 29 nabumetone disease_rheumatoid arthritis disease_ankylosing spondylitis 30 31 pizotifen disease_migraine disease_vasculitis 32 hydroxycarbamide disease_clotting disorder/excessivedisease_myeloproliferative bleeding disorder 33 risperidone disease_schizophrenia disease_mania/bipolar disorder/manic depression
34 baclofen disease_chronic/degenerative neurologicaldisease_cerebral problem palsy http://bmjopen.bmj.com/ 35 gamolenic acid disease_fibrocystic disease disease_breast cysts 36 37 strontium ranelate disease_osteoporosis disease_fracture pelvis & lower limb 38 alverine disease_irritable bowel syndromedisease_diverticular disease/diverticulitis 39 aqueous bp disease_eczema/dermatitis disease_psoriasis 40 cetraben disease_eczema/dermatitis disease_psoriasis 41 42 dermol disease_eczema/dermatitis disease_psoriasis on September 26, 2021 by guest. Protected copyright. 43 diprobase disease_eczema/dermatitis disease_psoriasis 44 doublebase disease_eczema/dermatitis disease_psoriasis 45 e45 cream disease_eczema/dermatitis disease_psoriasis 46 47 epaderm disease_eczema/dermatitis disease_blistering/desquamating skin disorder 48 oilatum disease_eczema/dermatitis disease_psoriasis 49 azathioprine disease_inflammatory bowel diseasedisease_renal failure requiring dialysis 50 ezetimibe disease_high cholesterol disease_angina 51 52 nicorandil disease_angina disease_heart attack/myocardial infarction 53 meloxicam disease_psoriatic arthropathy disease_rheumatoid arthritis 54 piroxicam disease_ankylosing spondylitis disease_rheumatoid arthritis 55 sildenafil disease_erectile dysfunction / impotencedisease_diabetic eye disease 56 57 tadalafil disease_erectile dysfunction / impotencedisease_diabetic eye disease 58 vardenafil disease_erectile dysfunction / impotencedisease_type 2 diabetes 59 orlistat disease_diabetic eye disease disease_sleep apnoea 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 45 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 promethazine disease_eczema/dermatitis disease_depression 3 chlorpromazine disease_schizophrenia disease_mania/bipolar disorder/manic depression 4 prochlorperazine disease_ear/vestibular disorder disease_fibromyalgia 5 6 trifluoperazine disease_schizophrenia disease_nervous breakdown 7 verapamil disease_heart arrhythmia disease_cardiomyopathy 8 cyclizine disease_migraine disease_bladder problem (not cancer) 9 cetirizine disease_urticaria disease_hayfever/allergic rhinitis 10 11 levocetirizine disease_hayfever/allergic rhinitisdisease_allergy/hypersensitivity/anaphylaxis 12 desloratadine disease_urticaria disease_hayfever/allergic rhinitis 13 fexofenadine disease_urticaria disease_allergy/hypersensitivity/anaphylaxis 14 loratadine disease_hayfever/allergic rhinitisdisease_urticaria 15 For peer review only 16 terfenadine disease_hayfever/allergic rhinitisdisease_allergy/hypersensitivity/anaphylaxis 17 acetylsalicylic acid disease_heart attack/myocardialdisease_angina infarction 18 clopidogrel disease_heart attack/myocardialdisease_angina infarction 19 dipyridamole disease_stroke disease_transient ischaemic attack (tia) 20 21 potassium disease_hypertension disease_stroke 22 potassium citrate disease_urinary tract infection/kidneydisease_irritable infection bowel syndrome 23 amiloride disease_lymphoedema disease_heart valve problem/heart murmur 24 spironolactone disease_heart failure/pulmonarydisease_cardiomyopathy odema 25 26 allopurinol disease_gout disease_renal failure requiring dialysis 27 colchicine disease_gout disease_heart arrhythmia 28 heparinoid disease_spine arthritis/spondylitisdisease_osteoarthritis 29 desogestrel disease_miscarriage disease_measles / morbillivirus 30 31 dydrogesterone disease_menopausal symptoms /disease_allergy/hypersensitivity/anaphylaxis menopause 32 etonogestrel disease_hayfever/allergic rhinitisdisease_depression 33 etynodiol disease_allergy/hypersensitivity/anaphylaxisdisease_other neurological problem
34 levonorgestrel disease_gynaecological disorder disease_cervical(not cancer) problem http://bmjopen.bmj.com/ 35 medroxyprogesterone disease_menopausal symptoms /disease_fibromyalgia menopause 36 37 norethisterone disease_menopausal symptoms /disease_adrenocortical menopause insufficiency/addison's disease 38 norgestimate disease_hayfever/allergic rhinitisdisease_depression 39 progesterone disease_retinal problem disease_eye/eyelid problem 40 progestogen disease_ovarian problem disease_hyperthyroidism/thyrotoxicosis 41 42 ibuprofen disease_neck problem/injury disease_back pain on September 26, 2021 by guest. Protected copyright. 43 ketoprofen disease_osteoarthritis disease_spine arthritis/spondylitis 44 naproxen disease_ankylosing spondylitis disease_rheumatoid arthritis 45 domperidone disease_scleroderma/systemic sclerosisdisease_oesophageal disorder 46 47 metoclopramide disease_migraine disease_stomach disorder 48 bimatoprost disease_glaucoma disease_cataract 49 latanoprost disease_glaucoma disease_eye/eyelid problem 50 travoprost disease_glaucoma disease_eye/eyelid problem 51 52 misoprostol disease_osteoarthritis disease_rheumatoid arthritis 53 esomeprazole disease_oesophagitis/barretts oesophagusdisease_hiatus hernia 54 lansoprazole disease_gastro-oesophageal refluxdisease_hiatus (gord) / gastric hernia reflux 55 omeprazole disease_gastro-oesophageal refluxdisease_oesophagitis/barretts (gord) / gastric reflux oesophagus 56 57 pantoprazole disease_oesophagitis/barretts oesophagusdisease_gastro-oesophageal reflux (gord) / gastric reflux 58 rabeprazole disease_oesophagitis/barretts oesophagusdisease_gastro-oesophageal reflux (gord) / gastric reflux 59 sodium bicarbonate disease_renal/kidney failure disease_renal failure requiring dialysis 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 46 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 formoterol disease_asthma disease_chronic obstructive airways disease/copd 3 salbutamol disease_asthma disease_chronic obstructive airways disease/copd 4 salmeterol disease_asthma disease_chronic obstructive airways disease/copd 5 6 terbutaline disease_asthma disease_chronic obstructive airways disease/copd 7 raloxifene disease_osteoporosis disease_osteopenia 8 leflunomide disease_rheumatoid arthritis disease_psoriatic arthropathy 9 mycophenolic acid disease_renal/kidney failure disease_renal failure requiring dialysis 10 11 almotriptan disease_migraine disease_irritable bowel syndrome 12 naratriptan disease_migraine disease_other neurological problem 13 rizatriptan disease_migraine disease_other neurological problem 14 sumatriptan disease_migraine disease_dry eyes 15 For peer review only 16 zolmitriptan disease_migraine disease_chronic/degenerative neurological problem 17 citalopram disease_depression disease_anxiety/panic attacks 18 escitalopram disease_depression disease_anxiety/panic attacks 19 fluoxetine disease_depression disease_stress 20 21 paroxetine disease_depression disease_anxiety/panic attacks 22 sertraline disease_depression disease_schizophrenia 23 selenium disease_peripheral vascular diseasedisease_allergy or anaphylactic reaction to food 24 docusate sodium disease_constipation disease_chronic/degenerative neurological problem 25 26 chlorphenamine disease_hayfever/allergic rhinitisdisease_allergy/hypersensitivity/anaphylaxis 27 bumetanide disease_heart failure/pulmonarydisease_cardiomyopathy odema 28 chlortalidone disease_hypertension disease_essential hypertension 29 furosemide disease_heart failure/pulmonarydisease_cardiomyopathy odema 30 31 indapamide disease_hypertension disease_erectile dysfunction / impotence 32 glibenclamide disease_diabetes disease_type 2 diabetes 33 gliclazide disease_diabetes disease_diabetic eye disease
34 glimepiride disease_diabetes disease_type 2 diabetes http://bmjopen.bmj.com/ 35 carbimazole disease_hyperthyroidism/thyrotoxicosisdisease_heart arrhythmia 36 37 aloe vera disease_irritable bowel syndromedisease_allergy or anaphylactic reaction to food 38 chondroitin sulfate disease_osteoarthritis disease_other joint disorder 39 cod liver oil disease_fibrocystic disease disease_osteoarthritis 40 co-enzyme q10/ubiquinone/bio-quinonedisease_chronic fatigue syndromedisease_cervical spondylosis 41 42 flax oil disease_chronic fatigue syndromedisease_allergy or anaphylactic reaction to food on September 26, 2021 by guest. Protected copyright. 43 food supplement/plant/herbal extractdisease_chronic fatigue syndromedisease_nervous breakdown 44 garlic disease_peripheral vascular diseasedisease_eye infection 45 ginkgo folium disease_peripheral vascular diseasedisease_bladder problem (not cancer) 46 47 ginseng disease_chronic fatigue syndromedisease_muscle/soft tissue problem 48 glucosamine disease_osteoarthritis disease_other joint disorder 49 kaolin disease_inflammatory bowel diseasedisease_irritable bowel syndrome 50 kelp disease_spine arthritis/spondylitisdisease_ear/vestibular disorder 51 52 lecithin disease_gall bladder disease disease_high cholesterol 53 omega-3-triglycerides disease_thyroiditis disease_parathyroid gland problem (not cancer) 54 peppermint oil disease_irritable bowel syndromedisease_fibromyalgia 55 saw palmetto disease_prostate problem (not cancer)disease_abdominal hernia 56 57 st john's wort/hypericum disease_chronic fatigue syndromedisease_depression 58 starflower oil disease_gestational hypertension/pre-eclampsiadisease_breast cysts 59 brimonidine disease_glaucoma disease_cataract 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 47 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 pseudoephedrine disease_nasal/sinus disorder disease_hayfever/allergic rhinitis 3 dicycloverine disease_irritable bowel syndromedisease_diverticular disease/diverticulitis 4 mebeverine disease_irritable bowel syndromedisease_diverticular disease/diverticulitis 5 6 coal tar disease_psoriasis disease_psoriatic arthropathy 7 procyclidine disease_schizophrenia disease_mania/bipolar disorder/manic depression 8 dutasteride disease_prostate problem (not cancer)disease_urinary frequency / incontinence 9 finasteride disease_prostate problem (not cancer)disease_urinary frequency / incontinence 10 11 doxycycline disease_rosacea disease_acne/acne vulgaris 12 lymecycline disease_acne/acne vulgaris disease_rosacea 13 minocycline disease_acne/acne vulgaris disease_rosacea 14 oxytetracycline disease_acne/acne vulgaris disease_rosacea 15 For peer review only 16 tetracycline disease_acne/acne vulgaris disease_rosacea 17 bendroflumethiazide disease_hypertension disease_essential hypertension 18 hydrochlorothiazide disease_hypertension disease_angina 19 pioglitazone disease_diabetes disease_type 2 diabetes 20 21 rosiglitazone disease_diabetes disease_type 2 diabetes 22 flupentixol disease_schizophrenia disease_anxiety/panic attacks 23 levothyroxine sodium disease_hypothyroidism/myxoedemadisease_hypopituitarism 24 trimethoprim disease_urinary tract infection/kidneydisease_cystitis infection 25 26 adalimumab disease_rheumatoid arthritis disease_psoriatic arthropathy 27 retinol (vit a) disease_eczema/dermatitis disease_uterine problem 28 cyanocobalamin (vit b12) disease_anaemia disease_malabsorption/coeliac disease 29 folic acid disease_rheumatoid arthritis disease_psoriatic arthropathy 30 31 hydroxocobalamin (vit b12) disease_anaemia disease_inflammatory bowel disease 32 vitamin b12 disease_anaemia disease_inflammatory bowel disease 33 pyridoxine (vit b6) disease_bone disorder disease_anaemia
34 thiamine (vit b1) disease_substance abuse/dependencydisease_liver failure/cirrhosis http://bmjopen.bmj.com/ 35 vitamin b disease_substance abuse/dependencydisease_liver failure/cirrhosis 36 37 ascorbic acid (vit c) disease_fibrocystic disease disease_thyroiditis 38 calcipotriol disease_psoriasis disease_psoriatic arthropathy 39 alfacalcidol disease_renal/kidney failure disease_renal failure requiring dialysis 40 colecalciferol (vit d3) disease_osteoporosis disease_osteopenia 41 42 ergocalciferol (vit d2) disease_osteopenia disease_osteoporosis on September 26, 2021 by guest. Protected copyright. 43 vitamin d disease_adrenocortical insufficiency/addison'sdisease_bone disorderdisease 44 tocopherol (vit e) disease_chronic fatigue syndromedisease_allergy/hypersensitivity/anaphylaxis 45 warfarin disease_heart arrhythmia disease_heart failure/pulmonary odema 46 47 caffeine disease_migraine disease_other neurological problem 48 aminophylline disease_chronic obstructive airwaysdisease_asthma disease/copd 49 theophylline disease_chronic obstructive airwaysdisease_asthma disease/copd 50 zinc disease_chronic fatigue syndromedisease_allergy or anaphylactic reaction to food 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 48 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 V3 V4 V5 3 disease_diabetes disease_gout disease_angina 4 disease_type 1 diabetes disease_renal failure requiring dialysisdisease_heart failure/pulmonary odema 5 6 disease_gout disease_high cholesterol disease_angina 7 disease_type 1 diabetes disease_scleroderma/systemic sclerosisdisease_renal failure not requiring dialysis 8 disease_stroke disease_heart attack/myocardialdisease_heart infarction failure/pulmonary odema 9 disease_gout disease_stroke disease_diabetes 10 11 disease_heart failure/pulmonarydisease_angina odema disease_cardiomyopathy 12 disease_diabetes disease_high cholesterol disease_stroke 13 disease_psoriatic arthropathy disease_ankylosing spondylitis disease_spine arthritis/spondylitis 14 disease_systemic lupus erythematosis/sledisease_osteoarthritis disease_vasculitis 15 For peer review only 16 disease_psoriatic arthropathy disease_rheumatoid arthritis disease_arthritis (nos) 17 disease_asthma disease_high cholesterol disease_hypertension 18 disease_eczema/dermatitis disease_asthma disease_migraine 19 disease_heart attack/myocardialdisease_heart/cardiac infarction problem disease_heart arrhythmia 20 21 disease_polycystic kidney disease_renal/kidney failure disease_renal failure not requiring dialysis 22 disease_urinary frequency / incontinencedisease_angina disease_heart attack/myocardial infarction 23 disease_erectile dysfunction / impotencedisease_bladder problem (not cancer)disease_ureteric obstruction/hydronephrosis 24 disease_diabetes disease_hypertension disease_gastro-oesophageal reflux (gord) / gastric reflux 25 26 disease_gynaecological disorder disease_anaemia(not cancer) disease_clotting disorder/excessive bleeding 27 disease_hayfever/allergic rhinitisdisease_osteoarthritis disease_high cholesterol 28 disease_rheumatoid arthritis disease_connective tissue disorderdisease_scleroderma/systemic sclerosis 29 disease_heart attack/myocardialdisease_angina infarction disease_diabetes 30 31 disease_bile duct disease disease_ankylosing spondylitis disease_bone disorder 32 disease_inflammatory bowel diseasedisease_ankylosing spondylitis disease_colitis/not crohns or ulcerative colitis 33 disease_erectile dysfunction / impotencedisease_testicular problems (notdisease_cranial cancer) nerve problem/palsy
34 disease_polycystic kidney disease_diabetic eye disease disease_cardiomyopathy http://bmjopen.bmj.com/ 35 disease_stroke disease_diabetes disease_high cholesterol 36 37 disease_renal/kidney failure disease_renal failure not requiringdisease_diabetic dialysis eye disease 38 disease_renal failure not requiringdisease_polycystic dialysis kidney disease_cardiomyopathy 39 disease_type 2 diabetes disease_high cholesterol disease_transient ischaemic attack (tia) 40 disease_type 2 diabetes disease_diabetes disease_transient ischaemic attack (tia) 41 42 disease_polycystic kidney disease_cardiomyopathy disease_diabetes on September 26, 2021 by guest. Protected copyright. 43 disease_spine arthritis/spondylitisdisease_other neurological problemdisease_rheumatoid arthritis 44 disease_hiatus hernia disease_oesophagitis/barretts oesophagusdisease_gastritis/gastric erosions 45 disease_allergy/hypersensitivity/anaphylaxisdisease_allergy or anaphylactic reactiondisease_eczema/dermatitis to food 46 47 disease_osteoarthritis disease_diabetes disease_hypertension 48 disease_heart failure/pulmonarydisease_heart odema attack/myocardialdisease_heart/cardiac infarction problem 49 disease_heart valve problem/heartdisease_vasculitis murmur disease_transient ischaemic attack (tia) 50 disease_chronic/degenerative neurologicaldisease_spinal problem cord disorder disease_spinal injury 51 52 disease_chronic/degenerative neurologicaldisease_urinary problem tract infection/kidneydisease_sleep infection apnoea 53 disease_chronic/degenerative neurologicaldisease_spinal problem cord disorder disease_urinary tract infection/kidney infection 54 disease_chronic/degenerative neurologicaldisease_urinary problem tract infection/kidneydisease_stroke infection 55 disease_emphysema/chronic bronchitisdisease_bronchiectasis disease_asthma 56 57 disease_emphysema/chronic bronchitisdisease_bronchiectasis disease_asbestosis 58 disease_hyperthyroidism/thyrotoxicosisdisease_spine arthritis/spondylitisdisease_inflammatory bowel disease 59 disease_bronchitis disease_pneumonia disease_epilepsy 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 49 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_sjogren's syndrome/siccadisease_scleroderma/systemic syndrome sclerosisdisease_psoriasis 3 disease_hiv/aids disease_colitis/not crohns or ulcerativedisease_other colitis abdominal problem 4 disease_cervical spondylosis disease_dry eyes disease_spine arthritis/spondylitis 5 6 disease_cervical spondylosis disease_bronchitis disease_irritable bowel syndrome 7 disease_osteoporosis disease_pulmonary embolism +/-disease_rheumatic dvt fever 8 disease_uterine problem disease_hypothyroidism/myxoedemadisease_diabetes 9 disease_glaucoma disease_hypothyroidism/myxoedemadisease_uterine problem 10 11 disease_eye/eyelid problem disease_chronic fatigue syndromedisease_rheumatoid arthritis 12 disease_eye/eyelid problem disease_cataract disease_glaucoma 13 disease_blepharitis / eyelid infectiondisease_eye/eyelid problem disease_eye infection 14 disease_blepharitis / eyelid infectiondisease_eye/eyelid problem disease_systemic lupus erythematosis/sle 15 For peer review only 16 disease_eye/eyelid problem disease_eye infection disease_eye trauma 17 disease_cataract disease_glaucoma disease_gall bladder disease 18 disease_eye/eyelid problem disease_rheumatoid arthritis disease_osteoporosis 19 disease_blepharitis / eyelid infectiondisease_eye/eyelid problem disease_eye infection 20 21 disease_stroke disease_osteoporosis disease_angina 22 disease_muscle/soft tissue problemdisease_gall bladder disease disease_inflammatory bowel disease 23 disease_chronic fatigue syndromedisease_peripheral nerve disorderdisease_muscle/soft tissue problem 24 disease_insomnia disease_psychological/psychiatricdisease_post-traumatic problem stress disorder 25 26 disease_emphysema/chronic bronchitisdisease_heart attack/myocardialdisease_irritable infarction bowel syndrome 27 disease_anxiety/panic attacks disease_cervical spondylosis disease_osteoporosis 28 disease_psychological/psychiatricdisease_mania/bipolar problem disorder/manicdisease_spinal depression injury 29 disease_chronic fatigue syndromedisease_depression disease_anxiety/panic attacks 30 31 disease_mania/bipolar disorder/manicdisease_schizophrenia depression disease_hiv/aids 32 disease_hypertension disease_chronic obstructive airwaysdisease_heart disease/copd failure/pulmonary odema 33 disease_retinal problem disease_cataract disease_hypertension
34 disease_migraine disease_oesophageal disorder disease_myeloproliferative disorder http://bmjopen.bmj.com/ 35 disease_heart/cardiac problem disease_heart valve problem/heartdisease_transient murmur ischaemic attack (tia) 36 37 disease_eye/eyelid problem disease_retinal problem disease_eye trauma 38 disease_heart attack/myocardialdisease_polycystic infarction kidney disease_renal failure requiring dialysis 39 disease_heart attack/myocardialdisease_angina infarction disease_heart arrhythmia 40 disease_angina disease_heart arrhythmia disease_heart/cardiac problem 41 42 disease_heart attack/myocardialdisease_transient infarction ischaemic attackdisease_heart (tia) arrhythmia on September 26, 2021 by guest. Protected copyright. 43 disease_emphysema/chronic bronchitisdisease_urinary tract infection/kidneydisease_bronchitis infection 44 disease_pulmonary embolism +/-disease_deep dvt venous thrombosisdisease_anaemia (dvt) 45 disease_eczema/dermatitis disease_diabetes disease_depression 46 47 disease_pulmonary embolism +/-disease_deep dvt venous thrombosisdisease_anaemia (dvt) 48 disease_diabetic eye disease disease_type 1 diabetes disease_erectile dysfunction / impotence 49 disease_bile duct disease disease_inflammatory bowel diseasedisease_osteoporosis 50 disease_gall bladder disease disease_anaemia disease_irritable bowel syndrome 51 52 disease_vasculitis disease_bone disorder disease_adrenocortical insufficiency/addison's disease 53 disease_angina disease_high cholesterol disease_hypothyroidism/myxoedema 54 disease_vasculitis disease_malabsorption/coeliac diseasedisease_rheumatoid arthritis 55 disease_osteopenia disease_systemic lupus erythematosis/sledisease_malabsorption/coeliac disease 56 57 disease_irritable bowel syndromedisease_dry eyes disease_rectal or colon adenoma/polyps 58 disease_diverticular disease/diverticulitisdisease_inflammatory bowel diseasedisease_hiatus hernia 59 disease_renal/kidney failure disease_renal failure not requiringdisease_liver dialysis failure/cirrhosis 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 50 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_bone disorder disease_vasculitis disease_malabsorption/coeliac disease 3 disease_vasculitis disease_malabsorption/coeliac diseasedisease_bone disorder 4 disease_retinal problem disease_eye/eyelid problem disease_prostate problem (not cancer) 5 6 disease_retinal problem disease_diabetic eye disease disease_eye/eyelid problem 7 disease_mania/bipolar disorder/manicdisease_schizophrenia depression disease_head injury 8 disease_deep venous thrombosisdisease_disc (dvt) problem disease_osteoarthritis 9 disease_muscle/soft tissue problemdisease_irritable bowel syndromedisease_emphysema/chronic bronchitis 10 11 disease_other abdominal problemdisease_sjogren's syndrome/siccadisease_spinal syndrome cord disorder 12 disease_hayfever/allergic rhinitisdisease_nasal/sinus disorder disease_chronic obstructive airways disease/copd 13 disease_lichen planus disease_lichen sclerosis disease_psoriatic arthropathy 14 disease_bronchiectasis disease_emphysema disease_emphysema/chronic bronchitis 15 For peer review only 16 disease_eczema/dermatitis disease_psoriasis disease_blistering/desquamating skin disorder 17 disease_psoriasis disease_blistering/desquamatingdisease_psoriatic skin disorder arthropathy 18 disease_eye infection disease_cataract disease_ear/vestibular disorder 19 disease_asthma disease_hayfever/allergic rhinitisdisease_osteoarthritis 20 21 disease_bronchiectasis disease_emphysema disease_emphysema/chronic bronchitis 22 disease_pituitary adenoma/tumourdisease_eczema/dermatitis disease_anal problem 23 disease_allergy to house dust mitedisease_bronchiectasis disease_dry eyes 24 disease_systemic lupus erythematosis/sledisease_sarcoidosis disease_renal/kidney failure 25 26 disease_sarcoidosis disease_rheumatoid arthritis disease_inflammatory bowel disease 27 disease_allergy/hypersensitivity/anaphylaxisdisease_asthma disease_diverticular disease/diverticulitis 28 disease_ankylosing spondylitis disease_osteoarthritis disease_fibromyalgia 29 disease_osteoarthritis disease_fibromyalgia disease_rheumatoid arthritis 30 31 disease_depression disease_osteoarthritis disease_hypothyroidism/myxoedema 32 disease_angina disease_stroke disease_spine arthritis/spondylitis 33 disease_nervous breakdown disease_psychological/psychiatricdisease_depression problem
34 disease_psychological/psychiatricdisease_substance problem abuse/dependencydisease_depression http://bmjopen.bmj.com/ 35 disease_renal failure requiring dialysisdisease_diabetes disease_essential hypertension 36 37 disease_myeloproliferative disorderdisease_essential hypertension disease_high cholesterol 38 disease_other renal/kidney problemdisease_diabetes disease_gout 39 disease_high cholesterol disease_diabetes disease_type 2 diabetes 40 disease_peripheral vascular diseasedisease_hypertension disease_renal failure requiring dialysis 41 42 disease_allergy or anaphylactic reactiondisease_psoriasis to drug disease_emphysema/chronic bronchitis on September 26, 2021 by guest. Protected copyright. 43 disease_stroke disease_spine arthritis/spondylitisdisease_angina 44 disease_stroke disease_angina disease_prostate problem (not cancer) 45 disease_angina disease_deep venous thrombosisdisease_cataract (dvt) 46 47 disease_diabetes disease_pulmonary embolism +/-disease_anaemia dvt 48 disease_constipation disease_menorrhagia (unknown disease_ovariancause) problem 49 disease_uterine problem disease_gynaecological disorder disease_cystitis(not cancer) 50 disease_urinary tract infection/kidneydisease_menorrhagia infection (unknown disease_urinarycause) frequency / incontinence 51 52 disease_hypothyroidism/myxoedemadisease_hayfever/allergic rhinitisdisease_eczema/dermatitis 53 disease_irritable bowel syndromedisease_depression disease_migraine 54 disease_ovarian problem disease_pleurisy disease_hayfever/allergic rhinitis 55 disease_allergy or anaphylactic reactiondisease_hypothyroidism/myxoedema to drug disease_irritable bowel syndrome 56 57 disease_uterine problem disease_urinary tract infection/kidneydisease_cervical infection problem 58 disease_schizophrenia disease_psychological/psychiatricdisease_nervous problem breakdown 59 disease_gynaecological disorder disease_uterine(not cancer) problem disease_chronic fatigue syndrome 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 51 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_diabetes disease_angina disease_pancreatic disease 3 disease_diabetic eye disease disease_type 2 diabetes disease_pancreatic disease 4 disease_bladder problem (not cancer)disease_other renal/kidney problemdisease_vasculitis 5 6 disease_emphysema/chronic bronchitisdisease_inflammatory bowel diseasedisease_prostate problem (not cancer) 7 disease_back problem disease_osteoarthritis disease_hypertension 8 disease_gastro-oesophageal refluxdisease_hiatus (gord) / gastric hernia reflux disease_psoriasis 9 disease_peptic ulcer disease_renal failure requiring dialysisdisease_duodenal ulcer 10 11 disease_angina disease_renal failure requiring dialysisdisease_diabetes 12 disease_heart attack/myocardialdisease_hypertension infarction disease_diabetes 13 disease_high cholesterol disease_heart failure/pulmonarydisease_angina odema 14 disease_heart attack/myocardialdisease_hiv/aids infarction disease_diabetic eye disease 15 For peer review only 16 disease_diabetic eye disease disease_type 2 diabetes disease_heart attack/myocardial infarction 17 disease_deep venous thrombosisdisease_osteoporosis (dvt) disease_prostate problem (not cancer) 18 disease_ear/vestibular disorder disease_emphysema/chronic bronchitisdisease_osteoporosis 19 disease_stroke disease_irritable bowel syndromedisease_depression 20 21 disease_eczema/dermatitis disease_allergy or anaphylactic reactiondisease_diverticular to drug disease/diverticulitis 22 disease_psoriasis disease_prostate problem (not cancer)disease_rheumatoid arthritis 23 disease_back pain disease_rheumatoid arthritis disease_irritable bowel syndrome 24 disease_type 2 diabetes disease_gout disease_other renal/kidney problem 25 26 disease_asthma disease_uterine problem disease_hayfever/allergic rhinitis 27 disease_diabetic eye disease disease_renal failure requiring dialysisdisease_type 2 diabetes 28 disease_osteoporosis disease_diabetes disease_cataract 29 disease_malabsorption/coeliac diseasedisease_renal failure requiring dialysisdisease_hereditary/genetic haematological disorder 30 31 disease_hereditary/genetic haematologicaldisease_rheumatoid disorder arthritis disease_psoriatic arthropathy 32 disease_chronic obstructive airwaysdisease_emphysema/chronic disease/copd bronchitisdisease_other respiratory problems 33 disease_psychological/psychiatricdisease_nervous problem breakdown disease_depression
34 disease_chronic obstructive airwaysdisease_asthma disease/copd disease_pneumonia http://bmjopen.bmj.com/ 35 disease_blistering/desquamatingdisease_allergy skin disorder or anaphylactic reactiondisease_emphysema/chronic to drug bronchitis 36 37 disease_osteopenia disease_allergy/hypersensitivity/anaphylaxisdisease_peripheral nerve disorder 38 disease_depression disease_hypothyroidism/myxoedemadisease_hayfever/allergic rhinitis 39 disease_osteoarthritis disease_asthma disease_hypothyroidism/myxoedema 40 disease_renal failure requiring dialysisdisease_renal/kidney failure disease_renal failure not requiring dialysis 41 42 disease_osteoporosis disease_hypothyroidism/myxoedemadisease_deep venous thrombosis (dvt) on September 26, 2021 by guest. Protected copyright. 43 disease_chronic fatigue syndromedisease_hiv/aids disease_allergy or anaphylactic reaction to drug 44 disease_emphysema/chronic bronchitisdisease_asthma disease_pleurisy 45 disease_allergy or anaphylactic reactiondisease_allergy to food or anaphylactic reactiondisease_hiv/aids to drug 46 47 disease_bladder problem (not cancer)disease_urinary frequency / incontinencedisease_chronic/degenerative neurological problem 48 disease_peripheral nerve injury disease_myositis/myopathy disease_muscle/soft tissue problem 49 disease_anxiety/panic attacks disease_mania/bipolar disorder/manicdisease_osteoporosis depression 50 disease_anxiety/panic attacks disease_fibromyalgia disease_nervous breakdown 51 52 disease_anxiety/panic attacks disease_irritable bowel syndromedisease_diabetes 53 disease_chronic fatigue syndromedisease_anxiety/panic attacks disease_chronic/degenerative neurological problem 54 disease_chronic fatigue syndromedisease_irritable bowel syndromedisease_spine arthritis/spondylitis 55 disease_depression disease_high cholesterol disease_asthma 56 57 disease_eye infection disease_blistering/desquamatingdisease_varicella skin disorder zoster virus 58 disease_spine arthritis/spondylitisdisease_peripheral nerve disorderdisease_cervical spondylosis 59 disease_osteoarthritis disease_cervical spondylosis disease_rheumatoid arthritis 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 52 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_spine arthritis/spondylitisdisease_back problem disease_cervical spondylosis 3 disease_fibromyalgia disease_spine arthritis/spondylitisdisease_post-traumatic stress disorder 4 disease_muscle/soft tissue problemdisease_spine arthritis/spondylitisdisease_osteoporosis 5 6 disease_disc problem disease_pancreatic disease disease_ankylosing spondylitis 7 disease_disc problem disease_heart attack/myocardialdisease_back infarction problem 8 disease_spine arthritis/spondylitisdisease_spinal stenosis disease_peripheral nerve injury 9 disease_heart failure/pulmonarydisease_leg odema claudication/ intermittentdisease_stroke claudication 10 11 disease_heart failure/pulmonarydisease_diabetic odema eye disease disease_leg claudication/ intermittent claudication 12 disease_chronic/degenerative neurologicaldisease_other problem abdominal problemdisease_renal failure requiring dialysis 13 disease_disc problem disease_angina disease_heart attack/myocardial infarction 14 disease_eczema/dermatitis disease_osteoporosis disease_hiatus hernia 15 For peer review only 16 disease_psoriasis disease_eye/eyelid problem disease_allergy/hypersensitivity/anaphylaxis 17 disease_mania/bipolar disorder/manicdisease_fibromyalgia depression disease_urinary frequency / incontinence 18 disease_mania/bipolar disorder/manicdisease_insomnia depression disease_schizophrenia 19 disease_mania/bipolar disorder/manicdisease_anxiety/panic depression attacks disease_nervous breakdown 20 21 disease_schizophrenia disease_post-traumatic stress disorderdisease_anorexia/bulimia/other eating disorder 22 disease_cranial nerve problem/palsydisease_spinal cord disorder disease_chronic/degenerative neurological problem 23 disease_stroke disease_head injury disease_chronic/degenerative neurological problem 24 disease_infection of nervous systemdisease_stroke disease_other neurological problem 25 26 disease_fibromyalgia disease_spinal injury disease_spinal cord disorder 27 disease_chronic/degenerative neurologicaldisease_stroke problem disease_other neurological problem 28 disease_irritable bowel syndromedisease_asthma disease_gastro-oesophageal reflux (gord) / gastric reflux 29 disease_spine arthritis/spondylitisdisease_osteoarthritis disease_emphysema/chronic bronchitis 30 31 disease_stroke disease_irritable bowel syndromedisease_other neurological problem 32 disease_stroke disease_psoriasis disease_deep venous thrombosis (dvt) 33 disease_psychological/psychiatricdisease_nervous problem breakdown disease_depression
34 disease_spinal cord disorder disease_spinal injury disease_cranial nerve problem/palsy http://bmjopen.bmj.com/ 35 disease_sjogren's syndrome/siccadisease_female syndrome infertility disease_breast disease (not cancer) 36 37 disease_cataract disease_gall bladder disease disease_emphysema/chronic bronchitis 38 disease_oesophagitis/barretts oesophagusdisease_urinary frequency / incontinencedisease_cervical spondylosis 39 disease_cataract disease_peripheral nerve disorderdisease_stroke 40 disease_diabetes disease_cataract disease_hiatus hernia 41 42 disease_allergy/hypersensitivity/anaphylaxisdisease_eye/eyelid problem disease_asthma on September 26, 2021 by guest. Protected copyright. 43 disease_psoriatic arthropathy disease_blistering/desquamatingdisease_allergy/hypersensitivity/anaphylaxis skin disorder 44 disease_cervical spondylosis disease_allergy/hypersensitivity/anaphylaxisdisease_allergy or anaphylactic reaction to drug 45 disease_diabetes disease_pulmonary embolism +/-disease_type dvt 2 diabetes 46 47 disease_psoriasis disease_allergy/hypersensitivity/anaphylaxisdisease_emphysema/chronic bronchitis 48 disease_muscle/soft tissue problemdisease_cervical spondylosis disease_asthma 49 disease_systemic lupus erythematosis/sledisease_bile duct disease disease_renal/kidney failure 50 disease_heart attack/myocardialdisease_myositis/myopathy infarction disease_renal failure requiring dialysis 51 52 disease_diabetic eye disease disease_chronic obstructive airwaysdisease_stroke disease/copd 53 disease_ankylosing spondylitis disease_osteoarthritis disease_arthritis (nos) 54 disease_osteoarthritis disease_arthritis (nos) disease_gout 55 disease_diabetes disease_type 2 diabetes disease_spinal cord disorder 56 57 disease_diabetes disease_type 2 diabetes disease_sleep apnoea 58 disease_diabetes disease_prostate problem (not cancer)disease_heart attack/myocardial infarction 59 disease_diabetes disease_fibromyalgia disease_type 2 diabetes 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 53 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_anxiety/panic attacks disease_heart attack/myocardialdisease_hiatus infarction hernia 3 disease_depression disease_anxiety/panic attacks disease_emphysema/chronic bronchitis 4 disease_migraine disease_chronic fatigue syndromedisease_cervical spondylosis 5 6 disease_mania/bipolar disorder/manicdisease_depression depression disease_anxiety/panic attacks 7 disease_constipation disease_heart/cardiac problem disease_angina 8 disease_ear/vestibular disorder disease_pulmonary embolism +/-disease_deep dvt venous thrombosis (dvt) 9 disease_allergy to house dust mitedisease_allergy/hypersensitivity/anaphylaxisdisease_allergy or anaphylactic reaction to food 10 11 disease_eczema/dermatitis disease_asthma disease_allergy or anaphylactic reaction to drug 12 disease_allergy/hypersensitivity/anaphylaxisdisease_allergy or anaphylactic reactiondisease_blistering/desquamating to food skin disorder 13 disease_hayfever/allergic rhinitisdisease_allergy to house dust mitedisease_allergy or anaphylactic reaction to food 14 disease_allergy to house dust mitedisease_allergy/hypersensitivity/anaphylaxisdisease_allergy or anaphylactic reaction to food 15 For peer review only 16 disease_allergy or anaphylactic reactiondisease_nasal/sinus to drug disorder disease_eczema/dermatitis 17 disease_transient ischaemic attackdisease_leg (tia) claudication/ intermittentdisease_stroke claudication 18 disease_transient ischaemic attackdisease_stroke (tia) disease_leg claudication/ intermittent claudication 19 disease_diabetic eye disease disease_heart attack/myocardialdisease_high infarction cholesterol 20 21 disease_heart arrhythmia disease_diabetes disease_deep venous thrombosis (dvt) 22 disease_uterine problem disease_gastro-oesophageal refluxdisease_hypothyroidism/myxoedema (gord) / gastric reflux 23 disease_diabetic eye disease disease_angina disease_hypertension 24 disease_liver failure/cirrhosis disease_renal failure not requiringdisease_heart dialysis attack/myocardial infarction 25 26 disease_renal/kidney failure disease_heart failure/pulmonarydisease_renal odema failure not requiring dialysis 27 disease_heart attack/myocardialdisease_hypertension infarction disease_stroke 28 disease_muscle/soft tissue problemdisease_arthritis (nos) disease_cervical spondylosis 29 disease_migraine disease_varicella zoster virus disease_irritable bowel syndrome 30 31 disease_throat or larynx disorderdisease_eye/eyelid problem disease_ovarian problem 32 disease_asthma disease_hypertension NA 33 disease_hayfever/allergic rhinitisdisease_asthma disease_irritable bowel syndrome
34 disease_uterine problem disease_menorrhagia (unknown disease_gestationalcause) hypertension/pre-eclampsia http://bmjopen.bmj.com/ 35 disease_gynaecological disorder disease_benign(not cancer) breast lump disease_infection of nervous system 36 37 disease_dysmenorrhoea / dysmenorrheadisease_gynaecological disorder disease_cervical(not cancer) problem 38 disease_asthma disease_hypertension NA 39 disease_cataract disease_uterine problem disease_osteoporosis 40 disease_allergy or anaphylactic reactiondisease_hypothyroidism/myxoedema to drug disease_irritable bowel syndrome 41 42 disease_migraine disease_other neurological problemdisease_soft tissue inflammation on September 26, 2021 by guest. Protected copyright. 43 disease_rheumatoid arthritis disease_gout disease_back problem 44 disease_psoriatic arthropathy disease_osteoarthritis disease_gout 45 disease_hiatus hernia disease_oesophagitis/barretts oesophagusdisease_stomach disorder 46 47 disease_oesophagitis/barretts oesophagusdisease_pancreatic disease disease_hiatus hernia 48 disease_eye/eyelid problem disease_diabetic eye disease disease_retinal problem 49 disease_cataract disease_retinal problem disease_diabetic eye disease 50 disease_retinal problem disease_cataract disease_pulmonary embolism +/- dvt 51 52 disease_arthritis (nos) disease_psoriatic arthropathy disease_fibromyalgia 53 disease_oesophageal disorder disease_gastro-oesophageal refluxdisease_gastritis/gastric (gord) / gastric reflux erosions 54 disease_oesophagitis/barretts oesophagusdisease_dyspepsia / indigestion disease_gastritis/gastric erosions 55 disease_hiatus hernia disease_gastritis/gastric erosionsdisease_dyspepsia / indigestion 56 57 disease_hiatus hernia disease_gastritis/gastric erosionsdisease_fibromyalgia 58 disease_hiatus hernia disease_peptic ulcer disease_gastritis/gastric erosions 59 disease_renal failure not requiringdisease_other dialysis renal/kidney problemdisease_gout 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 54 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_bronchiectasis disease_emphysema disease_emphysema/chronic bronchitis 3 disease_emphysema disease_emphysema/chronic bronchitisdisease_bronchiectasis 4 disease_emphysema disease_bronchiectasis disease_emphysema/chronic bronchitis 5 6 disease_bronchiectasis disease_emphysema/chronic bronchitisdisease_other respiratory problems 7 disease_bone disorder disease_malabsorption/coeliac diseasedisease_rheumatoid arthritis 8 disease_psoriasis disease_anaemia disease_osteoporosis 9 disease_scleroderma/systemic sclerosisdisease_polycystic kidney disease_renal failure not requiring dialysis 10 11 disease_uterine problem disease_hayfever/allergic rhinitisdisease_depression 12 disease_ovarian problem disease_bladder problem (not cancer)disease_irritable bowel syndrome 13 disease_spine arthritis/spondylitisdisease_arthritis (nos) disease_ovarian problem 14 disease_rosacea disease_chronic fatigue syndromedisease_other neurological problem 15 For peer review only 16 disease_irritable bowel syndromedisease_spine arthritis/spondylitisdisease_muscle/soft tissue problem 17 disease_stress disease_deliberate self-harm/suicidedisease_post-traumatic attempt stress disorder 18 disease_post-traumatic stress disorderdisease_nervous breakdown disease_schizophrenia 19 disease_deliberate self-harm/suicidedisease_anxiety/panic attempt attacks disease_anorexia/bulimia/other eating disorder 20 21 disease_nervous breakdown disease_psychological/psychiatricdisease_deliberate problem self-harm/suicide attempt 22 disease_post-traumatic stress disorderdisease_stress disease_anxiety/panic attacks 23 disease_bone disorder disease_chronic fatigue syndromedisease_pleurisy 24 disease_chronic fatigue syndromedisease_chronic obstructive airwaysdisease_peripheral disease/copd nerve disorder 25 26 disease_urticaria disease_allergy or anaphylactic reactiondisease_eczema/dermatitis to food 27 disease_renal failure not requiringdisease_heart dialysis attack/myocardialdisease_diabetic infarction eye disease 28 disease_high cholesterol disease_diabetes disease_type 2 diabetes 29 disease_renal failure requiring dialysisdisease_renal/kidney failure disease_renal failure not requiring dialysis 30 31 disease_diabetic eye disease disease_stroke disease_diabetes 32 disease_high cholesterol disease_hypertension disease_angina 33 disease_type 2 diabetes disease_erectile dysfunction / impotencedisease_heart failure/pulmonary odema
34 disease_diabetic eye disease disease_sleep apnoea disease_angina http://bmjopen.bmj.com/ 35 disease_other neurological problemdisease_osteoporosis disease_deep venous thrombosis (dvt) 36 37 disease_chronic fatigue syndromedisease_diverticular disease/diverticulitisdisease_allergy/hypersensitivity/anaphylaxis 38 disease_arthritis (nos) disease_female infertility disease_spine arthritis/spondylitis 39 disease_interstitial lung disease disease_cervical spondylosis disease_joint disorder 40 disease_benign breast lump disease_duodenal ulcer disease_bronchiectasis 41 42 disease_sciatica disease_muscle/soft tissue problemdisease_diverticular disease/diverticulitis on September 26, 2021 by guest. Protected copyright. 43 disease_allergy or anaphylactic reactiondisease_allergy to food or anaphylactic reactiondisease_gynaecological to drug disorder (not cancer) 44 disease_cervical spondylosis disease_psychological/psychiatricdisease_testicular problem problems (not cancer) 45 disease_chronic fatigue syndromedisease_cervical spondylosis disease_ear/vestibular disorder 46 47 disease_bronchitis disease_irritable bowel syndromedisease_spine arthritis/spondylitis 48 disease_arthritis (nos) disease_interstitial lung disease disease_cervical spondylosis 49 disease_osteoarthritis disease_hypothyroidism/myxoedemadisease_diabetes 50 disease_osteoporosis disease_osteoarthritis disease_uterine problem 51 52 disease_osteoarthritis disease_irritable bowel syndromedisease_angina 53 disease_chronic fatigue syndromedisease_fibrocystic disease disease_rectal prolapse 54 disease_diverticular disease/diverticulitisdisease_muscle/soft tissue problemdisease_stomach disorder 55 disease_kidney stone/ureter stone/bladderdisease_diverticular stone disease/diverticulitisdisease_ear/vestibular disorder 56 57 disease_anxiety/panic attacks disease_bladder problem (not cancer)disease_spine arthritis/spondylitis 58 disease_anaemia disease_allergy/hypersensitivity/anaphylaxisdisease_sciatica 59 disease_eye/eyelid problem disease_retinal problem disease_diabetes 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 55 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_disc problem disease_migraine disease_emphysema/chronic bronchitis 3 disease_cervical spondylosis disease_hiatus hernia disease_gastro-oesophageal reflux (gord) / gastric reflux 4 disease_lichen sclerosis disease_fibromyalgia disease_other abdominal problem 5 6 disease_eczema/dermatitis disease_angina disease_anaemia 7 disease_depression disease_anxiety/panic attacks disease_emphysema/chronic bronchitis 8 disease_bladder problem (not cancer)disease_heart arrhythmia disease_stroke 9 disease_angina disease_heart attack/myocardialdisease_abdominal infarction hernia 10 11 disease_bronchiectasis disease_eye infection disease_blistering/desquamating skin disorder 12 disease_blistering/desquamatingdisease_eczema/dermatitis skin disorder disease_inflammatory bowel disease 13 disease_eczema/dermatitis disease_disc problem disease_migraine 14 disease_blistering/desquamatingdisease_eczema/dermatitis skin disorder disease_back pain 15 For peer review only 16 disease_blistering/desquamatingdisease_asthma skin disorder disease_osteoarthritis 17 disease_high cholesterol disease_stroke disease_transient ischaemic attack (tia) 18 disease_heart attack/myocardialdisease_essential infarction hypertension disease_heart arrhythmia 19 disease_diabetic eye disease disease_hypertension disease_high cholesterol 20 21 disease_diabetic eye disease disease_hypertension disease_high cholesterol 22 disease_depression disease_irritable bowel syndromedisease_heart attack/myocardial infarction 23 disease_hyperthyroidism/thyrotoxicosisdisease_thyroiditis disease_thyroid problem (not cancer) 24 disease_bladder problem (not cancer)disease_other renal/kidney problemdisease_chronic/degenerative neurological problem 25 26 disease_ankylosing spondylitis disease_psoriasis disease_osteoporosis 27 disease_migraine disease_gastro-oesophageal refluxdisease_osteoarthritis (gord) / gastric reflux 28 disease_inflammatory bowel diseasedisease_hypothyroidism/myxoedemadisease_stroke 29 disease_renal failure requiring dialysisdisease_sjogren's syndrome/siccadisease_hereditary/genetic syndrome haematological disorder 30 31 disease_malabsorption/coeliac diseasedisease_hypothyroidism/myxoedemadisease_osteoporosis 32 disease_malabsorption/coeliac diseasedisease_chronic/degenerative neurologicaldisease_chronic problem fatigue syndrome 33 disease_irritable bowel syndromedisease_chronic/degenerative neurologicaldisease_ovarian problem problem
34 disease_pancreatic disease disease_liver/biliary/pancreas problemdisease_gastritis/gastric erosions http://bmjopen.bmj.com/ 35 disease_renal failure requiring dialysisdisease_deliberate self-harm/suicidedisease_liver/biliary/pancreas attempt problem 36 37 disease_chronic fatigue syndromedisease_allergy or anaphylactic reactiondisease_female to food infertility 38 disease_cervical spondylosis disease_eczema/dermatitis disease_emphysema/chronic bronchitis 39 disease_renal failure not requiringdisease_parathyroid dialysis gland problemdisease_polycystic (not cancer) kidney 40 disease_bone disorder disease_vasculitis disease_malabsorption/coeliac disease 41 42 disease_malabsorption/coeliac diseasedisease_heart valve problem/heartdisease_rheumatoid murmur arthritis on September 26, 2021 by guest. Protected copyright. 43 disease_osteopenia disease_osteoporosis disease_malabsorption/coeliac disease 44 disease_allergy or anaphylactic reactiondisease_breast to food cysts disease_chronic/degenerative neurological problem 45 disease_pulmonary embolism +/-disease_cardiomyopathy dvt disease_heart valve problem/heart murmur 46 47 disease_nasal/sinus disorder disease_breast cysts disease_cervical spondylosis 48 disease_emphysema/chronic bronchitisdisease_bronchiectasis disease_cataract 49 disease_emphysema/chronic bronchitisdisease_bronchiectasis disease_osteoporosis 50 disease_female infertility disease_anal problem disease_sarcoidosis 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 56 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 V6 V7 V8 3 disease_high cholesterol disease_prostate problem (not cancer)disease_deep venous thrombosis (dvt) 4 disease_polycystic kidney disease_diabetes disease_essential hypertension 5 6 disease_cataract disease_stroke disease_heart attack/myocardial infarction 7 disease_heart failure/pulmonarydisease_diabetic odema eye disease disease_leg claudication/ intermittent claudication 8 disease_erectile dysfunction / impotencedisease_angina disease_diabetic eye disease 9 disease_angina disease_high cholesterol disease_heart attack/myocardial infarction 10 11 disease_type 2 diabetes disease_diabetic eye disease disease_diabetes 12 disease_gout disease_angina disease_heart attack/myocardial infarction 13 disease_arthritis (nos) disease_cerebral palsy disease_spinal stenosis 14 disease_cervical spondylosis disease_spine arthritis/spondylitisdisease_muscle/soft tissue problem 15 For peer review only 16 disease_osteoarthritis disease_hypertension disease_disc problem 17 NA NA NA 18 disease_other neurological problemdisease_irritable bowel syndromedisease_depression 19 disease_angina disease_heart valve problem/heartdisease_gout murmur 20 21 disease_diabetic eye disease disease_spinal stenosis disease_diabetes 22 disease_oesophagitis/barretts oesophagusdisease_transient ischaemic attackdisease_type (tia) 2 diabetes 23 disease_testicular problems (notdisease_leg cancer) claudication/ intermittentdisease_angina claudication 24 disease_high cholesterol disease_osteoarthritis disease_asthma 25 26 disease_uterine problem disease_gestational hypertension/pre-eclampsiadisease_ovarian problem 27 disease_hypertension NA NA 28 disease_raynaud's phenomenon/diseasedisease_peripheral vascular diseasedisease_psoriatic arthropathy 29 disease_gastro-oesophageal refluxdisease_depression (gord) / gastric reflux disease_hypertension 30 31 disease_osteopenia disease_anaemia disease_osteoporosis 32 disease_sjogren's syndrome/siccadisease_dry syndrome eyes disease_bronchiectasis 33 disease_sleep apnoea disease_osteoporosis disease_chronic fatigue syndrome
34 disease_nephritis disease_renal failure requiring dialysisdisease_renal failure not requiring dialysis http://bmjopen.bmj.com/ 35 disease_angina disease_gout disease_hiatus hernia 36 37 disease_polycystic kidney disease_diabetes disease_nephritis 38 disease_heart failure/pulmonarydisease_renal/kidney odema failure disease_diabetes 39 disease_diabetes disease_stroke disease_gout 40 disease_heart/cardiac problem disease_gout disease_essential hypertension 41 42 disease_type 2 diabetes disease_heart attack/myocardialdisease_diabetic infarction eye disease on September 26, 2021 by guest. Protected copyright. 43 disease_migraine disease_osteoarthritis disease_back pain 44 disease_oesophageal disorder disease_dry eyes disease_helicobacter pylori 45 disease_asthma disease_eye/eyelid problem disease_irritable bowel syndrome 46 47 disease_depression disease_asthma NA 48 disease_heart valve problem/heartdisease_angina murmur disease_stroke 49 disease_allergy or anaphylactic reactiondisease_stroke to food disease_infection of nervous system 50 disease_urinary tract infection/kidneydisease_stroke infection disease_pulmonary embolism +/- dvt 51 52 disease_thyroid problem (not cancer)disease_prostate problem (not cancer)disease_menorrhagia (unknown cause) 53 disease_prostate problem (not cancer)disease_cranial nerve problem/palsydisease_stroke 54 disease_prostate problem (not cancer)disease_irritable bowel syndromedisease_angina 55 disease_other respiratory problemsdisease_bronchitis disease_sleep apnoea 56 57 disease_other respiratory problemsdisease_asthma disease_leg claudication/ intermittent claudication 58 disease_uterine problem disease_chronic/degenerative neurologicaldisease_hypothyroidism/myxoedema problem 59 disease_arthritis (nos) disease_sciatica disease_hyperthyroidism/thyrotoxicosis 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 57 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_vasculitis disease_systemic lupus erythematosis/sledisease_ankylosing spondylitis 3 disease_diverticular disease/diverticulitisdisease_fibromyalgia disease_pancreatic disease 4 disease_fibromyalgia disease_menorrhagia (unknown disease_heart/cardiaccause) problem 5 6 disease_angina disease_other neurological problemdisease_stroke 7 disease_deep venous thrombosisdisease_hyperthyroidism/thyrotoxicosis (dvt) disease_gall bladder disease 8 disease_irritable bowel syndromedisease_gastro-oesophageal refluxdisease_hypertension (gord) / gastric reflux 9 disease_osteoarthritis disease_other neurological problemdisease_gall bladder disease 10 11 disease_cataract disease_glaucoma disease_spine arthritis/spondylitis 12 disease_rheumatoid arthritis disease_diabetes disease_gall bladder disease 13 disease_systemic lupus erythematosis/sledisease_glaucoma disease_rheumatoid arthritis 14 disease_eye infection disease_diabetic eye disease disease_rheumatoid arthritis 15 For peer review only 16 disease_systemic lupus erythematosis/sledisease_cranial nerve problem/palsydisease_rheumatoid arthritis 17 disease_hiatus hernia disease_gastro-oesophageal refluxdisease_irritable (gord) / gastric bowel reflux syndrome 18 disease_hypothyroidism/myxoedemadisease_eczema/dermatitis disease_irritable bowel syndrome 19 disease_systemic lupus erythematosis/sledisease_diabetic eye disease disease_fibromyalgia 20 21 disease_diabetes disease_hayfever/allergic rhinitisdisease_hypothyroidism/myxoedema 22 disease_hiatus hernia disease_bladder problem (not cancer)disease_spine arthritis/spondylitis 23 disease_other neurological problemdisease_anxiety/panic attacks disease_infection of nervous system 24 disease_nervous breakdown disease_mania/bipolar disorder/manicdisease_anorexia/bulimia/other depression eating disorder 25 26 disease_diabetes disease_gastro-oesophageal refluxdisease_osteoarthritis (gord) / gastric reflux 27 disease_spine arthritis/spondylitisdisease_heart valve problem/heartdisease_diverticular murmur disease/diverticulitis 28 disease_depression disease_anxiety/panic attacks disease_chronic/degenerative neurological problem 29 disease_cervical spondylosis disease_spine arthritis/spondylitisdisease_emphysema/chronic bronchitis 30 31 disease_post-traumatic stress disorderdisease_depression disease_fibromyalgia 32 disease_heart/cardiac problem disease_renal failure not requiringdisease_heart dialysis arrhythmia 33 disease_diabetes disease_high cholesterol NA
34 disease_nervous breakdown disease_other neurological problemdisease_stress http://bmjopen.bmj.com/ 35 disease_heart attack/myocardialdisease_angina infarction disease_stroke 36 37 disease_diabetic eye disease disease_peripheral nerve disorderdisease_heart attack/myocardial infarction 38 disease_essential hypertension disease_high cholesterol disease_renal/kidney failure 39 disease_heart/cardiac problem disease_renal/kidney failure disease_renal failure requiring dialysis 40 disease_heart valve problem/heartdisease_hypertension murmur disease_diabetes 41 42 disease_pulmonary embolism +/-disease_stroke dvt disease_diabetes on September 26, 2021 by guest. Protected copyright. 43 disease_tuberculosis (tb) disease_pneumonia disease_nasal/sinus disorder 44 disease_diabetes disease_stroke disease_angina 45 disease_osteoarthritis disease_asthma disease_high cholesterol 46 47 disease_fracture pelvis & lower limbdisease_gout disease_cataract 48 disease_hypertension disease_high cholesterol disease_angina 49 disease_gall bladder disease disease_hiatus hernia disease_gastro-oesophageal reflux (gord) / gastric reflux 50 disease_diverticular disease/diverticulitisdisease_deep venous thrombosisdisease_depression (dvt) 51 52 disease_malabsorption/coeliac diseasedisease_parathyroid gland problemdisease_systemic (not cancer) lupus erythematosis/sle 53 disease_hayfever/allergic rhinitisdisease_asthma disease_depression 54 disease_hiatus hernia disease_ovarian problem disease_pulmonary embolism +/- dvt 55 disease_bone disorder disease_sjogren's syndrome/siccadisease_sarcoidosis syndrome 56 57 disease_bladder problem (not cancer)disease_gastritis/gastric erosionsdisease_urinary frequency / incontinence 58 disease_gastro-oesophageal refluxdisease_osteoporosis (gord) / gastric reflux disease_depression 59 disease_eczema/dermatitis disease_inflammatory bowel diseasedisease_pulmonary embolism +/- dvt 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 58 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_adrenocortical insufficiency/addison'sdisease_systemic disease lupus erythematosis/sledisease_sjogren's syndrome/sicca syndrome 3 disease_renal failure requiring dialysisdisease_systemic lupus erythematosis/sledisease_anorexia/bulimia/other eating disorder 4 disease_osteoporosis disease_diabetes disease_ear/vestibular disorder 5 6 disease_diverticular disease/diverticulitisdisease_prostate problem (not cancer)disease_type 2 diabetes 7 disease_stroke disease_chronic/degenerative neurologicaldisease_spinal problem cord disorder 8 disease_gastro-oesophageal refluxdisease_irritable (gord) / gastric bowel reflux syndromedisease_angina 9 disease_spine arthritis/spondylitisdisease_psoriasis disease_angina 10 11 disease_spinal injury disease_chronic/degenerative neurologicaldisease_dry problem eyes 12 disease_emphysema/chronic bronchitisdisease_emphysema disease_bronchiectasis 13 disease_blistering/desquamatingdisease_contact skin disorder dermatitis disease_urticaria 14 disease_asbestosis disease_other respiratory problemsdisease_oesophageal disorder 15 For peer review only 16 disease_gynaecological disorder disease_allergy/hypersensitivity/anaphylaxis(not cancer) disease_appendicitis 17 disease_allergy/hypersensitivity/anaphylaxisdisease_anal problem disease_chronic obstructive airways disease/copd 18 disease_glaucoma disease_retinal problem disease_ankylosing spondylitis 19 disease_hypertension disease_high cholesterol NA 20 21 disease_nasal/sinus disorder disease_allergy to house dust mitedisease_asbestosis 22 disease_blistering/desquamatingdisease_psoriasis skin disorder disease_renal failure not requiring dialysis 23 disease_eczema/dermatitis disease_blistering/desquamatingdisease_allergy/hypersensitivity/anaphylaxis skin disorder 24 disease_polycystic kidney disease_myositis/myopathy disease_iritis 25 26 disease_osteoporosis disease_pulmonary embolism +/-disease_emphysema/chronic dvt bronchitis 27 disease_emphysema/chronic bronchitisdisease_ear/vestibular disorder disease_gastro-oesophageal reflux (gord) / gastric reflux 28 disease_spine arthritis/spondylitisdisease_cervical spondylosis disease_muscle/soft tissue problem 29 disease_spine arthritis/spondylitisdisease_gout disease_joint disorder 30 31 disease_hypertension disease_asthma disease_high cholesterol 32 disease_osteoporosis disease_heart attack/myocardialdisease_pneumonia infarction 33 disease_anxiety/panic attacks disease_head injury disease_epilepsy
34 disease_anxiety/panic attacks disease_epilepsy disease_emphysema/chronic bronchitis http://bmjopen.bmj.com/ 35 disease_type 2 diabetes disease_high cholesterol disease_angina 36 37 disease_type 2 diabetes disease_diabetes disease_renal failure not requiring dialysis 38 disease_high cholesterol disease_stroke disease_pulmonary embolism +/- dvt 39 disease_gout disease_sleep apnoea disease_stroke 40 disease_renal/kidney failure disease_polycystic kidney disease_renal failure not requiring dialysis 41 42 disease_osteoporosis disease_depression disease_stroke on September 26, 2021 by guest. Protected copyright. 43 disease_osteoporosis disease_ear/vestibular disorder disease_heart attack/myocardial infarction 44 disease_hiatus hernia disease_emphysema/chronic bronchitisdisease_depression 45 disease_ear/vestibular disorder disease_osteoporosis disease_prostate problem (not cancer) 46 47 disease_heart attack/myocardialdisease_osteoporosis infarction disease_gall bladder disease 48 disease_fibromyalgia disease_gynaecological disorder disease_systemic(not cancer) lupus erythematosis/sle 49 disease_ovarian problem disease_breast disease (not cancer)disease_sjogren's syndrome/sicca syndrome 50 disease_uterine problem disease_cervical problem disease_irritable bowel syndrome 51 52 disease_asthma disease_osteoarthritis disease_depression 53 disease_osteoarthritis disease_gastro-oesophageal refluxdisease_hypothyroidism/myxoedema (gord) / gastric reflux 54 disease_anaemia disease_allergy/hypersensitivity/anaphylaxisdisease_measles / morbillivirus 55 disease_uterine problem disease_anaemia disease_gall bladder disease 56 57 disease_rheumatic fever disease_allergy or anaphylactic reactiondisease_ovarian to drug problem 58 disease_stroke disease_head injury disease_infection of nervous system 59 disease_ovarian problem disease_anaemia disease_migraine 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 59 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_heart attack/myocardialdisease_type infarction 2 diabetes disease_gout 3 disease_heart attack/myocardialdisease_angina infarction disease_hypertension 4 disease_urinary frequency / incontinencedisease_chronic/degenerative neurologicaldisease_kidney problem stone/ureter stone/bladder stone 5 6 disease_osteoporosis disease_hiatus hernia disease_uterine problem 7 disease_high cholesterol disease_gastro-oesophageal refluxdisease_angina (gord) / gastric reflux 8 disease_irritable bowel syndromedisease_angina disease_rheumatoid arthritis 9 disease_gastric/stomach ulcers disease_stomach disorder disease_gastritis/gastric erosions 10 11 disease_type 1 diabetes disease_diabetic eye disease disease_type 2 diabetes 12 disease_stroke disease_prostate problem (not cancer)disease_osteoporosis 13 disease_heart attack/myocardialdisease_stroke infarction disease_type 2 diabetes 14 disease_diabetes disease_heart failure/pulmonarydisease_type odema 2 diabetes 15 For peer review only 16 disease_angina disease_transient ischaemic attackdisease_type (tia) 1 diabetes 17 disease_nasal/sinus disorder disease_other neurological problemdisease_ear/vestibular disorder 18 disease_diabetes disease_hiatus hernia disease_stroke 19 disease_osteoarthritis disease_angina disease_deep venous thrombosis (dvt) 20 21 disease_inflammatory bowel diseasedisease_psoriasis disease_hiatus hernia 22 disease_muscle/soft tissue problemdisease_stroke disease_sciatica 23 disease_diverticular disease/diverticulitisdisease_chronic/degenerative neurologicaldisease_spine problem arthritis/spondylitis 24 disease_stroke disease_angina disease_high cholesterol 25 26 disease_migraine disease_angina disease_osteoarthritis 27 disease_renal failure not requiringdisease_renal/kidney dialysis failure disease_chronic skin ulcers 28 disease_uterine problem disease_depression disease_deep venous thrombosis (dvt) 29 disease_systemic lupus erythematosis/sledisease_renal failure not requiringdisease_diabetic dialysis eye disease 30 31 disease_malabsorption/coeliac diseasedisease_nervous breakdown disease_inflammatory bowel disease 32 disease_nasal/sinus disorder disease_sleep apnoea disease_bronchitis 33 disease_hypothyroidism/myxoedemadisease_bladder problem (not cancer)disease_anxiety/panic attacks
34 disease_diabetes disease_depression disease_hypertension http://bmjopen.bmj.com/ 35 disease_eye/eyelid problem disease_eczema/dermatitis disease_inflammatory bowel disease 36 37 disease_uterine problem disease_osteoporosis disease_ovarian problem 38 disease_osteoarthritis disease_asthma disease_hypertension 39 disease_high cholesterol disease_hypertension NA 40 disease_muscle/soft tissue problemdisease_chronic obstructive airwaysdisease_dry disease/copd eyes 41 42 disease_diabetes disease_osteoarthritis disease_angina on September 26, 2021 by guest. Protected copyright. 43 disease_peripheral vascular diseasedisease_muscle or soft tissue injuriesdisease_female infertility 44 disease_osteoporosis disease_rheumatoid arthritis disease_tuberculosis (tb) 45 disease_optic neuritis disease_bile duct disease disease_food intolerance 46 47 disease_other renal/kidney problemdisease_pulmonary embolism +/-disease_arthritis dvt (nos) 48 disease_peripheral nerve disorderdisease_spinal stenosis disease_connective tissue disorder 49 disease_hiatus hernia disease_irritable bowel syndromedisease_emphysema/chronic bronchitis 50 disease_chronic fatigue syndromedisease_cranial nerve problem/palsydisease_raynaud's phenomenon/disease 51 52 disease_angina disease_deep venous thrombosisdisease_gall (dvt) bladder disease 53 disease_spine arthritis/spondylitisdisease_stroke disease_migraine 54 disease_disc problem disease_depression disease_sciatica 55 disease_hayfever/allergic rhinitisdisease_hypertension NA 56 57 disease_eye/eyelid problem disease_hepatitis disease_cataract 58 disease_back problem disease_rheumatoid arthritis disease_sciatica 59 disease_spinal stenosis disease_ankylosing spondylitis disease_peripheral nerve injury 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 60 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_muscle/soft tissue problemdisease_pulmonary embolism +/-disease_osteoarthritis dvt 3 disease_cervical spondylosis disease_osteoarthritis disease_scoliosis 4 disease_disc problem disease_emphysema/chronic bronchitisdisease_sciatica 5 6 disease_peripheral nerve disorderdisease_sleep apnoea disease_spine arthritis/spondylitis 7 disease_deep venous thrombosisdisease_stroke (dvt) disease_angina 8 disease_cervical spondylosis disease_scoliosis disease_spinal cord disorder 9 disease_heart/cardiac problem disease_high cholesterol disease_chronic obstructive airways disease/copd 10 11 disease_renal failure not requiringdisease_diabetes dialysis disease_stroke 12 disease_liver failure/cirrhosis disease_anorexia/bulimia/other disease_spinaleating disorder cord disorder 13 disease_deep venous thrombosisdisease_osteoarthritis (dvt) disease_gastro-oesophageal reflux (gord) / gastric reflux 14 disease_irritable bowel syndromedisease_uterine problem disease_depression 15 For peer review only 16 disease_bronchitis disease_emphysema/chronic bronchitisdisease_asthma 17 disease_chronic fatigue syndromedisease_anxiety/panic attacks disease_peripheral nerve disorder 18 disease_nervous breakdown disease_post-traumatic stress disorderdisease_anxiety/panic attacks 19 disease_substance abuse/dependencydisease_chronic fatigue syndromedisease_chronic obstructive airways disease/copd 20 21 disease_nervous breakdown disease_anxiety/panic attacks disease_psychological/psychiatric problem 22 disease_fibromyalgia disease_spinal injury disease_spine arthritis/spondylitis 23 disease_infection of nervous systemdisease_depression disease_osteoporosis 24 disease_emphysema/chronic bronchitisdisease_osteoporosis disease_deep venous thrombosis (dvt) 25 26 disease_chronic/degenerative neurologicaldisease_cranial problem nerve problem/palsydisease_diabetic eye disease 27 disease_irritable bowel syndromedisease_depression disease_gall bladder disease 28 disease_osteoarthritis disease_diabetes disease_depression 29 disease_anaemia disease_hiatus hernia disease_angina 30 31 disease_chronic fatigue syndromedisease_muscle/soft tissue problemdisease_bladder problem (not cancer) 32 disease_gout disease_angina disease_gastro-oesophageal reflux (gord) / gastric reflux 33 disease_anxiety/panic attacks disease_emphysema/chronic bronchitisdisease_diabetes
34 disease_peripheral nerve disorderdisease_stroke disease_other neurological problem http://bmjopen.bmj.com/ 35 disease_chronic/degenerative neurologicaldisease_anorexia/bulimia/other problem disease_chroniceating disorder fatigue syndrome 36 37 disease_hiatus hernia disease_deep venous thrombosisdisease_uterine (dvt) problem 38 disease_hiatus hernia disease_breast cysts disease_essential hypertension 39 disease_emphysema/chronic bronchitisdisease_allergy/hypersensitivity/anaphylaxisdisease_pulmonary embolism +/- dvt 40 disease_asthma disease_angina disease_osteoarthritis 41 42 disease_angina disease_osteoporosis disease_hiatus hernia on September 26, 2021 by guest. Protected copyright. 43 disease_chronic obstructive airwaysdisease_allergy disease/copd or anaphylactic reactiondisease_eye/eyelid to food problem 44 disease_emphysema/chronic bronchitisdisease_angina disease_osteoporosis 45 disease_peripheral nerve disorderdisease_glaucoma disease_angina 46 47 disease_angina disease_diabetes disease_anaemia 48 disease_deep venous thrombosisdisease_pneumonia (dvt) disease_emphysema/chronic bronchitis 49 disease_vasculitis disease_colitis/not crohns or ulcerativedisease_polycystic colitis kidney 50 disease_type 2 diabetes disease_type 1 diabetes disease_diabetes 51 52 disease_diabetes disease_type 2 diabetes disease_high cholesterol 53 disease_spine arthritis/spondylitisdisease_cervical spondylosis disease_fibromyalgia 54 disease_hiatus hernia disease_angina disease_uterine problem 55 disease_chronic/degenerative neurologicaldisease_prostate problem problem (not cancer)disease_spinal injury 56 57 disease_prostate problem (not cancer)disease_chronic/degenerative neurologicaldisease_chronic problem obstructive airways disease/copd 58 disease_hypertension disease_high cholesterol disease_gastro-oesophageal reflux (gord) / gastric reflux 59 disease_spine arthritis/spondylitisdisease_hypertension disease_back pain 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 61 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_gastro-oesophageal refluxdisease_asthma (gord) / gastric reflux disease_osteoarthritis 3 disease_diabetes disease_hypothyroidism/myxoedemadisease_angina 4 disease_transient ischaemic attackdisease_diverticular (tia) disease/diverticulitisdisease_irritable bowel syndrome 5 6 disease_diabetes disease_high cholesterol disease_hypothyroidism/myxoedema 7 disease_hypertension disease_heart valve problem/heartdisease_essential murmur hypertension 8 disease_osteoporosis disease_muscle/soft tissue problemdisease_stroke 9 disease_eczema/dermatitis disease_dry eyes disease_blistering/desquamating skin disorder 10 11 disease_irritable bowel syndromedisease_nasal/sinus disorder disease_diverticular disease/diverticulitis 12 disease_eczema/dermatitis disease_asthma disease_allergy or anaphylactic reaction to drug 13 disease_blistering/desquamatingdisease_dry skin disorder eyes disease_eczema/dermatitis 14 disease_cystitis disease_fibromyalgia disease_dry eyes 15 For peer review only 16 disease_irritable bowel syndromedisease_asthma disease_uterine problem 17 disease_myeloproliferative disorderdisease_diabetes disease_diabetic eye disease 18 disease_myeloproliferative disorderdisease_renal/kidney failure disease_heart failure/pulmonary odema 19 disease_angina disease_hypertension disease_diabetes 20 21 disease_angina disease_irritable bowel syndromedisease_high cholesterol 22 disease_hayfever/allergic rhinitisdisease_osteoarthritis disease_asthma 23 disease_urinary frequency / incontinencedisease_sleep apnoea disease_heart/cardiac problem 24 disease_heart arrhythmia disease_heart valve problem/heartdisease_angina murmur 25 26 disease_myeloproliferative disorderdisease_polycystic kidney disease_erectile dysfunction / impotence 27 disease_diabetes disease_angina disease_psoriasis 28 disease_gastric/stomach ulcers disease_emphysema/chronic bronchitisdisease_stroke 29 disease_allergy or anaphylactic reactiondisease_allergy/hypersensitivity/anaphylaxis to drug disease_gestational hypertension/pre-eclampsia 30 31 disease_eczema/dermatitis disease_appendicitis disease_depression 32 NA NA NA 33 disease_uterine problem disease_depression disease_migraine
34 disease_ovarian problem disease_allergy or anaphylactic reactiondisease_benign to food breast lump http://bmjopen.bmj.com/ 35 disease_gestational hypertension/pre-eclampsiadisease_cervical problem disease_peritonitis 36 37 disease_cystitis disease_ovarian problem disease_miscarriage 38 NA NA NA 39 disease_ovarian problem disease_spine arthritis/spondylitisdisease_migraine 40 disease_uterine problem disease_anaemia disease_gall bladder disease 41 42 disease_plantar fascitis disease_back problem disease_herpes simplex on September 26, 2021 by guest. Protected copyright. 43 disease_diabetes disease_angina disease_prostate problem (not cancer) 44 disease_arthritis (nos) disease_cervical spondylosis disease_spine arthritis/spondylitis 45 disease_chronic/degenerative neurologicaldisease_gastro-oesophageal problem refluxdisease_systemic (gord) / gastric lupusreflux erythematosis/sle 46 47 disease_duodenal ulcer disease_gastro-oesophageal refluxdisease_spine (gord) / gastric arthritis/spondylitis reflux 48 disease_type 2 diabetes disease_prostate problem (not cancer)disease_heart arrhythmia 49 disease_eye trauma disease_type 2 diabetes disease_peripheral vascular disease 50 disease_angina disease_hypertension disease_prostate problem (not cancer) 51 52 disease_spine arthritis/spondylitisdisease_systemic lupus erythematosis/sledisease_ankylosing spondylitis 53 disease_helicobacter pylori disease_gastric/stomach ulcers disease_duodenal ulcer 54 disease_renal failure requiring dialysisdisease_gastric/stomach ulcers disease_oesophageal disorder 55 disease_scleroderma/systemic sclerosisdisease_oesophageal disorder disease_peptic ulcer 56 57 disease_stomach disorder disease_gastric/stomach ulcers disease_duodenal ulcer 58 disease_gastric/stomach ulcers disease_rheumatic fever disease_duodenal ulcer 59 disease_kidney stone/ureter stone/bladderdisease_inflammatory stone bowel diseasedisease_hypertension 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 62 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_other respiratory problemsdisease_heart failure/pulmonarydisease_bronchitis odema 3 disease_allergy to house dust mitedisease_asbestosis disease_other respiratory problems 4 disease_other respiratory problemsdisease_fibromyalgia disease_vasculitis 5 6 disease_bronchitis disease_muscle/soft tissue problemdisease_cervical spondylosis 7 disease_diverticular disease/diverticulitisdisease_hyperthyroidism/thyrotoxicosisdisease_muscle/soft tissue problem 8 disease_emphysema/chronic bronchitisdisease_angina disease_hypertension 9 disease_systemic lupus erythematosis/sledisease_liver failure/cirrhosis disease_vasculitis 10 11 disease_osteoarthritis disease_hypothyroidism/myxoedemadisease_asthma 12 disease_depression disease_diverticular disease/diverticulitisdisease_uterine problem 13 disease_cervical spondylosis disease_irritable bowel syndromedisease_nasal/sinus disorder 14 disease_irritable bowel syndromedisease_benign breast lump disease_vasculitis 15 For peer review only 16 disease_other neurological problemdisease_bladder problem (not cancer)disease_uterine problem 17 disease_nervous breakdown disease_mania/bipolar disorder/manicdisease_substance depression abuse/dependency 18 disease_mania/bipolar disorder/manicdisease_substance depression abuse/dependencydisease_fibromyalgia 19 disease_psychological/psychiatricdisease_post-traumatic problem stress disorderdisease_substance abuse/dependency 20 21 disease_post-traumatic stress disorderdisease_mania/bipolar disorder/manicdisease_anorexia/bulimia/other depression eating disorder 22 disease_psychological/psychiatricdisease_nervous problem breakdown disease_mania/bipolar disorder/manic depression 23 disease_allergy/hypersensitivity/anaphylaxisdisease_oesophagitis/barretts oesophagusdisease_prostate problem (not cancer) 24 disease_diverticular disease/diverticulitisdisease_muscle/soft tissue problemdisease_stroke 25 26 disease_allergy or anaphylactic reactiondisease_bronchiectasis to drug disease_asthma 27 disease_heart/cardiac problem disease_angina disease_heart valve problem/heart murmur 28 disease_stroke disease_angina disease_gout 29 disease_lymphoedema disease_heart attack/myocardialdisease_diabetic infarction eye disease 30 31 disease_type 2 diabetes disease_transient ischaemic attackdisease_high (tia) cholesterol 32 disease_gastro-oesophageal refluxdisease_hypothyroidism/myxoedema (gord) / gastric reflux disease_osteoarthritis 33 disease_renal/kidney failure disease_hypertension disease_heart attack/myocardial infarction
34 disease_peripheral nerve disorderdisease_essential hypertension disease_heart attack/myocardial infarction http://bmjopen.bmj.com/ 35 disease_gall bladder disease disease_hypothyroidism/myxoedemadisease_hiatus hernia 36 37 disease_inflammatory bowel diseasedisease_spine arthritis/spondylitisdisease_other joint disorder 38 disease_ectopic pregnancy disease_allergy or anaphylactic reactiondisease_cervical to food spondylosis 39 disease_allergy or anaphylactic reactiondisease_peripheral to drug vascular diseasedisease_ankylosing spondylitis 40 disease_high cholesterol disease_chronic/degenerative neurologicaldisease_allergy problem or anaphylactic reaction to drug 41 42 disease_eye/eyelid problem disease_spine arthritis/spondylitisdisease_allergy or anaphylactic reaction to drug on September 26, 2021 by guest. Protected copyright. 43 disease_muscle or soft tissue injuriesdisease_uterine problem disease_allergy/hypersensitivity/anaphylaxis 44 disease_helicobacter pylori disease_peritonitis disease_bladder problem (not cancer) 45 disease_allergy or anaphylactic reactiondisease_retinal to food problem disease_rheumatic fever 46 47 disease_disc problem disease_uterine problem disease_nasal/sinus disorder 48 disease_joint disorder disease_female infertility disease_spine arthritis/spondylitis 49 disease_hypertension disease_asthma disease_gastro-oesophageal reflux (gord) / gastric reflux 50 disease_deep venous thrombosisdisease_disc (dvt) problem disease_irritable bowel syndrome 51 52 disease_depression disease_uterine problem disease_hayfever/allergic rhinitis 53 disease_osteoarthritis disease_sjogren's syndrome/siccadisease_heart syndrome attack/myocardial infarction 54 disease_chronic fatigue syndromedisease_ankylosing spondylitis disease_bladder problem (not cancer) 55 disease_nasal/sinus disorder disease_hayfever/allergic rhinitisdisease_eczema/dermatitis 56 57 disease_irritable bowel syndromedisease_other joint disorder disease_cervical spondylosis 58 disease_uterine problem disease_eczema/dermatitis disease_hyperthyroidism/thyrotoxicosis 59 disease_asthma disease_hypertension disease_angina 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 63 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_back problem disease_hiatus hernia disease_irritable bowel syndrome 3 disease_anxiety/panic attacks disease_emphysema/chronic bronchitisdisease_disc problem 4 disease_constipation disease_dry eyes disease_dysmenorrhoea / dysmenorrhea 5 6 disease_cataract disease_rheumatoid arthritis disease_prostate problem (not cancer) 7 disease_diabetes disease_heart attack/myocardialdisease_high infarction cholesterol 8 disease_heart attack/myocardialdisease_angina infarction disease_glaucoma 9 disease_bladder problem (not cancer)disease_rectal or colon adenoma/polypsdisease_kidney stone/ureter stone/bladder stone 10 11 disease_nasal/sinus disorder disease_eye/eyelid problem disease_emphysema/chronic bronchitis 12 disease_nasal/sinus disorder disease_migraine disease_prostate problem (not cancer) 13 disease_asthma disease_osteoarthritis disease_hypothyroidism/myxoedema 14 disease_nasal/sinus disorder disease_fracture pelvis & lower limbdisease_bladder problem (not cancer) 15 For peer review only 16 disease_hypertension NA NA 17 disease_diabetes disease_type 2 diabetes disease_leg claudication/ intermittent claudication 18 disease_diabetes disease_heart/cardiac problem disease_high cholesterol 19 disease_sleep apnoea disease_peripheral nerve disorderdisease_angina 20 21 disease_sleep apnoea disease_angina disease_essential hypertension 22 disease_diabetes disease_osteoarthritis disease_high cholesterol 23 disease_adrenocortical insufficiency/addison'sdisease_thyroid disease goitre disease_pituitary adenoma/tumour 24 disease_urinary frequency / incontinencedisease_kidney stone/ureter stone/bladderdisease_prostate stone problem (not cancer) 25 26 disease_hypothyroidism/myxoedemadisease_hypertension disease_diabetes 27 disease_hypertension disease_high cholesterol disease_hayfever/allergic rhinitis 28 disease_type 2 diabetes disease_diabetes disease_glaucoma 29 disease_scleroderma/systemic sclerosisdisease_vasculitis disease_systemic lupus erythematosis/sle 30 31 disease_diabetic eye disease disease_rheumatoid arthritis disease_chronic/degenerative neurological problem 32 disease_osteoporosis disease_hypothyroidism/myxoedemadisease_other renal/kidney problem 33 disease_anxiety/panic attacks disease_allergy/hypersensitivity/anaphylaxisdisease_kidney stone/ureter stone/bladder stone
34 disease_chronic obstructive airwaysdisease_epilepsy disease/copd disease_stroke http://bmjopen.bmj.com/ 35 disease_pancreatic disease disease_chronic fatigue syndromedisease_peripheral vascular disease 36 37 disease_anorexia/bulimia/other disease_allergyeating disorder or anaphylactic reactiondisease_allergy/hypersensitivity/anaphylaxis to drug 38 disease_muscle or soft tissue injuriesdisease_angina disease_ear/vestibular disorder 39 disease_diabetic eye disease disease_other renal/kidney problemdisease_osteoporosis 40 disease_adrenocortical insufficiency/addison'sdisease_systemic disease lupus erythematosis/sledisease_sjogren's syndrome/sicca syndrome 41 42 disease_hypothyroidism/myxoedemadisease_cataract disease_osteoarthritis on September 26, 2021 by guest. Protected copyright. 43 disease_liver failure/cirrhosis disease_chronic fatigue syndromedisease_allergy or anaphylactic reaction to food 44 disease_rheumatic fever disease_bladder problem (not cancer)disease_osteoporosis 45 disease_deep venous thrombosisdisease_stroke (dvt) disease_heart/cardiac problem 46 47 disease_joint disorder disease_other joint disorder disease_anxiety/panic attacks 48 disease_osteoporosis disease_pneumonia disease_pulmonary embolism +/- dvt 49 disease_pulmonary embolism +/-disease_pneumonia dvt disease_nasal/sinus disorder 50 disease_urinary tract infection/kidneydisease_allergy infection or anaphylactic reactiondisease_bronchiectasis to drug 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 64 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 V9 V10 3 disease_osteoarthritis disease_hypothyroidism/myxoedema 4 disease_gout disease_leg claudication/ intermittent claudication 5 6 disease_osteoarthritis disease_hypothyroidism/myxoedema 7 disease_essential hypertension disease_high cholesterol 8 disease_diabetes disease_transient ischaemic attack (tia) 9 disease_osteoarthritis disease_uterine problem 10 11 disease_high cholesterol disease_essential hypertension 12 disease_osteoarthritis disease_gastro-oesophageal reflux (gord) / gastric reflux 13 disease_joint disorder disease_fibromyalgia 14 disease_joint disorder disease_psoriasis 15 For peer review only 16 disease_other neurological problemdisease_psoriasis 17 NA NA 18 disease_gall bladder disease disease_uterine problem 19 disease_diabetes disease_pulmonary embolism +/- dvt 20 21 disease_leg claudication/ intermittentdisease_type claudication 2 diabetes 22 disease_emphysema/chronic bronchitisdisease_kidney stone/ureter stone/bladder stone 23 disease_abdominal hernia disease_heart attack/myocardial infarction 24 disease_hayfever/allergic rhinitisNA 25 26 disease_migraine disease_depression 27 NA NA 28 disease_fibromyalgia disease_sarcoidosis 29 disease_osteoarthritis disease_asthma 30 31 disease_rectal or colon adenoma/polypsdisease_chronic obstructive airways disease/copd 32 disease_psoriasis disease_joint disorder 33 disease_diabetes disease_type 2 diabetes
34 disease_diabetes disease_heart attack/myocardial infarction http://bmjopen.bmj.com/ 35 disease_heart attack/myocardialdisease_osteoarthritis infarction 36 37 disease_type 1 diabetes disease_type 2 diabetes 38 disease_essential hypertension disease_heart attack/myocardial infarction 39 disease_infection of nervous systemdisease_hyperthyroidism/thyrotoxicosis 40 disease_angina disease_other renal/kidney problem 41 42 disease_angina disease_essential hypertension on September 26, 2021 by guest. Protected copyright. 43 disease_neck problem/injury disease_dysmenorrhoea / dysmenorrhea 44 disease_constipation disease_stomach disorder 45 disease_chronic fatigue syndromedisease_anal problem 46 47 NA NA 48 disease_hypothyroidism/myxoedemadisease_diabetes 49 disease_pulmonary embolism +/-disease_cataract dvt 50 disease_prostate problem (not cancer)disease_oesophagitis/barretts oesophagus 51 52 disease_hiatus hernia disease_irritable bowel syndrome 53 disease_depression disease_angina 54 disease_other neurological problemdisease_back problem 55 disease_substance abuse/dependencydisease_angina 56 57 disease_pneumothorax disease_liver failure/cirrhosis 58 disease_varicella zoster virus disease_gall bladder disease 59 disease_emphysema/chronic bronchitisdisease_glaucoma 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 65 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_sarcoidosis disease_dry eyes 3 disease_malabsorption/coeliac diseasedisease_oesophagitis/barretts oesophagus 4 disease_stroke disease_stomach disorder 5 6 disease_migraine disease_hiatus hernia 7 disease_peripheral nerve disorderdisease_breast cysts 8 disease_depression disease_asthma 9 disease_deep venous thrombosisdisease_depression (dvt) 10 11 disease_osteoporosis disease_muscle/soft tissue problem 12 disease_angina disease_hiatus hernia 13 disease_cataract disease_retinal problem 14 disease_raynaud's phenomenon/diseasedisease_eye trauma 15 For peer review only 16 disease_osteopenia disease_retinal problem 17 disease_osteoarthritis disease_hypothyroidism/myxoedema 18 disease_angina disease_osteoarthritis 19 disease_glaucoma disease_bronchiectasis 20 21 disease_depression disease_osteoarthritis 22 disease_other renal/kidney problemdisease_gastric/stomach ulcers 23 disease_depression disease_pulmonary embolism +/- dvt 24 disease_substance abuse/dependencydisease_schizophrenia 25 26 disease_hypertension disease_high cholesterol 27 disease_angina disease_emphysema/chronic bronchitis 28 disease_chronic obstructive airwaysdisease_sleep disease/copd apnoea 29 disease_diverticular disease/diverticulitisdisease_irritable bowel syndrome 30 31 disease_substance abuse/dependencydisease_renal failure not requiring dialysis 32 disease_myeloproliferative disorderdisease_emphysema/chronic bronchitis 33 NA NA
34 disease_polycystic kidney disease_substance abuse/dependency http://bmjopen.bmj.com/ 35 disease_bladder problem (not cancer)disease_hypertension 36 37 disease_prostate problem (not cancer)disease_type 2 diabetes 38 disease_diabetes disease_type 2 diabetes 39 disease_heart valve problem/heartdisease_renal murmur failure not requiring dialysis 40 disease_transient ischaemic attackdisease_stroke (tia) 41 42 disease_high cholesterol disease_gout on September 26, 2021 by guest. Protected copyright. 43 disease_heart valve problem/heartdisease_kidney murmur stone/ureter stone/bladder stone 44 disease_heart attack/myocardialdisease_eczema/dermatitis infarction 45 disease_hayfever/allergic rhinitisdisease_hypertension 46 47 disease_pneumonia disease_stroke 48 disease_sleep apnoea disease_heart attack/myocardial infarction 49 disease_hypothyroidism/myxoedemadisease_heart attack/myocardial infarction 50 disease_disc problem disease_gastro-oesophageal reflux (gord) / gastric reflux 51 52 disease_bile duct disease disease_sarcoidosis 53 disease_hypertension NA 54 disease_fracture upper limb & shoulderdisease_diverticular disease/diverticulitis 55 disease_rheumatoid arthritis disease_inflammatory bowel disease 56 57 disease_anal problem disease_peripheral vascular disease 58 disease_anxiety/panic attacks disease_uterine problem 59 disease_stroke disease_gout 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 66 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_parathyroid gland problemdisease_renal (not cancer) failure requiring dialysis 3 disease_renal failure not requiringdisease_sjogren's dialysis syndrome/sicca syndrome 4 disease_asthma disease_stroke 5 6 disease_diabetes disease_angina 7 disease_infection of nervous systemdisease_nervous breakdown 8 disease_uterine problem disease_high cholesterol 9 disease_depression disease_hiatus hernia 10 11 disease_stroke disease_spine arthritis/spondylitis 12 disease_asbestosis disease_eczema/dermatitis 13 disease_allergy/hypersensitivity/anaphylaxisdisease_allergy or anaphylactic reaction to food 14 disease_nasal/sinus disorder disease_bronchitis 15 For peer review only 16 disease_back pain disease_arthritis (nos) 17 disease_allergy or anaphylactic reactiondisease_bladder to food problem (not cancer) 18 disease_eczema/dermatitis disease_rheumatoid arthritis 19 NA NA 20 21 disease_other respiratory problemsdisease_adrenocortical insufficiency/addison's disease 22 disease_psoriatic arthropathy disease_dry eyes 23 disease_asthma disease_sjogren's syndrome/sicca syndrome 24 disease_rheumatoid arthritis disease_renal failure not requiring dialysis 25 26 disease_eye/eyelid problem disease_stroke 27 disease_eczema/dermatitis disease_angina 28 disease_arthritis (nos) disease_joint disorder 29 disease_cervical spondylosis disease_arthritis (nos) 30 31 NA NA 32 disease_disc problem disease_back problem 33 disease_emphysema/chronic bronchitisdisease_stroke
34 disease_allergy or anaphylactic reactiondisease_diabetes to drug http://bmjopen.bmj.com/ 35 disease_renal/kidney failure disease_renal failure not requiring dialysis 36 37 disease_cerebral aneurysm disease_transient ischaemic attack (tia) 38 disease_angina disease_cataract 39 disease_heart/cardiac problem disease_glaucoma 40 disease_leg claudication/ intermittentdisease_systemic claudication lupus erythematosis/sle 41 42 disease_asthma disease_pneumonia on September 26, 2021 by guest. Protected copyright. 43 disease_deep venous thrombosisdisease_other (dvt) neurological problem 44 disease_gastro-oesophageal refluxdisease_osteoarthritis (gord) / gastric reflux 45 disease_heart attack/myocardialdisease_osteoarthritis infarction 46 47 disease_angina disease_stroke 48 disease_benign breast lump disease_bladder problem (not cancer) 49 disease_fibromyalgia disease_dysmenorrhoea / dysmenorrhea 50 disease_osteoporosis disease_chronic fatigue syndrome 51 52 disease_hypertension disease_high cholesterol 53 disease_asthma disease_hayfever/allergic rhinitis 54 disease_eczema/dermatitis disease_uterine problem 55 disease_depression disease_arthritis (nos) 56 57 disease_breast cysts disease_urinary frequency / incontinence 58 disease_chronic/degenerative neurologicaldisease_transient problem ischaemic attack (tia) 59 disease_cervical spondylosis disease_irritable bowel syndrome 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 67 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_hypertension disease_stroke 3 disease_sleep apnoea disease_gout 4 disease_diverticular disease/diverticulitisdisease_osteoporosis 5 6 disease_asthma disease_diabetes 7 disease_diabetes disease_uterine problem 8 disease_osteoarthritis disease_stroke 9 disease_urticaria disease_hiatus hernia 10 11 disease_leg claudication/ intermittentdisease_heart claudication failure/pulmonary odema 12 disease_heart arrhythmia disease_hiatus hernia 13 disease_transient ischaemic attackdisease_diabetes (tia) 14 disease_transient ischaemic attackdisease_leg (tia) claudication/ intermittent claudication 15 For peer review only 16 disease_stroke disease_leg claudication/ intermittent claudication 17 disease_angina disease_migraine 18 disease_rheumatoid arthritis disease_gall bladder disease 19 disease_heart attack/myocardialdisease_high infarction cholesterol 20 21 disease_stroke disease_migraine 22 disease_angina disease_allergy or anaphylactic reaction to drug 23 disease_osteoarthritis disease_hypothyroidism/myxoedema 24 disease_heart attack/myocardialdisease_kidney infarction stone/ureter stone/bladder stone 25 26 disease_hypertension disease_high cholesterol 27 disease_pancreatic disease disease_heart failure/pulmonary odema 28 disease_hypothyroidism/myxoedemadisease_eczema/dermatitis 29 disease_heart failure/pulmonarydisease_type odema 1 diabetes 30 31 disease_allergy or anaphylactic reactiondisease_measles to food / morbillivirus 32 disease_osteoporosis disease_allergy or anaphylactic reaction to food 33 disease_chronic/degenerative neurologicaldisease_stroke problem
34 disease_osteoarthritis disease_high cholesterol http://bmjopen.bmj.com/ 35 disease_nasal/sinus disorder disease_anaemia 36 37 disease_allergy or anaphylactic reactiondisease_migraine to drug 38 NA NA 39 NA NA 40 disease_diabetic eye disease disease_type 1 diabetes 41 42 disease_depression disease_uterine problem on September 26, 2021 by guest. Protected copyright. 43 disease_irritable bowel syndromedisease_spinal cord disorder 44 disease_pneumonia disease_nasal/sinus disorder 45 disease_chronic skin ulcers disease_fibrocystic disease 46 47 disease_deep venous thrombosisdisease_diverticular (dvt) disease/diverticulitis 48 disease_chronic fatigue syndromedisease_chronic/degenerative neurological problem 49 disease_gastro-oesophageal refluxdisease_high (gord) / gastric cholesterol reflux 50 disease_substance abuse/dependencydisease_spinal injury 51 52 disease_gastro-oesophageal refluxdisease_hypertension (gord) / gastric reflux 53 disease_gall bladder disease disease_emphysema/chronic bronchitis 54 disease_other neurological problemdisease_migraine 55 NA NA 56 57 disease_allergy or anaphylactic reactiondisease_emphysema/chronic to drug bronchitis 58 disease_muscle/soft tissue problemdisease_duodenal ulcer 59 disease_emphysema disease_arthritis (nos) 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 68 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_disc problem disease_allergy or anaphylactic reaction to drug 3 disease_rheumatoid arthritis disease_spinal injury 4 disease_deep venous thrombosisdisease_angina (dvt) 5 6 disease_emphysema/chronic bronchitisdisease_chronic fatigue syndrome 7 disease_emphysema/chronic bronchitisdisease_osteoarthritis 8 disease_osteoarthritis disease_peripheral nerve disorder 9 disease_emphysema disease_asbestosis 10 11 disease_cardiomyopathy disease_high cholesterol 12 disease_diverticular disease/diverticulitisdisease_irritable bowel syndrome 13 disease_diabetes disease_depression 14 disease_migraine disease_angina 15 For peer review only 16 disease_cataract disease_nasal/sinus disorder 17 disease_muscle/soft tissue problemdisease_stroke 18 disease_substance abuse/dependencydisease_fibromyalgia 19 disease_spine arthritis/spondylitisdisease_emphysema/chronic bronchitis 20 21 disease_fibromyalgia disease_substance abuse/dependency 22 disease_diabetic eye disease disease_cervical spondylosis 23 disease_anxiety/panic attacks disease_emphysema/chronic bronchitis 24 disease_depression disease_gall bladder disease 25 26 disease_disc problem disease_dry eyes 27 disease_disc problem disease_osteoporosis 28 disease_hypothyroidism/myxoedemadisease_hypertension 29 disease_disc problem disease_osteoporosis 30 31 disease_cervical spondylosis disease_arthritis (nos) 32 disease_heart attack/myocardialdisease_hypertension infarction 33 disease_heart attack/myocardialdisease_hypothyroidism/myxoedema infarction
34 disease_bladder problem (not cancer)disease_chronic fatigue syndrome http://bmjopen.bmj.com/ 35 disease_uterine problem disease_peripheral vascular disease 36 37 disease_osteoarthritis disease_eczema/dermatitis 38 disease_spine arthritis/spondylitisdisease_duodenal ulcer 39 disease_angina disease_spine arthritis/spondylitis 40 disease_hypothyroidism/myxoedemadisease_hayfever/allergic rhinitis 41 42 disease_emphysema/chronic bronchitisdisease_hayfever/allergic rhinitis on September 26, 2021 by guest. Protected copyright. 43 disease_urinary frequency / incontinencedisease_bladder problem (not cancer) 44 disease_stroke disease_hiatus hernia 45 disease_muscle/soft tissue problemdisease_emphysema/chronic bronchitis 46 47 disease_deep venous thrombosisdisease_hiatus (dvt) hernia 48 disease_diabetes disease_angina 49 disease_hepatitis disease_sjogren's syndrome/sicca syndrome 50 disease_stroke disease_leg claudication/ intermittent claudication 51 52 disease_sleep apnoea disease_peripheral vascular disease 53 disease_muscle/soft tissue problemdisease_cranial nerve problem/palsy 54 disease_disc problem disease_gastro-oesophageal reflux (gord) / gastric reflux 55 disease_gout disease_sleep apnoea 56 57 disease_gout disease_rectal or colon adenoma/polyps 58 disease_angina disease_osteoarthritis 59 disease_angina disease_depression 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 69 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_angina disease_diabetes 3 disease_osteoarthritis disease_asthma 4 disease_allergy or anaphylactic reactiondisease_stroke to drug 5 6 disease_asthma disease_hypertension 7 disease_bronchiectasis disease_heart attack/myocardial infarction 8 disease_rheumatoid arthritis disease_emphysema/chronic bronchitis 9 disease_sjogren's syndrome/siccadisease_asthma syndrome 10 11 disease_anaemia disease_emphysema/chronic bronchitis 12 disease_chronic obstructive airwaysdisease_nasal/sinus disease/copd disorder 13 disease_asthma disease_allergy or anaphylactic reaction to drug 14 disease_asthma disease_eczema/dermatitis 15 For peer review only 16 disease_depression disease_migraine 17 disease_type 2 diabetes disease_high cholesterol 18 disease_heart/cardiac problem disease_diabetic eye disease 19 disease_type 2 diabetes disease_clotting disorder/excessive bleeding 20 21 disease_gastro-oesophageal refluxdisease_hypothyroidism/myxoedema (gord) / gastric reflux 22 disease_hypertension disease_high cholesterol 23 disease_rheumatic fever disease_vasculitis 24 disease_diabetic eye disease disease_heart/cardiac problem 25 26 disease_other renal/kidney problemdisease_hypertension 27 disease_osteoarthritis disease_high cholesterol 28 disease_rheumatoid arthritis disease_angina 29 disease_anaemia disease_ovarian problem 30 31 disease_hypothyroidism/myxoedemadisease_asthma 32 NA NA 33 disease_hypothyroidism/myxoedemadisease_hypertension
34 disease_anaemia disease_eczema/dermatitis http://bmjopen.bmj.com/ 35 disease_chronic fatigue syndromedisease_irritable bowel syndrome 36 37 disease_peripheral vascular diseasedisease_gestational hypertension/pre-eclampsia 38 NA NA 39 disease_irritable bowel syndromedisease_nasal/sinus disorder 40 disease_depression disease_arthritis (nos) 41 42 disease_sciatica disease_other joint disorder on September 26, 2021 by guest. Protected copyright. 43 disease_hypothyroidism/myxoedemadisease_hypertension 44 disease_soft tissue inflammationdisease_constipation 45 disease_diabetic eye disease disease_irritable bowel syndrome 46 47 disease_ankylosing spondylitis disease_chronic obstructive airways disease/copd 48 disease_gout disease_diabetes 49 disease_prostate problem (not cancer)disease_peripheral nerve disorder 50 disease_hiatus hernia disease_high cholesterol 51 52 disease_spinal injury disease_joint disorder 53 disease_stomach disorder disease_renal failure not requiring dialysis 54 disease_gastrointestinal bleedingdisease_peptic ulcer 55 disease_gastric/stomach ulcers disease_stomach disorder 56 57 disease_vasculitis disease_gall bladder disease 58 disease_diverticular disease/diverticulitisdisease_ankylosing spondylitis 59 disease_diabetes disease_stroke 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 70 of 75 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_nasal/sinus disorder disease_sarcoidosis 3 disease_bronchitis disease_interstitial lung disease 4 disease_eczema/dermatitis disease_allergy or anaphylactic reaction to food 5 6 disease_eczema/dermatitis disease_sleep apnoea 7 disease_hypothyroidism/myxoedemadisease_emphysema/chronic bronchitis 8 disease_diabetes disease_hypothyroidism/myxoedema 9 disease_hepatitis disease_other renal/kidney problem 10 11 disease_high cholesterol disease_hypertension 12 disease_allergy or anaphylactic reactiondisease_gall to drug bladder disease 13 disease_epilepsy disease_disc problem 14 disease_osteoporosis disease_uterine problem 15 For peer review only 16 disease_depression disease_eczema/dermatitis 17 disease_fibromyalgia disease_psychological/psychiatric problem 18 disease_chronic fatigue syndromedisease_sleep apnoea 19 disease_nervous breakdown disease_fibromyalgia 20 21 disease_stress disease_substance abuse/dependency 22 disease_anorexia/bulimia/other disease_chroniceating disorder fatigue syndrome 23 disease_helicobacter pylori disease_bronchiectasis 24 disease_other renal/kidney problemdisease_angina 25 26 disease_oesophagitis/barretts oesophagusdisease_pneumonia 27 disease_gout disease_other renal/kidney problem 28 disease_cataract disease_kidney stone/ureter stone/bladder stone 29 disease_chronic skin ulcers disease_angina 30 31 disease_essential hypertension disease_gout 32 disease_asthma NA 33 disease_sleep apnoea disease_angina
34 disease_hypertension disease_high cholesterol http://bmjopen.bmj.com/ 35 disease_irritable bowel syndromedisease_diabetes 36 37 disease_sciatica disease_nasal/sinus disorder 38 disease_rheumatic fever disease_osteomyelitis 39 disease_bladder problem (not cancer)disease_helicobacter pylori 40 disease_rheumatic fever disease_irritable bowel syndrome 41 42 disease_osteoporosis disease_chronic/degenerative neurological problem on September 26, 2021 by guest. Protected copyright. 43 disease_helicobacter pylori disease_urinary tract infection/kidney infection 44 disease_other abdominal problemdisease_high cholesterol 45 disease_osteoarthritis disease_tuberculosis (tb) 46 47 disease_back problem disease_hiatus hernia 48 disease_bladder problem (not cancer)disease_ankylosing spondylitis 49 disease_high cholesterol disease_hayfever/allergic rhinitis 50 disease_depression disease_gastro-oesophageal reflux (gord) / gastric reflux 51 52 disease_hypertension disease_hypothyroidism/myxoedema 53 disease_helicobacter pylori disease_peripheral vascular disease 54 disease_rectal or colon adenoma/polypsdisease_spine arthritis/spondylitis 55 disease_pneumonia disease_heart arrhythmia 56 57 disease_uterine problem disease_anaemia 58 disease_anxiety/panic attacks disease_other joint disorder 59 disease_osteoarthritis disease_high cholesterol 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 71 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 disease_asthma disease_eczema/dermatitis 3 disease_migraine disease_osteoarthritis 4 disease_stomach disorder disease_chronic fatigue syndrome 5 6 disease_emphysema/chronic bronchitisdisease_heart attack/myocardial infarction 7 disease_angina disease_hypertension 8 disease_cataract disease_high cholesterol 9 disease_type 2 diabetes disease_transient ischaemic attack (tia) 10 11 disease_urinary tract infection/kidneydisease_pulmonary infection embolism +/- dvt 12 disease_hiatus hernia disease_uterine problem 13 disease_depression disease_hayfever/allergic rhinitis 14 disease_eye/eyelid problem disease_gastro-oesophageal reflux (gord) / gastric reflux 15 For peer review only 16 NA NA 17 disease_chronic skin ulcers disease_cerebral aneurysm 18 disease_transient ischaemic attackdisease_stroke (tia) 19 disease_vasculitis disease_heart attack/myocardial infarction 20 21 disease_peripheral nerve disorderdisease_stroke 22 disease_hypertension disease_asthma 23 disease_vitiligo disease_lichen sclerosis 24 disease_eye/eyelid problem disease_osteoporosis 25 26 disease_depression disease_high cholesterol 27 disease_hypothyroidism/myxoedemadisease_asthma 28 disease_osteoporosis disease_irritable bowel syndrome 29 disease_renal/kidney failure disease_anaemia 30 31 disease_chronic fatigue syndromedisease_hyperthyroidism/thyrotoxicosis 32 disease_peripheral nerve disorderdisease_cervical spondylosis 33 disease_depression disease_gall bladder disease
34 disease_duodenal ulcer disease_head injury http://bmjopen.bmj.com/ 35 disease_hereditary/genetic haematologicaldisease_peripheral disorder nerve disorder 36 37 disease_peripheral vascular diseasedisease_ankylosing spondylitis 38 disease_diabetes disease_eye/eyelid problem 39 disease_osteopenia disease_vasculitis 40 disease_scleroderma/systemic sclerosisdisease_connective tissue disorder 41 42 disease_migraine disease_uterine problem on September 26, 2021 by guest. Protected copyright. 43 disease_vasculitis disease_breast cysts 44 disease_pleurisy disease_eye/eyelid problem 45 disease_renal failure requiring dialysisdisease_rheumatic fever 46 47 disease_urinary tract infection/kidneydisease_bladder infection problem (not cancer) 48 disease_glaucoma disease_angina 49 disease_stroke disease_diverticular disease/diverticulitis 50 disease_helicobacter pylori disease_peripheral vascular disease 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 72 of 75
Legends for supplementary figures and tables 1 2
3 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from 4 5 Supplementary Figure 1 6 7 All medications are presented according to the three classification levels used for analysis (i.e. chemical 8 substance, chemical subgroup and therapeutic subgroup) and aggregated by their anatomical groups (see 9 10 Methods). Numbers in parenthesis next to a medication name on the left indicate the classification level of 11 the medication: (1) chemical substance, (2) chemical subgroup, (3) therapeutic subgroup and (4) 12 anatomical group. Some extra formatting is included in the Y-axis to ease visual inspection of the drug 13 classification tree. First, all labels are sorted such that, for any given category, the descendants in the 14 15 classification tree appear below. Secondly, an arrow is included besides each label such that its length 16 represents how deep the drug or drug group is in the classification tree. Namely, no arrow for the 17 anatomical group, “<-“ forFor therapeutic peer subgroup, review“<--“ for chemical subgrouponly and “<---“ for chemical 18 substance. 19 20 Relationship between medication and each cognitive test are represented by effect size and 95% 21 22 confidence intervals across three columns: verbal-numerical reasoning test (score), memory test (score) 23 and reaction time test (ms). For all three tests, negative values indicate poorer cognitive performance and 24 vice versa. The corresponding p-values after false discovery rate (FDR) correction for multiple comparisons 25 were indicated by filled circles with red line (p < .005), empty circle (p < .05) and ‘x’ with black line (p > .05). 26 27 *Abbreviations: ACE = angiotensin converting enzyme, TNF = tumour necrosis factor, RTI = reverse 28 transcriptase inhibitor, GI = gastroinstestinal. 29 30 31 32 Supplementary table 1 33 34 35 As described in the Methods section, for every medication, odds ratios (OR) between the medication of 36 interest and each of all other 367 medications were calculated. The 10 medications with highest OR were 37 selected as covariates in the linear model. The table shows all studied medication (total 368 rows) and their 38 http://bmjopen.bmj.com/ 39 top 10 OR medications (10 columns: highest on the left). To avoid anomalously high OR values in the low 40 frequency medications, medications with less than 10 co-prescriptions with the medication of interest (e.g. if 41 Medication of interest A and Medication B were taken together by only 3 participants, Medication B was not 42 considered as a covariate regardless of its OR) were excluded. Due to this exclusion, few medications had 43 44 less than 10 medications in the model (displayed as NA, not available). 45 46 47 on September 26, 2021 by guest. Protected copyright. 48 Supplementary table 2 49 50 51 As described in the Methods section, for every medication, odds ratios (OR) between the medication of 52 interest and each of all 278 diagnoses were calculated. The 10 diagnoses with highest OR were selected 53 as covariates in the linear model. The table shows all studied medication (total 368 rows) and their top 10 54 55 OR diagnoses (10 columns: highest on the left). To avoid anomalously high OR values in the low frequency 56 medications, diagnoses with less than 10 co-occurrences with the medication of interest (e.g. if Medication 57 of interest A and Diagnosis B co-occurred in only 3 participants, Diagnosis B was not considered as a 58 covariate regardless of its OR) were excluded. Due to this exclusion, few medications had less than 10 59 60 diagnoses in the model (displayed as NA, not available).
1
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Page 73 of 75 BMJ Open
1 2 3 4
5
6
7 8 skeletal -
9 10 11 For peer review only 12 cardiovascular immune/cancer nervoussystem respiratorysystem & metabolismGI urinary supplements blood organs antiinfectives hormones and modulators ophthalmologicals musculo dermatologicals 13 61.12 ± 56.84 ± 57.01 ± 57.42 ± 59.7 ± 62.06 ± 59.01 ± 61.24 ± 58.49 ± 57 ± 61.97 ± 61.57 ± 57.25 ± Age (years) 14 6.51** 8.17** 8.15 8.2** 7.41** 6.26** 7.54** 6.81** 7.97** 7.94 6.37** 6.33** 7.73 15 Gender (women) 16 46.7%** 60.5%** 64.5%** 59.3%** 53.5%** 24%** 65.1%** 38.6%** 55.7%** 90.4%** 59%** 55.3%* 78.8%** Education
17 http://bmjopen.bmj.com/ 18 A-levels and above 33.8%** 41%** 36.1%** 39.5%** 31.8%** 37%** 40.3%** 35.4%** 37.9%** 41.7%** 37.7%** 35.2%** 38.7%** 19 Other educational qualifications 32.2%** 33.7%** 33.9%** 32.3%* 33.3%** 30.5%** 33% 30.7%** 31.6%** 33.8%** 30.2%** 32.10% 34.9%** 20 21 Professional qualifications only 6.2%** 5.3%* 5.3%** 5.20% 6.2%** 6%** 5.9%** 5.9%** 5.40% 5.8%** 6.4%** 6%** 5.20% 22 None of the above 25.5%** 18.4%** 22.9%** 20.9%** 26.4%** 24.6%** 19%** 25.8%** 23.2%** 16.80% 23.1%** 24.8%** 19.5%** 23 Prefer not to answer 2.3%** 1.7%** 1.9%** 2.1% 2.3%** 1.9% 1.8%** 2.3%** 2% 1.8%** 2.5%** 1.9% 1.7%* 24 Household income (GBP/year) 25 26 < 18,000 27%** 21.7%** 26.9%** 25%** 29.3%** 28%** 22.4%** 27.8%** 27.3%** on September 26, 2021 by guest. Protected copyright. 20.8%** 27.9%** 27.4%** 23%** 27 18,000-30,999 24%** 21.5%* 21.6%* 21.3%* 22.6%** 24.9%** 23.9%** 23.8%** 21.80% 21.80% 24%** 24.2%** 22.40% 28 31,000-51,999 18.3%** 21.5%** 19.2%** 20%** 17.4%** 19%** 20.7%** 17.9%** 18.3%** 21.2%** 16.4%** 16.8%** 20.9%** 29 30 52,000-100,000 11.1%** 16.4%** 13%** 14.7%** 10.5%** 11.3%** 13.4%** 11.4%** 13%** 15.7%** 9.6%** 10.3%** 13.7%** 31 > 100,000 2.8%** 4.1%** 2.9%** 3.4%** 2.4%** 2.6%** 3%** 3.1%** 3.2%** 4.2%** 2.3%** 3%** 2.9%** 32 Do not know 5.4%** 4.7%** 6%** 5.4%** 6.3%** 4.3% 5.1%** 5.2%** 6%** 5.2%** 6.7%** 6.2%** 5.7%** 33 Prefer not to answer 34 11.4%** 9.9% 10.4%** 10.10% 11.5%** 9.8% 11.6%** 10.7%** 10.5% 11.1%** 13%** 12%** 11.5%** 35 36 Supplementary Table 3. Baseline characteristics of drug users The table shows summary statistics for all users of drugs belonging to each anatomical 37 category. As in Table 1, values indicate mean ± standard deviation for age, or percentages for gender, education and household income. Age of drug users 38 (row two) is compared with the average age of all participants (row three column two of Table 1) with a Wilcoxon test. All other proportions in the table (which 39 40 were calculated for drug users) are compared with those corresponding to all participants (i.e. drug users and non-drug users, column 2 of supplementary 41 Table 2) using a binomial test. FDR corrected p-value below .005 is indicated with two stars, while p-value below .05 is indicated with one star. 42 43 2 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 74 of 75
Participants completed cognitive test 1 All 2 participants Verbal-numerical
Memory Reaction time BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from 3 reasoning 4 5 cardiovascular 28.3% 29%** 28%** 28.2% 6 immune/cancer 25.2% 24.8%** 25.4% 25.3% 7 nervous system 28.2% 27.1%** 28%* 28.1% 8 9 respiratory system 9.3% 9.2% 9.3% 9.3% 10 GI & metabolism 16.7% 16.6% 16.5%** 16.6% 11 urinary 2.7% 2.8%* 2.7% 2.7% 12 supplements 19.5% 14.8%** 19.5% 19.5% 13 14 blood organs 15.4% 13.7%** 15.2%** 15.3% 15 antiinfectives 2.8% 2.7%** 2.8% 2.8% 16 hormones and modulators 10.6% 10.7% 10.6% 10.6% 17 For peer review only 18 ophthalmologicals 1.8% 1.8% 1.7% 1.7% 19 musculo-skeletal 3.1% 3.4%** 3.1% 3.1% 20 dermatologicals 2.7% 1.9%** 2.7% 2.7% 21 22 Supplementary Table 4. Drug users per cognitive test. For the participants of each cognitive test 23 24 (columns two, three and fourth), the table shows the proportion of them that was using drugs belonging to 25 each anatomical category (rows). The total proportion of drugs users is shown in column two. A binomial 26 test was used to compare columns three-fourth with column two. FDR corrected p-value below .005 is 27 indicated with two stars, while p-value below .05 is indicated with one star. 28 29
30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 26, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60
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For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from 4 4 NA NA 1,2 1,2
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5 5 4 4 NA Reported on page # Reported on page 2 2 4 4
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BMJ Open http://bmjopen.bmj.com/ on September 26, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
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Page 75 of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from Page 76 of 75 7 7 5,11 4 4
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Participants 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
Commonly prescribed drugs associate with cognitive function: a cross-sectional study in UK Biobank
ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2016-012177.R2
Article Type: Research
Date Submitted by the Author: 28-Jul-2016
Complete List of Authors: Nevado-Holgado, Alejo; University of Oxford, Psychiatry Kim, Chi-Hun; University of Oxford, Psychiatry Winchester, Laura; University of Oxford, Psychiatry Gallacher, John; University of Oxford, Psychiatry Lovestone, Simon; University of Oxford, Psychiatry
Primary Subject Public health Heading:
Secondary Subject Heading: Mental health, Pharmacology and therapeutics, Neurology
Keywords: PUBLIC HEALTH, MENTAL HEALTH, Cognition, UK biobank
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1 2 3 Commonly prescribed drugs associate with cognitive function: a cross- 4 sectional study in UK Biobank 5 6 7 8 Authors 9 10 Alejo J Nevado Holgado*, Chi Hun Kim*, Laura Winchester, John Gallacher, Simon Lovestone 11 12 13 14 15 Address For peer review only 16 17 Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK 18 19 20 21 22 23 Authors’ names and positions 24 25 Alejo J Nevado Holgado*: Postdoctoral researcher 26 27 Chi Hun Kim*: Postdoctoral researcher 28 29 Laura Winchester: Postdoctoral researcher 30 31 John Gallacher: Professor 32 33 Simon Lovestone: Professor
34 http://bmjopen.bmj.com/ 35 *These authors contributed equally to this work. 36
37 38
39 40 Correspondence to: S Lovestone [email protected] 41 42 on September 26, 2021 by guest. Protected copyright. 43 44
45 46
47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 21 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from Abstract 1 2 Objective To investigate medications associated with cognitive function 3 4 Design Population based cross sectional cohort study 5 6 Setting UK Biobank 7 8 Participants UK Biobank participants aged 37 73 years who completed cognitive tests at the baseline visit 9 in 2006 2010 10 11 Main outcome measures Cognitive test outcomes on verbal numerical reasoning test (n=165493), 12 memory test (n=482766) and reaction time test (n=496813). 13 14 Results Most drugs (262 of 368) were not associated with any cognitive tests after adjusting for age, 15 For peer review only 16 gender, education, household income, smoking, alcohol status, psychostimulant/nootropic medication use, 17 assessment centre and concurrent diagnoses and medications. Drugs used for nervous system disorders 18 were associated with poorer cognitive performance (antiepileptics e.g. topiramate breasoning(score) 0.65
19 [95%CI: 1.05, 0.24], bmemory(score) 1.41[ 1.79, 1.04]; antipsychotics e.g. risperidone breaction time(ms) 33[ 46, 20 20], negative values indicate poor cognitive performance and vice versa). Drugs used for non nervous 21 system conditions also showed significant negative association with cognitive score, including those where 22 23 such an association might have been predicted (antihypertensives e.g. amlodipine breasoning 0.1[ 0.15, 24 0.06], bmemory 0.08[ 0.13, 0.03], breaction time 3[ 5, 2]; antidiabetics e.g. insulin breaction time 13[ 17, 10]) and 25 others where such an association was a surprising observation (proton pump inhibitors e.g. omeprazole
26 breasoning 0.11[ 0.15, 0.06], bmemory 0.08[ 0.12, 0.04], breaction time 5[ 6, 3]; laxatives e.g. contact laxatives 27 breaction time 13[ 19, 8]). Finally, only a few medications and health supplements showed association towards 28 a positive effect on cognitive function (anti inflammatory agents e.g. ibuprofen b 0.05[0.02, 0.08], 29 reasoning 30 breaction time 4[3, 5]; glucosamine breasoning 0.09[0.03, 0.14], breaction time 5[3, 6]). 31 32 Conclusions In this large volunteer study, some commonly prescribed medications were associated with 33 poor cognitive performance. Some associations may reflect underlying diseases for which the medications
34 were prescribed, although the analysis controlled for the possible effect of diagnosis. Other drugs, whose http://bmjopen.bmj.com/ 35 association cannot be linked to the effect of any disease, may need vigilance for their implications in clinical 36 practice. 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from Strengths and limitations of this study 1 2 • Using a very large UK population cohort, this study was sufficiently powered to perform a systematic 3 investigation for a range of medications and its association with cognitive function. 4 5 • We report multiple associations between commonly prescribed medications and poorer or better 6 cognitive performance, which may have implications for clinicians and patients. 7 • Due to the cross sectional design, it is difficult to make causal inferences between medication and 8 cognitive function. 9 • Although trained nurses interviewed participants to obtain medications and diagnoses, this self 10 11 reported nature may limit the accuracy of information. 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 21 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from Introduction 1 2 A significant number of drugs are used for therapeutic indications other than those they were either 3 designed, or first used for. Well known examples include Viagra, developed for cardiac indications but used 4 for erectile failure, and aspirin, used in an increasingly wide range of indications. This phenomenon has 5 6 prompted systematic efforts to repurpose compounds already in clinical practice.[1,2] In the field of 7 cognitive performance, repurposing approaches have included consensus building using understanding 8 from epidemiology to molecular sciences,[3] and informatics driven approaches using platforms such as the 9 connectivity map,[1] which derives gene expression signatures from in vitro cells exposed to drugs and 10 matches these to disease associated signatures. In this paper we adopt a real world evidence approach, 11 analysing data from UK Biobank, a large scale population based cohort study to identify compounds that 12 13 are associated with cognitive performance. 14 15 For peer review only 16 17 Methods 18 19 UK Biobank is a prospective study of a half million participants across the UK with extensive data from 20 questionnaires, interviews, physical measures, biological samples and imaging.[4] This study used baseline 21 data from 502647 subjects aged between 37 and 73 years collected at 21 assessment centres from 2006 22 2010. 23 24 Outcome and other measures 25 26 Three cognitive tests (verbal numeric reasoning, memory and reaction time), were administered using a 27 touch screen.[5–7] These tests cover domains that have been shown to be sensitive to change over time 28 29 and are widely used in studies of ageing and brain disorders.[8–10] For verbal numerical reasoning, 30 subjects were asked to solve as many multiple choice questions as possible (maximum 13) within two 31 minutes. Performance was assessed as the total number of correct responses. Memory was assessed 32 using the pairs matching test in which subjects had to remember 6 pairs of shapes and their locations 33 displayed for 5 seconds. Performance was assessed as the total number of errors made in matching all 6
34 http://bmjopen.bmj.com/ pairs. Reaction time was measured by pressing a button as quickly as possible when two identical shapes 35 36 were presented. Performance was assessed as the mean reaction time (ms) of eight trials for correctly 37 identified matching pairs. 38 39 Medications and diagnoses were obtained by nurse led interview. Only regular medications and health 40 supplements taken weekly, monthly or three monthly were recorded. Medications were recorded using 41 6745 categories adapted from Read code version 3 (CTV3) used in the general practice in the UK. Of 42 these, 1192 medications were taken by 30 or more participants, and were classified using the Anatomical on September 26, 2021 by guest. Protected copyright. 43 Therapeutic Chemical (ATC) classification [11] as a backbone. For example, brand names with different 44 45 doses were allocated into their chemical substance (e.g. Lipitor and atorvastatin were treated as 46 atorvastatin), chemical subgroup (e.g. HMG CoA reductase), therapeutic subgroup (e.g. lipid modifying 47 agents) and anatomical group (e.g. cardiovascular system). Compound medications were divided into 48 single chemical substances (e.g. CoAprovel into irbesartan and hydrochlorothiazide). Duration and dosage 49 of the medications were not collected by UK Biobank and hence not available for analysis. 50 51 Demographic and lifestyle variables included in the model were age, gender, education, household income, 52 smoking, alcohol status, psychostimulant/nootropic medication use and assessment centre. 53 54 Statistical analyses 55 56 For each cognitive test, performance was regressed on each medication, adjusting for other medication 57 58 use, comorbidity (diagnosis), and a range of demographic variables using multivariable linear regression on 59 all participants with complete data. Medications and comorbidities were modelled as binary variables. Due 60 to the large number of medications, the problem was simplified by identifying for each the 10 medications For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from that were most strongly associated with use of the target medication as indicated by the odds ratio. The 1 number of potential comorbidities was reduced to 10 using the same method (see Supplementary tables 1 2 and 2 for top 10 odds ratio tables). Education was modelled as a 5 level factor (A levels and above, O 3 4 levels or equivalent, professional qualifications only, none of the above, prefer not to answer), annual 5 household income as a 7 level factor (£<18K, 18 30.9K, 31K 51.9K, 52 100K, >100K, do not know, prefer 6 not to answer), and smoking and alcohol status as 4 level factors (current, previous, never, prefer not to 7 answer). Nominal scales were due to non ordinal options such as the ‘prefer not to answer’ option. Gender 8 and use of psychostimulants or nootropics were each modelled as binary variables. 9 10 Full adjustment was made in all models. Analyses were conducted at three medication classification levels 11 (chemical substance, chemical subgroup and therapeutic subgroup) separately and are presented 12 13 according to functional system (e.g. nervous, cardiovascular, gastrointestinal and metabolism, immune, 14 others). Results are presented as regression coefficients (b, unstandardised) with 95% confidence 15 intervals. For peer review only 16 17 Statistical power was estimated on the basis of a binomial test with unequal group sizes. To detect an 18 effect size of b=0.25 SD with 80% power at a significance level of 0.05, 125 reported users were required. 19 This criterion was met for 368 chemical substances, 165 chemical subgroups and 68 therapeutic 20 subgroups. If the criterion was not met the medication was omitted from the analysis. False discovery rate 21 22 was used to correct for multiple comparisons. 23 24 25 26 Results 27 28 Table 1 gives the distributions of the cognitive and demographic variables (see Supplementary tables 3 and 29 4 for further details). The numbers available for the analysis varied as the cognitive tests were introduced at 30 different times during the baseline assessment. Verbal and numeric reasoning was normally distributed 31 with a test retest correlation of 0.62. The memory score was positively skewed with a test retest correlation 32 of 0.15. Reaction time was log normally distributed with a test retest correlation of 0.85. 33
34 Most drugs were not associated with significant difference in any of the cognitive tests after adjustment for http://bmjopen.bmj.com/ 35 36 confounding. Figure 1 shows the effect sizes for the 32 medications and 31 higher medication classification 37 categories (e.g. amlodipine as a medication and calcium channel blockers as a higher category). Results 38 for all 368 medications and their higher categories can be found in Supplementary Figure 1. In Figure 1 39 most drugs were associated with poorer cognitive performance i.e. fewer correct answers on the reasoning 40 test, more errors on the memory test, and longer reaction time. The scores are presented such that 41 negative values correspond to poor cognitive performance and vice versa. 42 on September 26, 2021 by guest. Protected copyright. 43 Medications prescribed for nervous system disorders showed the strongest associations with cognitive 44 45 performance relative to the other systems. For example, users of levetiracetam and toparimate had one 46 more error on the memory test, and users of benzamides and primidone had a 50ms slower mean reaction 47 time when compared to non users. Among anti epileptics, topiramate was associated with poor cognitive
48 scores (breasoning(score) 0.65[ 1.05, 0.24], bmemory(score) 1.41[ 1.79, 1.04]) as was levetiracetam (bmemory 0.75[ 49 1.12, 0.37], breaction time(ms) 32[ 44, 20]). Among antipsychotics, risperidone were associated with slower 50 reaction time ( 33[ 46, 20]). 51 52 Among cardiovascular medications, first line antihypertensives such as ACE inhibitors were associated with 53 54 more correct responses in the reasoning test (e.g. perindopril 0.17[0.08, 0.25]). However calcium blocking 55 channels (e.g. amlodipine breasoning 0.1[ 0.15, 0.06], bmemory 0.08[ 0.13, 0.03], breaction time 3[ 5, 2]) and 56 some diuretics (e.g. furosemide breaction time 9[ 12, 5]) were associated with poorer cognitive function. 57 58 In the gastroinstestinal (GI) tract and metabolism system, drugs for diabetes were adversely associated 59 with cognitive performance. Insulin was related to slower reaction time ( 13[ 17, 10]). Proton pump 60 inhibitors (PPI) were adversely related to reasoning, memory and reaction time (e.g. omeprazole breasoning For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 21 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
0.11[ 0.15, 0.06], bmemory 0.08[ 0.12, 0.04], breaction time 5[ 6, 3]). Laxatives (including contact and osmotic 1 but not bulk form laxatives) were associated with slower reaction time. 2 3 Immunomodulating medications were among the very few drugs that showed beneficial cognitive 4 associations. For example, ibuprofen was related to significantly better reasoning test and reaction time 5 6 (breasoning 0.05[0.02, 0.08], breaction time 4[3, 5]), as were some cancer medications when tested at the 7 subgroup level (e.g. aromatase inhibitors, breasoning 0.28[0.13, 0.43]). Similar but non significant beneficial 8 trends were found in anti inflammatory/antineoplastic medication such as meloxicam, methotrexate and 9 TNF alpha inhibitors. However these associations were not found in other anti inflammatory medications 10 e.g. diclofenac and corticosteroids, and were reversed in some non inflammatory analgesics (e.g. 11 paracetamol b 0.19[ 0.21, 0.16], b 0.11[ 0.13, 0.08], b 5[ 6, 4]). 12 reasoning memory reaction time 13 Some health supplements (e.g. glucosamine b 0.09[0.03, 0.14], b 5[3, 6]) showed beneficial 14 reasoning reaction time 15 cognitive association.For But supplements peer used for review anaemia (e.g. iron b reasoningonly 0.16[ 0.27, 0.06]) or 16 osteoporosis (e.g. calcium breaction time 4[ 7, 2]) were related to poor cognitive function. 17 18 19 20 Discussion 21 22 This analysis of a large and diverse population based cohort has shown considerable evidence for an 23 association between commonly prescribed medications and cognitive performance. Of interest is the extent 24 to which these associations reflect an effect of the medication on cognitive performance or a wider context, 25 such as an effect of the underlying disorder, comorbidity or socioeconomic context. 26 27 Examples of associations where there is an a priori reason to suspect a primary relationship with an 28 underlying disease includes antipsychotics, drugs used to treat Parkinson’s disease and antiepileptics. In 29 30 each case these classes of compound are most commonly used for diseases known to have an element of 31 cognitive impairment as part of the core syndrome [9,12,13] although, in addition, antipsychotics and 32 antiepileptics are known to have independent effects on cognitive performance.[14–17] 33
34 We also find associations with medications for which there is a plausible association with a cognitive http://bmjopen.bmj.com/ 35 component of the underlying disease but where cognitive ability is not a necessary or well established part 36 of the underlying syndrome. Examples include anti diabetes medications (e.g. insulin and sulfonylurea), 37 antihypertensives (e.g. calcium channel blockers and diuretics) and anaemia medications. Both diabetes 38 39 and hypertension are associated with cognitive impairment.[18,19] That we find an association between 40 drugs used to treat anaemia iron and thiamine (i.e. vitamin B1) and poor cognitive performance lends 41 weight to those studies that suggest poor cognitive function is associated with anaemia.[20] Our findings 42 show that this association is not limited to elderly or frail populations. on September 26, 2021 by guest. Protected copyright. 43 44 For several medications however, associations with cognitive performance might not be expected. 45 Examples include PPIs, calcium and laxatives. Recent studies have found PPIs to be associated with an 46 increased risk of dementia.[21,22] Osteoporosis, one of the most common indications for calcium, has also 47 48 been associated with increased risk of dementia.[23,24] In the present study, participants in their middle 49 age taking PPIs or calcium showed poorer cognitive performance compared to non takers. Additionally 50 many laxatives showed a strong association with increased reaction time. It is unclear whether these 51 associations were due to the side effects of medications or underlying syndromes for which they were 52 prescribed. 53
54 55 For a small number of medications, use was associated with better cognitive performance. It is interesting 56 that there is a small but significant association with ibuprofen and comparable but non significant trends 57 with other anti inflammatories including meloxicam, methotrexate and TNF alpha inhibitors. The importance 58 of inflammation in Alzheimer’s disease and other dementias is increasingly recognised [25] and these 59 findings are consistent with the known effect of anti inflammatory medication including nonsteroidal anti 60 inflammatory medication in reducing incidence of dementia [26,27]. These data suggest that an effect of For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from anti inflammatory medication may be detectable within the normal range of cognitive function. Alternatively, 1 it might be that anti inflammatory medications have a dementia independent beneficial effect on cognitive 2 function and that previous evidence suggesting a protective effect in relation to dementia reflects this. This 3 4 is clearly a critical distinction as is the observation that the association we observe is not present in all anti 5 inflammatory medications including, for example acetic acid derivatives and fenamates. 6 7 The limitations of the study suggest these findings should be interpreted cautiously. The data are cross 8 sectional, and medications and diagnoses are self reported. Residual confounding cannot be discounted. 9 The cognitive battery is not exhaustive and the tests are indicative of cognitive function rather than 10 11 definitive. Also, the tests are of variable psychometric quality. Nevertheless, that associations were 12 detected using relatively coarse cognitive measures does not suggest that the associations are spurious, 13 but that more detailed testing would be informative. As with all real world data, these findings require 14 replication in other cohort and clinical datasets. Moreover, although in a cross sectional study such as this 15 we cannot concludeFor that the associations peer we observe review are due to change only in cognition for a given individual, 16 clearly that is a possibility and if medications do influence change then any decline is likely to be of 17 18 importance to that person. Limitations notwithstanding, that associations have been detected at a 19 population level and within the normal distribution of cognitive performance is consistent with 20 neurodegeneration being an incremental process that begins many decades before clinical presentation, 21 and which might be amenable to prophylaxis. 22 23 In summary, in a large and diverse population cohort, associations between medication and cognitive 24 performance have been found. Causal inferences cannot be drawn from these data, but the findings 25 illustrate the opportunities and challenges of real world data. 26 27
28 29
30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 21 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from This research has been conducted using the UK Biobank resource. 1 2 3 4 Contributors: ANH, CHK, LW, JG and SL contributed to study design and wrote the manuscript; ANH, 5 CHK and LW contributed to data acquisition; ANH and CHK conducted data processing and statistical 6 analyses; SL is the guarantor. 7 8 9 10 Funding: We received funding for this analysis through the Medical Research Council Dementias Platform 11 UK (MR/L015382/1) and the Wellcome Trust Consortium for Neuroimmunology for Mood Disorders and 12 13 Alzheimer’s Disease (104025/Z/14/Z). The funders had no influence on study design, data collection and 14 analysis, decision to publish, or preparation of the manuscript. 15 For peer review only 16 17 18 Competing interests: All authors have completed the ICMJE uniform disclosure form at 19 www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work ; 20 no financial relationships with any organisations that might have an interest in the submitted work in the 21 previous three years; no other relationships or activities that could appear to have influenced the submitted 22 work. 23 24
25 26 Ethical approval: This study has been conducted using UK Biobank data. UK Biobank has received ethics 27 28 approval from the UK Biobank Research Ethics Committee (ref 11/NW/0382). 29 30 31 32 Transparency statement: The lead author (the manuscript’s guarantor) affirms that this manuscript is an 33 honest, accurate, and transparent account of the study being reported; that no important aspects of the
34 study have been omitted; and that any discrepancies from the study as planned (and, if relevant, http://bmjopen.bmj.com/ 35 registered) have been explained. 36 37 38 39 Data sharing: No additional data are available.. 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 Copyright The Corresponding Author has the right to grant on behalf of all authors and does grant on 44 behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all forms, 45 formats and media (whether known now or created in the future), to i) publish, reproduce, distribute, display 46 and store the Contribution, ii) translate the Contribution into other languages, create adaptations, reprints, 47 48 include within collections and create summaries, extracts and/or, abstracts of the Contribution, iii) create 49 any other derivative work(s) based on the Contribution, iv) to exploit all subsidiary rights in the Contribution, 50 v) the inclusion of electronic links from the Contribution to third party material where ever it may be located; 51 and, vi) licence any third party to do any or all of the above. All research articles will be made available on 52 an Open Access basis (with authors being asked to pay an open access fee. The terms of such Open 53 Access shall be governed by a Creative Commons licence—details as to which Creative Commons licence 54 55 will apply to the research article are set out in our worldwide licence referred to above. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from References 1 2 1 Chung F H, Chiang Y R, Tseng A L, et al. Functional Module Connectivity Map (FMCM): a framework 3 for searching repurposed drug compounds for systems treatment of cancer and an application to 4 colorectal adenocarcinoma. PloS One 2014;9:e86299. doi:10.1371/journal.pone.0086299 5 6 2 Corbett A, Pickett J, Burns A, et al. Drug repositioning for Alzheimer’s disease. Nat Rev Drug Discov 7 2012;11:833–46. doi:10.1038/nrd3869 8 9 3 Corbett A, Williams G, Ballard C. Drug repositioning in Alzheimer’s disease. Front Biosci Sch Ed 10 2015;7:184–8. 11 12 4 Sudlow C, Gallacher J, Allen N, et al. UK Biobank: An Open Access Resource for Identifying the 13 Causes of a Wide Range of Complex Diseases of Middle and Old Age. PLoS Med 2015;12:e1001779. 14 doi:10.1371/journal.pmed.1001779 15 For peer review only 16 5 Hagenaars SP, Harris SE, Davies G, et al. Shared genetic aetiology between cognitive functions and 17 physical and mental health in UK Biobank (N=112 151) and 24 GWAS consortia. Mol Psychiatry 18 Published Online First: 26 January 2016. doi:10.1038/mp.2015.225 19 20 6 Davies G, Marioni RE, Liewald DC, et al. Genome wide association study of cognitive functions and 21 educational attainment in UK Biobank (N=112 151). Mol Psychiatry 2016;21:758–67. 22 doi:10.1038/mp.2016.45 23 24 7 Lyall DM, Cullen B, Allerhand M, et al. Cognitive Test Scores in UK Biobank: Data Reduction in 25 480,416 Participants and Longitudinal Stability in 20,346 Participants. PLOS ONE 2016;11:e0154222. 26 doi:10.1371/journal.pone.0154222 27 28 8 Harada CN, Natelson Love MC, Triebel KL. Normal cognitive aging. Clin Geriatr Med 2013;29:737–52. 29 doi:10.1016/j.cger.2013.07.002 30 31 9 Svenningsson P, Westman E, Ballard C, et al. Cognitive impairment in patients with Parkinson’s 32 disease: diagnosis, biomarkers, and treatment. Lancet Neurol 2012;11:697–707. doi:10.1016/S1474 33 4422(12)70152 7
34 http://bmjopen.bmj.com/ 35 10 Weintraub S, Wicklund AH, Salmon DP. The Neuropsychological Profile of Alzheimer Disease. Cold 36 Spring Harb Perspect Med 2012;2. doi:10.1101/cshperspect.a006171 37 38 11 WHO Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC classification and DDD 39 assignment 2016. Oslo: 2016. http://www.whocc.no/atc_ddd_publications/guidelines/ 40 41 12 Barch DM, Ceaser A. Cognition in schizophrenia: core psychological and neural mechanisms. Trends 42 Cogn Sci 2012;16:27–34. doi:10.1016/j.tics.2011.11.015 on September 26, 2021 by guest. Protected copyright. 43 44 13 Berg AT. Epilepsy, cognition, and behavior: The clinical picture. Epilepsia 2011;52 Suppl 1:7–12. 45 doi:10.1111/j.1528 1167.2010.02905.x 46 47 14 Bédard MA, Schérer H, Stip E, et al. Procedural learning in schizophrenia: further consideration on the 48 deleterious effect of neuroleptics. Brain Cogn 2000;43:31–9. 49 50 15 Reilly JL, Harris MSH, Keshavan MS, et al. Adverse effects of risperidone on spatial working memory in 51 first episode schizophrenia. Arch Gen Psychiatry 2006;63:1189–97. doi:10.1001/archpsyc.63.11.1189 52 53 16 Mula M, Trimble MR. Antiepileptic drug induced cognitive adverse effects: potential mechanisms and 54 contributing factors. CNS Drugs 2009;23:121–37. 55 56 17 Park S P, Kwon S H. Cognitive Effects of Antiepileptic Drugs. J Clin Neurol Seoul Korea 2008;4:99– 57 106. doi:10.3988/jcn.2008.4.3.99 58 59 18 Sadanand S, Balachandar R, Bharath S. Memory and executive functions in persons with type 2 60 diabetes: a meta analysis. Diabetes Metab Res Rev 2016;32:132–42. doi:10.1002/dmrr.2664 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 21 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from 19 Elias MF, Goodell AL, Dore GA. Hypertension and Cognitive Functioning A Perspective in Historical 1 Context. Hypertension 2012;60:260–8. doi:10.1161/HYPERTENSIONAHA.111.186429 2 3 20 Andro M, Le Squere P, Estivin S, et al. Anaemia and cognitive performances in the elderly: a 4 systematic review. Eur J Neurol 2013;20:1234–40. doi:10.1111/ene.12175 5 6 21 Gomm W, von Holt K, Thomé F, et al. Association of proton pump inhibitors with risk of dementia: A 7 pharmacoepidemiological claims data analysis. JAMA Neurol Published Online First: 15 February 2016. 8 doi:10.1001/jamaneurol.2015.4791 9 10 22 Haenisch B, Holt K von, Wiese B, et al. Risk of dementia in elderly patients with the use of proton pump 11 inhibitors. Eur Arch Psychiatry Clin Neurosci 2014;265:419–28. doi:10.1007/s00406 014 0554 0 12 13 23 Chang K H, Chung C J, Lin C L, et al. Increased risk of dementia in patients with osteoporosis: a 14 population based retrospective cohort analysis. AGE 2013;36:967–75. doi:10.1007/s11357 013 9608 x 15 For peer review only 16 24 Zhou R, Zhou H, Rui L, et al. Bone loss and osteoporosis are associated with conversion from mild 17 cognitive impairment to Alzheimer’s disease. Curr Alzheimer Res 2014;11:706–13. 18 19 25 Heneka MT, Carson MJ, Khoury JE, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 20 2015;14:388–405. doi:10.1016/S1474 4422(15)70016 5 21 22 26 Zandi PP, Anthony JC, Hayden KM, et al. Reduced incidence of AD with NSAID but not H2 receptor 23 antagonists: the Cache County Study. Neurology 2002;59:880–6. 24 25 27 Szekely CA, Breitner JCS, Fitzpatrick AL, et al. NSAID use and dementia risk in the Cardiovascular 26 Health Study: role of APOE and NSAID type. Neurology 2008;70:17–24. 27 doi:10.1212/01.wnl.0000284596.95156.48 28 29 30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
Participants completed cognitive test 1 All
2 participants Verbal-numerical reasoning Memory Reaction time 3 (n = 502647) (n = 165493) (n = 482766) (n = 496813) 4 5.98 ± 2.16 4.25 ± 3.36 559 ± 118 Cognitive test score 5 (max. correct of 13) (no. of errors) (ms) 6 Age (years) 57.03 ± 8.09 57.20 ± 8.14 56.96 ± 8.08 57.02 ± 8.09 7 Gender (women) 55.0% 54.5% 54.5% 54.4% 8 Education 9 A levels and above 43.6% 45.7% 44.0% 43.4% 10 Other educational qualifications 33.2% 33.9% 33.4% 33.0% 11 Professional qualifications only 5.2% 5.2% 5.2% 5.1% 12 None of the above 17.2% 14.3% 16.4% 16.7% 13 Prefer not to answer 2.0% 2.0% 2.0% 1.7% Household income (GBP/year) 14 < 18,000 19.6% 18.8% 19.2% 19.2% 15 18,000 30,999 For peer21.8% review22.0% only21.9% 22.2% 16 31,000 51,999 22.3% 22.6% 22.6% 22.2% 17 52,000 100,000 17.4% 17.9% 17.7% 17.4% 18 > 100,000 4.6% 5.1% 4.7% 4.6% 19 Do not know 4.3% 3.9% 4.0% 4.1% 20 Prefer not to answer 10.0% 9.4% 9.7% 9.9% 21 22 Table 1. Baseline characteristics of participants The table shows summary statistics of all UK Biobank 23 participants (first column) and the participants who completed each cognitive test during their baseline visit 24 25 (second to fourth columns). Values indicate mean ± standard deviation for cognitive test score and age, or 26 percentages for gender, education and household income. 27 28 29 30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 21 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 Figure legend 3 4 5 6 Figure 1. Medication use and cognitive performance according to anatomical system A summary of 7 selected medications are presented here (for all medications see Supplementary Figure 1). As analyses 8 were conducted at three medication classification levels (see Methods), numbers in parenthesis next to a 9 medication name on the left indicate the classification level of the medication: (1) chemical substance, (2) 10 11 chemical subgroup and (3) therapeutic subgroup. Relationship between medication and each cognitive test 12 are represented by effect size and 95% confidence intervals across three columns: verbal numerical 13 reasoning test (score), memory test (score) and reaction time test (ms). For all three tests, negative values 14 correspond to poor cognitive performance and vice versa. The corresponding p values after false discovery 15 rate correction for multipleFor comparisons peer were indicated review by filled circles only with red line (p < .005), empty circle 16 (p < .05) and ‘x’ with black line (p > .05) *Abbreviations: ACE = angiotensin converting enzyme, TNF = 17 18 tumour necrosis factor, GI = gastroinstestinal 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 Figure 1. Medication use and cognitive performance according to anatomical system A summary of selected medications are presented here (for all medications see Supplementary Figure 1). As analyses were 48 conducted at three medication classification levels (see Methods), numbers in parenthesis next to a 49 medication name on the left indicate the classification level of the medication: (1) chemical substance, (2) 50 chemical subgroup and (3) therapeutic subgroup. Relationship between medication and each cognitive test 51 are represented by effect size and 95% confidence intervals across three columns: verbal-numerical 52 reasoning test (score), memory test (score) and reaction time test (ms). For all three tests, negative values 53 correspond to poor cognitive performance and vice versa. The corresponding p-values after false discovery 54 rate correction for multiple comparisons were indicated by filled circles with red line (p < .005), empty circle 55 (p < .05) and ‘x’ with black line (p > .05) *Abbreviations: ACE = angiotensin converting enzyme, TNF = tumour necrosis factor, GI = gastroinstestinal 56 Figure 1 57 304x365mm (300 x 300 DPI) 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 21 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
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1 Drug V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 captopril nifedipine furosemide doxazosin warfarin atenolol gliclazide glyceryl trinitrate bendroflumethiazide simvastatin amlodipine enalapril hydrochlorothiazide doxazosin moxonidine bendroflumethiazide carvedilol nifedipine furosemide bumetanide gliclazide mycophenolic acid fosinopril doxazosin pravastatin bendroflumethiazide rosuvastatin felodipine metformin diltiazem furosemide allopurinol amlodipine lisinopril glibenclamide glimepiride pioglitazone rosiglitazone hydrochlorothiazide insulin bendroflumethiazide metformin gliclazide doxazosin perindopril indapamide dipyridamole carvedilol lercanidipine spironolactone bisoprolol moxonidine nicorandil clopidogrel doxazosin 2 quinapril felodipine bendroflumethiazide doxazosin furosemide metformin amlodipine allopurinol bisoprolol atorvastatin acetylsalicylic acid ramipril carvedilol clopidogrel bisoprolol glyceryl trinitrate nicorandil isosorbide mononitrate metoprolol metformin pioglitazone acetylsalicylic acid trandolapril lercanidipine furosemide rosuvastatin doxazosin gliclazide nifedipine bendroflumethiazide insulin metformin felodipine diclofenac misoprostol tramadol leflunomide dihydrocodeine sulfasalazine methotrexate codeine hydroxychloroquine fentanyl morphine etodolac hydroxychloroquine sulfasalazine methotrexate folic acid dihydrocodeine tramadol viscotears codeine amitriptyline gabapentin indometacin allopurinol sulfasalazine methotrexate dihydrocodeine dosulepin folic acid salmeterol tramadol nifedipine codeine BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from 3 amantadine benserazide carbidopa levodopa pramipexole ropinirole baclofen oxybutynin domperidone gabapentin lactulose acrivastine pseudoephedrine cromoglicic acid fluticasone salbutamol beclometasone mometasone budesonide ranitidine codeine paracetamol carvedilol spironolactone bumetanide furosemide amiodarone warfarin isosorbide mononitrate nicorandil glyceryl trinitrate clopidogrel ramipril doxazosin moxonidine sodium bicarbonate bumetanide fosinopril mycophenolic acid tacrolimus alfacalcidol lercanidipine furosemide trandolapril alfuzosin dutasteride finasteride saw palmetto tolterodine nicorandil tadalafil glyceryl trinitrate pregabalin sildenafil clopidogrel tamsulosin dutasteride finasteride bicalutamide saw palmetto vardenafil sildenafil goserelin solifenacin tolterodine amiodarone 4 terazosin finasteride furosemide acetylsalicylic acid metformin simvastatin atenolol lisinopril ramipril lansoprazole codeine tranexamic acid mefenamic acid ferrous sulfate iron norethisterone fexofenadine gamolenic acid ibuprofen paracetamol loratadine fluoxetine diphenhydramine citalopram multivitamins codeine beclometasone paracetamol salbutamol omega-3-triglycerides omeprazole cod liver oil ibuprofen hydroxychloroquine methotrexate leflunomide folic acid sulfasalazine etodolac nabumetone prednisone prednisolone mycophenolic acid celluvisc balsalazide azathioprine mesalazine prednisolone calcium carbonate colecalciferol (vit d3) calcium bisoprolol codeine amitriptyline amlodipine mesalazine azathioprine colestyramine balsalazide ursodeoxycholic acid prednisolone prednisone hydroxocobalamin (vit b12) vitamin b12 loperamide cyanocobalamin (vit b12) 5 sulfasalazine methotrexate hydroxychloroquine folic acid leflunomide nabumetone adalimumab etodolac indometacin celecoxib meloxicam testosterone hydrocortisone estrogen sildenafil tadalafil gabapentin levothyroxine sodium alendronic acid insulin carbamazepine calcium carbonate candesartan carvedilol moxonidine spironolactone amiodarone nebivolol bumetanide furosemide bendroflumethiazide doxazosin lercanidipine eprosartan bendroflumethiazide indapamide rosuvastatin doxazosin felodipine diltiazem gliclazide furosemide formoterol nifedipine irbesartan sodium bicarbonate hydrochlorothiazide moxonidine alfacalcidol mycophenolic acid glimepiride vardenafil doxazosin insulin pioglitazone losartan hydrochlorothiazide moxonidine doxazosin carvedilol bumetanide bendroflumethiazide diltiazem furosemide spironolactone amiodarone 6 olmesartan medoxomil nebivolol rosuvastatin lercanidipine indapamide pioglitazone felodipine doxazosin bendroflumethiazide gliclazide amlodipine telmisartan hydrochlorothiazide moxonidine glimepiride lacidipine indapamide lercanidipine doxazosin etoricoxib diltiazem rosiglitazone valsartan hydrochlorothiazide moxonidine doxazosin piroxicam carvedilol spironolactone indapamide lercanidipine amiodarone bumetanide paracetamol dextropropoxyphene codeine dihydrocodeine caffeine heparinoid metoclopramide morphine tramadol buprenorphine docusate sodium alginic acid domperidone heparinoid esomeprazole clotrimazole aqueous bp pantoprazole dicycloverine e45 cream metoclopramide oilatum cromoglicic acid fexofenadine loratadine acrivastine desloratadine levocetirizine cetirizine oilatum beclometasone montelukast viscotears bicalutamide goserelin tamsulosin atorvastatin atenolol lansoprazole simvastatin acetylsalicylic acid amlodipine bendroflumethiazide omeprazole 7 amiodarone warfarin spironolactone carvedilol furosemide bumetanide bisoprolol amiloride nicorandil pravastatin isosorbide mononitrate flecainide warfarin verapamil bisoprolol metoprolol acetylsalicylic acid diltiazem irbesartan clopidogrel hydrochlorothiazide esomeprazole oxybutynin amantadine baclofen cefalexin nitrofurantoin carbidopa levodopa docusate sodium senna glycosides domperidone gabapentin solifenacin nitrofurantoin baclofen carbidopa cefalexin levodopa trimethoprim estriol butylscopolamine prochlorperazine lactulose tolterodine baclofen nitrofurantoin carbidopa docusate sodium levodopa cefalexin ropinirole senna glycosides glimepiride quinine trospium senna glycosides lactulose mebeverine quinine gabapentin warfarin lansoprazole amitriptyline dihydrocodeine glyceryl trinitrate 8 ipratropium bromide theophylline aminophylline salbutamol carbocisteine azithromycin montelukast salmeterol fluticasone formoterol bumetanide tiotropium bromide azithromycin carbocisteine aminophylline theophylline salbutamol fluticasone montelukast formoterol budesonide salmeterol tamoxifen goserelin escitalopram quinine anastrozole zopiclone gamolenic acid venlafaxine sertraline calcium colecalciferol (vit d3) terbinafine oxybutynin selenium betamethasone hydrocortisone quinine ginkgo folium minerals prednisolone doxazosin diclofenac methotrexate adalimumab folic acid leflunomide hydroxychloroquine sulfasalazine nabumetone prednisolone etodolac celecoxib prednisone loperamide colestyramine kaolin tenofovir disoproxil multienzymes (lipase, protease etc.) butylscopolamine cyclizine hydroxocobalamin (vit b12) alverine cyanocobalamin (vit b12) metoclopramide 9 betahistine cinnarizine prochlorperazine cyclizine alverine amiloride lactulose senna glycosides quinine pizotifen orlistat cinnarizine betahistine prochlorperazine domperidone hypromellose dosulepin alginic acid dihydrocodeine mebeverine gabapentin glyceryl trinitrate anastrozole goserelin colecalciferol (vit d3) calcium ibandronic acid calcium carbonate alendronic acid risedronic acid vitamin d clonidine venlafaxine exemestane colecalciferol (vit d3) calcium alendronic acid fluoxetine amitriptyline levothyroxine sodium gamolenic acid omeprazole fluticasone metformin letrozole ibandronic acid colecalciferol (vit d3) calcium alendronic acid calcium carbonate vitamin d quinine gamolenic acid codeine levothyroxine sodium carbomers lacri-lube hypromellose dexamethasone dorzolamide hydroxychloroquine ispaghula (psylla seeds) senna glycosides lactulose gabapentin timolol 10 carmellose lacri-lube hypromellose ispaghula (psylla seeds) prednisolone alginic acid gliclazide colecalciferol (vit d3) furosemide cetirizine lansoprazole celluvisc lacri-lube viscotears bimatoprost dexamethasone hydroxychloroquine hypromellose timolol sulfasalazine prednisolone methotrexate hypromellose dexamethasone lacri-lube carbomers carmellose viscotears e45 cream oilatum hydroxychloroquine celluvisc cinnarizine lacri-lube carmellose celluvisc liquifilm tears viscotears carbomers hypromellose dexamethasone hydroxychloroquine doxycycline senna glycosides liquifilm tears lacri-lube viscotears lactulose colecalciferol (vit d3) fluticasone calcium alendronic acid omeprazole codeine salbutamol tears naturale tramadol amitriptyline colecalciferol (vit d3) codeine calcium beclometasone levothyroxine sodium paracetamol bendroflumethiazide omeprazole 11 viscotears lacri-lube liquifilm tears celluvisc hypromellose hydroxychloroquine cromoglicic acid dexamethasone lactulose etodolac bimatoprost primidone phenytoin valproic acid propranolol colecalciferol (vit d3) calcium ramipril levothyroxine sodium simvastatin acetylsalicylic acid salbutamol butylscopolamine peppermint oil docusate sodium domperidone loperamide morphine alverine mebeverine diazepam tramadol ispaghula (psylla seeds) clonazepam carbidopa levodopa pramipexole baclofen valproic acid lamotrigine pregabalin temazepam gabapentin venlafaxine diazepam oxycodone quetiapine temazepam nitrazepam procyclidine mirtazapine zopiclone morphine baclofen risperidone lorazepam mirtazapine zopiclone venlafaxine propranolol citalopram omeprazole codeine lansoprazole atorvastatin paracetamol 12 nitrazepam diazepam senna glycosides dihydrocodeine lactulose venlafaxine alginic acid furosemide glyceryl trinitrate tramadol amitriptyline temazepam diazepam morphine baclofen quetiapine clonazepam trazodone olanzapine mirtazapine senna glycosides lithium zolpidem escitalopram venlafaxine mirtazapine diazepam tramadol sertraline citalopram dosulepin lactulose alginic acid zopiclone chlorpromazine procyclidine diazepam quetiapine mirtazapine tenofovir disoproxil lorazepam olanzapine risperidone duloxetine diltiazem nicorandil isosorbide mononitrate glyceryl trinitrate moxonidine clopidogrel acetylsalicylic acid furosemide tiotropium bromide hydrochlorothiazide theophylline levobunolol latanoprost acetylsalicylic acid bendroflumethiazide omeprazole simvastatin paracetamol NA NA NA NA 13 propranolol naratriptan almotriptan zolmitriptan sumatriptan primidone lorazepam carbimazole rizatriptan clonazepam chlorpromazine sotalol warfarin hydrochlorothiazide nicorandil spironolactone acetylsalicylic acid clopidogrel isosorbide mononitrate indapamide furosemide glyceryl trinitrate timolol dorzolamide bimatoprost latanoprost brimonidine travoprost brinzolamide dexamethasone celluvisc carbomers viscotears atenolol chlortalidone isosorbide mononitrate glyceryl trinitrate nicorandil acetylsalicylic acid clopidogrel moxonidine captopril nifedipine atorvastatin bisoprolol clopidogrel spironolactone amiodarone nicorandil glyceryl trinitrate bumetanide isosorbide mononitrate warfarin furosemide acetylsalicylic acid metoprolol glyceryl trinitrate isosorbide mononitrate acetylsalicylic acid warfarin clopidogrel nicorandil flecainide spironolactone furosemide atorvastatin 14 nebivolol olmesartan medoxomil indapamide spironolactone rosuvastatin nicorandil glyceryl trinitrate furosemide doxazosin clopidogrel candesartan amoxicillin ciprofloxacin carbocisteine nitrofurantoin metronidazole doxycycline cefalexin trimethoprim tiotropium bromide prednisolone montelukast benzathine benzylpenicillin folic acid bisoprolol lansoprazole omeprazole codeine calcium colecalciferol (vit d3) simvastatin multivitamins metformin flucloxacillin metronidazole dihydrocodeine diclofenac codeine paracetamol metformin lansoprazole amlodipine omeprazole acetylsalicylic acid phenoxymethylpenicillin folic acid warfarin prednisolone furosemide ferrous sulfate dihydrocodeine insulin colecalciferol (vit d3) allopurinol tramadol metformin glibenclamide gliclazide glimepiride pioglitazone rosiglitazone insulin fenofibrate vardenafil sildenafil simvastatin 15 ursodeoxycholic acid azathioprine mesalazine prednisolone colecalciferol (vit d3) calcium carbonate calcium alendronic acid furosemide insulin omeprazole colestyramine loperamide vitamin b12 mesalazine hydroxocobalamin (vit b12) folic acid codeine colecalciferol (vit d3) fluoxetine omeprazole calcium alendronic acid colecalciferol (vit d3) calcium calcium carbonate prednisone prednisolone mycophenolic acid azathioprine azithromycin ergocalciferol (vit d2) letrozole etidronic acid prednisolone amitriptyline codeine fluticasone lansoprazole salbutamol omeprazole atorvastatin paracetamol atenolol ibandronic acid letrozole colecalciferol (vit d3) calcium calcium carbonate anastrozole prednisolone methotrexate tiotropium bromide vitamin d lactulose risedronic acid colecalciferol (vit d3) calcium prednisone prednisolone calcium carbonate mycophenolic acid azathioprine leflunomide ergocalciferol (vit d2) theophylline 16 ispaghula (psylla seeds) bisacodyl alverine lactulose peppermint oil senna glycosides carmellose carbomers mebeverine heparinoid docusate sodium sterculia alverine mebeverine esomeprazole alginic acid lactulose fluoxetine fluticasone codeine citalopram cetirizine tacrolimus sodium bicarbonate mycophenolic acid alfacalcidol prednisolone prednisone azathioprine clobetasone clobetasol diprobase nifedipine calcium colecalciferol (vit d3) ergocalciferol (vit d2) vitamin d alendronic acid strontium ranelate risedronic acid magnesium carbonate ibandronic acid magnesium magnesium citrate calcium carbonate alendronic acid risedronic acid ibandronic acid strontium ranelate prednisone alfacalcidol mycophenolic acid prednisolone azathioprine raloxifene brinzolamide bimatoprost latanoprost travoprost brimonidine timolol prednisolone tamsulosin gliclazide doxazosin budesonide 17 dorzolamide timolol bimatoprost latanoprost Fortravoprost brimonidinepeerdexamethasone carbomersreviewhypromellose viscotears onlyprednisolone carbamazepine levetiracetam topiramate lamotrigine phenytoin valproic acid risperidone baclofen olanzapine quetiapine clonazepam sibutramine metformin furosemide tramadol codeine lisinopril atorvastatin diclofenac lansoprazole omeprazole paracetamol bisacodyl baclofen lactulose senna glycosides ispaghula (psylla seeds) pregabalin quinine tramadol gabapentin dihydrocodeine amitriptyline senna glycosides docusate sodium lactulose morphine bisacodyl baclofen fentanyl oxycodone cyclizine nitrofurantoin alfacalcidol beclometasone salbutamol salmeterol cromoglicic acid nedocromil ipratropium bromide loratadine azelastine aminophylline cetirizine desloratadine 18 betamethasone fusidic acid calcipotriol coal tar epaderm oilatum diprobase dermol clobetasone cetraben ketoconazole budesonide formoterol terbutaline montelukast theophylline carbocisteine aminophylline tiotropium bromide ipratropium bromide azithromycin salbutamol clobetasol cetraben dermol diprobase epaderm doublebase aqueous bp hydroxyzine fusidic acid tacrolimus coal tar clobetasone coal tar dermol diprobase epaderm oilatum ketoconazole cetraben doublebase aqueous bp calcipotriol dexamethasone hypromellose celluvisc dorzolamide lacri-lube carbomers aciclovir metoclopramide domperidone timolol viscotears fluocinolone acetonide calcipotriol betamethasone fluticasone beclometasone salbutamol multivitamins simvastatin omeprazole paracetamol acetylsalicylic acid 19 fluticasone salbutamol theophylline aminophylline tiotropium bromide montelukast carbocisteine azithromycin ipratropium bromide azelastine nedocromil hydrocortisone miconazole fludrocortisone clotrimazole testosterone fusidic acid oilatum ketoconazole epaderm diprobase e45 cream mometasone azithromycin nedocromil diprobase cetraben doublebase montelukast epaderm oilatum levocetirizine cromoglicic acid prednisolone mycophenolic acid azathioprine tacrolimus azithromycin alendronic acid leflunomide adalimumab risedronic acid hydroxychloroquine methotrexate prednisone mycophenolic acid tacrolimus azathioprine alendronic acid risedronic acid hydroxychloroquine calcium carbonate montelukast colecalciferol (vit d3) methotrexate triamcinolone desloratadine terbutaline formoterol cetirizine loratadine budesonide ispaghula (psylla seeds) salmeterol hydrocortisone fluticasone celecoxib adalimumab leflunomide methotrexate dextropropoxyphene buprenorphine hydroxychloroquine sulfasalazine folic acid tramadol pregabalin 20 etoricoxib buprenorphine morphine methotrexate sulfasalazine hydroxychloroquine tramadol montelukast pregabalin orlistat folic acid benserazide amantadine carbidopa levodopa pramipexole ropinirole domperidone lactulose amitriptyline omeprazole codeine carbidopa amantadine benserazide levodopa pramipexole ropinirole clonazepam domperidone oxybutynin sildenafil lactulose olanzapine lithium procyclidine valproic acid lamotrigine venlafaxine lofepramine clomipramine mirtazapine zopiclone diazepam quetiapine lithium lamotrigine duloxetine valproic acid venlafaxine mirtazapine diazepam trazodone zopiclone temazepam amlodipine moxonidine doxazosin tacrolimus nicorandil bendroflumethiazide fosinopril perindopril indapamide isosorbide mononitrate enalapril 21 felodipine quinapril fosinopril moxonidine trandolapril bendroflumethiazide eprosartan indapamide doxazosin potassium olmesartan medoxomil lacidipine moxonidine telmisartan doxazosin indapamide valsartan bendroflumethiazide allopurinol gliclazide candesartan furosemide lercanidipine moxonidine trandolapril indapamide doxazosin olmesartan medoxomil telmisartan irbesartan valsartan bendroflumethiazide perindopril nifedipine captopril tacrolimus mycophenolic acid fluvastatin trandolapril moxonidine imipramine doxazosin alfacalcidol enalapril hydroxyzine epaderm diprobase clobetasol betamethasone fexofenadine hydrocortisone prednisolone cetirizine quinine lactulose levodopa amantadine benserazide carbidopa pramipexole ropinirole fludrocortisone clonazepam domperidone lactulose sildenafil 22 pramipexole amantadine benserazide carbidopa levodopa clonazepam domperidone lactulose quinine amitriptyline propranolol ropinirole amantadine benserazide carbidopa levodopa domperidone sildenafil tolterodine lactulose isosorbide mononitrate quinine multienzymes (lipase, protease etc.) thiamine (vit b1) insulin loperamide gabapentin clopidogrel vitamin b alginic acid ferrous sulfate omeprazole lansoprazole conjugated estrogens medroxyprogesterone dextropropoxyphene levocetirizine zolmitriptan butylscopolamine rizatriptan naratriptan duloxetine etodolac peppermint oil estradiol estrone dydrogesterone norethisterone estriol medroxyprogesterone nedocromil potassium citrate nitrofurantoin almotriptan fludrocortisone estriol estrone trimethoprim estradiol clobetasol solifenacin peppermint oil hypromellose zolmitriptan viscotears meloxicam 23 estrogen progesterone testosterone levothyroxine sodium multivitamins ibuprofen paracetamol salbutamol omega-3-triglycerides beclometasone glucosamine estrone estradiol estriol levothyroxine sodium multivitamins paracetamol omeprazole salbutamol omega-3-triglycerides bendroflumethiazide ibuprofen ethinylestradiol levonorgestrel norgestimate desogestrel norethisterone iron cromoglicic acid loratadine chlorphenamine ibuprofen fluoxetine mestranol progestogen iron gamolenic acid dosulepin food supplement/plant/herbal extract vitamin d ascorbic acid (vit c) amitriptyline omega-3-triglycerides mometasone tibolone escitalopram cromoglicic acid tocopherol (vit e) sumatriptan magnesium pregabalin zopiclone solifenacin meloxicam ispaghula (psylla seeds) valproic acid quetiapine lamotrigine levetiracetam olanzapine risperidone primidone topiramate procyclidine clonazepam phenytoin 24 mefenamic acid tranexamic acid ferrous sulfate norethisterone ibuprofen propranolol loratadine gamolenic acid paracetamol codeine dihydrocodeine bezafibrate glyceryl trinitrate isosorbide mononitrate gliclazide nicorandil ezetimibe metformin pioglitazone insulin rosiglitazone allopurinol fenofibrate pioglitazone metformin insulin glimepiride gliclazide rosuvastatin ezetimibe nicorandil irbesartan rosiglitazone cefalexin nitrofurantoin trimethoprim amoxicillin oxybutynin solifenacin tolterodine prednisolone alginic acid furosemide lactulose ciprofloxacin carbocisteine amoxicillin trimethoprim prednisolone gabapentin lactulose tramadol fluticasone furosemide colecalciferol (vit d3) goserelin bicalutamide tamoxifen anastrozole selenium tamsulosin colecalciferol (vit d3) calcium alendronic acid diclofenac codeine 25 cimetidine alginic acid ranitidine cetirizine naproxen dihydrocodeine amitriptyline glyceryl trinitrate mebeverine codeine losartan ranitidine sodium bicarbonate alginic acid bisacodyl domperidone cimetidine fentanyl multienzymes (lipase, protease etc.) mycophenolic acid morphine butylscopolamine atorvastatin clopidogrel nicorandil glyceryl trinitrate isosorbide mononitrate sodium bicarbonate rosiglitazone glimepiride ezetimibe carvedilol acetylsalicylic acid fluvastatin ezetimibe isosorbide mononitrate bisoprolol prednisolone nifedipine warfarin diltiazem doxazosin acetylsalicylic acid glyceryl trinitrate pravastatin mycophenolic acid tacrolimus amiodarone carvedilol ezetimibe fosinopril isosorbide mononitrate warfarin glimepiride glyceryl trinitrate rosuvastatin ezetimibe fenofibrate nebivolol trandolapril olmesartan medoxomil pioglitazone nicorandil fosinopril eprosartan rosiglitazone 26 simvastatin dipyridamole metformin gliclazide pioglitazone isosorbide mononitrate acetylsalicylic acid glyceryl trinitrate glibenclamide nicorandil rosiglitazone phenytoin primidone carbamazepine valproic acid warfarin folic acid colecalciferol (vit d3) alendronic acid calcium codeine lansoprazole clotrimazole hydrocortisone betamethasone alginic acid quinine ispaghula (psylla seeds) lactulose tramadol prednisolone dihydrocodeine methotrexate ketoconazole miconazole clobetasone hydrocortisone diprobase betamethasone calcipotriol mometasone alginic acid clopidogrel furosemide metronidazole flucloxacillin amoxicillin lymecycline oxytetracycline betamethasone prednisolone mebeverine glyceryl trinitrate cetirizine omeprazole miconazole hydrocortisone ketoconazole oilatum fusidic acid e45 cream coal tar clobetasone diprobase calcipotriol betamethasone 27 clonidine naratriptan peppermint oil gabapentin prochlorperazine ispaghula (psylla seeds) domperidone pregabalin celecoxib quinine orlistat moxonidine doxazosin lacidipine lercanidipine furosemide irbesartan pioglitazone spironolactone diltiazem indapamide verapamil influenza vaccines salbutamol metformin beclometasone fluticasone acetylsalicylic acid calcium atenolol paracetamol atorvastatin ramipril insulin metformin multienzymes (lipase, protease etc.) sodium bicarbonate bumetanide vardenafil fenofibrate glimepiride alfacalcidol furosemide spironolactone ferrous fumarate vitamin b12 prednisolone folic acid colecalciferol (vit d3) insulin calcium tramadol metformin lansoprazole amitriptyline ferrous sulfate sodium bicarbonate tranexamic acid cyanocobalamin (vit b12) hydroxocobalamin (vit b12) leflunomide alfacalcidol adalimumab mycophenolic acid vitamin b12 bumetanide 28 iron folic acid methotrexate multivitamins vitamin b12 magnesium zinc ascorbic acid (vit c) tranexamic acid alfacalcidol vitamin d montelukast theophylline aminophylline azithromycin carbocisteine salbutamol formoterol fluticasone budesonide tiotropium bromide ipratropium bromide lithium quetiapine chlorpromazine olanzapine risperidone procyclidine trifluoperazine clomipramine venlafaxine lamotrigine mirtazapine azithromycin tiotropium bromide carbocisteine montelukast prednisolone salmeterol ipratropium bromide fluticasone salbutamol formoterol mometasone erythromycin zinc prednisolone furosemide mometasone fluticasone norethisterone cetirizine estradiol ranitidine beclometasone magnesium zinc tocopherol (vit e) vitamin d vitamin b pyridoxine (vit b6) lecithin co-enzyme q10/ubiquinone/bio-quinone calcium selenium kelp 29 magnesium carbonate zinc tocopherol (vit e) calcium selenium co-enzyme q10/ubiquinone/bio-quinone vitamin d ginkgo folium vitamin b ascorbic acid (vit c) omega-3-triglycerides magnesium citrate zinc tocopherol (vit e) pyridoxine (vit b6) flax oil co-enzyme q10/ubiquinone/bio-quinone selenium vitamin b ascorbic acid (vit c) vitamin d calcium quinine e45 cream buprenorphine senna glycosides alfacalcidol oxycodone heparinoid docusate sodium bisacodyl morphine clotrimazole fludrocortisone hydrocortisone levodopa alendronic acid levothyroxine sodium colecalciferol (vit d3) calcium estradiol fluticasone codeine salbutamol minerals multivitamins ginseng food supplement/plant/herbal extract co-enzyme q10/ubiquinone/bio-quinone st john's wort/hypericum kelp ginkgo folium omega-3-triglycerides aloe vera starflower oil carbocisteine tiotropium bromide azithromycin aminophylline theophylline ciprofloxacin montelukast amoxicillin salbutamol ipratropium bromide fluticasone 30 multivitamins minerals ginseng iron co-enzyme q10/ubiquinone/bio-quinone omega-3-triglycerides magnesium citrate ginkgo folium lecithin st john's wort/hypericum flax oil nitrofurantoin cefalexin trimethoprim amoxicillin baclofen oxybutynin senna glycosides tolterodine solifenacin lactulose gabapentin amitriptyline oxycodone morphine fentanyl baclofen nefopam buprenorphine gabapentin pregabalin tramadol docusate sodium clomipramine lithium olanzapine diazepam propranolol colecalciferol (vit d3) ranitidine calcium lansoprazole codeine garlic dosulepin cinnarizine baclofen temazepam diazepam zolpidem naratriptan zopiclone senna glycosides butylscopolamine pregabalin imipramine diazepam lactulose nifedipine glyceryl trinitrate insulin dihydrocodeine tramadol doxazosin metformin omeprazole 31 lofepramine olanzapine diazepam lactulose zopiclone propranolol ferrous sulfate codeine estradiol tramadol lansoprazole nortriptyline pregabalin gabapentin senna glycosides tramadol lactulose mebeverine quinine dihydrocodeine propranolol alginic acid tenofovir disoproxil aciclovir loperamide zopiclone citalopram atorvastatin multivitamins salbutamol omeprazole ibuprofen acetylsalicylic acid aciclovir tenofovir disoproxil dexamethasone prednisolone hypromellose loperamide dihydrocodeine tramadol formoterol norethisterone folic acid buprenorphine cyclizine pregabalin morphine gabapentin etoricoxib prochlorperazine tramadol amitriptyline lactulose celecoxib codeine kaolin paracetamol caffeine heparinoid piroxicam e45 cream etodolac nefopam ketoconazole celecoxib 32 dextropropoxyphene paracetamol celecoxib meloxicam methotrexate misoprostol folic acid zopiclone amitriptyline diclofenac esomeprazole dihydrocodeine paracetamol nitrazepam ketoprofen buprenorphine nabumetone fentanyl etodolac adalimumab senna glycosides piroxicam fentanyl morphine pregabalin gabapentin senna glycosides mirtazapine lactulose amitriptyline tramadol prednisolone alginic acid morphine fentanyl cyclizine docusate sodium pregabalin senna glycosides gabapentin buprenorphine metoclopramide lactulose domperidone oxycodone pregabalin gabapentin docusate sodium lactulose diazepam senna glycosides amitriptyline glyceryl trinitrate clopidogrel isosorbide mononitrate tramadol pregabalin gabapentin buprenorphine fentanyl nabumetone nefopam amitriptyline morphine senna glycosides heparinoid glyceryl trinitrate isosorbide mononitrate nicorandil acetylsalicylic acid clopidogrel diltiazem bisoprolol metoprolol bumetanide carvedilol furosemide 33 isosorbide mononitrate glyceryl trinitrate nicorandil diltiazem acetylsalicylic acid clopidogrel bumetanide carvedilol furosemide bisoprolol metoprolol lactulose senna glycosides bisacodyl docusate sodium oxycodone morphine fentanyl amantadine ispaghula (psylla seeds) baclofen benserazide nefopam gabapentin amitriptyline tramadol isosorbide mononitrate furosemide naproxen clopidogrel folic acid codeine glyceryl trinitrate nedocromil desloratadine loratadine cetirizine fexofenadine mometasone fluticasone beclometasone budesonide salbutamol colecalciferol (vit d3) fusidic acid betamethasone epaderm diprobase hydrocortisone miconazole clobetasone clobetasol montelukast chlorphenamine calcipotriol duloxetine quetiapine lithium lamotrigine pregabalin trazodone zopiclone diazepam mirtazapine valproic acid senna glycosides 34 mirtazapine quetiapine lithium chlorpromazine fentanyl olanzapine lorazepam diazepam zopiclone venlafaxine morphine trazodone quetiapine lithium lamotrigine duloxetine venlafaxine temazepam zopiclone senna glycosides sertraline gabapentin venlafaxine lithium quetiapine chlorpromazine olanzapine risperidone mirtazapine lorazepam zolpidem trazodone procyclidine gabapentin oxycodone baclofen morphine fentanyl buprenorphine nortriptyline amantadine nefopam docusate sodium tramadol lamotrigine levetiracetam quetiapine valproic acid topiramate lithium olanzapine duloxetine carbamazepine clonazepam trazodone levetiracetam carbamazepine lamotrigine topiramate valproic acid pregabalin gabapentin folic acid alendronic acid warfarin citalopram 35 pregabalin oxycodone fentanyl buprenorphine morphine baclofen nortriptyline clonazepam cyclizine tramadol heparinoid topiramate levetiracetam lamotrigine carbamazepine rizatriptan valproic acid sumatriptan zolmitriptan gabapentin propranolol amitriptyline azelastine fexofenadine cetirizine fluticasone loratadine mometasone beclometasone salbutamol lansoprazole omeprazole codeine nabumetone methotrexate sulfasalazine hydroxychloroquine folic acid tramadol dihydrocodeine prednisolone ferrous sulfate amitriptyline codeine pizotifen rizatriptan sumatriptan naratriptan zolmitriptan cyclizine prochlorperazine alverine caffeine propranolol domperidone hydroxycarbamide acetylsalicylic acid allopurinol warfarin lansoprazole ranitidine amlodipine atenolol omeprazole simvastatin ramipril 36 risperidone procyclidine lithium valproic acid venlafaxine diazepam sertraline carbamazepine zopiclone mirtazapine paroxetine baclofen amantadine gabapentin bisacodyl pregabalin oxybutynin clonazepam nitrofurantoin docusate sodium senna glycosides tolterodine gamolenic acid pyridoxine (vit b6) starflower oil potassium citrate kelp tocopherol (vit e) st john's wort/hypericum magnesium carbonate magnesium cod liver oil aloe vera strontium ranelate colecalciferol (vit d3) calcium calcium carbonate prednisolone esomeprazole vitamin d folic acid ranitidine fluticasone codeine alverine sterculia peppermint oil ispaghula (psylla seeds) domperidone butylscopolamine loperamide esomeprazole pizotifen lactulose alginic acid aqueous bp oilatum doublebase epaderm dermol coal tar clobetasone diprobase clobetasol betamethasone hydrocortisone 37 cetraben clobetasol clobetasone betamethasone calcipotriol hydrocortisone mometasone prednisolone alginic acid tramadol insulin dermol doublebase epaderm oilatum aqueous bp clobetasone diprobase clobetasol betamethasone hydrocortisone calcipotriol diprobase oilatum epaderm dermol clobetasone clobetasol coal tar fusidic acid betamethasone aqueous bp ketoconazole doublebase dermol epaderm oilatum aqueous bp clobetasone clobetasol diprobase betamethasone hydrocortisone calcipotriol e45 cream oilatum coal tar miconazole hydrocortisone clobetasone betamethasone diprobase hypromellose calcipotriol senna glycosides epaderm dermol oilatum doublebase hydroxyzine diprobase fusidic acid aqueous bp clobetasone betamethasone clobetasol 38 oilatum diprobase dermol epaderm coal tar doublebase aqueous bp e45 cream clobetasone betamethasone hydrocortisone azathioprine balsalazide prednisolone mesalazine prednisone tacrolimus alfacalcidol ursodeoxycholic acid risedronic acid hydroxychloroquine alendronic acid http://bmjopen.bmj.com/ ezetimibe fluvastatin rosuvastatin clopidogrel nicorandil fenofibrate glyceryl trinitrate isosorbide mononitrate pravastatin atorvastatin bezafibrate nicorandil glyceryl trinitrate isosorbide mononitrate acetylsalicylic acid clopidogrel diltiazem bumetanide bisoprolol carvedilol furosemide morphine meloxicam methotrexate heparinoid dextropropoxyphene sulfasalazine buprenorphine hydroxychloroquine folic acid tramadol dihydrocodeine codeine piroxicam dihydrocodeine tramadol methotrexate quinine amitriptyline valsartan codeine alginic acid glyceryl trinitrate folic acid 39 sildenafil testosterone carbidopa pioglitazone ropinirole e45 cream levodopa rosiglitazone metformin gliclazide insulin tadalafil rosiglitazone testosterone insulin metformin pioglitazone gliclazide indapamide alfuzosin sildenafil tamsulosin vardenafil insulin metformin gliclazide irbesartan tamsulosin perindopril losartan atorvastatin amlodipine acetylsalicylic acid orlistat bumetanide pioglitazone pregabalin glimepiride rosiglitazone metformin furosemide etoricoxib insulin montelukast promethazine quinine tramadol glyceryl trinitrate dihydrocodeine citalopram ranitidine lansoprazole amitriptyline codeine omeprazole chlorpromazine lithium procyclidine zopiclone venlafaxine mirtazapine fluoxetine propranolol amitriptyline citalopram ranitidine 40 prochlorperazine betahistine cinnarizine cyclizine buprenorphine naratriptan morphine diazepam rizatriptan pizotifen caffeine trifluoperazine procyclidine lithium sertraline citalopram simvastatin metformin amlodipine atenolol atorvastatin levothyroxine sodium verapamil warfarin carbocisteine moxonidine nicorandil flecainide furosemide glyceryl trinitrate isosorbide mononitrate tiotropium bromide amiloride cyclizine caffeine morphine buprenorphine docusate sodium pizotifen domperidone senna glycosides pregabalin prochlorperazine gabapentin cetirizine nedocromil cromoglicic acid azelastine montelukast oilatum dermol hydroxyzine diprobase theophylline triamcinolone levocetirizine montelukast cromoglicic acid mometasone fluticasone formoterol esomeprazole salbutamol budesonide quinine betamethasone 41 desloratadine nedocromil cromoglicic acid montelukast triamcinolone mometasone fluticasone alverine hypromellose formoterol prochlorperazine fexofenadine cromoglicic acid nedocromil azelastine hydroxyzine montelukast dermol doublebase mometasone oilatum theophylline loratadine nedocromil cromoglicic acid azelastine mometasone triamcinolone montelukast dermol pseudoephedrine beclometasone oilatum terfenadine beclometasone gamolenic acid multivitamins salbutamol ascorbic acid (vit c) fluticasone minerals estradiol ibuprofen cod liver oil acetylsalicylic acid dipyridamole nicorandil glyceryl trinitrate isosorbide mononitrate hydroxycarbamide bisoprolol metoprolol diltiazem glimepiride rosiglitazone clopidogrel nicorandil glyceryl trinitrate isosorbide mononitrate bisoprolol carvedilol atorvastatin oxycodone diltiazem ezetimibe metoprolol 42 dipyridamole acetylsalicylic acid simvastatin indapamide perindopril nicorandil baclofen glimepiride isosorbide mononitrate thiamine (vit b1) atorvastatin potassium bendroflumethiazide hydrochlorothiazide valsartan nifedipine felodipine enalapril doxazosin warfarin atenolol candesartan potassium citrate selenium garlic chondroitin sulfate gamolenic acid zinc omega-3-triglycerides glucosamine multivitamins ascorbic acid (vit c) calcium amiloride furosemide hydrochlorothiazide amiodarone theophylline warfarin temazepam verapamil ipratropium bromide betahistine senna glycosides spironolactone carvedilol bumetanide furosemide amiodarone thiamine (vit b1) warfarin bisoprolol isosorbide mononitrate moxonidine nicorandil allopurinol colchicine sodium bicarbonate indometacin bumetanide mycophenolic acid hydroxycarbamide alfacalcidol moxonidine carvedilol glibenclamide 43 colchicine allopurinol furosemide warfarin doxazosin bisoprolol naproxen glyceryl trinitrate clopidogrel ezetimibe tramadol heparinoid diprobase alginic acid pregabalin meloxicam ispaghula (psylla seeds) tramadol lactulose quinine esomeprazole codeine desogestrel ethinylestradiol fexofenadine zinc ibuprofen citalopram propranolol mebeverine fluoxetine cetirizine vitamin b dydrogesterone estradiol gamolenic acid mometasone loratadine ibuprofen citalopram formoterol vitamin d minerals beclometasone etonogestrel ibuprofen paracetamol salbutamol NA NA NA NA NA NA NA etynodiol loratadine gamolenic acid beclometasone ibuprofen salbutamol paracetamol multivitamins omega-3-triglycerides codeine levothyroxine sodium 44 levonorgestrel ethinylestradiol cromoglicic acid ibuprofen chlorphenamine escitalopram caffeine iron estradiol gamolenic acid fluoxetine medroxyprogesterone conjugated estrogens estradiol vitamin b12 dosulepin mesalazine fexofenadine fluoxetine meloxicam sumatriptan loperamide norethisterone estradiol ethinylestradiol tranexamic acid mefenamic acid rizatriptan erythromycin aciclovir peppermint oil caffeine lofepramine norgestimate ethinylestradiol ibuprofen multivitamins paracetamol NA NA NA NA NA NA progesterone estrogen co-enzyme q10/ubiquinone/bio-quinone selenium tocopherol (vit e) ginkgo folium magnesium zinc vitamin b minerals chondroitin sulfate progestogen mestranol iron gamolenic acid dosulepin food supplement/plant/herbal extract vitamin d ascorbic acid (vit c) amitriptyline omega-3-triglycerides mometasone 45 ibuprofen paracetamol pseudoephedrine mefenamic acid almotriptan rizatriptan sumatriptan tranexamic acid naratriptan zolmitriptan caffeine ketoprofen lactulose dihydrocodeine tramadol quinine mometasone amitriptyline glyceryl trinitrate codeine folic acid gliclazide naproxen nefopam leflunomide sulfasalazine methotrexate adalimumab colchicine dihydrocodeine tramadol morphine nitrofurantoin domperidone amantadine benserazide levodopa ropinirole carbidopa esomeprazole cyclizine docusate sodium morphine butylscopolamine metoclopramide morphine docusate sodium dexamethasone senna glycosides rizatriptan esomeprazole loperamide alginic acid pantoprazole lactulose bimatoprost timolol brinzolamide dorzolamide brimonidine celluvisc viscotears doxazosin prednisolone candesartan allopurinol latanoprost timolol brinzolamide dorzolamide brimonidine levobunolol celluvisc carbomers viscotears e45 cream hypromellose 46 travoprost brinzolamide dorzolamide brimonidine timolol diltiazem clopidogrel glyceryl trinitrate doxazosin felodipine dihydrocodeine misoprostol diclofenac dextropropoxyphene methotrexate tramadol baclofen dihydrocodeine quinine codeine hydroxychloroquine pregabalin esomeprazole domperidone metoclopramide alginic acid heparinoid strontium ranelate alverine sterculia morphine butylscopolamine cyclizine on September 26, 2021 by guest. Protected copyright. lansoprazole mycophenolic acid domperidone metoclopramide tacrolimus nefopam adalimumab morphine docusate sodium prednisone nicorandil omeprazole domperidone metoclopramide multienzymes (lipase, protease etc.) heparinoid alginic acid buprenorphine morphine nabumetone nicorandil butylscopolamine pantoprazole domperidone alginic acid metoclopramide clopidogrel alverine nicorandil celecoxib hydroxychloroquine peppermint oil isosorbide mononitrate 47 rabeprazole domperidone alginic acid viscotears metoclopramide senna glycosides ipratropium bromide oxybutynin betahistine montelukast ispaghula (psylla seeds) sodium bicarbonate tacrolimus mycophenolic acid alfacalcidol allopurinol ferrous sulfate prednisolone irbesartan doxazosin furosemide insulin formoterol budesonide terbutaline montelukast theophylline carbocisteine aminophylline tiotropium bromide azithromycin ipratropium bromide salbutamol salbutamol aminophylline theophylline tiotropium bromide fluticasone ipratropium bromide montelukast carbocisteine salmeterol beclometasone azithromycin salmeterol salbutamol azithromycin beclometasone theophylline montelukast ipratropium bromide aminophylline tiotropium bromide carbocisteine fluticasone terbutaline budesonide formoterol montelukast theophylline aminophylline tiotropium bromide carbocisteine salmeterol amoxicillin triamcinolone 48 raloxifene colecalciferol (vit d3) calcium calcium carbonate hydrocortisone alginic acid prednisolone alendronic acid quinine vitamin d folic acid leflunomide methotrexate hydroxychloroquine folic acid sulfasalazine prednisolone celecoxib risedronic acid ferrous sulfate naproxen alendronic acid mycophenolic acid tacrolimus prednisolone prednisone sodium bicarbonate alfacalcidol hydroxychloroquine risedronic acid calcium carbonate alendronic acid pravastatin almotriptan propranolol amitriptyline paracetamol estradiol diclofenac ibuprofen codeine omeprazole salbutamol glucosamine naratriptan pizotifen caffeine propranolol clonidine prochlorperazine domperidone dosulepin amitriptyline lactulose paracetamol rizatriptan pizotifen topiramate metoclopramide prochlorperazine propranolol valproic acid amitriptyline sumatriptan codeine conjugated estrogens 49 sumatriptan pizotifen topiramate propranolol caffeine metoclopramide prochlorperazine amitriptyline domperidone zolmitriptan rizatriptan zolmitriptan pizotifen topiramate propranolol caffeine domperidone amitriptyline prochlorperazine estriol sumatriptan zopiclone citalopram zolpidem quetiapine zopiclone lorazepam olanzapine chlorpromazine diazepam risperidone thiamine (vit b1) promethazine escitalopram zolpidem quetiapine zopiclone diazepam thiamine (vit b1) propranolol pregabalin mirtazapine etoricoxib valproic acid fluoxetine chlorpromazine fentanyl buprenorphine docusate sodium olanzapine diazepam nitrazepam risperidone oxycodone trazodone paroxetine risperidone diazepam olanzapine quetiapine lithium zopiclone temazepam trazodone propranolol hydroxocobalamin (vit b12) 50 sertraline trifluoperazine risperidone olanzapine zolpidem trazodone quetiapine diazepam temazepam domperidone pregabalin selenium retinol (vit a) saw palmetto zinc tocopherol (vit e) magnesium carbonate co-enzyme q10/ubiquinone/bio-quinone magnesium citrate kelp magnesium ginkgo folium docusate sodium senna glycosides morphine oxycodone cyclizine lactulose baclofen alfacalcidol metoclopramide butylscopolamine domperidone chlorphenamine aqueous bp fusidic acid diprobase cromoglicic acid clobetasol clobetasone montelukast betamethasone prochlorperazine hydrocortisone bumetanide spironolactone carvedilol amiodarone alfacalcidol warfarin isosorbide mononitrate nicorandil bisoprolol glyceryl trinitrate ipratropium bromide chlortalidone atenolol nifedipine enalapril finasteride gliclazide metformin simvastatin doxazosin felodipine pravastatin 51 furosemide amiloride spironolactone carvedilol amiodarone warfarin isosorbide mononitrate sodium bicarbonate moxonidine nicorandil alfacalcidol indapamide perindopril moxonidine nebivolol lercanidipine dipyridamole eprosartan doxazosin telmisartan olmesartan medoxomil valsartan glibenclamide metformin rosiglitazone lisinopril allopurinol simvastatin acetylsalicylic acid ramipril atorvastatin amlodipine omeprazole gliclazide metformin pioglitazone rosiglitazone fenofibrate sildenafil vardenafil simvastatin bezafibrate acetylsalicylic acid trandolapril glimepiride metformin rosiglitazone pioglitazone fenofibrate insulin orlistat atorvastatin acetylsalicylic acid irbesartan telmisartan carbimazole propranolol warfarin levothyroxine sodium calcium furosemide colecalciferol (vit d3) alendronic acid bisoprolol omeprazole codeine 52 aloe vera ginkgo folium ginseng selenium magnesium co-enzyme q10/ubiquinone/bio-quinone tocopherol (vit e) peppermint oil garlic zinc omega-3-triglycerides chondroitin sulfate glucosamine potassium citrate ginseng ginkgo folium omega-3-triglycerides co-enzyme q10/ubiquinone/bio-quinone magnesium saw palmetto selenium magnesium carbonate cod liver oil garlic glucosamine retinol (vit a) gamolenic acid ascorbic acid (vit c) multivitamins tocopherol (vit e) ginseng kelp zinc co-enzyme q10/ubiquinone/bio-quinone magnesium citrate selenium lecithin kelp magnesium carbonate magnesium tocopherol (vit e) saw palmetto ginkgo folium flax oil flax oil magnesium citrate lecithin starflower oil kelp tocopherol (vit e) co-enzyme q10/ubiquinone/bio-quinone ginkgo folium magnesium ginseng selenium food supplement/plant/herbal extract magnesium kelp lecithin co-enzyme q10/ubiquinone/bio-quinone ginseng saw palmetto ginkgo folium pyridoxine (vit b6) flax oil minerals 53 garlic kelp lecithin ginseng ginkgo folium potassium citrate cod liver oil selenium saw palmetto aloe vera omega-3-triglycerides ginkgo folium ginseng kelp saw palmetto aloe vera selenium co-enzyme q10/ubiquinone/bio-quinone lecithin flax oil magnesium carbonate glucosamine ginseng ginkgo folium saw palmetto st john's wort/hypericum aloe vera selenium co-enzyme q10/ubiquinone/bio-quinone tocopherol (vit e) garlic food supplement/plant/herbal extract flax oil glucosamine chondroitin sulfate ginkgo folium omega-3-triglycerides cod liver oil ginseng selenium saw palmetto kelp co-enzyme q10/ubiquinone/bio-quinone garlic kaolin codeine loperamide amitriptyline paracetamol lansoprazole diclofenac beclometasone omeprazole salbutamol lisinopril kelp garlic lecithin pyridoxine (vit b6) ginkgo folium zinc co-enzyme q10/ubiquinone/bio-quinone flax oil selenium magnesium food supplement/plant/herbal extract 54 lecithin kelp flax oil garlic co-enzyme q10/ubiquinone/bio-quinone magnesium zinc tocopherol (vit e) ginkgo folium vitamin b selenium omega-3-triglycerides glucosamine ginkgo folium tocopherol (vit e) magnesium citrate lecithin selenium co-enzyme q10/ubiquinone/bio-quinone garlic aloe vera magnesium carbonate peppermint oil butylscopolamine dicycloverine alverine mebeverine ispaghula (psylla seeds) aloe vera docusate sodium senna glycosides domperidone clonidine saw palmetto selenium ginseng ginkgo folium co-enzyme q10/ubiquinone/bio-quinone zinc garlic food supplement/plant/herbal extract alfuzosin tocopherol (vit e) glucosamine st john's wort/hypericum ginseng pyridoxine (vit b6) ginkgo folium starflower oil flax oil co-enzyme q10/ubiquinone/bio-quinone gamolenic acid zinc food supplement/plant/herbal extract minerals starflower oil flax oil pyridoxine (vit b6) tocopherol (vit e) magnesium gamolenic acid ginseng st john's wort/hypericum co-enzyme q10/ubiquinone/bio-quinone ginkgo folium selenium 55 brimonidine timolol brinzolamide dorzolamide bimatoprost latanoprost travoprost prednisolone insulin fluticasone metformin pseudoephedrine acrivastine loratadine fluticasone cetirizine paracetamol beclometasone ibuprofen minerals salbutamol multivitamins dicycloverine peppermint oil domperidone ispaghula (psylla seeds) alginic acid loperamide tramadol dihydrocodeine amitriptyline glyceryl trinitrate codeine mebeverine peppermint oil ispaghula (psylla seeds) butylscopolamine loperamide trospium domperidone sterculia docusate sodium lactulose alginic acid coal tar calcipotriol oilatum betamethasone clobetasone aqueous bp diprobase e45 cream miconazole clobetasol hydrocortisone procyclidine risperidone chlorpromazine trifluoperazine flupentixol olanzapine lithium valproic acid zopiclone diazepam venlafaxine 56 dutasteride alfuzosin tamsulosin sildenafil clopidogrel doxazosin ezetimibe warfarin bisoprolol irbesartan furosemide finasteride tamsulosin alfuzosin terazosin miconazole doxazosin clopidogrel glyceryl trinitrate nicorandil isosorbide mononitrate spironolactone doxycycline carbocisteine amoxicillin lacri-lube tiotropium bromide prednisolone zopiclone mometasone fluticasone furosemide calcium carbonate lymecycline metronidazole cetirizine loratadine tramadol budesonide losartan candesartan colecalciferol (vit d3) diclofenac calcium minocycline estradiol ibuprofen paracetamol glucosamine salbutamol atenolol multivitamins levothyroxine sodium acetylsalicylic acid omeprazole oxytetracycline metronidazole amoxicillin terbutaline lactulose finasteride norethisterone sumatriptan felodipine ispaghula (psylla seeds) estradiol 57 tetracycline omeprazole salbutamol ibuprofen acetylsalicylic acid paracetamol simvastatin NA NA NA NA bendroflumethiazide potassium eprosartan quinapril fosinopril moxonidine enalapril lercanidipine doxazosin trandolapril losartan hydrochlorothiazide amiloride losartan telmisartan irbesartan sotalol valsartan bisoprolol enalapril potassium diltiazem pioglitazone metformin gliclazide glimepiride fenofibrate moxonidine sildenafil orlistat acetylsalicylic acid simvastatin rosuvastatin rosiglitazone metformin glimepiride glibenclamide gliclazide tadalafil sildenafil atorvastatin hydroxocobalamin (vit b12) acetylsalicylic acid moxonidine flupentixol procyclidine tramadol codeine metformin simvastatin omeprazole ramipril paracetamol levothyroxine sodium salbutamol 58 levothyroxine sodium fludrocortisone alfacalcidol testosterone hydroxocobalamin (vit b12) amiodarone lithium cyanocobalamin (vit b12) tears naturale hydrocortisone chlorpromazine trimethoprim nitrofurantoin cefalexin ciprofloxacin amoxicillin estriol solifenacin lactulose gabapentin mebeverine prednisolone adalimumab methotrexate folic acid celecoxib sulfasalazine prednisolone ferrous sulfate alendronic acid dihydrocodeine colecalciferol (vit d3) tramadol retinol (vit a) vitamin d tocopherol (vit e) selenium ascorbic acid (vit c) zinc vitamin b cod liver oil omega-3-triglycerides ginkgo folium garlic cyanocobalamin (vit b12) ferrous sulfate azathioprine loperamide folic acid iron mesalazine calcium carbonate irbesartan quinine colecalciferol (vit d3) folic acid methotrexate adalimumab leflunomide hydroxychloroquine sulfasalazine iron nabumetone prednisolone etodolac hydroxocobalamin (vit b12) hydroxocobalamin (vit b12) colestyramine ferrous sulfate loperamide folic acid rosiglitazone azathioprine mesalazine lacri-lube sulfasalazine hydroxychloroquine 59 vitamin b12 colestyramine pyridoxine (vit b6) ferrous fumarate folic acid iron ferrous sulfate azathioprine loperamide mesalazine magnesium pyridoxine (vit b6) magnesium citrate kelp starflower oil magnesium tocopherol (vit e) vitamin b12 gamolenic acid st john's wort/hypericum zinc food supplement/plant/herbal extract thiamine (vit b1) vitamin b spironolactone multienzymes (lipase, protease etc.) folic acid tiotropium bromide diazepam furosemide tocopherol (vit e) zopiclone mirtazapine vitamin b thiamine (vit b1) tocopherol (vit e) magnesium retinol (vit a) magnesium citrate ascorbic acid (vit c) zinc lecithin magnesium carbonate selenium ascorbic acid (vit c) retinol (vit a) zinc tocopherol (vit e) vitamin b magnesium citrate magnesium magnesium carbonate lecithin kelp selenium calcipotriol betamethasone coal tar fluocinolone acetonide clobetasone oilatum cetraben ketoconazole diprobase epaderm miconazole 60 alfacalcidol tacrolimus sodium bicarbonate mycophenolic acid bumetanide azathioprine docusate sodium prednisolone calcium carbonate senna glycosides furosemide colecalciferol (vit d3) calcium alendronic acid risedronic acid strontium ranelate ibandronic acid prednisolone prednisone letrozole raloxifene anastrozole ergocalciferol (vit d2) calcium alendronic acid risedronic acid ginkgo folium ferrous sulfate folic acid prednisolone ezetimibe irbesartan codeine vitamin d retinol (vit a) calcium tocopherol (vit e) magnesium magnesium carbonate magnesium citrate kelp zinc ascorbic acid (vit c) vitamin b tocopherol (vit e) retinol (vit a) magnesium citrate magnesium carbonate ascorbic acid (vit c) selenium vitamin d magnesium vitamin b zinc pyridoxine (vit b6) warfarin amiodarone carvedilol sotalol flecainide spironolactone bumetanide furosemide verapamil bisoprolol colchicine caffeine cyclizine codeine naratriptan zolmitriptan sumatriptan paracetamol prochlorperazine pizotifen flax oil peppermint oil aminophylline tiotropium bromide carbocisteine salbutamol ipratropium bromide montelukast fluticasone formoterol salmeterol budesonide prednisolone theophylline tiotropium bromide montelukast carbocisteine salbutamol ipratropium bromide fluticasone formoterol salmeterol budesonide prednisolone zinc magnesium magnesium citrate magnesium carbonate selenium ascorbic acid (vit c) kelp retinol (vit a) tocopherol (vit e) lecithin vitamin b
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1 Drug V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 captopril disease_hypertension disease_heart attack/myocardial infarction disease_diabetes disease_gout disease_angina disease_high cholesterol disease_prostate problem (not cancer) disease_deep venous thrombosis (dvt) disease_osteoarthritis disease_hypothyroidism/myxoedema enalapril disease_hypertension disease_diabetic eye disease disease_type 1 diabetes disease_renal failure requiring dialysis disease_heart failure/pulmonary odema disease_polycystic kidney disease_diabetes disease_essential hypertension disease_gout disease_leg claudication/ intermittent claudication fosinopril disease_hypertension disease_diabetes disease_gout disease_high cholesterol disease_angina disease_cataract disease_stroke disease_heart attack/myocardial infarction disease_osteoarthritis disease_hypothyroidism/myxoedema 2 lisinopril disease_hypertension disease_diabetes disease_type 1 diabetes disease_scleroderma/systemic sclerosis disease_renal failure not requiring dialysis disease_heart failure/pulmonary odema disease_diabetic eye disease disease_leg claudication/ intermittent claudication disease_essential hypertension disease_high cholesterol perindopril disease_hypertension disease_cardiomyopathy disease_stroke disease_heart attack/myocardial infarction disease_heart failure/pulmonary odema disease_erectile dysfunction / impotence disease_angina disease_diabetic eye disease disease_diabetes disease_transient ischaemic attack (tia) quinapril disease_hypertension disease_type 2 diabetes disease_gout disease_stroke disease_diabetes disease_angina disease_high cholesterol disease_heart attack/myocardial infarction disease_osteoarthritis disease_uterine problem ramipril disease_hypertension disease_heart attack/myocardial infarction disease_heart failure/pulmonary odema disease_angina disease_cardiomyopathy disease_type 2 diabetes disease_diabetic eye disease disease_diabetes disease_high cholesterol disease_essential hypertension 3 trandolapril disease_hypertension disease_type 2 diabetes disease_diabetes disease_high cholesterol disease_stroke disease_gout disease_angina disease_heart attack/myocardial infarction disease_osteoarthritis disease_gastro-oesophageal reflux (gord) / gastric reflux diclofenac disease_osteoarthritis disease_rheumatoid arthritis disease_psoriatic arthropathy disease_ankylosing spondylitis disease_spine arthritis/spondylitis disease_arthritis (nos) disease_cerebral palsy disease_spinal stenosis disease_joint disorder disease_fibromyalgia etodolac disease_psoriatic arthropathy disease_rheumatoid arthritis disease_systemic lupus erythematosis/sle disease_osteoarthritis disease_vasculitis disease_cervical spondylosis disease_spine arthritis/spondylitis disease_muscle/soft tissue problem disease_joint disorder disease_psoriasis indometacin disease_gout disease_ankylosing spondylitis disease_psoriatic arthropathy disease_rheumatoid arthritis disease_arthritis (nos) disease_osteoarthritis disease_hypertension disease_disc problem disease_other neurological problem disease_psoriasis amantadine disease_chronic/degenerative neurological problem disease_depression disease_asthma disease_high cholesterol disease_hypertension NA NA NA NA NA 4 acrivastine disease_hayfever/allergic rhinitis disease_allergy/hypersensitivity/anaphylaxis disease_eczema/dermatitis disease_asthma disease_migraine disease_other neurological problem disease_irritable bowel syndrome disease_depression disease_gall bladder disease disease_uterine problem carvedilol disease_heart failure/pulmonary odema disease_cardiomyopathy disease_heart attack/myocardial infarction disease_heart/cardiac problem disease_heart arrhythmia disease_angina disease_heart valve problem/heart murmur disease_gout disease_diabetes disease_pulmonary embolism +/- dvt doxazosin disease_hypertension disease_renal failure requiring dialysis disease_polycystic kidney disease_renal/kidney failure disease_renal failure not requiring dialysis disease_diabetic eye disease disease_spinal stenosis disease_diabetes disease_leg claudication/ intermittent claudication disease_type 2 diabetes alfuzosin disease_prostate problem (not cancer) disease_bladder problem (not cancer) disease_urinary frequency / incontinence disease_angina disease_heart attack/myocardial infarction disease_oesophagitis/barretts oesophagus disease_transient ischaemic attack (tia) disease_type 2 diabetes disease_emphysema/chronic bronchitis disease_kidney stone/ureter stone/bladder stone 5 tamsulosin disease_prostate problem (not cancer) disease_urinary frequency / incontinence disease_erectile dysfunction / impotence disease_bladder problem (not cancer) disease_ureteric obstruction/hydronephrosis disease_testicular problems (not cancer) disease_leg claudication/ intermittent claudication disease_angina disease_abdominal hernia disease_heart attack/myocardial infarction terazosin disease_prostate problem (not cancer) disease_angina disease_diabetes disease_hypertension disease_gastro-oesophageal reflux (gord) / gastric reflux disease_high cholesterol disease_osteoarthritis disease_asthma disease_hayfever/allergic rhinitis NA tranexamic acid disease_dysmenorrhoea / dysmenorrhea disease_menorrhagia (unknown cause) disease_gynaecological disorder (not cancer) disease_anaemia disease_clotting disorder/excessive bleeding disease_uterine problem disease_gestational hypertension/pre-eclampsia disease_ovarian problem disease_migraine disease_depression diphenhydramine disease_depression disease_asthma disease_hayfever/allergic rhinitis disease_osteoarthritis disease_high cholesterol disease_hypertension NA NA NA NA hydroxychloroquine disease_systemic lupus erythematosis/sle disease_sjogren's syndrome/sicca syndrome disease_rheumatoid arthritis disease_connective tissue disorder disease_scleroderma/systemic sclerosis disease_raynaud's phenomenon/disease disease_peripheral vascular disease disease_psoriatic arthropathy disease_fibromyalgia disease_sarcoidosis 6 balsalazide disease_inflammatory bowel disease disease_colitis/not crohns or ulcerative colitis disease_heart attack/myocardial infarction disease_angina disease_diabetes disease_gastro-oesophageal reflux (gord) / gastric reflux disease_depression disease_hypertension disease_osteoarthritis disease_asthma mesalazine disease_colitis/not crohns or ulcerative colitis disease_inflammatory bowel disease disease_bile duct disease disease_ankylosing spondylitis disease_bone disorder disease_osteopenia disease_anaemia disease_osteoporosis disease_rectal or colon adenoma/polyps disease_chronic obstructive airways disease/copd sulfasalazine disease_rheumatoid arthritis disease_psoriatic arthropathy disease_inflammatory bowel disease disease_ankylosing spondylitis disease_colitis/not crohns or ulcerative colitis disease_sjogren's syndrome/sicca syndrome disease_dry eyes disease_bronchiectasis disease_psoriasis disease_joint disorder testosterone disease_pituitary adenoma/tumour disease_hypopituitarism disease_erectile dysfunction / impotence disease_testicular problems (not cancer) disease_cranial nerve problem/palsy disease_sleep apnoea disease_osteoporosis disease_chronic fatigue syndrome disease_diabetes disease_type 2 diabetes 7 candesartan disease_hypertension disease_heart failure/pulmonary odema disease_polycystic kidney disease_diabetic eye disease disease_cardiomyopathy disease_nephritis disease_renal failure requiring dialysis disease_renal failure not requiring dialysis disease_diabetes disease_heart attack/myocardial infarction eprosartan disease_hypertension disease_type 2 diabetes disease_stroke disease_diabetes disease_high cholesterol disease_angina disease_gout disease_hiatus hernia disease_heart attack/myocardial infarction disease_osteoarthritis irbesartan disease_hypertension disease_renal failure requiring dialysis disease_renal/kidney failure disease_renal failure not requiring dialysis disease_diabetic eye disease disease_polycystic kidney disease_diabetes disease_nephritis disease_type 1 diabetes disease_type 2 diabetes losartan disease_hypertension disease_scleroderma/systemic sclerosis disease_renal failure not requiring dialysis disease_polycystic kidney disease_cardiomyopathy disease_heart failure/pulmonary odema disease_renal/kidney failure disease_diabetes disease_essential hypertension disease_heart attack/myocardial infarction 8 olmesartan medoxomil disease_hypertension disease_essential hypertension disease_type 2 diabetes disease_high cholesterol disease_transient ischaemic attack (tia) disease_diabetes disease_stroke disease_gout disease_infection of nervous system disease_hyperthyroidism/thyrotoxicosis telmisartan disease_hypertension disease_high cholesterol disease_type 2 diabetes disease_diabetes disease_transient ischaemic attack (tia) disease_heart/cardiac problem disease_gout disease_essential hypertension disease_angina disease_other renal/kidney problem valsartan disease_hypertension disease_renal failure not requiring dialysis disease_polycystic kidney disease_cardiomyopathy disease_diabetes disease_type 2 diabetes disease_heart attack/myocardial infarction disease_diabetic eye disease disease_angina disease_essential hypertension paracetamol disease_fibromyalgia disease_cervical spondylosis disease_spine arthritis/spondylitis disease_other neurological problem disease_rheumatoid arthritis disease_migraine disease_osteoarthritis disease_back pain disease_neck problem/injury disease_dysmenorrhoea / dysmenorrhea alginic acid disease_gastro-oesophageal reflux (gord) / gastric reflux disease_dyspepsia / indigestion disease_hiatus hernia disease_oesophagitis/barretts oesophagus disease_gastritis/gastric erosions disease_oesophageal disorder disease_dry eyes disease_helicobacter pylori disease_constipation disease_stomach disorder 9 cromoglicic acid disease_hayfever/allergic rhinitis disease_dry eyes disease_allergy/hypersensitivity/anaphylaxis disease_allergy or anaphylactic reaction to food disease_eczema/dermatitis disease_asthma disease_eye/eyelid problem disease_irritable bowel syndrome disease_chronic fatigue syndrome disease_anal problem bicalutamide disease_angina disease_high cholesterol disease_osteoarthritis disease_diabetes disease_hypertension disease_depression disease_asthma NA NA NA amiodarone disease_cardiomyopathy disease_heart arrhythmia disease_heart failure/pulmonary odema disease_heart attack/myocardial infarction disease_heart/cardiac problem disease_heart valve problem/heart murmur disease_angina disease_stroke disease_hypothyroidism/myxoedema disease_diabetes flecainide disease_heart arrhythmia disease_heart/cardiac problem disease_heart valve problem/heart murmur disease_vasculitis disease_transient ischaemic attack (tia) disease_allergy or anaphylactic reaction to food disease_stroke disease_infection of nervous system disease_pulmonary embolism +/- dvt disease_cataract 10 oxybutynin disease_bladder problem (not cancer) disease_urinary frequency / incontinence disease_chronic/degenerative neurological problem disease_spinal cord disorder disease_spinal injury disease_urinary tract infection/kidney infection disease_stroke disease_pulmonary embolism +/- dvt disease_prostate problem (not cancer) disease_oesophagitis/barretts oesophagus solifenacin disease_urinary frequency / incontinence disease_bladder problem (not cancer) disease_chronic/degenerative neurological problem disease_urinary tract infection/kidney infection disease_sleep apnoea disease_thyroid problem (not cancer) disease_prostate problem (not cancer) disease_menorrhagia (unknown cause) disease_hiatus hernia disease_irritable bowel syndrome tolterodine disease_bladder problem (not cancer) disease_urinary frequency / incontinence disease_chronic/degenerative neurological problem disease_spinal cord disorder disease_urinary tract infection/kidney infection disease_prostate problem (not cancer) disease_cranial nerve problem/palsy disease_stroke disease_depression disease_angina trospium disease_bladder problem (not cancer) disease_urinary frequency / incontinence disease_chronic/degenerative neurological problem disease_urinary tract infection/kidney infection disease_stroke disease_prostate problem (not cancer) disease_irritable bowel syndrome disease_angina disease_other neurological problem disease_back problem ipratropium bromide disease_chronic obstructive airways disease/copd disease_emphysema disease_emphysema/chronic bronchitis disease_bronchiectasis disease_asthma disease_other respiratory problems disease_bronchitis disease_sleep apnoea disease_substance abuse/dependency disease_angina 11 tiotropium bromide disease_chronic obstructive airways disease/copd disease_emphysema disease_emphysema/chronic bronchitis disease_bronchiectasis disease_asbestosis disease_other respiratory problems disease_asthma disease_leg claudication/ intermittent claudication disease_pneumothorax disease_liver failure/cirrhosis tamoxifen disease_ovarian problem disease_osteoporosis disease_hyperthyroidism/thyrotoxicosis disease_spine arthritis/spondylitis disease_inflammatory bowel disease disease_uterine problem disease_chronic/degenerative neurological problem disease_hypothyroidism/myxoedema disease_varicella zoster virus disease_gall bladder disease terbinafine disease_infection of nervous system disease_type 2 diabetes disease_bronchitis disease_pneumonia disease_epilepsy disease_arthritis (nos) disease_sciatica disease_hyperthyroidism/thyrotoxicosis disease_emphysema/chronic bronchitis disease_glaucoma methotrexate disease_rheumatoid arthritis disease_psoriatic arthropathy disease_sjogren's syndrome/sicca syndrome disease_scleroderma/systemic sclerosis disease_psoriasis disease_vasculitis disease_systemic lupus erythematosis/sle disease_ankylosing spondylitis disease_sarcoidosis disease_dry eyes 12 loperamide disease_irritable bowel syndrome disease_inflammatory bowel disease disease_hiv/aids disease_colitis/not crohns or ulcerative colitis disease_other abdominal problem disease_diverticular disease/diverticulitis disease_fibromyalgia disease_pancreatic disease disease_malabsorption/coeliac disease disease_oesophagitis/barretts oesophagus betahistine disease_ear/vestibular disorder disease_sjogren's syndrome/sicca syndrome disease_cervical spondylosis disease_dry eyes disease_spine arthritis/spondylitis disease_fibromyalgia disease_menorrhagia (unknown cause) disease_heart/cardiac problem disease_stroke disease_stomach disorder cinnarizine disease_ear/vestibular disorder disease_chronic/degenerative neurological problem disease_cervical spondylosis disease_bronchitis disease_irritable bowel syndrome disease_angina disease_other neurological problem disease_stroke disease_migraine disease_hiatus hernia anastrozole disease_lymphoedema disease_osteopenia disease_osteoporosis disease_pulmonary embolism +/- dvt disease_rheumatic fever disease_deep venous thrombosis (dvt) disease_hyperthyroidism/thyrotoxicosis disease_gall bladder disease disease_peripheral nerve disorder disease_breast cysts exemestane disease_ovarian problem disease_gall bladder disease disease_uterine problem disease_hypothyroidism/myxoedema disease_diabetes disease_irritable bowel syndrome disease_gastro-oesophageal reflux (gord) / gastric reflux disease_hypertension disease_depression disease_asthma 13 letrozole disease_osteoporosis disease_ovarian problem disease_glaucoma disease_hypothyroidism/myxoedema disease_uterine problem disease_osteoarthritis disease_other neurological problem disease_gall bladder disease disease_deep venous thrombosis (dvt) disease_depression carbomers disease_dry eyes disease_sjogren's syndrome/sicca syndrome disease_eye/eyelid problem disease_chronic fatigue syndrome disease_rheumatoid arthritis disease_cataract disease_glaucoma disease_spine arthritis/spondylitis disease_osteoporosis disease_muscle/soft tissue problem carmellose disease_dry eyes disease_sjogren's syndrome/sicca syndrome disease_eye/eyelid problem disease_cataract disease_glaucoma disease_rheumatoid arthritis disease_diabetes disease_gall bladder disease disease_angina disease_hiatus hernia celluvisc disease_sjogren's syndrome/sicca syndrome disease_dry eyes disease_blepharitis / eyelid infection disease_eye/eyelid problem disease_eye infection disease_systemic lupus erythematosis/sle disease_glaucoma disease_rheumatoid arthritis disease_cataract disease_retinal problem 14 hypromellose disease_dry eyes disease_sjogren's syndrome/sicca syndrome disease_blepharitis / eyelid infection disease_eye/eyelid problem disease_systemic lupus erythematosis/sle disease_eye infection disease_diabetic eye disease disease_rheumatoid arthritis disease_raynaud's phenomenon/disease disease_eye trauma lacri-lube disease_sjogren's syndrome/sicca syndrome disease_dry eyes disease_eye/eyelid problem disease_eye infection disease_eye trauma disease_systemic lupus erythematosis/sle disease_cranial nerve problem/palsy disease_rheumatoid arthritis disease_osteopenia disease_retinal problem liquifilm tears disease_dry eyes disease_eye/eyelid problem disease_cataract disease_glaucoma disease_gall bladder disease disease_hiatus hernia disease_gastro-oesophageal reflux (gord) / gastric reflux disease_irritable bowel syndrome disease_osteoarthritis disease_hypothyroidism/myxoedema tears naturale disease_sjogren's syndrome/sicca syndrome disease_dry eyes disease_eye/eyelid problem disease_rheumatoid arthritis disease_osteoporosis disease_hypothyroidism/myxoedema disease_eczema/dermatitis disease_irritable bowel syndrome disease_angina disease_osteoarthritis 15 viscotears disease_dry eyes disease_sjogren's syndrome/sicca syndrome disease_blepharitis / eyelid infection disease_eye/eyelid problem disease_eye infection disease_systemic lupus erythematosis/sle disease_diabetic eye disease disease_fibromyalgia disease_glaucoma disease_bronchiectasis primidone disease_epilepsy disease_other neurological problem disease_stroke disease_osteoporosis disease_angina disease_diabetes disease_hayfever/allergic rhinitis disease_hypothyroidism/myxoedema disease_depression disease_osteoarthritis butylscopolamine disease_irritable bowel syndrome disease_diverticular disease/diverticulitis disease_muscle/soft tissue problem disease_gall bladder disease disease_inflammatory bowel disease disease_hiatus hernia disease_bladder problem (not cancer) disease_spine arthritis/spondylitis disease_other renal/kidney problem disease_gastric/stomach ulcers clonazepam disease_chronic/degenerative neurological problem disease_epilepsy disease_chronic fatigue syndrome disease_peripheral nerve disorder disease_muscle/soft tissue problem disease_other neurological problem disease_anxiety/panic attacks disease_infection of nervous system disease_depression disease_pulmonary embolism +/- dvt diazepam disease_deliberate self-harm/suicide attempt disease_anxiety/panic attacks disease_insomnia disease_psychological/psychiatric problem disease_post-traumatic stress disorder disease_nervous breakdown disease_mania/bipolar disorder/manic depression disease_anorexia/bulimia/other eating disorder disease_substance abuse/dependency disease_schizophrenia 16 lorazepam disease_anxiety/panic attacks disease_depression disease_emphysema/chronic bronchitis disease_heart attack/myocardial infarction disease_irritable bowel syndrome disease_diabetes disease_gastro-oesophageal reflux (gord) / gastric reflux disease_osteoarthritis disease_hypertension disease_high cholesterol nitrazepam disease_insomnia disease_depression disease_anxiety/panic attacks disease_cervical spondylosis disease_osteoporosis disease_spine arthritis/spondylitis disease_heart valve problem/heart murmur disease_diverticular disease/diverticulitis disease_angina disease_emphysema/chronic bronchitis temazepam disease_insomnia disease_liver failure/cirrhosis disease_psychological/psychiatric problem disease_mania/bipolar disorder/manic depression disease_spinal injury disease_depression disease_anxiety/panic attacks disease_chronic/degenerative neurological problem disease_chronic obstructive airways disease/copd disease_sleep apnoea zolpidem disease_insomnia disease_mania/bipolar disorder/manic depression disease_chronic fatigue syndrome disease_depression disease_anxiety/panic attacks disease_cervical spondylosis disease_spine arthritis/spondylitis disease_emphysema/chronic bronchitis disease_diverticular disease/diverticulitis disease_irritable bowel syndrome 17 zopiclone disease_insomnia disease_deliberate self-harm/suicide attempt disease_mania/bipolar disorder/manic depression disease_schizophrenia disease_hiv/aids disease_post-traumatic stress disorder disease_depression disease_fibromyalgia disease_substance abuse/dependency disease_renal failure not requiring dialysis diltiazem disease_angina disease_heart attack/myocardial infarction disease_hypertension disease_chronic obstructive airways disease/copd disease_heart failure/pulmonary odema disease_heart/cardiac problem disease_renal failure not requiring dialysis disease_heart arrhythmia disease_myeloproliferative disorder disease_emphysema/chronic bronchitis levobunolol disease_glaucoma disease_eye/eyelid problem disease_retinal problem disease_cataract disease_hypertension disease_diabetes disease_high cholesterol NA NA NA propranolol disease_anxiety/panic attacks disease_liver failure/cirrhosis disease_migraine disease_oesophageal disorder disease_myeloproliferative disorder disease_nervous breakdown disease_other neurological problem disease_stress disease_polycystic kidney disease_substance abuse/dependency sotalol disease_heart arrhythmia disease_cardiomyopathy disease_heart/cardiac problem disease_heart valve problem/heart murmur disease_transient ischaemic attack (tia) disease_heart attack/myocardial infarction disease_angina disease_stroke disease_bladder problem (not cancer) disease_hypertension 18 timolol disease_glaucoma disease_cataract disease_eye/eyelid problem disease_retinal problem disease_eye trauma disease_diabetic eye disease disease_peripheral nerve disorder disease_heart attack/myocardial infarction disease_prostate problem (not cancer) disease_type 2 diabetes atenolol disease_hypertension disease_angina disease_heart attack/myocardial infarction disease_polycystic kidney disease_renal failure requiring dialysis disease_essential hypertension disease_high cholesterol disease_renal/kidney failure disease_diabetes disease_type 2 diabetes bisoprolol disease_heart failure/pulmonary odema disease_cardiomyopathy disease_heart attack/myocardial infarction disease_angina disease_heart arrhythmia disease_heart/cardiac problem disease_renal/kidney failure disease_renal failure requiring dialysis disease_heart valve problem/heart murmur disease_renal failure not requiring dialysis metoprolol disease_heart attack/myocardial infarction disease_cardiomyopathy disease_angina disease_heart arrhythmia disease_heart/cardiac problem disease_heart valve problem/heart murmur disease_hypertension disease_diabetes disease_transient ischaemic attack (tia) disease_stroke 19 nebivolol disease_hypertension disease_angina disease_heart attack/myocardial infarction disease_transient ischaemic attack (tia) disease_heart arrhythmia disease_pulmonary embolism +/- dvt disease_stroke disease_diabetes disease_high cholesterol disease_gout amoxicillin disease_bronchiectasis disease_chronic obstructive airways disease/copd disease_emphysema/chronic bronchitis disease_urinary tract infection/kidney infection disease_bronchitis disease_tuberculosis (tb) disease_pneumonia disease_nasal/sinus disorder disease_heart valve problem/heart murmur disease_kidney stone/ureter stone/bladder stone benzathine benzylpenicillin disease_hereditary/genetic haematological disorder disease_clotting disorder/excessive bleeding disease_pulmonary embolism +/- dvt disease_deep venous thrombosis (dvt) disease_anaemia disease_diabetes disease_stroke disease_angina disease_heart attack/myocardial infarction disease_eczema/dermatitis flucloxacillin disease_stroke disease_deep venous thrombosis (dvt) disease_eczema/dermatitis disease_diabetes disease_depression disease_osteoarthritis disease_asthma disease_high cholesterol disease_hayfever/allergic rhinitis disease_hypertension 20 phenoxymethylpenicillin disease_clotting disorder/excessive bleeding disease_hereditary/genetic haematological disorder disease_pulmonary embolism +/- dvt disease_deep venous thrombosis (dvt) disease_anaemia disease_fracture pelvis & lower limb disease_gout disease_cataract disease_pneumonia disease_stroke metformin disease_diabetes disease_type 2 diabetes disease_diabetic eye disease disease_type 1 diabetes disease_erectile dysfunction / impotence disease_hypertension disease_high cholesterol disease_angina disease_sleep apnoea disease_heart attack/myocardial infarction ursodeoxycholic acid disease_liver/biliary/pancreas problem disease_liver failure/cirrhosis disease_bile duct disease disease_inflammatory bowel disease disease_osteoporosis disease_gall bladder disease disease_hiatus hernia disease_gastro-oesophageal reflux (gord) / gastric reflux disease_hypothyroidism/myxoedema disease_heart attack/myocardial infarction colestyramine disease_inflammatory bowel disease disease_malabsorption/coeliac disease disease_gall bladder disease disease_anaemia disease_irritable bowel syndrome disease_diverticular disease/diverticulitis disease_deep venous thrombosis (dvt) disease_depression disease_disc problem disease_gastro-oesophageal reflux (gord) / gastric reflux alendronic acid disease_osteoporosis disease_osteopenia disease_vasculitis disease_bone disorder disease_adrenocortical insufficiency/addison's disease disease_malabsorption/coeliac disease disease_parathyroid gland problem (not cancer) disease_systemic lupus erythematosis/sle disease_bile duct disease disease_sarcoidosis 21 etidronic acid disease_osteoporosis disease_osteoarthritis disease_angina disease_high cholesterol disease_hypothyroidism/myxoedema disease_hayfever/allergic rhinitis disease_asthma disease_depression disease_hypertension NA ibandronic acid disease_osteoporosis disease_osteopenia disease_vasculitis disease_malabsorption/coeliac disease disease_rheumatoid arthritis disease_hiatus hernia disease_ovarian problem disease_pulmonary embolism +/- dvt disease_fracture upper limb & shoulder disease_diverticular disease/diverticulitis risedronic acid disease_osteoporosis disease_vasculitis disease_osteopenia disease_systemic lupus erythematosis/sle disease_malabsorption/coeliac disease disease_bone disorder disease_sjogren's syndrome/sicca syndrome disease_sarcoidosis disease_rheumatoid arthritis disease_inflammatory bowel disease ispaghula (psylla seeds) disease_constipation disease_diverticular disease/diverticulitis disease_irritable bowel syndrome disease_dry eyes disease_rectal or colon adenoma/polyps disease_bladder problem (not cancer) disease_gastritis/gastric erosions disease_urinary frequency / incontinence disease_anal problem disease_peripheral vascular disease 22 sterculia disease_constipation disease_irritable bowel syndrome disease_diverticular disease/diverticulitis disease_inflammatory bowel disease disease_hiatus hernia disease_gastro-oesophageal reflux (gord) / gastric reflux disease_osteoporosis disease_depression disease_anxiety/panic attacks disease_uterine problem tacrolimus disease_renal failure requiring dialysis disease_polycystic kidney disease_renal/kidney failure disease_renal failure not requiring dialysis disease_liver failure/cirrhosis disease_eczema/dermatitis disease_inflammatory bowel disease disease_pulmonary embolism +/- dvt disease_stroke disease_gout calcium disease_osteopenia disease_osteoporosis disease_bone disorder disease_vasculitis disease_malabsorption/coeliac disease disease_adrenocortical insufficiency/addison's disease disease_systemic lupus erythematosis/sle disease_sjogren's syndrome/sicca syndrome disease_parathyroid gland problem (not cancer) disease_renal failure requiring dialysis calcium carbonate disease_osteoporosis disease_osteopenia disease_vasculitis disease_malabsorption/coeliac disease disease_bone disorder disease_renal failure requiring dialysis disease_systemic lupus erythematosis/sle disease_anorexia/bulimia/other eating disorder disease_renal failure not requiring dialysis disease_sjogren's syndrome/sicca syndrome brinzolamide disease_glaucoma disease_cataract disease_retinal problem disease_eye/eyelid problem disease_prostate problem (not cancer) disease_osteoporosis disease_diabetes disease_ear/vestibular disorder disease_asthma disease_stroke 23 dorzolamide disease_glaucoma disease_cataract disease_retinal problem disease_diabetic eye disease disease_eye/eyelid problem disease_diverticular disease/diverticulitis disease_prostate problem (not cancer) disease_type 2 diabetes disease_diabetes disease_angina carbamazepine disease_epilepsy disease_cranial nerve problem/palsy disease_mania/bipolar disorder/manic depression disease_schizophrenia disease_head injury disease_stroke disease_chronic/degenerative neurological problem disease_spinal cord disorder disease_infection of nervous system disease_nervous breakdown sibutramine disease_diabetes disease_gall bladder disease disease_deep venous thrombosis (dvt) disease_disc problem disease_osteoarthritis disease_gastro-oesophageal reflux (gord) / gastric reflux disease_irritable bowel syndrome disease_angina disease_uterine problem disease_high cholesterol bisacodyl disease_constipation disease_chronic/degenerative neurological problem disease_muscle/soft tissue problem disease_irritable bowel syndrome disease_emphysema/chronic bronchitis disease_spine arthritis/spondylitis disease_psoriasis disease_angina disease_depression disease_hiatus hernia 24 senna glycosides disease_constipation disease_renal failure requiring dialysis disease_other abdominal problem disease_sjogren's syndrome/sicca syndrome disease_spinal cord disorder disease_spinal injury disease_chronic/degenerative neurological problem disease_dry eyes disease_stroke disease_spine arthritis/spondylitis beclometasone disease_asthma disease_allergy to house dust mite disease_hayfever/allergic rhinitis disease_nasal/sinus disorder disease_chronic obstructive airways disease/copd disease_emphysema/chronic bronchitis disease_emphysema disease_bronchiectasis disease_asbestosis disease_eczema/dermatitis betamethasone disease_psoriasis disease_eczema/dermatitis disease_lichen planus disease_lichen sclerosis disease_psoriatic arthropathy disease_blistering/desquamating skin disorder disease_contact dermatitis disease_urticaria disease_allergy/hypersensitivity/anaphylaxis disease_allergy or anaphylactic reaction to food budesonide disease_asthma disease_chronic obstructive airways disease/copd disease_bronchiectasis disease_emphysema disease_emphysema/chronic bronchitis disease_asbestosis disease_other respiratory problems disease_oesophageal disorder disease_nasal/sinus disorder disease_bronchitis clobetasol disease_lichen planus disease_lichen sclerosis disease_eczema/dermatitis disease_psoriasis disease_blistering/desquamating skin disorder disease_gynaecological disorder (not cancer) disease_allergy/hypersensitivity/anaphylaxis disease_appendicitis disease_back pain disease_arthritis (nos) 25 clobetasone disease_lichen sclerosis disease_eczema/dermatitis disease_psoriasis disease_blistering/desquamating skin disorder disease_psoriatic arthropathy disease_allergy/hypersensitivity/anaphylaxis disease_anal problem disease_chronic obstructive airways disease/copd disease_allergy or anaphylactic reaction to food disease_bladder problem (not cancer) dexamethasone disease_dry eyes disease_eye/eyelid problem disease_eye infection disease_cataract disease_ear/vestibular disorder disease_glaucoma disease_retinal problem disease_ankylosing spondylitis disease_eczema/dermatitis disease_rheumatoid arthritis fluocinolone acetonide disease_eczema/dermatitis disease_psoriasis disease_asthma disease_hayfever/allergic rhinitis disease_osteoarthritis disease_hypertension disease_high cholesterol NA NA NA fluticasone disease_asthma disease_chronic obstructive airways disease/copd disease_bronchiectasis disease_emphysema disease_emphysema/chronic bronchitis disease_nasal/sinus disorder disease_allergy to house dust mite disease_asbestosis disease_other respiratory problems disease_adrenocortical insufficiency/addison's disease 26 hydrocortisone disease_adrenocortical insufficiency/addison's disease disease_hypopituitarism disease_pituitary adenoma/tumour disease_eczema/dermatitis disease_anal problem disease_blistering/desquamating skin disorder disease_psoriasis disease_renal failure not requiring dialysis disease_psoriatic arthropathy disease_dry eyes mometasone disease_nasal/sinus disorder disease_hayfever/allergic rhinitis disease_allergy to house dust mite disease_bronchiectasis disease_dry eyes disease_eczema/dermatitis disease_blistering/desquamating skin disorder disease_allergy/hypersensitivity/anaphylaxis disease_asthma disease_sjogren's syndrome/sicca syndrome prednisolone disease_vasculitis disease_renal failure requiring dialysis disease_systemic lupus erythematosis/sle disease_sarcoidosis disease_renal/kidney failure disease_polycystic kidney disease_myositis/myopathy disease_iritis disease_rheumatoid arthritis disease_renal failure not requiring dialysis prednisone disease_vasculitis disease_systemic lupus erythematosis/sle disease_sarcoidosis disease_rheumatoid arthritis disease_inflammatory bowel disease disease_osteoporosis disease_pulmonary embolism +/- dvt disease_emphysema/chronic bronchitis disease_eye/eyelid problem disease_stroke 27 triamcinolone disease_nasal/sinus disorder disease_hayfever/allergic rhinitis disease_allergy/hypersensitivity/anaphylaxis disease_asthma disease_diverticular disease/diverticulitis disease_emphysema/chronic bronchitis disease_ear/vestibular disorder disease_gastro-oesophageal reflux (gord) / gastric reflux disease_eczema/dermatitis disease_angina celecoxib disease_psoriatic arthropathy disease_rheumatoid arthritis disease_ankylosing spondylitis disease_osteoarthritis disease_fibromyalgia disease_spine arthritis/spondylitis disease_cervical spondylosis disease_muscle/soft tissue problem disease_arthritis (nos) disease_joint disorder etoricoxib disease_ankylosing spondylitis disease_psoriatic arthropathy disease_osteoarthritis disease_fibromyalgia disease_rheumatoid arthritis disease_spine arthritis/spondylitis disease_gout disease_joint disorder disease_cervical spondylosis disease_arthritis (nos) benserazide disease_chronic/degenerative neurological problem disease_gastro-oesophageal reflux (gord) / gastric reflux disease_depression disease_osteoarthritis disease_hypothyroidism/myxoedema disease_hypertension disease_asthma disease_high cholesterol NA NA carbidopa disease_chronic/degenerative neurological problem disease_prostate problem (not cancer) disease_angina disease_stroke disease_spine arthritis/spondylitis disease_osteoporosis disease_heart attack/myocardial infarction disease_pneumonia disease_disc problem disease_back problem 28 olanzapine disease_schizophrenia disease_mania/bipolar disorder/manic depression disease_nervous breakdown disease_psychological/psychiatric problem disease_depression disease_anxiety/panic attacks disease_head injury disease_epilepsy disease_emphysema/chronic bronchitis disease_stroke quetiapine disease_schizophrenia disease_mania/bipolar disorder/manic depression disease_psychological/psychiatric problem disease_substance abuse/dependency disease_depression disease_anxiety/panic attacks disease_epilepsy disease_emphysema/chronic bronchitis disease_allergy or anaphylactic reaction to drug disease_diabetes amlodipine disease_hypertension disease_diabetic eye disease disease_renal failure requiring dialysis disease_diabetes disease_essential hypertension disease_type 2 diabetes disease_high cholesterol disease_angina disease_renal/kidney failure disease_renal failure not requiring dialysis felodipine disease_hypertension disease_leg claudication/ intermittent claudication disease_myeloproliferative disorder disease_essential hypertension disease_high cholesterol disease_type 2 diabetes disease_diabetes disease_renal failure not requiring dialysis disease_cerebral aneurysm disease_transient ischaemic attack (tia) 29 lacidipine disease_hypertension disease_type 2 diabetes disease_other renal/kidney problem disease_diabetes disease_gout disease_high cholesterol disease_stroke disease_pulmonary embolism +/- dvt disease_angina disease_cataract lercanidipine disease_hypertension disease_essential hypertension disease_high cholesterol disease_diabetes disease_type 2 diabetes disease_gout disease_sleep apnoea disease_stroke disease_heart/cardiac problem disease_glaucoma nifedipine disease_scleroderma/systemic sclerosis disease_raynaud's phenomenon/disease disease_peripheral vascular disease disease_hypertension disease_renal failure requiring dialysis disease_renal/kidney failure disease_polycystic kidney disease_renal failure not requiring dialysis disease_leg claudication/ intermittent claudication disease_systemic lupus erythematosis/sle hydroxyzine disease_eczema/dermatitis disease_allergy/hypersensitivity/anaphylaxis disease_allergy or anaphylactic reaction to drug disease_psoriasis disease_emphysema/chronic bronchitis disease_osteoporosis disease_depression disease_stroke disease_asthma disease_pneumonia levodopa disease_chronic/degenerative neurological problem disease_prostate problem (not cancer) disease_stroke disease_spine arthritis/spondylitis disease_angina disease_osteoporosis disease_ear/vestibular disorder disease_heart attack/myocardial infarction disease_deep venous thrombosis (dvt) disease_other neurological problem 30 pramipexole disease_chronic/degenerative neurological problem disease_other neurological problem disease_stroke disease_angina disease_prostate problem (not cancer) disease_hiatus hernia disease_emphysema/chronic bronchitis disease_depression disease_gastro-oesophageal reflux (gord) / gastric reflux disease_osteoarthritis ropinirole disease_chronic/degenerative neurological problem disease_other neurological problem disease_angina disease_deep venous thrombosis (dvt) disease_cataract disease_ear/vestibular disorder disease_osteoporosis disease_prostate problem (not cancer) disease_heart attack/myocardial infarction disease_osteoarthritis multienzymes (lipase, protease etc.) disease_pancreatic disease disease_liver/biliary/pancreas problem disease_diabetes disease_pulmonary embolism +/- dvt disease_anaemia disease_heart attack/myocardial infarction disease_osteoporosis disease_gall bladder disease disease_angina disease_stroke conjugated estrogens disease_menopausal symptoms / menopause disease_uterine problem disease_constipation disease_menorrhagia (unknown cause) disease_ovarian problem disease_fibromyalgia disease_gynaecological disorder (not cancer) disease_systemic lupus erythematosis/sle disease_benign breast lump disease_bladder problem (not cancer) 31 estradiol disease_menopausal symptoms / menopause disease_adrenocortical insufficiency/addison's disease disease_uterine problem disease_gynaecological disorder (not cancer) disease_cystitis disease_ovarian problem disease_breast disease (not cancer) disease_sjogren's syndrome/sicca syndrome disease_fibromyalgia disease_dysmenorrhoea / dysmenorrhea estriol disease_gynaecological disorder (not cancer) disease_bladder problem (not cancer) disease_urinary tract infection/kidney infection disease_menorrhagia (unknown cause) disease_urinary frequency / incontinence disease_uterine problem disease_cervical problem disease_irritable bowel syndrome disease_osteoporosis disease_chronic fatigue syndrome estrogen disease_uterine problem disease_migraine disease_hypothyroidism/myxoedema disease_hayfever/allergic rhinitis disease_eczema/dermatitis disease_asthma disease_osteoarthritis disease_depression disease_hypertension disease_high cholesterol estrone disease_uterine problem disease_gall bladder disease disease_irritable bowel syndrome disease_depression disease_migraine disease_osteoarthritis disease_gastro-oesophageal reflux (gord) / gastric reflux disease_hypothyroidism/myxoedema disease_asthma disease_hayfever/allergic rhinitis ethinylestradiol disease_cervical problem disease_allergy or anaphylactic reaction to food disease_ovarian problem disease_pleurisy disease_hayfever/allergic rhinitis disease_anaemia disease_allergy/hypersensitivity/anaphylaxis disease_measles / morbillivirus disease_eczema/dermatitis disease_uterine problem 32 mestranol disease_ovarian problem disease_hyperthyroidism/thyrotoxicosis disease_allergy or anaphylactic reaction to drug disease_hypothyroidism/myxoedema disease_irritable bowel syndrome disease_uterine problem disease_anaemia disease_gall bladder disease disease_depression disease_arthritis (nos) tibolone disease_menopausal symptoms / menopause disease_osteopenia disease_uterine problem disease_urinary tract infection/kidney infection disease_cervical problem disease_rheumatic fever disease_allergy or anaphylactic reaction to drug disease_ovarian problem disease_breast cysts disease_urinary frequency / incontinence valproic acid disease_epilepsy disease_mania/bipolar disorder/manic depression disease_schizophrenia disease_psychological/psychiatric problem disease_nervous breakdown disease_stroke disease_head injury disease_infection of nervous system disease_chronic/degenerative neurological problem disease_transient ischaemic attack (tia) mefenamic acid disease_dysmenorrhoea / dysmenorrhea disease_menorrhagia (unknown cause) disease_gynaecological disorder (not cancer)Fordisease_uterine problem peerdisease_chronic fatigue syndromereviewdisease_ovarian problem onlydisease_anaemia disease_migraine disease_cervical spondylosis disease_irritable bowel syndrome 33 bezafibrate disease_diabetic eye disease disease_high cholesterol disease_diabetes disease_angina disease_pancreatic disease disease_heart attack/myocardial infarction disease_type 2 diabetes disease_gout disease_hypertension disease_stroke fenofibrate disease_high cholesterol disease_diabetes disease_diabetic eye disease disease_type 2 diabetes disease_pancreatic disease disease_heart attack/myocardial infarction disease_angina disease_hypertension disease_sleep apnoea disease_gout cefalexin disease_urinary tract infection/kidney infection disease_cystitis disease_bladder problem (not cancer) disease_other renal/kidney problem disease_vasculitis disease_urinary frequency / incontinence disease_chronic/degenerative neurological problem disease_kidney stone/ureter stone/bladder stone disease_diverticular disease/diverticulitis disease_osteoporosis ciprofloxacin disease_bronchiectasis disease_urinary tract infection/kidney infection disease_emphysema/chronic bronchitis disease_inflammatory bowel disease disease_prostate problem (not cancer) disease_osteoporosis disease_hiatus hernia disease_uterine problem disease_asthma disease_diabetes 34 goserelin disease_stroke disease_heart attack/myocardial infarction disease_back problem disease_osteoarthritis disease_hypertension disease_high cholesterol disease_gastro-oesophageal reflux (gord) / gastric reflux disease_angina disease_diabetes disease_uterine problem cimetidine disease_duodenal ulcer disease_gastric/stomach ulcers disease_gastro-oesophageal reflux (gord) / gastric reflux disease_hiatus hernia disease_psoriasis disease_irritable bowel syndrome disease_angina disease_rheumatoid arthritis disease_osteoarthritis disease_stroke ranitidine disease_dyspepsia / indigestion disease_gastro-oesophageal reflux (gord) / gastric reflux disease_peptic ulcer disease_renal failure requiring dialysis disease_duodenal ulcer disease_gastric/stomach ulcers disease_stomach disorder disease_gastritis/gastric erosions disease_urticaria disease_hiatus hernia atorvastatin disease_high cholesterol disease_heart attack/myocardial infarction disease_angina disease_renal failure requiring dialysis disease_diabetes disease_type 1 diabetes disease_diabetic eye disease disease_type 2 diabetes disease_leg claudication/ intermittent claudication disease_heart failure/pulmonary odema fluvastatin disease_angina disease_high cholesterol disease_heart attack/myocardial infarction disease_hypertension disease_diabetes disease_stroke disease_prostate problem (not cancer) disease_osteoporosis disease_heart arrhythmia disease_hiatus hernia 35 pravastatin disease_renal failure requiring dialysis disease_hiv/aids disease_high cholesterol disease_heart failure/pulmonary odema disease_angina disease_heart attack/myocardial infarction disease_stroke disease_type 2 diabetes disease_transient ischaemic attack (tia) disease_diabetes rosuvastatin disease_high cholesterol disease_angina disease_heart attack/myocardial infarction disease_hiv/aids disease_diabetic eye disease disease_diabetes disease_heart failure/pulmonary odema disease_type 2 diabetes disease_transient ischaemic attack (tia) disease_leg claudication/ intermittent claudication simvastatin disease_high cholesterol disease_diabetes disease_diabetic eye disease disease_type 2 diabetes disease_heart attack/myocardial infarction disease_angina disease_transient ischaemic attack (tia) disease_type 1 diabetes disease_stroke disease_leg claudication/ intermittent claudication phenytoin disease_epilepsy disease_stroke disease_deep venous thrombosis (dvt) disease_osteoporosis disease_prostate problem (not cancer) disease_nasal/sinus disorder disease_other neurological problem disease_ear/vestibular disorder BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. 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azithromycin disease_bronchiectasis disease_emphysema/chronic bronchitis disease_chronic obstructive airways disease/copd disease_asthma disease_pneumonia disease_diabetes disease_depression disease_hypertension disease_osteoarthritis disease_high cholesterol erythromycin disease_acne/acne vulgaris disease_rosacea disease_blistering/desquamating skin disorder disease_allergy or anaphylactic reaction to drug disease_emphysema/chronic bronchitis disease_eye/eyelid problem disease_eczema/dermatitis disease_inflammatory bowel disease disease_nasal/sinus disorder disease_anaemia magnesium disease_chronic fatigue syndrome disease_allergy or anaphylactic reaction to food disease_osteopenia disease_allergy/hypersensitivity/anaphylaxis disease_peripheral nerve disorder disease_uterine problem disease_osteoporosis disease_ovarian problem disease_allergy or anaphylactic reaction to drug disease_migraine magnesium carbonate disease_irritable bowel syndrome disease_migraine disease_depression 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spondylosis disease_scoliosis disease_spinal cord disorder disease_osteoarthritis disease_peripheral nerve disorder 45 glyceryl trinitrate disease_angina disease_heart attack/myocardial infarction disease_heart failure/pulmonary odema disease_leg claudication/ intermittent claudication disease_stroke disease_heart/cardiac problem disease_high cholesterol disease_chronic obstructive airways disease/copd disease_emphysema disease_asbestosis isosorbide mononitrate disease_angina disease_heart attack/myocardial infarction disease_heart failure/pulmonary odema disease_diabetic eye disease disease_leg claudication/ intermittent claudication disease_renal failure not requiring dialysis disease_diabetes disease_stroke disease_cardiomyopathy disease_high cholesterol lactulose disease_constipation disease_rectal prolapse disease_chronic/degenerative neurological problem disease_other abdominal problem disease_renal failure requiring dialysis disease_liver failure/cirrhosis 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disease_depression disease_bladder problem (not cancer) disease_mania/bipolar disorder/manic depression disease_fibromyalgia disease_urinary frequency / incontinence disease_chronic fatigue syndrome disease_anxiety/panic attacks disease_peripheral nerve disorder disease_muscle/soft tissue problem disease_stroke mirtazapine disease_depression disease_deliberate self-harm/suicide attempt disease_mania/bipolar disorder/manic depression disease_insomnia disease_schizophrenia disease_nervous breakdown disease_post-traumatic stress disorder disease_anxiety/panic attacks disease_substance abuse/dependency disease_fibromyalgia trazodone disease_depression disease_insomnia disease_mania/bipolar disorder/manic depression disease_anxiety/panic attacks disease_nervous breakdown disease_substance abuse/dependency disease_chronic fatigue syndrome disease_chronic obstructive airways disease/copd disease_spine arthritis/spondylitis disease_emphysema/chronic bronchitis 47 venlafaxine disease_depression disease_mania/bipolar disorder/manic depression disease_schizophrenia disease_post-traumatic stress disorder disease_anorexia/bulimia/other eating disorder disease_nervous breakdown disease_anxiety/panic attacks disease_psychological/psychiatric problem disease_fibromyalgia disease_substance abuse/dependency gabapentin disease_peripheral nerve injury disease_peripheral nerve disorder disease_cranial nerve problem/palsy disease_spinal cord disorder disease_chronic/degenerative neurological problem disease_fibromyalgia disease_spinal injury disease_spine arthritis/spondylitis disease_diabetic eye disease disease_cervical spondylosis lamotrigine disease_epilepsy disease_mania/bipolar disorder/manic depression disease_stroke disease_head injury disease_chronic/degenerative neurological problem disease_infection of nervous system disease_depression disease_osteoporosis disease_anxiety/panic attacks disease_emphysema/chronic bronchitis levetiracetam disease_epilepsy disease_head injury disease_infection of nervous system disease_stroke disease_other neurological problem disease_emphysema/chronic bronchitis disease_osteoporosis disease_deep venous thrombosis (dvt) disease_depression disease_gall bladder disease 48 pregabalin disease_peripheral nerve disorder disease_peripheral nerve injury disease_fibromyalgia disease_spinal injury disease_spinal cord disorder disease_chronic/degenerative neurological problem disease_cranial nerve problem/palsy disease_diabetic eye disease disease_disc problem disease_dry eyes topiramate disease_epilepsy disease_migraine disease_chronic/degenerative neurological problem disease_stroke disease_other neurological problem disease_irritable bowel syndrome disease_depression disease_gall bladder disease disease_disc problem disease_osteoporosis azelastine disease_nasal/sinus disorder disease_hayfever/allergic rhinitis disease_irritable bowel syndrome disease_asthma disease_gastro-oesophageal reflux (gord) / gastric reflux disease_osteoarthritis disease_diabetes disease_depression disease_hypothyroidism/myxoedema disease_hypertension nabumetone disease_rheumatoid arthritis disease_ankylosing spondylitis disease_spine arthritis/spondylitis disease_osteoarthritis disease_emphysema/chronic bronchitis disease_anaemia disease_hiatus hernia disease_angina disease_disc problem disease_osteoporosis pizotifen disease_migraine disease_vasculitis disease_stroke disease_irritable bowel syndrome disease_other neurological problem disease_chronic fatigue syndrome disease_muscle/soft tissue problem disease_bladder problem (not cancer) disease_cervical spondylosis disease_arthritis (nos) 49 hydroxycarbamide disease_clotting disorder/excessive bleeding disease_myeloproliferative disorder disease_stroke disease_psoriasis disease_deep venous thrombosis (dvt) disease_gout disease_angina disease_gastro-oesophageal reflux (gord) / gastric reflux disease_heart attack/myocardial infarction disease_hypertension risperidone disease_schizophrenia disease_mania/bipolar disorder/manic depression disease_psychological/psychiatric problem disease_nervous breakdown disease_depression disease_anxiety/panic attacks disease_emphysema/chronic bronchitis disease_diabetes disease_heart attack/myocardial infarction disease_hypothyroidism/myxoedema baclofen disease_chronic/degenerative neurological problem disease_cerebral palsy disease_spinal cord disorder disease_spinal injury disease_cranial nerve problem/palsy disease_peripheral nerve disorder disease_stroke disease_other neurological problem disease_bladder problem (not cancer) disease_chronic fatigue syndrome gamolenic acid disease_fibrocystic disease disease_breast cysts disease_sjogren's syndrome/sicca syndrome disease_female infertility disease_breast disease (not cancer) disease_chronic/degenerative neurological problem disease_anorexia/bulimia/other eating disorder disease_chronic fatigue syndrome disease_uterine problem disease_peripheral vascular disease 50 strontium ranelate disease_osteoporosis disease_fracture pelvis & lower limb disease_cataract disease_gall bladder disease disease_emphysema/chronic bronchitis disease_hiatus hernia disease_deep venous thrombosis (dvt) disease_uterine problem disease_osteoarthritis disease_eczema/dermatitis alverine disease_irritable bowel syndrome disease_diverticular disease/diverticulitis disease_oesophagitis/barretts oesophagus disease_urinary frequency / incontinence disease_cervical spondylosis disease_hiatus hernia disease_breast cysts disease_essential hypertension disease_spine arthritis/spondylitis disease_duodenal ulcer aqueous bp disease_eczema/dermatitis disease_psoriasis disease_cataract disease_peripheral nerve disorder disease_stroke disease_emphysema/chronic bronchitis disease_allergy/hypersensitivity/anaphylaxis disease_pulmonary embolism +/- dvt disease_angina disease_spine arthritis/spondylitis cetraben disease_eczema/dermatitis disease_psoriasis disease_diabetes disease_cataract disease_hiatus hernia disease_asthma disease_angina disease_osteoarthritis disease_hypothyroidism/myxoedema disease_hayfever/allergic rhinitis 51 dermol disease_eczema/dermatitis disease_psoriasis disease_allergy/hypersensitivity/anaphylaxis disease_eye/eyelid problem disease_asthma disease_angina disease_osteoporosis disease_hiatus hernia disease_emphysema/chronic bronchitis disease_hayfever/allergic rhinitis diprobase disease_eczema/dermatitis disease_psoriasis disease_psoriatic arthropathy disease_blistering/desquamating skin disorder disease_allergy/hypersensitivity/anaphylaxis disease_chronic obstructive airways disease/copd disease_allergy or anaphylactic reaction to food disease_eye/eyelid problem disease_urinary frequency / incontinence disease_bladder problem (not cancer) doublebase disease_eczema/dermatitis disease_psoriasis disease_cervical spondylosis disease_allergy/hypersensitivity/anaphylaxis disease_allergy or anaphylactic reaction to drug disease_emphysema/chronic bronchitis disease_angina disease_osteoporosis disease_stroke disease_hiatus hernia e45 cream disease_eczema/dermatitis disease_psoriasis disease_diabetes disease_pulmonary embolism +/- dvt disease_type 2 diabetes disease_peripheral nerve disorder disease_glaucoma disease_angina disease_muscle/soft tissue problem disease_emphysema/chronic bronchitis epaderm disease_eczema/dermatitis disease_blistering/desquamating skin disorder disease_psoriasis disease_allergy/hypersensitivity/anaphylaxis disease_emphysema/chronic bronchitis disease_angina disease_diabetes disease_anaemia disease_deep venous thrombosis (dvt) disease_hiatus hernia 52 oilatum disease_eczema/dermatitis disease_psoriasis disease_muscle/soft tissue problem disease_cervical spondylosis disease_asthma disease_deep venous thrombosis (dvt) disease_pneumonia disease_emphysema/chronic bronchitis disease_diabetes disease_angina azathioprine disease_inflammatory bowel disease disease_renal failure requiring dialysis disease_systemic lupus erythematosis/sle disease_bile duct disease disease_renal/kidney failure disease_vasculitis disease_colitis/not crohns or ulcerative colitis disease_polycystic kidney disease_hepatitis disease_sjogren's syndrome/sicca syndrome ezetimibe disease_high cholesterol disease_angina disease_heart attack/myocardial infarction disease_myositis/myopathy disease_renal failure requiring dialysis disease_type 2 diabetes disease_type 1 diabetes disease_diabetes disease_stroke disease_leg claudication/ intermittent claudication nicorandil disease_angina disease_heart attack/myocardial infarction disease_diabetic eye disease disease_chronic obstructive airways disease/copd disease_stroke disease_diabetes disease_type 2 diabetes disease_high cholesterol disease_sleep apnoea disease_peripheral vascular disease 53 meloxicam disease_psoriatic arthropathy disease_rheumatoid arthritis disease_ankylosing spondylitis disease_osteoarthritis disease_arthritis (nos) disease_spine arthritis/spondylitis disease_cervical spondylosis disease_fibromyalgia disease_muscle/soft tissue problem disease_cranial nerve problem/palsy piroxicam disease_ankylosing spondylitis disease_rheumatoid arthritis disease_osteoarthritis disease_arthritis (nos) disease_gout disease_hiatus hernia disease_angina disease_uterine problem disease_disc problem disease_gastro-oesophageal reflux (gord) / gastric reflux sildenafil disease_erectile dysfunction / impotence disease_diabetic eye disease disease_diabetes disease_type 2 diabetes disease_spinal cord disorder disease_chronic/degenerative neurological problem disease_prostate problem (not cancer) disease_spinal injury disease_gout disease_sleep apnoea tadalafil disease_erectile dysfunction / impotence disease_diabetic eye disease disease_diabetes disease_type 2 diabetes disease_sleep apnoea disease_prostate problem (not cancer) disease_chronic/degenerative neurological problem disease_chronic obstructive airways disease/copd disease_gout disease_rectal or colon adenoma/polyps vardenafil disease_erectile dysfunction / impotence disease_type 2 diabetes disease_diabetes disease_prostate problem (not cancer) disease_heart attack/myocardial infarction disease_hypertension disease_high cholesterol disease_gastro-oesophageal reflux (gord) / gastric reflux disease_angina disease_osteoarthritis 54 orlistat disease_diabetic eye disease disease_sleep apnoea disease_diabetes disease_fibromyalgia disease_type 2 diabetes disease_spine arthritis/spondylitis disease_hypertension disease_back pain disease_angina disease_depression promethazine disease_eczema/dermatitis disease_depression disease_anxiety/panic attacks disease_heart attack/myocardial infarction disease_hiatus hernia disease_gastro-oesophageal reflux (gord) / gastric reflux disease_asthma disease_osteoarthritis disease_angina disease_diabetes chlorpromazine disease_schizophrenia disease_mania/bipolar disorder/manic depression disease_depression disease_anxiety/panic attacks disease_emphysema/chronic bronchitis disease_diabetes disease_hypothyroidism/myxoedema disease_angina disease_osteoarthritis disease_asthma prochlorperazine disease_ear/vestibular disorder disease_fibromyalgia disease_migraine disease_chronic fatigue syndrome disease_cervical spondylosis disease_transient ischaemic attack (tia) disease_diverticular disease/diverticulitis disease_irritable bowel syndrome disease_allergy or anaphylactic reaction to drug disease_stroke 55 trifluoperazine disease_schizophrenia disease_nervous breakdown disease_mania/bipolar disorder/manic depression disease_depression disease_anxiety/panic attacks disease_diabetes disease_high cholesterol disease_hypothyroidism/myxoedema disease_asthma disease_hypertension verapamil disease_heart arrhythmia disease_cardiomyopathy disease_constipation disease_heart/cardiac problem disease_angina disease_hypertension disease_heart valve problem/heart murmur disease_essential hypertension disease_bronchiectasis disease_heart attack/myocardial infarction cyclizine disease_migraine disease_bladder problem (not cancer) disease_ear/vestibular disorder disease_pulmonary embolism +/- dvt disease_deep venous thrombosis (dvt) disease_osteoporosis disease_muscle/soft tissue problem disease_stroke disease_rheumatoid arthritis disease_emphysema/chronic bronchitis cetirizine disease_urticaria disease_hayfever/allergic rhinitis disease_allergy to house dust mite disease_allergy/hypersensitivity/anaphylaxis disease_allergy or anaphylactic reaction to food disease_eczema/dermatitis disease_dry eyes disease_blistering/desquamating skin disorder disease_sjogren's syndrome/sicca syndrome disease_asthma levocetirizine disease_hayfever/allergic rhinitis disease_allergy/hypersensitivity/anaphylaxis disease_eczema/dermatitis disease_asthma disease_allergy or anaphylactic reaction to drug disease_irritable bowel syndrome disease_nasal/sinus disorder disease_diverticular disease/diverticulitis disease_anaemia disease_emphysema/chronic bronchitis 56 desloratadine disease_urticaria disease_hayfever/allergic rhinitis disease_allergy/hypersensitivity/anaphylaxis disease_allergy or anaphylactic reaction to food disease_blistering/desquamating skin disorder disease_eczema/dermatitis disease_asthma disease_allergy or anaphylactic reaction to drug disease_chronic obstructive airways disease/copd disease_nasal/sinus disorder fexofenadine disease_urticaria disease_allergy/hypersensitivity/anaphylaxis disease_hayfever/allergic rhinitis disease_allergy to house dust mite disease_allergy or anaphylactic reaction to food disease_blistering/desquamating skin disorder disease_dry eyes disease_eczema/dermatitis disease_asthma disease_allergy or anaphylactic reaction to drug loratadine disease_hayfever/allergic rhinitis disease_urticaria disease_allergy to house dust mite disease_allergy/hypersensitivity/anaphylaxis disease_allergy or anaphylactic reaction to food disease_cystitis disease_fibromyalgia disease_dry eyes disease_asthma disease_eczema/dermatitis terfenadine disease_hayfever/allergic rhinitis disease_allergy/hypersensitivity/anaphylaxis disease_allergy or anaphylactic reaction to drug disease_nasal/sinus disorder disease_eczema/dermatitis disease_irritable bowel syndrome disease_asthma disease_uterine problem disease_depression disease_migraine 57 acetylsalicylic acid disease_heart attack/myocardial infarction disease_angina disease_transient ischaemic attack (tia) disease_leg claudication/ intermittent claudication disease_stroke disease_myeloproliferative disorder disease_diabetes disease_diabetic eye disease disease_type 2 diabetes disease_high cholesterol clopidogrel disease_heart attack/myocardial infarction disease_angina disease_transient ischaemic attack (tia) disease_stroke disease_leg claudication/ intermittent claudication disease_myeloproliferative disorder disease_renal/kidney failure disease_heart failure/pulmonary odema disease_heart/cardiac problem disease_diabetic eye disease dipyridamole disease_stroke disease_transient ischaemic attack (tia) disease_diabetic eye disease disease_heart attack/myocardial infarction disease_high cholesterol disease_angina disease_hypertension disease_diabetes disease_type 2 diabetes disease_clotting disorder/excessive bleeding potassium disease_hypertension disease_stroke disease_heart arrhythmia disease_diabetes disease_deep venous thrombosis (dvt) disease_angina disease_irritable bowel syndrome disease_high cholesterol disease_gastro-oesophageal reflux (gord) / gastric reflux disease_hypothyroidism/myxoedema 58 potassium citrate disease_urinary tract infection/kidney infection disease_irritable bowel syndrome disease_uterine problem disease_gastro-oesophageal reflux (gord) / gastric reflux disease_hypothyroidism/myxoedema disease_hayfever/allergic rhinitis disease_osteoarthritis disease_asthma disease_hypertension disease_high cholesterol amiloride disease_lymphoedema disease_heart valve problem/heart murmur disease_diabetic eye disease disease_angina disease_hypertension disease_urinary frequency / incontinence disease_sleep apnoea disease_heart/cardiac problem disease_rheumatic fever disease_vasculitis spironolactone disease_heart failure/pulmonary odema disease_cardiomyopathy disease_liver failure/cirrhosis disease_renal failure not requiring dialysis disease_heart attack/myocardial infarction disease_heart arrhythmia disease_heart valve problem/heart murmur disease_angina disease_diabetic eye disease disease_heart/cardiac problem allopurinol disease_gout disease_renal failure requiring dialysis disease_renal/kidney failure disease_heart failure/pulmonary odema disease_renal failure not requiring dialysis disease_myeloproliferative disorder disease_polycystic kidney disease_erectile dysfunction / impotence disease_other renal/kidney problem disease_hypertension colchicine disease_gout disease_heart arrhythmia disease_heart attack/myocardial infarction disease_hypertension disease_stroke disease_diabetes disease_angina disease_psoriasis disease_osteoarthritis disease_high cholesterol 59 heparinoid disease_spine arthritis/spondylitis disease_osteoarthritis disease_muscle/soft tissue problem disease_arthritis (nos) disease_cervical spondylosis disease_gastric/stomach ulcers disease_emphysema/chronic bronchitis disease_stroke disease_rheumatoid arthritis disease_angina desogestrel disease_miscarriage disease_measles / morbillivirus disease_migraine disease_varicella zoster virus disease_irritable bowel syndrome disease_allergy or anaphylactic reaction to drug disease_allergy/hypersensitivity/anaphylaxis disease_gestational hypertension/pre-eclampsia disease_anaemia disease_ovarian problem dydrogesterone disease_menopausal symptoms / menopause disease_allergy/hypersensitivity/anaphylaxis disease_throat or larynx disorder disease_eye/eyelid problem disease_ovarian problem disease_eczema/dermatitis disease_appendicitis disease_depression disease_hypothyroidism/myxoedema disease_asthma etonogestrel disease_hayfever/allergic rhinitis disease_depression disease_asthma disease_hypertension NA NA NA NA NA NA 60 etynodiol disease_allergy/hypersensitivity/anaphylaxis disease_other neurological problem disease_hayfever/allergic rhinitis disease_asthma disease_irritable bowel syndrome disease_uterine problem disease_depression disease_migraine disease_hypothyroidism/myxoedema disease_hypertension levonorgestrel disease_gynaecological disorder (not cancer) disease_cervical problem disease_uterine problem disease_menorrhagia (unknown cause) disease_gestational hypertension/pre-eclampsia disease_ovarian problem disease_allergy or anaphylactic reaction to food disease_benign breast lump disease_anaemia disease_eczema/dermatitis medroxyprogesterone disease_menopausal symptoms / menopause disease_fibromyalgia disease_gynaecological disorder (not cancer) disease_benign breast lump disease_infection of nervous system 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carbimazole disease_hyperthyroidism/thyrotoxicosis disease_heart arrhythmia disease_other neurological problem disease_osteoporosis disease_deep venous thrombosis (dvt) disease_gall bladder disease disease_hypothyroidism/myxoedema disease_hiatus hernia http://bmjopen.bmj.com/ disease_irritable bowel syndrome disease_diabetes aloe vera disease_irritable bowel syndrome disease_allergy or anaphylactic reaction to food disease_chronic fatigue syndrome disease_diverticular disease/diverticulitis disease_allergy/hypersensitivity/anaphylaxis disease_inflammatory bowel disease disease_spine arthritis/spondylitis disease_other joint disorder disease_sciatica disease_nasal/sinus disorder chondroitin sulfate disease_osteoarthritis disease_other joint disorder disease_arthritis (nos) disease_female infertility disease_spine arthritis/spondylitis disease_ectopic pregnancy disease_allergy or anaphylactic reaction to food disease_cervical spondylosis disease_rheumatic fever disease_osteomyelitis cod 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disease_emphysema/chronic bronchitis disease_disc problem disease_migraine disease_osteoarthritis mebeverine disease_irritable bowel syndrome disease_diverticular disease/diverticulitis disease_lichen sclerosis disease_fibromyalgia disease_other abdominal problem disease_constipation disease_dry eyes disease_dysmenorrhoea / dysmenorrhea disease_stomach disorder disease_chronic fatigue syndrome coal tar disease_psoriasis disease_psoriatic arthropathy disease_eczema/dermatitis disease_angina disease_anaemia disease_cataract disease_rheumatoid arthritis disease_prostate problem (not cancer) disease_emphysema/chronic bronchitis disease_heart attack/myocardial infarction procyclidine disease_schizophrenia disease_mania/bipolar disorder/manic depression disease_depression disease_anxiety/panic attacks disease_emphysema/chronic bronchitis disease_diabetes disease_heart attack/myocardial infarction disease_high cholesterol disease_angina disease_hypertension dutasteride disease_prostate problem (not cancer) disease_urinary frequency / incontinence disease_bladder problem (not cancer) disease_heart arrhythmia disease_stroke disease_heart attack/myocardial infarction disease_angina disease_glaucoma disease_cataract disease_high cholesterol finasteride disease_prostate problem (not cancer) disease_urinary frequency / incontinence disease_angina disease_heart attack/myocardial infarction disease_abdominal hernia disease_bladder problem (not cancer) disease_rectal or colon adenoma/polyps disease_kidney stone/ureter stone/bladder stone disease_type 2 diabetes disease_transient ischaemic attack (tia) doxycycline disease_rosacea disease_acne/acne vulgaris disease_bronchiectasis disease_eye infection disease_blistering/desquamating skin disorder disease_nasal/sinus disorder disease_eye/eyelid problem disease_emphysema/chronic bronchitis disease_urinary tract infection/kidney infection disease_pulmonary embolism +/- dvt lymecycline disease_acne/acne vulgaris disease_rosacea disease_blistering/desquamating skin disorder disease_eczema/dermatitis disease_inflammatory bowel disease disease_nasal/sinus disorder disease_migraine disease_prostate problem (not cancer) disease_hiatus hernia disease_uterine problem minocycline disease_acne/acne vulgaris disease_rosacea disease_eczema/dermatitis disease_disc problem disease_migraine disease_asthma disease_osteoarthritis disease_hypothyroidism/myxoedema disease_depression disease_hayfever/allergic rhinitis oxytetracycline disease_acne/acne vulgaris disease_rosacea disease_blistering/desquamating skin disorder disease_eczema/dermatitis disease_back pain disease_nasal/sinus disorder disease_fracture pelvis & lower limb disease_bladder problem (not cancer) disease_eye/eyelid problem disease_gastro-oesophageal reflux (gord) / gastric reflux tetracycline disease_acne/acne vulgaris disease_rosacea disease_blistering/desquamating skin disorder disease_asthma disease_osteoarthritis disease_hypertension NA NA NA NA bendroflumethiazide disease_hypertension disease_essential hypertension disease_high cholesterol disease_stroke disease_transient ischaemic attack (tia) disease_diabetes disease_type 2 diabetes disease_leg claudication/ intermittent claudication disease_chronic skin ulcers disease_cerebral aneurysm hydrochlorothiazide disease_hypertension disease_angina disease_heart attack/myocardial infarction disease_essential hypertension disease_heart arrhythmia disease_diabetes disease_heart/cardiac problem disease_high cholesterol disease_transient ischaemic attack (tia) disease_stroke pioglitazone disease_diabetes disease_type 2 diabetes disease_diabetic eye disease disease_hypertension disease_high cholesterol disease_sleep apnoea disease_peripheral nerve disorder disease_angina disease_vasculitis disease_heart attack/myocardial infarction rosiglitazone disease_diabetes disease_type 2 diabetes disease_diabetic eye disease disease_hypertension disease_high cholesterol disease_sleep apnoea disease_angina disease_essential hypertension disease_peripheral nerve disorder disease_stroke flupentixol disease_schizophrenia disease_anxiety/panic attacks disease_depression disease_irritable bowel syndrome disease_heart attack/myocardial infarction disease_diabetes disease_osteoarthritis disease_high cholesterol disease_hypertension disease_asthma on September 26, 2021 by guest. Protected copyright. levothyroxine sodium disease_hypothyroidism/myxoedema disease_hypopituitarism disease_hyperthyroidism/thyrotoxicosis disease_thyroiditis disease_thyroid problem (not cancer) disease_adrenocortical insufficiency/addison's disease disease_thyroid goitre disease_pituitary adenoma/tumour disease_vitiligo disease_lichen sclerosis trimethoprim disease_urinary tract infection/kidney infection disease_cystitis disease_bladder problem (not cancer) disease_other renal/kidney problem disease_chronic/degenerative neurological problem disease_urinary frequency / incontinence disease_kidney stone/ureter stone/bladder stone disease_prostate problem (not cancer) disease_eye/eyelid problem disease_osteoporosis adalimumab disease_rheumatoid arthritis disease_psoriatic arthropathy disease_ankylosing spondylitis disease_psoriasis disease_osteoporosis disease_hypothyroidism/myxoedema disease_hypertension disease_diabetes disease_depression disease_high cholesterol retinol (vit a) disease_eczema/dermatitis disease_uterine problem disease_migraine disease_gastro-oesophageal reflux (gord) / gastric reflux disease_osteoarthritis disease_hypertension disease_high cholesterol disease_hayfever/allergic rhinitis disease_hypothyroidism/myxoedema disease_asthma cyanocobalamin (vit b12) disease_anaemia disease_malabsorption/coeliac disease disease_inflammatory bowel disease disease_hypothyroidism/myxoedema disease_stroke disease_type 2 diabetes disease_diabetes disease_glaucoma disease_osteoporosis disease_irritable bowel syndrome folic acid disease_rheumatoid arthritis disease_psoriatic arthropathy disease_renal failure requiring dialysis disease_sjogren's syndrome/sicca syndrome disease_hereditary/genetic haematological disorder disease_scleroderma/systemic sclerosis disease_vasculitis disease_systemic lupus erythematosis/sle disease_renal/kidney failure disease_anaemia hydroxocobalamin (vit b12) disease_anaemia disease_inflammatory bowel disease disease_malabsorption/coeliac disease disease_hypothyroidism/myxoedema disease_osteoporosis disease_diabetic eye disease disease_rheumatoid arthritis disease_chronic/degenerative neurological problem disease_chronic fatigue syndrome disease_hyperthyroidism/thyrotoxicosis vitamin b12 disease_anaemia disease_inflammatory bowel disease disease_malabsorption/coeliac disease disease_chronic/degenerative neurological problem disease_chronic fatigue syndrome disease_osteoporosis disease_hypothyroidism/myxoedema disease_other renal/kidney problem disease_peripheral nerve disorder disease_cervical spondylosis pyridoxine (vit b6) disease_bone disorder disease_anaemia disease_irritable bowel syndrome disease_chronic/degenerative neurological problem disease_ovarian problem disease_anxiety/panic attacks disease_allergy/hypersensitivity/anaphylaxis disease_kidney stone/ureter stone/bladder stone disease_depression disease_gall bladder disease thiamine (vit b1) disease_substance abuse/dependency disease_liver failure/cirrhosis disease_pancreatic disease disease_liver/biliary/pancreas problem disease_gastritis/gastric erosions disease_chronic obstructive airways disease/copd disease_epilepsy disease_stroke disease_duodenal ulcer disease_head injury vitamin b disease_substance abuse/dependency disease_liver failure/cirrhosis disease_renal failure requiring dialysis disease_deliberate self-harm/suicide attempt disease_liver/biliary/pancreas problem disease_pancreatic disease disease_chronic fatigue syndrome disease_peripheral vascular disease disease_hereditary/genetic haematological disorder disease_peripheral nerve disorder ascorbic acid (vit c) disease_fibrocystic disease disease_thyroiditis disease_chronic fatigue syndrome disease_allergy or anaphylactic reaction to food disease_female infertility disease_anorexia/bulimia/other eating disorder disease_allergy or anaphylactic reaction to drug disease_allergy/hypersensitivity/anaphylaxis disease_peripheral vascular disease disease_ankylosing spondylitis calcipotriol disease_psoriasis disease_psoriatic arthropathy disease_cervical spondylosis disease_eczema/dermatitis disease_emphysema/chronic bronchitis disease_muscle or soft tissue injuries disease_angina disease_ear/vestibular disorder disease_diabetes disease_eye/eyelid problem alfacalcidol disease_renal/kidney failure disease_renal failure requiring dialysis disease_renal failure not requiring dialysis disease_parathyroid gland problem (not cancer) disease_polycystic kidney disease_diabetic eye disease disease_other renal/kidney problem disease_osteoporosis disease_osteopenia disease_vasculitis colecalciferol (vit d3) disease_osteoporosis disease_osteopenia disease_bone disorder disease_vasculitis disease_malabsorption/coeliac disease disease_adrenocortical insufficiency/addison's disease disease_systemic lupus erythematosis/sle disease_sjogren's syndrome/sicca syndrome disease_scleroderma/systemic sclerosis disease_connective tissue disorder ergocalciferol (vit d2) disease_osteopenia disease_osteoporosis disease_malabsorption/coeliac disease disease_heart valve problem/heart murmur disease_rheumatoid arthritis disease_hypothyroidism/myxoedema disease_cataract disease_osteoarthritis disease_migraine disease_uterine problem vitamin d disease_adrenocortical insufficiency/addison's disease disease_bone disorder disease_osteopenia disease_osteoporosis disease_malabsorption/coeliac disease disease_liver failure/cirrhosis disease_chronic fatigue syndrome disease_allergy or anaphylactic reaction to food disease_vasculitis disease_breast cysts tocopherol (vit e) disease_chronic fatigue syndrome disease_allergy/hypersensitivity/anaphylaxis disease_allergy or anaphylactic reaction to food disease_breast cysts disease_chronic/degenerative neurological problem disease_rheumatic fever disease_bladder problem (not cancer) disease_osteoporosis disease_pleurisy disease_eye/eyelid problem warfarin disease_heart arrhythmia disease_heart failure/pulmonary odema disease_pulmonary embolism +/- dvt disease_cardiomyopathy disease_heart valve problem/heart murmur disease_deep venous thrombosis (dvt) disease_stroke disease_heart/cardiac problem disease_renal failure requiring dialysis disease_rheumatic fever caffeine disease_migraine disease_other neurological problem disease_nasal/sinus disorder disease_breast cysts disease_cervical spondylosis disease_joint disorder disease_other joint disorder disease_anxiety/panic attacks disease_urinary tract infection/kidney infection disease_bladder problem (not cancer) aminophylline disease_chronic obstructive airways disease/copd disease_asthma disease_emphysema/chronic bronchitis disease_bronchiectasis disease_cataract disease_osteoporosis disease_pneumonia disease_pulmonary embolism +/- dvt disease_glaucoma disease_angina theophylline disease_chronic obstructive airways disease/copd disease_asthma disease_emphysema/chronic bronchitis disease_bronchiectasis disease_osteoporosis disease_pulmonary embolism +/- dvt disease_pneumonia disease_nasal/sinus disorder disease_stroke disease_diverticular disease/diverticulitis zinc disease_chronic fatigue syndrome disease_allergy or anaphylactic reaction to food disease_female infertility disease_anal problem disease_sarcoidosis disease_urinary tract infection/kidney infection disease_allergy or anaphylactic reaction to drug disease_bronchiectasis disease_helicobacter pylori disease_peripheral vascular disease
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Legends for supplementary figures and tables 1 2
3 BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from 4 5 Supplementary Figure 1 6 7 All medications are presented according to the three classification levels used for analysis (i.e. chemical 8 substance, chemical subgroup and therapeutic subgroup) and aggregated by their anatomical groups (see 9 10 Methods). Numbers in parenthesis next to a medication name on the left indicate the classification level of 11 the medication: (1) chemical substance, (2) chemical subgroup, (3) therapeutic subgroup and (4) 12 anatomical group. Some extra formatting is included in the Y-axis to ease visual inspection of the drug 13 classification tree. First, all labels are sorted such that, for any given category, the descendants in the 14 15 classification tree appear below. Secondly, an arrow is included besides each label such that its length 16 represents how deep the drug or drug group is in the classification tree. Namely, no arrow for the 17 anatomical group, “<-“ forFor therapeutic peer subgroup, review“<--“ for chemical subgrouponly and “<---“ for chemical 18 substance. 19 20 Relationship between medication and each cognitive test are represented by effect size and 95% 21 22 confidence intervals across three columns: verbal-numerical reasoning test (score), memory test (score) 23 and reaction time test (ms). For all three tests, negative values indicate poorer cognitive performance and 24 vice versa. The corresponding p-values after false discovery rate (FDR) correction for multiple comparisons 25 were indicated by filled circles with red line (p < .005), empty circle (p < .05) and ‘x’ with black line (p > .05). 26 27 *Abbreviations: ACE = angiotensin converting enzyme, TNF = tumour necrosis factor, RTI = reverse 28 transcriptase inhibitor, GI = gastroinstestinal. 29 30 31 32 Supplementary table 1 33 34 35 As described in the Methods section, for every medication, odds ratios (OR) between the medication of 36 interest and each of all other 367 medications were calculated. The 10 medications with highest OR were 37 selected as covariates in the linear model. The table shows all studied medication (total 368 rows) and their 38 http://bmjopen.bmj.com/ 39 top 10 OR medications (10 columns: highest on the left). To avoid anomalously high OR values in the low 40 frequency medications, medications with less than 10 co-prescriptions with the medication of interest (e.g. if 41 Medication of interest A and Medication B were taken together by only 3 participants, Medication B was not 42 considered as a covariate regardless of its OR) were excluded. Due to this exclusion, few medications had 43 44 less than 10 medications in the model (displayed as NA, not available). 45 46 47 on September 26, 2021 by guest. Protected copyright. 48 Supplementary table 2 49 50 51 As described in the Methods section, for every medication, odds ratios (OR) between the medication of 52 interest and each of all 278 diagnoses were calculated. The 10 diagnoses with highest OR were selected 53 as covariates in the linear model. The table shows all studied medication (total 368 rows) and their top 10 54 55 OR diagnoses (10 columns: highest on the left). To avoid anomalously high OR values in the low frequency 56 medications, diagnoses with less than 10 co-occurrences with the medication of interest (e.g. if Medication 57 of interest A and Diagnosis B co-occurred in only 3 participants, Diagnosis B was not considered as a 58 covariate regardless of its OR) were excluded. Due to this exclusion, few medications had less than 10 59 60 diagnoses in the model (displayed as NA, not available).
1
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Page 19 of 21 BMJ Open
1 2 3 4
5
6
7 8 skeletal -
9 10 11 For peer review only 12 cardiovascular immune/cancer nervoussystem respiratorysystem & metabolismGI urinary supplements blood organs antiinfectives hormones and modulators ophthalmologicals musculo dermatologicals 13 61.12 ± 56.84 ± 57.01 ± 57.42 ± 59.7 ± 62.06 ± 59.01 ± 61.24 ± 58.49 ± 57 ± 61.97 ± 61.57 ± 57.25 ± Age (years) 14 6.51** 8.17** 8.15 8.2** 7.41** 6.26** 7.54** 6.81** 7.97** 7.94 6.37** 6.33** 7.73 15 Gender (women) 16 46.7%** 60.5%** 64.5%** 59.3%** 53.5%** 24%** 65.1%** 38.6%** 55.7%** 90.4%** 59%** 55.3%* 78.8%** Education
17 http://bmjopen.bmj.com/ 18 A-levels and above 33.8%** 41%** 36.1%** 39.5%** 31.8%** 37%** 40.3%** 35.4%** 37.9%** 41.7%** 37.7%** 35.2%** 38.7%** 19 Other educational qualifications 32.2%** 33.7%** 33.9%** 32.3%* 33.3%** 30.5%** 33% 30.7%** 31.6%** 33.8%** 30.2%** 32.10% 34.9%** 20 21 Professional qualifications only 6.2%** 5.3%* 5.3%** 5.20% 6.2%** 6%** 5.9%** 5.9%** 5.40% 5.8%** 6.4%** 6%** 5.20% 22 None of the above 25.5%** 18.4%** 22.9%** 20.9%** 26.4%** 24.6%** 19%** 25.8%** 23.2%** 16.80% 23.1%** 24.8%** 19.5%** 23 Prefer not to answer 2.3%** 1.7%** 1.9%** 2.1% 2.3%** 1.9% 1.8%** 2.3%** 2% 1.8%** 2.5%** 1.9% 1.7%* 24 Household income (GBP/year) 25 26 < 18,000 27%** 21.7%** 26.9%** 25%** 29.3%** 28%** 22.4%** 27.8%** 27.3%** on September 26, 2021 by guest. Protected copyright. 20.8%** 27.9%** 27.4%** 23%** 27 18,000-30,999 24%** 21.5%* 21.6%* 21.3%* 22.6%** 24.9%** 23.9%** 23.8%** 21.80% 21.80% 24%** 24.2%** 22.40% 28 31,000-51,999 18.3%** 21.5%** 19.2%** 20%** 17.4%** 19%** 20.7%** 17.9%** 18.3%** 21.2%** 16.4%** 16.8%** 20.9%** 29 30 52,000-100,000 11.1%** 16.4%** 13%** 14.7%** 10.5%** 11.3%** 13.4%** 11.4%** 13%** 15.7%** 9.6%** 10.3%** 13.7%** 31 > 100,000 2.8%** 4.1%** 2.9%** 3.4%** 2.4%** 2.6%** 3%** 3.1%** 3.2%** 4.2%** 2.3%** 3%** 2.9%** 32 Do not know 5.4%** 4.7%** 6%** 5.4%** 6.3%** 4.3% 5.1%** 5.2%** 6%** 5.2%** 6.7%** 6.2%** 5.7%** 33 Prefer not to answer 34 11.4%** 9.9% 10.4%** 10.10% 11.5%** 9.8% 11.6%** 10.7%** 10.5% 11.1%** 13%** 12%** 11.5%** 35 36 Supplementary Table 3. Baseline characteristics of drug users The table shows summary statistics for all users of drugs belonging to each anatomical 37 category. As in Table 1, values indicate mean ± standard deviation for age, or percentages for gender, education and household income. Age of drug users 38 (row two) is compared with the average age of all participants (row three column two of Table 1) with a Wilcoxon test. All other proportions in the table (which 39 40 were calculated for drug users) are compared with those corresponding to all participants (i.e. drug users and non-drug users, column 2 of supplementary 41 Table 2) using a binomial test. FDR corrected p-value below .005 is indicated with two stars, while p-value below .05 is indicated with one star. 42 43 2 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 20 of 21
Participants completed cognitive test 1 All 2 participants Verbal-numerical
Memory Reaction time BMJ Open: first published as 10.1136/bmjopen-2016-012177 on 30 November 2016. Downloaded from 3 reasoning 4 5 cardiovascular 28.3% 29%** 28%** 28.2% 6 immune/cancer 25.2% 24.8%** 25.4% 25.3% 7 nervous system 28.2% 27.1%** 28%* 28.1% 8 9 respiratory system 9.3% 9.2% 9.3% 9.3% 10 GI & metabolism 16.7% 16.6% 16.5%** 16.6% 11 urinary 2.7% 2.8%* 2.7% 2.7% 12 supplements 19.5% 14.8%** 19.5% 19.5% 13 14 blood organs 15.4% 13.7%** 15.2%** 15.3% 15 antiinfectives 2.8% 2.7%** 2.8% 2.8% 16 hormones and modulators 10.6% 10.7% 10.6% 10.6% 17 For peer review only 18 ophthalmologicals 1.8% 1.8% 1.7% 1.7% 19 musculo-skeletal 3.1% 3.4%** 3.1% 3.1% 20 dermatologicals 2.7% 1.9%** 2.7% 2.7% 21 22 Supplementary Table 4. Drug users per cognitive test. For the participants of each cognitive test 23 24 (columns two, three and fourth), the table shows the proportion of them that was using drugs belonging to 25 each anatomical category (rows). The total proportion of drugs users is shown in column two. A binomial 26 test was used to compare columns three-fourth with column two. FDR corrected p-value below .005 is 27 indicated with two stars, while p-value below .05 is indicated with one star. 28 29
30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 26, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60
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For peer )relevant, If consider translating estimatesrelativerisk of into absolute for risk meaningfulperioda time review only c b a similar studies,similar and other relevant evidence confounders magnitude of magnitude potential any bias confirmed eligible,confirmed included in study, the completing follow-up, analysed and interval). Make interval). clear confounderswhich were adjusted they why and for were included which the presentthe which is based article
( ( number Indicate (b) of participants missingwith eachfor data of interest variable Consider (c) diagram use flow of a reasons Give (b) non-participationfor each at stage 18 18 Summarise results key to reference withstudy objectives 16 16 ( 22 22 sourcethe Give of funding and role the of fundersthe thefor studypresent if and, applicable, originalthe for study on 19 19 Discuss of study, the limitations taking into sourcesaccount biasof potential imprecision.or Discussboth direction and 13* 13* Report (a) numbers of individuals each at stage of study—eg numbers eligible, potentially examinedfor eligibility, An Explanation and Elaboration article discusses itemeach checklist and gives methodological backgroundand published examples of transparent reporting. The STROBE checklist is best used in thiswith conjunction (freely available article onsites the Medicine of PLoS Web http://www.plosmedicine.org/, at Annals of Internal Medicine at http://www.annals.org/, Epidemiologyhttp://www.epidem.com/). at and Information on InitiativeSTROBE the is www.strobe-statement.org.available at information*Give separately cases for and controls studiesin case-controlfor applicable, if and, exposedunexposed and groups in cohort and cross-sectional studies. Note: Funding Other information Generalisability 21 Discuss (externalgeneralisabilitythe of validity) studythe results Interpretation 20 cautious Give interpretationa of overall resultsconsidering limitations, objectives, multiplicity of resultsanalyses, from Limitations Key Key results Discussion Other analyses 17 other Report analyses done—eg analyses of subgroups sensitivity interactions, and and analyses
Main resultsMain Outcome Outcome data 15* numbers Report of outcome events or summary measures
Descriptive data 14* characteristicsGive (a) participantsof study (eg demographic, clinical, social) and information on exposures potential and
Participants 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60