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1.  Non-Steroidal Anti-Inflammatory Drugs and Antibiotics Prescription Trends at a Central West Bank Hospital 
Objectives:
We aimed to reliably describe the pattern of outpatient prescription of non-steroidal anti-inflammatory drugs (NSAIDs) and antibiotics (ATBs) at a central hospital in the West Bank, Palestine.
Methods:
This was a retrospective, cross-sectional study investigating a cohort of 2,208 prescriptions ordered by outpatient clinics and the emergency room over one year in Beit Jala Hospital in Bethlehem, West Bank. The orders were analysed for the rate and types of NSAIDs and ATBs utilised, and the appropriateness of these drugs to the diagnosis.
Results:
Of the total prescriptions, 410 contained NSAIDs (18.6%), including diclofenac (40.2%), low dose aspirin (23.9%), ibuprofen (17.8%) and indomethacin (15.1%). A minority of these prescriptions contained a combination of these agents (2.5%). Only one prescription contained cyclooxyeganse-2 inhibitors (0.2%). The appropriateness of NSAID use to the diagnosis was as follows: appropriate (58.3%), inappropriate (14.4%) and difficult to tell (27.3%). The rate of ATB use was 30.3% (669 prescriptions). The ATBs prescribed were amoxicillin (23.3%), augmentin (14.3%), quinolones (12.7%), first and second generation cephalosporins (9.4% and 12.7%, respectively) and macrolides (7.2%). ATB combinations were identified in 9.4%, with the most common being second-generation cephalopsorins and metronidazole (4.3%). Regarding the appropriateness of prescribing ATBs according to the diagnosis, it was appropriate in 44.8%, inappropriate in 20.6% and difficult to tell in 34.6% of the prescriptions.
Conclusion:
These findings revealed a relatively large number and inappropriate utilisation of ATBs and NSAIDs. An interventional programme needs to be adopted to reinforce physicians’ knowledge of the rational prescription of these agents.
PMCID: PMC3836647  PMID: 24273668
NSAIDs; Antibiotics; Prescription; Palestine
2.  OTC analgesics and drug interactions: clinical implications 
The risk of drug interactions with concurrent use of multiple medications is a clinically relevant issue. Many patients are unaware that over-the-counter (OTC) analgesics can cause potentially serious adverse effects when used in combination with other common medications such as anticoagulants, corticosteroids, or antihypertensive agents. Of particular significance is the increased risk of upper abdominal gastrointestinal adverse events in patients who take traditional nonsteroidal anti-inflammatory drugs (NSAIDs). This risk is dose dependent and further increased in patients who take more than one NSAID or use NSAIDs in combination with certain other medications. Some NSAIDs may also mitigate the antiplatelet benefits of aspirin and may increase blood pressure in patients with hypertension. Clinicians should be aware of potential drug interactions with OTC analgesics when prescribing new medications. Additionally, patients should be properly counseled on the appropriate and safe use of OTC analgesics.
doi:10.1186/1750-4732-2-2
PMCID: PMC2257951  PMID: 18257920
3.  Non-Steroidal Anti-Inflammatory Drugs and Prostate Cancer Risk in the VITamins And Lifestyle (VITAL) Cohort 
Introduction
Chronic inflammation may be important in prostate carcinogenesis. Several epidemiologic studies have reported inverse associations between non-steroidal anti-inflammatory drugs (NSAIDs) and prostate cancer risk, although many studies are limited by assessment of short-term use only.
Methods
Participants were male members of the VITamins And Lifestyle cohort, comprised of 34,132 men, age 50-76 years, living in western Washington State. Cox proportional hazards models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) of 10-year average use of individual NSAIDs with total prostate cancer (n=1,550) and prostate cancer by grade.
Results
Low-dose aspirin, regular-strength aspirin, ibuprofen, and any non-aspirin NSAID (ibuprofen, naproxen, and COX-2 inhibitors) were not associated with prostate cancer risk. There was a suggestion that regular-strength aspirin was inversely associated with risk of high-grade cancer (HR 0.73, 95% CI: 0.53-1.02).
Conclusion
NSAID use was not associated with prostate cancer risk in the VITAL cohort.
Impact
Our findings do not support the use of NSAIDs for chemoprevention of prostate cancer.
doi:10.1158/1055-9965.EPI-10-0942
PMCID: PMC3005534  PMID: 20935064
4.  General practitioners' use of non-steroidal anti-inflammatory drugs in Tayside and Fife regions. 
The objectives of this study were to assess the prescribing of non-steroidal anti-inflammatory drugs (NSAIDs) by general practitioners and to determine their attitudes to problems caused by this class of drugs. The study consisted of two parts. The first was a questionnaire survey among general practitioners in Fife and Tayside, and the second was an analysis of NSAID prescribing over 12 months among the doctors in the Carnoustie Health Centre, using duplicate prescriptions. In the questionnaire survey 61% of the general practitioners responded. The three most preferred drugs were buprofen (56%), naproxen (20%) and mefenamic acid (7%); choice of drug was determined by efficacy and personal experience. Gastrointestinal side effects were most frequently encountered, although there was little consensus amongst respondents as to their management. The duplicate prescription study showed that 14% of patients (1607 individuals) received at least one NSAID prescription in the year of study. Ibuprofen (31%), naproxen (20%) and piroxicam (15%) were most frequently prescribed and up to 16% of the patients were co-prescribed a gastroprotective agent; ranitidine (75%) was the most commonly prescribed. Despite the introduction of newer NSAIDs, ibuprofen and naproxen are still the most commonly prescribed drugs. Furthermore, although gastrointestinal side effects are commonly encountered, there is some uncertainty about their management.
PMCID: PMC1293583  PMID: 1404187
5.  Non-steroidal anti-inflammatory drug use and levels of estrogens and androgens in men 
Clinical Endocrinology  2012;76(2):272-280.
Objective
Studies suggest that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) may lower estrogen levels in women. However, no large, population-based studies have assessed NSAID/hormone associations in men. Our objective was to examine the association between use of prescription and over-the-counter NSAIDs and levels of estrogens and androgens in men.
Design
The Boston Area Community Health Survey, an observational survey with initial data collection in 2002–2005.
Patients
1,766 men who provided a blood sample and data on recent analgesic use.
Measurements
Adjusted geometric mean levels of androgens, estrogens, SHBG, LH, and FSH for each category of NSAID use and the percent difference in hormone levels for users vs. non-users.
Results
There was no significant association between prescription or over-the-counter NSAID use and any hormone examined after adjustment for potential confounders. For example, geometric mean testosterone levels were 13.8, 13.6, and 14.2 nmol/L in non-users, prescription, and over-the-counter NSAID users, respectively; the corresponding levels for estradiol were 80.3, 70.4, and 79.9 pmol/L. In stratified analyses, however, prescription NSAID use was associated with lower testosterone, estradiol, and estrone levels in obese men and lower testosterone and dehydroepiandrosterone sulfate levels in inactive men.
Conclusions
While overall these data do not provide strong support for an association between NSAID use and hormone levels in men, prescription NSAIDs may decrease levels of certain estrogens and androgens in obese and inactive men.
doi:10.1111/j.1365-2265.2011.04188.x
PMCID: PMC3219794  PMID: 21815903
Androgens; Anti-Inflammatory Agents; Non-Steroidal; Cyclooxygenase 2 Inhibitors; Estrogens; Hormones
6.  Accounting for the increase in NSAID expenditure: substitution or leakage? 
Background
National Institute of Health and Clinical Excellence (NICE) guidance stated that a new form of non-steroidal anti-inflammatory drug (NSAID) (selective COX-2 inhibitors) should only be an option for arthritis patients at high risk of a gastro-intestinal (GI) event. Total expenditure on NSAIDs has risen by 57% over five years, to £247 million in 2004. We assess whether this expenditure increase can be accounted for by substitution – an increased prescribing of two (more expensive) selective COX-2 inhibitors (celecoxib and rofecoxib) and a simultaneous equivalent reduction in the prescribing volume of three (cheaper) older NSAIDs (diclofenac, ibuprofen and naproxen).
Methods
Quarterly prescription data was collated from January 1999 to September 2004. Over this period, the level of correlation between the total prescribing volumes for i) celecoxib and rofecoxib, and ii) diclofenac, ibuprofen, and naproxen were compared, the change in total expenditure on the five NSAIDs was also estimated. The latter was apportioned into that which was estimated to have arisen due to i) substitution, and ii) increased NSAID prescription volume.
Results
Total prescription volumes for the two NSAID groups were negatively correlated (r = -0.97, p < 0.001). In the last quarter there were 1.23 million prescriptions for celecoxib and rofecoxib, and 0.46 million fewer prescriptions for naproxen, diclofenac, and ibuprofen (than in the first quarter, when celecoxib and rofecoxib were not prescribed). Total expenditure for the five NSAIDs was £32.7 million higher in the last quarter, than the first, £12.2 million of which was estimated to be due to substitution, and £20.4 million due to increased volume.
Conclusion
The introduction of celecoxib and rofecoxib was associated with a reduction in the prescription volume for naproxen, diclofenac, and ibuprofen. However, overall quarterly prescription volume for these five NSAIDs increased by 0.76 million, and we estimate that quarterly expenditure increased by £20.4 million more than would have been expected if overall NSAID volume had remained constant. This suggests that the prescription of both celecoxib and rofecoxib may have 'leaked' to population groups who would not previously have received an older NSAID.
doi:10.1186/1478-7547-4-9
PMCID: PMC1501056  PMID: 16737538
7.  Non-steroidal anti-inflammatory drugs: effects on mortality after colorectal cancer diagnosis 
Cancer  2009;115(24):5662-5671.
Background
Non-steroidal anti-inflammatory drug (NSAID) use has been associated with decreased colorectal cancer (CRC) risk. However, NSAID effects on clinical outcomes after CRC diagnosis are not well-defined. We investigated the association of pre-diagnosis NSAID use and mortality after CRC diagnosis among women in the California Teachers Study (CTS) cohort.
Methods
Women under 85 years participating in the CTS, without prior CRC diagnosis at baseline (1995-1996), and diagnosed with CRC during follow-up through December 2005, were eligible for analysis of the association of pre-diagnosis NSAID use and mortality. NSAID use (including aspirin, and ibuprofen) was collected through a self-administered questionnaire. Cancer occurrence was identified through California Cancer Registry linkage. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HR) for death and 95% confidence intervals (CI).
Results
Among 621 CRC cases identified, 64% reported no pre-diagnosis regular NSAID use, 17% reported use 1-6 days/week, and 20% reported daily use; duration of NSAID use < 5 years was reported by 17% and ≥5 years reported by 18%. Regular pre-diagnosis NSAID use (1-3 days/week, 4-6 days/week, daily) vs. none was associated with improved overall survival (OS) (HR=0.71, 95% CI 0.53-0.95) and CRC-specific survival (CRC-SS) (HR=0.58, 95% CI 0.40-0.84) after adjustment for clinically relevant factors. Pre-diagnosis NSAID use ≥5 years (versus none) was associated with improved OS (HR=0.55, 95% CI 0.37-0.84) and CRC-SS (HR=0.40, 95% CI 0.23-0.71) in adjusted analyses.
Conclusions
When used regularly or over a prolonged duration prior to CRC diagnosis, NSAIDs are associated with decreased mortality among female CRC cases.
doi:10.1002/cncr.24705
PMCID: PMC3008399  PMID: 19827153
Colon cancer; colorectal cancer; non-steroidal anti-inflammatory drugs; NSAIDs; rectal cancer; survival
8.  Recurrent aseptic meningitis following non- steroidal anti-inflammatory drugs - a reminder 
Postgraduate Medical Journal  1999;75(890):771-772.
Non-steroidal anti-inflammatory drugs (NSAIDs) are rarely associated with side-effects affecting the central nervous system. A case of NSAID-induced recurrent aseptic meningitis is presented. Seven episodes of aseptic meningitis were documented in the patient's life-time (up to the age of 30). General practitioners' records available for the latest four episodes showed that a NSAID (naproxen, piroxicam or diclofenac) was prescribed in the month prior to admission on each occasion. The patient was symptom free for a 3-year period during which no NSAID was prescribed. Clinicians should always elicit a careful drug history (including over-the-counter medications) in patients with aseptic meningitis and be aware of this unusual side-effect of NSAIDs.


Keywords: non-steroidal anti-inflammatory drugs; meningitis; adverse drug reaction
PMCID: PMC1741440  PMID: 10567617
9.  Exposure to Non-Steroidal Anti-Inflammatory Drugs during Pregnancy and the Risk of Selected Birth Defects: A Prospective Cohort Study 
PLoS ONE  2011;6(7):e22174.
Background
Since use of non-steroidal anti-inflammatory drugs (NSAIDs) during pregnancy is common, small increases in the risk of birth defects may have significant implications for public health. Results of human studies on the teratogenic risks of NSAIDs are inconsistent. Therefore, we evaluated the risk of selected birth defects after prenatal exposure to prescribed and over-the-counter NSAIDs.
Methods and Findings
We used data on 69,929 women enrolled in the Norwegian Mother and Child Cohort Study between 1999 and 2006. Data on NSAID exposure were available from a self-administered questionnaire completed around gestational week 17. Information on pregnancy outcome was obtained from the Medical Birth Registry of Norway. Only birth defects suspected to be associated with NSAID exposure based upon proposed teratogenic mechanisms and previous studies were included in the multivariable logistic regression analyses. A total of 3,023 women used NSAIDs in gestational weeks 0–12 and 64,074 women did not report NSAID use in early pregnancy. No associations were observed between overall exposure to NSAIDs during pregnancy and the selected birth defects separately or as a group (adjusted odds ratio 0.7, 95% confidence interval 0.4–1.1). Associations between maternal use of specific types of NSAIDs and the selected birth defects were not found either, although an increased risk was seen for septal defects and exposure to multiple NSAIDs based on small numbers (2 exposed cases; crude odds ratio 3.9, 95% confidence interval 0.9–15.7).
Conclusions
Exposure to NSAIDs during the first 12 weeks of gestation does not seem to be associated with an increased risk of the selected birth defects. However, due to the small numbers of NSAID-exposed infants for the individual birth defect categories, increases in the risks of specific birth defects could not be excluded.
doi:10.1371/journal.pone.0022174
PMCID: PMC3138772  PMID: 21789231
10.  Gastrointestinal-Sparing Effects of Novel NSAIDs in Rats with Compromised Mucosal Defence 
PLoS ONE  2012;7(4):e35196.
Nonsteroidal anti-inflammatory drugs are among the most commonly used prescription and over-the-counter medications, but they often produce significant gastrointestinal ulceration and bleeding, particularly in elderly patients and patients with certain co-morbidities. Novel anti-inflammatory drugs are seldom tested in animal models that mimic the high risk human users, leading to an underestimate of the true toxicity of the drugs. In the present study we examined the effects of two novel NSAIDs and two commonly used NSAIDs in models in which mucosal defence was expected to be impaired. Naproxen, celecoxib, ATB-346 (a hydrogen sulfide- and naproxen-releasing compound) and NCX 429 (a nitric oxide- and naproxen-releasing compound) were evaluated in healthy, arthritic, obese, and hypertensive rats and in rats of advanced age (19 months) and rats co-administered low-dose aspirin and/or omeprazole. In all models except hypertension, greater gastric and/or intestinal damage was observed when naproxen was administered in these models than in healthy rats. Celecoxib-induced damage was significantly increased when co-administered with low-dose aspirin and/or omeprazole. In contrast, ATB-346 and NCX 429, when tested at doses that were as effective as naproxen and celecoxib in reducing inflammation and inhibiting cyclooxygenase activity, did not produce significant gastric or intestinal damage in any of the models. These results demonstrate that animal models of human co-morbidities display the same increased susceptibility to NSAID-induced gastrointestinal damage as observed in humans. Moreover, two novel NSAIDs that release mediators of mucosal defence (hydrogen sulfide and nitric oxide) do not induce significant gastrointestinal damage in these models of impaired mucosal defence.
doi:10.1371/journal.pone.0035196
PMCID: PMC3322164  PMID: 22496907
11.  Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells 
Cellular immunology  2009;258(1):18-28.
The widely used non-steroidal anti-inflammatory drugs (NSAIDs) function mainly through inhibition of cyclooxygenases 1 and 2 (Cox-1 and Cox-2). Unlike Cox-1, Cox-2 is considered an inducible and pro-inflammatory enzyme. We previously reported that Cox-2 is upregulated in activated human B lymphocytes and using Cox-2 selective inhibitors that Cox-2 is required for optimal antibody synthesis. It is not known whether commonly used non-prescription and non-Cox-2 selective drugs also influence antibody synthesis. Herein, we tested a variety of Cox-1/Cox-2 non-selective NSAIDs, namely ibuprofen, tylenol, aspirin and naproxen and report that they blunt IgM and IgG synthesis in stimulated human peripheral blood mononuclear cells (PBMC). Ibuprofen had its most profound effects in inhibiting human PBMCs and purified B lymphocyte IgM and IgG synthesis when administered in the first few days after activation. As shown by viability assays, ibuprofen did not kill B cells. The implications of this research are that the use of widely available NSAIDs after infection or vaccination may lower host defense. This may be especially true for the elderly who respond poorly to vaccines and heavily use NSAIDs.
doi:10.1016/j.cellimm.2009.03.007
PMCID: PMC2693360  PMID: 19345936
human B lymphocytes; Cox-2; NSAIDs; antibody
12.  Non-steroidal anti-inflammatory drugs activate NADPH oxidase in adipocytes and raise the H2O2 pool to prevent cAMP-stimulated protein kinase a activation and inhibit lipolysis 
BMC Biochemistry  2013;14:13.
Background
Non-steroidal anti-inflammatory drugs (NSAIDs) —aspirin, naproxen, nimesulide, and piroxicam— lowered activation of type II cAMP-dependent protein kinase A (PKA-II) in isolated rat adipocytes, decreasing adrenaline- and dibutyryl cAMP (Bt2cAMP)-stimulated lipolysis. The molecular bases of insulin-like actions of NSAID were studied.
Results
Based on the reported inhibition of lipolysis by H2O2, catalase was successfully used to block NSAID inhibitory action on Bt2cAMP-stimulated lipolysis. NSAID, at (sub)micromolar range, induced an H2O2 burst in rat adipocyte plasma membranes and in whole adipocytes. NSAID-mediated rise of H2O2 was abrogated in adipocyte plasma membranes by: diphenyleneiodonium, an inhibitor of NADPH oxidase (NOX); the NOX4 antibody; and cytochrome c, trapping the NOX-formed superoxide. These three compounds prevented the inhibition of Bt2cAMP-stimulated lipolysis by NSAIDs. Inhibition of aquaporin-mediated H2O2 transport with AgNO3 in adipocytes allowed NOX activation but prevented the lipolysis inhibition promoted by NSAID: i.e., once synthesized, H2O2 must reach the lipolytic machinery. Since insulin inhibits adrenaline-stimulated lipolysis, the effect of aspirin on isoproterenol-stimulated lipolysis in rat adipocytes was studied. As expected, isoproterenol-mediated lipolysis was blunted by both insulin and aspirin.
Conclusions
NSAIDs activate NOX4 in adipocytes to produce H2O2, which impairs cAMP-dependent PKA-II activation, thus preventing isoproterenol-activated lipolysis. H2O2 signaling in adipocytes is a novel and important cyclooxygenase-independent effect of NSAID.
doi:10.1186/1471-2091-14-13
PMCID: PMC3671242  PMID: 23718778
Non-steroidal anti-inflammatory drug(s) (NSAID); Protein kinase A (PKA); H2O2; Lipolysis; Acetylsalicylic acid; Aspirin
13.  TOIB Study. Are topical or oral ibuprofen equally effective for the treatment of chronic knee pain presenting in primary care: a randomised controlled trial with patient preference study. [ISRCTN79353052] 
Background
Many older people have chronic knee pain. Both topical and oral non- steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat this. Oral NSAIDS are effective, at least in the short term, but can have severe adverse effects. Topical NSAIDs also appear to be effective, at least in the short term. One might expect topical NSAIDs both to be less effective and to have fewer adverse effects than oral NSAIDs. If topical NSAIDs have fewer adverse effects this may outweigh both the reduction in effectiveness and the higher cost of topical compared to oral treatment. Patient preferences may influence the comparative effectiveness of drugs delivered via different routes.
Methods
TOIB is a randomised trial comparing topical and oral ibuprofen, with a parallel patient preference study. We are recruiting people aged 50 or over with chronic knee pain, from 27 MRC General Practice Research Framework practices across the UK. We are seeking to recruit 283 participants to the RCT and 379 to the PPS. Participants will be followed up for up to two years (with the majority reaching one year). Outcomes will be assessed by postal questionnaire, nurse examination, laboratory tests and medical record searches at one and two years or the end of the study.
Discussion
This study will provide new evidence on the overall costs and benefits of treating chronic knee pain with either oral or topical ibuprofen. The use of a patient preference design is unusual, but will allow us to explore how preference influences response to a medication. In addition, it will provide more information on adverse events. This study will provide evidence to inform primary care practitioners, and possibly influence practice.
doi:10.1186/1471-2474-6-55
PMCID: PMC1314890  PMID: 16274477
14.  Cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib 
Annals of the Rheumatic Diseases  2007;66(6):764-770.
Background
Evidence suggests that both selective cyclooxygenase (COX)‐2 inhibitors and non‐selective non‐steroidal anti‐inflammatory drugs (NSAIDs) increase the risk of cardiovascular events. However, evidence from prospective studies of currently available COX‐2 inhibitors and non‐selective NSAIDs is lacking in patients at high cardiovascular risk who are taking aspirin.
Objective
To determine the cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib.
Methods
The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) of 18 325 patients with osteoarthritis comprised two parallel substudies, comparing lumiracoxib (COX‐2 inhibitor) with either ibuprofen or naproxen. A post hoc analysis by baseline cardiovascular risk, treatment assignment, and low‐dose aspirin use was performed. The primary composite end point was cardiovascular mortality, non‐fatal myocardial infarction, and stroke at 1 year; a secondary end point was the development of congestive heart failure (CHF).
Results
In high risk patients among aspirin users, patients in the ibuprofen substudy had more primary events with ibuprofen than lumiracoxib (2.14% vs 0.25%, p = 0.038), whereas in the naproxen substudy rates were similar for naproxen and lumiracoxib (1.58% vs 1.48%, p = 0.899). High risk patients not taking aspirin had fewer primary events with naproxen than with lumiracoxib (0% vs 1.57%, p = 0.027), but not for ibuprofen versus lumiracoxib (0.92% vs 0.80%, p = 0.920). Overall, CHF developed more often with ibuprofen than lumiracoxib (1.28% vs 0.14%; p = 0.031), whereas no difference existed between naproxen and lumiracoxib.
Conclusions
These data suggest that ibuprofen may confer an increased risk of thrombotic and CHF events relative to lumiracoxib among aspirin users at high cardiovascular risk. The study indicates that naproxen may be associated with lower risk relative to lumiracoxib among non‐aspirin users. This study is subject to inherent limitations, and therefore should be interpreted as a hypothesis‐generating study.
doi:10.1136/ard.2006.066001
PMCID: PMC1954641  PMID: 17412741
coronary disease; osteoarthritis; anti‐inflammatory agents, non‐steroidal anti‐inflammatory drugs; COX‐2 inhibitors; aspirin
15.  Statin and Non-steroidal Anti-inflammatory Drug (NSAID) Use In Relation to Clinical Outcome Among Patients with Rai Stage 0 Chronic Lymphocytic Leukemia (CLL) 
Leukemia & lymphoma  2010;51(7):1233-1240.
Statins and nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications. In vitro studies suggest that statins and NSAIDs may have potential as anti-cancer therapies in low grade non-Hodgkin lymphomas including chronic lymphocytic leukemia (CLL) and a recent observational study found statin use was associated with improved event free survival in patients with follicular lymphoma. Other studies have suggested that statins reduce the efficacy of rituximab by inhibiting binding to CD20. We therefore conducted an observational cohort study of 686 patients with newly diagnosed Rai stage 0 CLL to evaluate whether statin or NSAID use was related to their clinical outcome or influenced the efficacy of rituximab therapy. At diagnosis, 136 (20%) patients took statins and 230 (34%) scheduled daily aspirin, ibuprofen, or naproxen. No difference in time to treatment was observed based on statin or NSAID use. Among patients receiving a rituximab containing first-line therapy, no difference in time to salvage treatment was observed based on statin use. Although previous studies suggested statins may improve event free survival among patients with follicular lymphoma, we find no impact of statins on time to initial therapy in this large study of patients with Rai stage 0 CLL. The in vitro observation that statins reduce rituximab efficacy does not appear to have clinical significance in CLL care.
doi:10.3109/10428194.2010.486877
PMCID: PMC3913168  PMID: 20496995
16.  Medications (NSAID, Statins, PPI) and the Risk of Esophageal Adenocarcinoma in Patients with Barrett’s Esophagus 
Gastroenterology  2010;138(7):2260-2266.
Background & Aims
Limited evidence suggests that proton pump inhibitors (PPI), non-steroidal anti inflammatory drugs (NSAID)/aspirin and statins may be associated with low risk of esophageal neoplasia. However, the possible effect these medications may have on the risk of esophageal adenocarcinoma (EAC) in patients with existing Barrett’s esophagus (BE) is unclear.
Methods
We conducted a nested case-control study in a cohort of patients with BE identified in the national Department of Veterans Affairs (VA) computerized databases. Cases with incident EAC were matched by incidence density sampling to controls with BE who remained without EAC at the date of the EAC diagnosis for the corresponding case. We identified prescriptions for PPI, NSAID/aspirin, and statins that were filled between BE diagnosis and EAC diagnosis. Incidence density ratios were calculated using conditional logistic regression models that adjusted for race, outpatient encounters, a disease comorbidity index, and socio-economic status.
Results
In a cohort of 11,823 patients with first time BE diagnosis, we examined 116 EAC cases and 696 matched controls. Most cases and controls had at least one filled PPI prescription (95% vs. 94%, p=0.5). In this setting of almost universal PPI use, filled NSAID/aspirin prescriptions were associated with a reduced risk of EAC (adjusted incidence density ratio: 0.64; 95% CI, 0.42–0.97). Filled statin prescriptions were also associated with a reduction in EAC risk (0.55; 95% CI, 0.36–0.86), with a significant trend toward greater risk reduction with longer duration of statin use. However, the strong inverse associations with even short periods of use raise concerns of uncontrolled confounding.
Conclusion
This observational study indicates that in patients with Barrett’s esophagus using PPI, NSAID/aspirin or statin therapy might reduce the risk of developing esophageal adenocarcinoma.
doi:10.1053/j.gastro.2010.02.045
PMCID: PMC2883678  PMID: 20188100
epidemiology; chemoprevention; GERD; VA; Medicare
17.  Use of Aspirin postdiagnosis improves survival for colon cancer patients 
British Journal of Cancer  2012;106(9):1564-1570.
Background:
The preventive role of non-steroid anti-inflammatory drugs (NSAIDs) and aspirin, in particular, on colorectal cancer is well established. More recently, it has been suggested that aspirin may also have a therapeutic role. Aim of the present observational population-based study was to assess the therapeutic effect on overall survival of aspirin/NSAIDs as adjuvant treatment used after the diagnosis of colorectal cancer patients.
Methods:
Data concerning prescriptions were obtained from PHARMO record linkage systems and all patients diagnosed with colorectal cancer (1998–2007) were selected from the Eindhoven Cancer Registry (population-based cancer registry). Aspirin/NSAID use was classified as none, prediagnosis and postdiagnosis and only postdiagnosis. Patients were defined as non-user of aspirin/NSAIDs from the date of diagnosis of the colorectal cancer to the date of first use of aspirin or NSAIDs and user from first use to the end of follow-up. Poisson regression was performed with user status as time-varying exposure.
Results:
In total, 1176 (26%) patients were non-users, 2086 (47%) were prediagnosis and postdiagnosis users and 1219 (27%) were only postdiagnosis users (total n=4481). Compared with non-users, a survival gain was observed for aspirin users; the adjusted rate ratio (RR) was 0.77 (95% confidence interval (CI) 0.63–0.95; P=0.015). Stratified for colon and rectal, the survival gain was only present in colon cancer (adjusted RR 0.65 (95%CI 0.50–0.84; P=0.001)). For frequent users survival gain was larger (adjusted RR 0.61 (95%CI 0.46–0.81; P=0.001). In rectal cancer, aspirin use was not associated with survival (adjusted RR 1.10 (95%CI 0.79–1.54; P=0.6). The NSAIDs use was associated with decreased survival (adjusted RR 1.93 (95%CI 1.70–2.20; P<0.001).
Conclusion:
Aspirin use initiated or continued after diagnosis of colon cancer is associated with a lower risk of overall mortality. These findings strongly support initiation of a placebo-controlled trial that investigates the role of aspirin as adjuvant treatment in colon cancer patients.
doi:10.1038/bjc.2012.101
PMCID: PMC3341868  PMID: 22454078
colorectal cancer; aspirin; NSAIDs; survival; population based
18.  Prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), More Than Meets the Eye: A Critical Review 
The design and the synthesis of prodrugs for nonsteroidal anti-inflammatory drugs (NSAIDs) have been given much attention by medicinal chemists, especially in the last decade. As a therapeutic group, NSAIDs are among the most widely used prescribed and over the counter (OTC) medications. The rich literature about potential NSAID prodrugs clearly shows a shift from alkyl, aryalkyl or aryl esters with the sole role of masking the carboxylic acid group, to more elaborate conjugates that contain carefully chosen groups to serve specific purposes, such as enhancement of water solubility and dissolution, nitric oxide release, hydrogen sulfide release, antioxidant activity, anticholinergic and acetylcholinesterase inhibitory (AChEI) activity and site-specific targeting and delivery. This review will focus on NSAID prodrugs that have been designed or were, later, found to possess intrinsic pharmacological activity as an intact chemical entity. Such intrinsic activity might augment the anti-inflammatory activity of the NSAID, reduce its side effects or transform the potential therapeutic use from classical anti-inflammatory action to something else. Reports discussed in this review will be those of NO-NSAIDs, anticholinergic and AChEI-NSAIDs, Phospho-NSAIDs and some miscellaneous agents. In most cases, this review will cover literature dealing with these NSAID prodrugs from the year 2006 and later. Older literature will be used when necessary, e.g., to explain the chemical and biological mechanisms of action.
doi:10.3390/ijms131217244
PMCID: PMC3546748  PMID: 23247285
anti-inflammatory; cyclooxygenase; codrug; mutual prodrug; NO-NSAIDs; NSAIDs; Phospho-NSAIDs; prodrug
19.  The Diamine Oxidase Gene Is Associated with Hypersensitivity Response to Non-Steroidal Anti-Inflammatory Drugs 
PLoS ONE  2012;7(11):e47571.
Non-steroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in hypersensitivity drug reactions. Histamine is released in the allergic response to NSAIDs and is responsible for some of the clinical symptoms. The aim of this study is to analyze clinical association of functional polymorphisms in the genes coding for enzymes involved in histamine homeostasis with hypersensitivity response to NSAIDs. We studied a cohort of 442 unrelated Caucasian patients with hypersensitivity to NSAIDs. Patients who experienced three or more episodes with two or more different NSAIDs were included. If this requirement was not met diagnosis was established by challenge. A total of 414 healthy unrelated controls ethnically matched with patients and from the same geographic area were recruited. Analyses of the SNPs rs17740607, rs2073440, rs1801105, rs2052129, rs10156191, rs1049742 and rs1049793 in the HDC, HNMT and DAO genes were carried out by means of TaqMan assays. The detrimental DAO 16 Met allele (rs10156191), which causes decreased metabolic capacity, is overrepresented among patients with crossed-hypersensitivity to NSAIDs with an OR  = 1.7 (95% CI  = 1.3–2.1; Pc  = 0.0003) with a gene-dose effect (P = 0.0001). The association was replicated in two populations from different geographic areas (Pc  = 0.008 and Pc  = 0.004, respectively).
Conclusions and implications
The DAO polymorphism rs10156191 which causes impaired metabolism of circulating histamine is associated with the clinical response in crossed-hypersensitivity to NSAIDs and could be used as a biomarker of response.
doi:10.1371/journal.pone.0047571
PMCID: PMC3495953  PMID: 23152756
20.  Use of low-dose aspirin and non-aspirin nonsteroidal anti-inflammatory drugs and risk of glioma: a case–control study 
British Journal of Cancer  2013;108(5):1189-1194.
Background:
Few studies have examined the association between use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) and risk of glioma and the results have been equivocal. We therefore investigated the influence of NSAID use on glioma risk in a nationwide setting.
Methods:
We used national registries in Denmark to identify all patients aged 20–85 years with a first diagnosis of histologically verified glioma during 2000–2009. Each case was matched on birth year and sex to eight population controls using risk-set sampling. We used prescription data to assess NSAID use and classified exposure to low-dose aspirin or non-aspirin (NA) NSAIDs into ever use or long-term use, defined as continuous use for ⩾5 years. Conditional logistic regression was used to compute odds ratios (ORs), with 95% confidence intervals (CIs), for glioma associated with NSAID use, adjusted for potential confounders.
Results:
A total of 2688 glioma cases and 18 848 population controls were included in the study. Ever use of low-dose aspirin (OR=0.90; 95% CI: 0.77–1.04) or NA-NSAIDs (OR=1.05; 95% CI: 0.96–1.14) was not associated with glioma risk. Compared with never use, long-term use of low-dose aspirin or of NA-NSAIDs was associated with ORs of 0.80 (95% CI: 0.53–1.21) and 1.11 (0.57–2.17), respectively. We observed no clear patterns of risk in stratified analysis according to estimated doses of low-dose aspirin (⩽100 mg, 150 mg).
Conclusion:
We did not find any apparent association between aspirin or NA-NSAID use and risk of glioma, although our results may be consistent with a slight reduction in glioma risk with long-term use of low-dose aspirin.
doi:10.1038/bjc.2013.87
PMCID: PMC3619088  PMID: 23449355
aspirin; non-aspirin NSAIDs; glioma; risk; epidemiology
21.  The coronary risk of cyclo‐oxygenase‐2 inhibitors in patients with a previous myocardial infarction 
Heart  2006;93(2):189-194.
Background
Cyclo‐oxygenase‐2 selective inhibitors have been associated with cardiovascular side effects, but previous studies have generally excluded people with previous myocardial infarction, thereby limiting our knowledge of their cardiotoxicity in this population.
Objectives
To determine whether a history of myocardial infarction modified the risk of acute myocardial infarction associated with the use of various non‐steroidal anti‐inflammatory drugs (NSAIDs).
Methods
A population‐based cohort of 122 079 elderly people with and without previous myocardial infarction newly treated with an NSAID between 1 January 1999 and 30 June 2002 were identified using the computerised health databases of Québec, Canada. A nested‐case–control approach was used for the analysis, with controls matched by cohort entry and age. Current users of NSAIDs, those whose last prescription overlapped with the index date, were compared with those who were not exposed to NSAIDs in the year preceding the event. Rate ratios of acute myocardial infarction were estimated using conditional logistic regression and adjusted for potential confounders.
Results
Users of rofecoxib, both with and without previous myocardial infarction, were at increased risk of myocardial infarction, with a trend for greater risk among those with a previous event (rate ratio (RR) 1.59, 95% confidence interval (CI) 1.15 to 2.18 v RR 1.23, 95% CI 1.05 to 1.45; p = 0.14 for interaction). By contrast, celecoxib was only associated with an increased risk in people with previous myocardial infarction (RR 1.40, 95% CI 1.06 to 1.84 v RR 1.03, 95% CI 0.88 to 1.20; p = 0.04 for interaction). The available power was insufficient to reliably assess risks among patients with previous myocardial infarction treated with other NSAIDs, dose–response relationships or interaction with aspirin.
Conclusions
Although only rofecoxib use was associated with an increased risk of myocardial infarction in those without a previous event, both rofecoxib and celecoxib were associated with an excess risk of acute myocardial infarction for current users with a history of myocardial infarction. A large randomised trial is required to more completely and reliably assess the cardiovascular safety of celecoxib and traditional NSAIDs in this population of high‐risk patients.
doi:10.1136/hrt.2006.089367
PMCID: PMC1861373  PMID: 16849374
22.  Channelling bias and the incidence of gastrointestinal haemorrhage in users of meloxicam, coxibs, and older, non-specific non-steroidal anti-inflammatory drugs 
Gut  2003;52(9):1265-1270.
Background: Although clinical trial results suggest that meloxicam has less gastrointestinal toxicity than most other non-steroidal anti-inflammatory drugs (NSAIDs), in practice it has been associated with a large number of yellow card reports of gastrointestinal complications.
Aims: To estimate whether meloxicam and the coxibs, rofecoxib and celecoxib, have been channelled towards high risk patients, and to estimate the risk of hospitalisation for gastrointestinal haemorrhage associated with the use of these drugs, allowing for the effects of channelling.
Patients: Using the UK General Practice Research Database, this study included 7.1 thousand patient years (tpy) exposure to meloxicam, 1.6 tpy exposure to coxibs, and 628 tpy exposure to older non-specific NSAIDs.
Methods: Cohort study of patients who received a prescription for an NSAID between June 1987 and January 2001. Exposure to newer NSAIDs (meloxicam, rofecoxib, celecoxib) and to older non-specific NSAIDs was identified. Channelling was assessed on factors including: demographic variables; diagnosis of arthritis; history of NSAID use or gastrointestinal events, including gastrointestinal haemorrhage; and use of ulcer healing drugs.
Results: Most risk factors for gastrointestinal haemorrhage were more prevalent among patients prescribed the newer NSAIDs. Adjusting for these risk factors reduced the relative risks of gastrointestinal haemorrhage on meloxicam and coxibs versus older non-specific NSAIDs to 0.84 (95% confidence interval 0.60, 1.17) and 0.36 (0.14, 0.97), respectively.
Conclusions: Channelling towards high risk gastrointestinal patients occurred in the prescribing of newer NSAIDs. After attempting to correct for channelling bias, coxib exposure, but not meloxicam exposure, was associated with a significantly lower risk of gastrointestinal haemorrhage than older non-specific NSAID exposure.
PMCID: PMC1773795  PMID: 12912856
meloxicam, cyclooxygenase 2; non-steroidal anti-inflammatory drugs; gastrointestinal haemorrhage; General Practice Research Database
23.  Prescription Pattern of NSAIDs and the Prevalence of NSAID-induced Gastrointestinal Risk Factors of Orthopaedic Patients in Clinical Practice in Korea 
Journal of Korean Medical Science  2011;26(4):561-567.
This is a cross-sectional observational study undertaken to explore the current prescription pattern of non-steroidal anti-inflammatory drugs (NSAIDs) and the prevalence of NSAID-induced gastrointestinal (GI) risk factors of orthopaedic patients in real clinical practice in Korea. Study cohort included 3,140 orthopaedic outpatients at 131 hospitals and clinics between January 2008 and August 2008. A self-administered questionnaire was completed by each patient and physician. A simplified risk scoring scale (the Standardized Calculator of Risk for Events; SCORE) was used to measure patients' risk for GI complications. The pattern of NSAIDs prescription was identified from medical recordings. Forty-five percents of the patients belonged to high risk or very high risk groups for GI complications. The cyclooxygenase-2 enzyme (COX-2) selective NSAID showed a propensity to be prescribed more commonly for high/very high GI risk groups, but the rate was still as low as 51%. In conclusion, physician's considerate prescription of NSAIDs with well-understanding of each patient's GI risk factors is strongly encouraged in order to maximize cost effectiveness and to prevent serious GI complications in Korea. Other strategic efforts such as medical association-led education programs and application of Korean electronic SCORE system to hospital order communication system (OCS) should also be accompanied in a way to promote physician's attention.
doi:10.3346/jkms.2011.26.4.561
PMCID: PMC3069577  PMID: 21468265
Anti-Inflammatory Agents, Non-Steroidal; GI risk factor; Cyclooxygenase 2 Inhibitors; SCORE; Korea
24.  Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs: population based study 
BMJ : British Medical Journal  2005;330(7504):1370.
Objectives To compare the risk of death and recurrent congestive heart failure in elderly patients prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs (NSAIDs) and to determine whether there are class differences between celecoxib and rofecoxib.
Design Population based retrospective cohort study.
Setting Databases of hospital discharge summaries and prescription drug claims in Quebec.
Participants 2256 patients aged 66 or more prescribed celecoxib, rofecoxib, or an NSAID after an index admission for congestive heart failure between April 2000 and March 2002.
Main outcome measures Time to all cause death and recurrent congestive heart failure, combined and separately.
Results The risk of death and recurrent congestive heart failure combined was higher in patients prescribed NSAIDs or rofexocib than in those prescribed celecoxib (hazard ratio 1.26, 95% confidence interval 1.00 to 1.57 and 1.27, 1.09 to 1.49, respectively). The findings were similar when the outcomes were assessed separately. In pairwise analysis, the risks of death and recurrent congestive heart failure, combined and separate, were similar between patients prescribed NSAIDs and rofecoxib.
Conclusions Celecoxib seems safer than rofecoxib and NSAIDs in elderly patients with congestive heart failure. Differences were found among cyclo-oxygenase-2 inhibitors.
PMCID: PMC558290  PMID: 15947399
25.  Association of Use of Nonsteroidal Anti-inflammatory Drugs and Cutaneous Squamous Cell Carcinoma 
Archives of dermatology  2010;146(4):388-395.
OBJECTIVE
To examine the association between non-steroidal anti-inflammatory drug (NSAID) use and cutaneous squamous cell carcinoma (SCC).
DESIGN
Retrospective case-control.
SETTING
Kaiser Permanente Northern California (KPNC), a large population based-health maintenance organization.
PATIENTS
Random sample of 415 KPNC members diagnosed with a pathology-verified SCC in 2004 and 415 age-, sex, and race-matched controls with no history of skin cancer.
MAIN EXPOSURE MEASURE
Self-reported NSAID use in the 10 years prior to baseline. NSAID use was categorized based on type (any NSAIDs, aspirin, ibuprofen, non-aspirin NSAIDs). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression to estimate the association of SCC with regular use, dose and duration of exposure to the different NSAID types. Information on pharmacy-dispensed NSAIDs was also examined to assess its association with SCC risk. Models were adjusted for all ascertained SCC risk factors (fully adjusted model) and only those variables associated with both SCC risk and NSAID use (parsimonious model).
RESULTS
Fully adjusted analyses showed no statistically significant reduction in SCC risk with self-reported regular use of any NSAID (OR=1.32, 95% CI: 0.92–1.89), aspirin (OR=1.38, 95% CI: 0.96–1.97), ibuprofen (OR=0.74, 95% CI: 0.46–1.19), or non-aspirin NSAIDs (OR=0.84, 95% CI: 0.56–1.26). Analyses examining duration, dose, and variables combining duration and dose of NSAID exposure did not appreciably change results. Analysis using the parsimonious model showed similar results. The data on pharmacy dispensed NSAIDs also showed no association with SCC risk.
CONCLUSIONS
Neither self-reported, nor pharmacy-dispensed NSAID exposure was associated with cutaneous SCC risk.
doi:10.1001/archdermatol.2009.374
PMCID: PMC2857681  PMID: 20157019

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