NSAID Group Research Articles

Intranasal Ketorolac

Ketorolac is a member of the pyrrolo-pyrrole group of NSAIDs, and has been available in several formulations for some time, for the treatment of pain. Intranasal ketorolac has recently become available. Intranasal ketorolac was effective in providing short-term relief from postoperative pain in four well designed, phase II or III trials. In the two phase III trials, a single intranasal dose of ketorolac 31.5 mg, with or without backup analgesia, was associated with significantly higher 6-hour summed post-treatment pain intensity difference scores (primary endpoint) than placebo in adult patients with acute pain following major surgery, including abdominal and orthopaedic surgery. Intranasal ketorolac 31.5 mg up to three or four times daily for ≤5 days also had an opioid-sparing effect in these trials, with significantly less morphine used among ketorolac than among placebo recipients over the first 48 hours of treatment. Moreover, a greater proportion of ketorolac recipients experienced analgesia onset within 1 and 1.5 hours but not 2 hours than placebo recipients, indicating a more rapid onset with intranasal ketorolac. In adult patients with acute pain following major surgery, intranasal ketorolac 31.5 mg three or four times daily for ≤5 days was generally well tolerated. Most adverse events in clinical trials were considered to be of mild severity and transient in nature, with those in the phase III trials generally being characteristic of common events following major abdominal surgery and morphine administration.

RETRACTED ARTICLE: Membrane-Bound Mucins and Mucin Terminal Glycans Expression in Idiopathic or Helicobacter pylori, NSAID Associated Peptic Ulcers

The ratio of Helicobacter pylori/NSAID-negative gastric ulcers is increasing. Idiopathic gastric ulcers have unique clinical and endoscopic features, and are associated with more bleeding complications and a higher mortality. Alterations in gastric mucin expression and sialylation pattern may be important in ulcer pathogenesis. The purpose of this study was to determine the expression pattern of membrane-bound mucins and side chain sugars in H. pylori associated-, NSAID-, and idiopathic-gastric ulcers. We randomly selected 92 patients with H. pylori (group 1, n = 30), NSAID (group 2, n = 18), combined H. pylori and NSAID associated gastric ulcers (group 3, n = 24), and patients with idiopathic gastric ulcers (group 4, n = 20). Immunohistochemistry for T-cell CD4/CD8, MUC1, MUC4, MUC17, and ECA and SNA lectins staining was performed on sections from the ulcer margins. Inflammation score was assessed according to the Sydney system. Bleeding and mortality rates were significantly higher in group 4. CD4 positive T cell count was higher in H. pylori positive patients (P = 0.009). Staining intensity of MUC17 was higher in group 1 than in group 4, foveola and glands alike, with 11.50 ± 3.47 versus 6.80 ± 4.02, and 9.61 ± 4.26 versus 7.59 ± 3.26, respectively (P < 0.0001). This was a mirror image with MUC1. SNA lectin staining was increased in group 4, in parallel to MUC1 expression, indicating more abundant α2-6 sialylation in that group. Cytoplasmic MUC17 staining was significantly decreased in the cases with idiopathic ulcer. The opposite was demonstrated for MUC1. This observation might be important, since different mucins with altered sialylation patterns likely differ in their protection efficiency against acid and pepsin.

Docosahexaenoic acid sensitizes colon cancer cells to sulindac sulfide-induced apoptosis

Sulindac analogs represent one of the most efficacious groups of NSAIDs reducing the risk of colon cancer. Recent studies have shown that sulindac sulfide, a sulindac analog effective at lower doses compared to its parent compound, triggers the death receptor (DR)5-dependent extrinsic apoptotic pathway. Induction of apoptosis via activation of the DR-mediated pathway would be an ideal therapeutic strategy to eliminate cancer cells. In this study, we investigated the possibility that colon cancer cells are sensitized to sulindac sulfide-induced apoptosis by docosahexaenoic acid (DHA), via activation of the DR/extrinsic apoptotic pathway. Our data demonstrated that DHA combination sensitized colon cancer cells to sulindac sulfide-induced apoptosis, leading to enhanced growth suppression of human colon cancer xenografts. The combination effect was primarily attributed to increased cleavage of poly(ADP-ribose) polymerase (PARP) and caspase-8 activation. Moreover, pretreatment with z-IETD-FMK (caspase-8 inhibitor) or stable expression of dominant negative caspase-8 genes blocked DHA/sulindac sulfide cotreatment-induced apoptosis. In view of the finding that DR5 silencing abrogated the combination-stimulated apoptosis, we propose that apoptotic synergy induced by sulindac sulfide plus DHA is mediated via DR5. Our findings collectively support the utility of a combination of sulindac sulfide and DHA in the effective prevention and treatment of colon cancer.

Comparison between Soft Gelatin Capsule Containing Ibuprofen and Ibuprofen Regular Tablet in Pain Control Following Scaling and Root Planing

Aim: Scaling and root planing (SRP) is a major component of periodontal therapy which is often accompanied by painful experiences for the patient. The objective of the present study is to evaluate the pain control of two available types of ibuprofen, soft gelatin capsules and tablets, following SRP in patients with chronic periodontitis.&#x0D; Methodology: 75 patients with chronic periodontitis, undergoing routine periodontal SRP were selected. Following probing the amount of pain perceived was recorded as the baseline pain using visual analog scale (VAS). Further, they received either 800 mg ibuprofen tablet, 800 mg ibuprofen capsule or placebo and the pain level was measured thirty minutes thereafter. Participants underwent SRP procedure and the pain levels were recorded immediately and then at 30 and 60 minutes after SRP.&#x0D; Results: The mean VAS pain scores assessed immediately, thirty minutes and an hour after SRP for both ibuprofen and ibuprofen capsule groups were lower than placebo. Significant difference in the pain parameter only immediately after SRP between three groups were observed (p=0.012).The mean VAS pain score difference after thirty minutes and an hour upon SRP with baseline was insignificant in all study groups (p≤0.0001). However, the mean VAS pain score measured an hour after SRP showed significant difference between both NSAID groups and placebo group (p=0.012)&#x0D; Conclusions: Soft gelatin ibuprofen capsules are well suitable for pain management during SRP procedure in patients with chronic periodontitis due to reported rapid onset of action and less gastrointestinal intolerance. &#x0D; How to cite this article: Jenabian N, Naderi E, Moghadamnia AA, Zahedpasha S. Comparison between Soft Gelatin Capsule Containing Ibuprofen and Ibuprofen Regular Tablet in Pain Control Following Scaling and Root Planing. Int Dent Res 2011;2:42-47.&#x0D; Linguistic Revision: The English in this manuscript has been checked by at least two professional editors, both native speakers of English.

Chemoprevention for advanced CR neoplasia

Colorectal cancer (CRC) is a major health concern worldwide. In 2011 1,200,000 new cases are predicted and half of them are going to die from the disease. CRC carcinogenesis is a multi-step process that spans over 10-20 years, providing a window of opportunity for effective intervention. CRC can be prevented by life style modification and screening program. However, although these strategies are standard clinical practice, their impact is limited due to low adherence. The number of deaths due to CRC remains alarming high, and makes CRC prevention a paramount. Chemoprevention interferes with the carcinogenesis process by targeting key molecular pathways. It involves the use of a variety of natural or chemical compounds that can delay, prevent or even reverse the adenoma to carcinoma sequence. Numerous chemopreventive agents have been studied but the most efficient are the NSAID group of agents. Much of their efficacy and toxicity has been attributed to their potent inhibition of the cyclooxygenase (COX) enzymes. Chemoprevention has the potential to represent a cost-effective intervention, particularly when targeted at intermediate-risk populations, ages 61-70, following polypectomy. Chemoprevention in this setting is as very important as polyp recurrence in this population can be as high as 50%, even with surveillance colonoscopy every 1-3 years. The most challenging task is to find the proper place for these interventions in the entire effort of general wellbeing. Subjects are likely to be more adherent to prescribed regimens if cancer prevention may be combined with a cardiovascular and Alzheimer prophylaxis. Subjects with a normal colon or non advanced adenomas can be safely monitored with surveillance colonoscopy every 5-10 years. The ideal chemopreventive agent remains to be discovered with great emphasis on the need not to harm. Possibly, combinations of agents will maximize effectiveness while limiting drug toxicity. Finally, personalized approaches would include the ability to predict risk, as well as benefit for a specific individual based on specific SNP's or other genetic profiles.

High Concomitant Use of Interacting Drugs and Low Use of Gastroprotective Drugs among NSAID Users in an Unselected Elderly Population

NSAIDs are commonly used in the elderly and carry significant risks of adverse events when used concomitantly with potentially interacting drugs. The aim of this study was to provide a valid estimate of concomitant use of potentially interacting drugs and gastroprotective agents among elderly NSAID users. This was a nationwide Swedish register-based study of drug prescriptions for 1 529 267 persons aged ≥65 years in 2008, using the Swedish Prescribed Drug Register. The proportions of concomitant use of potentially interacting drugs and gastroprotective agents were analysed among NSAID users, categorized by age group, sex and NSAID use, defined as: non-users, people with 0-30 days of treatment, people with >30-180 days of treatment and people with >180 days of treatment. Use of the following concomitant drugs was evaluated: potentially harmful interacting drugs, i.e. antithrombotic drugs, antihypertensive drugs or drugs for congestive heart failure (digitalis glycosides, thiazide diuretics, loop diuretics, β-adrenoceptor antagonists, calcium channel antagonists, ACE inhibitors and angiotensin II type 1 receptor antagonists [angiotensin receptor blockers]) and other drugs (systemic corticosteroids, selective serotonin reuptake inhibitors [SSRIs], methotrexate and lithium); and gastroprotective drugs. In the study cohort, 257 963 (16.9%) people had collected at least one prescription for an NSAID in 2008. This use was higher in females than in males and decreased in older age groups in both sexes. In the age groups 65-69, 70-74, 75-79, 80-84 and ≥85 years, the frequencies of NSAID users were 20.6%, 20.5%, 18.9%, 15.6% and 11.6% among women, and 16.8%, 16.7%, 15.2%, 13.5% and 11.1% among men, respectively. NSAID users often concomitantly used potentially interacting drugs, e.g. over 30% used antithrombotic agents, and women had higher concomitant use of SSRIs, i.e. 12% compared with 6% in men in the youngest age group. Concomitant use of potentially harmful interacting drugs generally increased with age and with increasing use of NSAIDs. Among the eldest (age ≥85 years), concomitant drug use was stable over NSAID groups. Only 40% of regular NSAID users (i.e. those prescribed NSAIDs for >180 days) were prescribed any gastroprotective medication. Prescribers should be alert to the possibility of potentially harmful interactions between NSAIDs and commonly prescribed drugs in the elderly. Increased use of gastroprotective medication might be justified in this context.

Dose Variations Associated with Formulations of NSAID Prescriptions for Children

NSAIDs, particularly ibuprofen, are commonly prescribed for children but there is limited published research on real-life prescribed doses for this class of drugs. The aim of the study was to investigate if variations in NSAID doses prescribed to children can be explained by patient age, indication, dosage form, type of NSAID or year of prescription. Recorded daily doses for drugs within the 'Anti-rheumatics, non-steroidal plain' anatomical classification were studied. First prescriptions of a distinct NSAID substance within 13-month time periods in a patient's history were included. To enable grouping and comparison of NSAIDs, doses were analysed as prescribed daily doses (PDDs) relative to the adult defined daily dose, stated as the relative PDD (rPDD) in this study. Multiple regression analysis was performed with the rPDD as the response variable, and age, indication, dosage form, NSAID substance and year of prescription as the explanatory variables. Prescriptions from the Intercontinental Medical Statistics (IMS) Health Disease Analyzer database containing electronic health records of general practitioners in the UK issued from 1988 to December 2005. Data for children aged 2-11 years with NSAID prescriptions including daily dose information. A total of 21 473 first prescriptions for 19 695 patients were studied. The vast majority of prescriptions were for ibuprofen (n = 20 855), which were therefore analysed separately. The other NSAID prescriptions were grouped (n = 618), containing diclofenac, indometacin, mefenamic acid, naproxen and piroxicam ('NSAID group'). The rPDD varied considerably with dosage form in both the ibuprofen and NSAID groups. In particular, tablets/capsules were prescribed at higher doses than liquid dosage forms. In the NSAID group, naproxen was prescribed at noticeably higher doses. The rPDD varied only slightly with age in both groups. Prescriptions indicated for rheumatic disease were associated with lower doses than other indications in the NSAID group. The rPDD was not influenced by year of prescription. This study shows a correlation between higher prescribed NSAID doses and tablet/capsule formulation, and highlights the need for careful choice of dose formulation when prescribing medicines for children.

Non-steroidal and steroidal anti-inflammatory use in the context of orthodontic movement

The early phase of orthodontic tooth movement involves sterile acute inflammation of the periodontal ligament in response to biomechanical forces. Anti-inflammatories are pharmacologic agents used in medical and dentistry clinics. The aim of the study was to analyse the bone remodelling during orthodontic movement under non-steroidal and steroidal treatment. Male Wistar rats (n = 90) were randomly divided into three groups: C (control), non-steroidal anti-inflammatory drug (NSAID; potassium diclofenac), and steroidal anti-inflammatory drug (SAID; dexamethasone dissodium phosphate). The animals of the C group received 0.9 per cent saline solution, the NSAID group received potassium diclofenac CATAFLAM® (5 mg/kg), and the SAID group received dexamethasone dissodium phosphate DEXANIL® (2 mg/kg). Animals were sacrificed 3, 7, or 14 days after placement of the orthodontic appliance. The upper first molars were processed histologically; we quantified the blood vessels, Howship lacunae, and osteoclast-like cells present on the tension and compression sides of the periodontal ligament. Bone formation was evaluated under polarized light microscopy; 4.5 Image Pro-Plus® software calculated the percentage of immature/mature collagen present. The results showed that, in 3 and 7 days, NSAID and SAID groups presented fewer blood vessels, Howship lacunae, and osteoclast-like cells when compared to the control group. On the 7th and 14th days, there was a lower percentage of mature collagen in the SAID group (P < 0.001). These data demonstrate that potassium diclofenac and dexamethasone inhibit bone resorption during the initial period of orthodontic movement and that dexamethasone delays the collagen maturation process in established bone matrix.

A comparative study of efficacy of oral nonsteroidal antiinflammatory agents and locally injectable steroid for the treatment of plantar fasciitis.

Objectives:To compare the effectiveness of oral nonsteroidal antiinflammatory drugs (NSAIDs) and locally injectable steroid (methylprednisolone) in the treatment of plantar fasciitis.Materials and Methods:One hundred and twenty subjects with unilateral plantar fasciitis were recruited and randomly allocated to two study groups. Group I (NSAIDs group) (n=60) received oral tablet diclofenac (50 mg) and paracetamol (500 mg) twice a day (BD) along with tab. ranitidine 150 mg BD. Group II (injectable steroid group) (n=60) received injection of 1 ml of methylprednisolone (Depomedrol) (40 mg) and 2 ml of 0.5% bupivacaine into the inflammed plantar fascia. Pain intensity was measured using 10 cm visual analog scale (VAS). Subjects were evaluated clinically before, and 1 week, 2 weeks, 4 weeks, and 8 weeks (2 months) after the initiation of treatment in both the groups. The outcome was assessed in terms of VAS score and recurrence of the heel pain.Statistical Analysis Used:“Z” test and Chi-square test were used wherever applicable.Results:Pain relief was significant after steroid injection (P<0.001) and the improvement was sustained. The recurrence of heel pain was significantly higher in the oral NSAIDS group (P<0.001).Conclusion:Local injection of steroid is more effective in the treatment of plantar fasciitis than oral NSAIDs.

Rhabdomyolysis/myoglobinemia and NSAID during 48 h ultra-endurance exercise (adventure racing)

Our purpose is to determine whether rhabdomyolysis with myoglobinemia exists during a 48+ h adventure race and if there is a correlation with NSAID use, race time and perceived pain or exertion. Blood samples for analyses of myoglobin (Mb) were collected, and perception of exertion and pain was registered on the Borg-RPE and CR scales, from 20 subjects (3 female, 17 male) Pre-, Mid- and Post-race. Subjects were asked about NSAID use at each sampling and within 12 h pre-race. The result observed was a significant rise in Mb throughout the race, with the NSAID group (n = 6) having significantly lower Mb-Post than the no-NSAID group (n = 14). High Mb-Pre and Post correlated to shorter race time and high Mb-Pre to lower Pain-post. Race time also correlated to NSAID use, with the NSAID group having significantly longer race time than the no-NSAID group. Rhabdomyolysis with myoglobinemia, which might be reduced with NSAID use, exists during a 48+ h adventure race. Indications that high Mb-levels correlate with shorter race time and less pain, and the reasons for the NSAID groups longer race time, warrants further investigation.

Influence of anti‐inflammatory administration in collagen maturation process during orthodontic tooth movement

Bone formation is essential to orthodontic tooth movement and bone is formed by collagen. To analyze the collagen maturation process on bone matrix neoformed under nonsteroidal and steroidal treatment during orthodontic tooth movement by polarized microscopy, male Wistar rats (n = 90) were randomly divided into three groups (n = 30): C (control), NSAID (potassium diclofenac) and SAID (disodic phosphate dexamethasone). The animals of the C group received 0.9% saline solution; NSAID group received 5 mg/kg potassium diclofenac (CATAFLAM®); and SAID group received 2 mg/kg phosphate dissodic dexamethasone (DEXANIL®). Animals were sacrificed 3, 7 or 14 days after the placement of orthodontic appliances and the upper first molars were processed histologically and stained with picrosirius. Bone formation was evaluated under polarized light microscopy and 4.5 Image Pro-Plus® software calculated the percentage of immature/mature collagen present in the groups. On the third days after force application, SAID and NSAID groups showed greater proportion of immature collagen than C group. On the seventh and fourteenth days, there was a lower proportion of mature collagen only in the SAID group (P < 0.001). These data demonstrate that dexamethasone delays the collagen maturation process in established bone matrix.

The clinical features and quality of life study of juvenile idiopathic arthritis

Objective To explore the clinical features and long-term prognosis of juvenile idiopathic arthritis (JIA)in children, as well as particular quality of life associated with the clinical features and therapeutic options. Methods Seventy patients from August 1997 to August 2007 were retrospectively reviewed and survey was conducted using a questionnaire indicating quality of life(CHAQ questionnaires and CHQ questionnaire, adjusted appropriately) either by phone,letter or out-patient follow-up approach.The manner of correlation and logistic regression was used to analyze quality of life associated with the clinical features and therapeutic options. Results (l)The majority (74.3%) of patients were diagnosed as systemic onset JIA. The Cronbach Alpha coefficient of questionnaire is 0.9599, with a higher inernal consistency reliability. The scales validity also had the higher construction. Sixty nine cases with 76.8 percent of the score showed good quality of life. Quality of life in children less than 5 years old was significantly different from those more than 5-year old( P < 0.05). The rank sum test of single-use NSAIDs group and NSAIDs adding other medicine group suggested that the two groups had differences in quality of life( P = 0.026) .The correlation coefficient between the variables of time from onset to formal treatment and quality of life scores was 0.329( P < 0.05), and walkingas the dependent variable for the regression analysis showed regression coefficient was 0.15( P = 0.016). The variable grip had the significant relationship with the onset to regular treatment, the initial number of joint involvement respectively. Conclusion Systemic oneset JIA is the most common type of JIA. Most of JIA patients have a good prognosis.The major factors which may cause the decline in the quality of life are age, duration without therapy after the disease onset,and the compliance to medication.To achieve a better prognosis,more aggressive therapy may be needed and individulized. Key words: Juvenile rheumatoid arthritis; Health related quality of life

Update von 10 Empfehlungen zur Therapie mit NSAR

Hintergrund: Seit dem Jahr 2005/2006, als die ersten Empfehlungen einer österreichischen Gruppe von Rheumatologen erschienen, werden nicht nur COX-2 Hemmer sondern auch die traditionellen NSAR kritischer vor allem wegen cardiovasculärer Risikofaktoren gesehen. Unter anderem auch deshalb sollten daher die damals verfassten Empfehlungen überarbeitet werden.

Comparison of the Effects of Prophylactic Nonsteroidal Anti-inflammatory Drugs on Macular Edema After Cataract Surgery

Purpose: To evaluate and compare the efficacy of prophylactic administration of topical nonsteroidal anti-inflammatory (NSAID) drugs on macular edema (ME) following cataract surgery. Methods: The present open-label non-masked randomized (random number assignment) study was comprised of 90 eyes. Thirty eyes were administered Diclofenac sodium 0.1%, and 30 eyes were administered Pranoprofen 0.1% starting three days before surgery and continued for one month after surgery. The remaining 30 eyes made up the control group. The results consisted of the measurements of foveal thickness (FT), macular thickness (MT), and total macular volume (TMV), which were quantified by optical coherence tomography (OCT, Carl Zeiss Meditec) before and one month after phacoemulsification surgery. Results: At one month, there were statistically significant differences in FT in the Diclofenac group (0.4810.9 ) and the Pranoprofen group (1.8714.7 ) (p18.6 ). In addition, there was a statistically significant difference in MT between the control group (71.0690.8 ) and the Diclofenac group (15.1936.1 ) (p70.93 ). Between the control group and the NSAID groups, only the Diclofenac group showed statistical differences in TMV throughout the observational period. Conclusions: Used prophylactically after cataract surgery, the NSAIDS eye drops were effective in reducing postoperative ME.

Are Marsh Patients Really Celiac Patients?

Purpose: The duodenal biopsy is regarded as the gold standard in the diagnosis of celiac disease when biopsy samples are correctly orientated. The endomisyal antibodies (EMA) are virtually 100% specific for celiac disease, but sensitivity correlates with the degree of villous atrophy. According to Marsh's classification, the increase in intraepithelial lymphocytes (IEL) is one of the histological abnormalities which is compatible with the diagnosis of celiac disease. The experts disagree as to whether a gluten-free diet is necessary in this condition. The aim of the study was to investigate the histological and clinical effects of the gluten free diet in patients with increase in IEL. Methods: The study was made on 17 patients (12 women, 5 men, median age 42 yrs, range 23–69) who were negative for AGA/EMA, infections caused by H. Pylori, autoimmune disorders, IBD and for use of NSAIDS (group A). All patients underwent upper gastrointestinal endoscopy and duodenal biopsy; immunohistochemical staining with anti-CD3 monoclonal antibody was used to visualize intraepithelial lymphocytes on forceps biopsy. Each patient was examined according to symptoms and quality of life and this was reported with visual analogic scale (VAS) In the same way the study was made on 12 patients (8 women, 4 men, median age 41 yrs, range 25–51) as a control group (group B). Data of IEL were analysed by t-Student's test and data of quality of life were analysed by the Wilcoxon test Then, group A was kept on gluten free diet and group B was kept on normal gluten containing diet. Results: One year later, after the second examination, group A showed an improvement in quality of life (P 0,0001) and histological condition (P 0,0004) with statistically significant difference. On the contrary group B showed an improvement in histological condition (P 0,0255) but not in quality of life (P 0,825) Conclusion: The clinical improvement on a gluten-free diet is not diagnostic for celiac disease: the improvement might be due to a placebo response in IBS patients or to a generic intolerance to gluten. The relationship between IEL and diet is ambiguous and variations in the number of intraepithelial lymphocytes occur also in diet-free patients. Patients with increase of IEL should not be kept on a gluten -free diet.

A new model of pharmacovigilance? A pilot study

This multicenter study tested the actuation of a new model of pharmacovigilance, focused on three pharmacological wide-used categories (non-steroidal anti-inflammatory drugs, NSAID, oral anticoagulants, and antihypertensive drugs). Besides the traditional way of pharmacovigilance, an active investigation was performed, using a phone-structured interview. Patients discharged from the participating hospitals were included into the study, if their prescribed therapy included some of the above drugs and after informed consent. Three hundred subjects were interviewed, 100 for each pharmacological category. For a period of six months after patient's discharge from the hospital, a traditional pharmacovigilance survey was carried out. About 30 days after discharge from the hospital, patients were interviewed by the medical staff and data recorded. NSAID group stratification evidenced a significant percentage of severe haemorrhage among the patients who were using acetylsalicylic acid (ASA) as antiaggregant (6.8%) compared to the patients who were using non-ASA NSAID, at therapeutic dosage (1.8%). From this data, it seems that the active pharmacovigilance model was able to better highlight a real problem for the NSAID category, in particular it evidenced a pharmacological subclass (ASA) more prone to cause ADR than expected from literature data related to whole pharmacological class. Given the required economical effort, this pharmacovigilance method could take place as a selected tool when pharmacovigilance signals from the international databases become consistent or for new wide-used drugs, to screen potentially dangerous pharmacological subclasses, normally “hidden” because of a “camouflage” among ADRs of the entire pharmacological class.

4 years after withdrawal of rofecoxib: where do we stand today?

On the 24th of October 2006, the European Medicines Agency (EMEA) stated that "it cannot be excluded that non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) may be associated with a small increase in the absolute risk for thrombotic events". Reviewing the most recent literature including meta-analyses of randomized clinical studies and pharmacoepidemiological studies show that this statement contrasts with the 2005 EMEA evaluation of cyclooxygenase-2 inhibitors, which contained a number of regulations including several contraindications for coxibs. Recent clinical data indicate that the entire substance group of NSAIDs may have cardiovascular side effects but to different degrees. Results of basic research support these observations showing that the increase for cardiovascular risk not only depends on the ratio of inhibition of thromboxan and prostacyclin but also on other mechanisms including blood pressure elevation and cyclooxygenase independent actions. In clinical practice, many patients require anti-inflammatory therapy with NSAIDs but are at high cardiovascular and gastrointestinal risk. The combination of nsNSAIDs with proton pump inhibitors shows comparable safety to coxibs in averting upper gastrointestinal events, but evidence is increasing coxibs have advantages regarding lower gastrointestinal side effects. Concomitant therapy with aspirin is another issue. There is a negative effect on gastrointestinal safety, as well as the influence of nsNSAIDs on the cardioprotective effect of aspirin. As the contraindications for coxibs announced by the EMEA may prevent some patients from receiving optimal treatment, a warning for the entire substance group, as issued by the American Food and Drug Administration, with no contraindictions, would certainly be more reasonable.

Evaluation of Risk Profiles for Gastrointestinal and Cardiovascular Adverse Effects in Nonselective NSAID and COX-2 Inhibitor Users

Newly approved drugs, in comparison with older drugs, are more often prescribed to patients who have not responded satisfactorily to established related drugs or as first-line therapy to patients with a high baseline risk for adverse outcomes (i.e. channelling). However, these patients are less likely to benefit from the prescribed drug and/or are more prone to adverse drug reactions. Therefore, it is difficult to unravel whether observed risks or increases in risk of new drugs are real, i.e. related to the pharmacology, or whether these are related to selective prescribing to patients who are more susceptible to adverse events because of some underlying risk factor(s). The channelling paradox may exist for cyclo-oxygenase (COX)-2 selective inhibitors ('coxibs') instead of traditional nonselective NSAIDs in relation to both gastrointestinal (GI) and cardiovascular (CV) safety. To evaluate the risk profiles for GI and CV adverse effects in nonselective NSAID and coxib new-user populations over time, in terms of a quantitative measure since the introduction of coxibs. This was a population-based cohort study using the Dutch pharmaceutical claims database (Foundation for Pharmaceutical Statistics). Eligible patients (>/=18 years) were those where the date of their first prescription (index date) of an NSAID (first-line [e.g. ibuprofen] or second-line [e.g. piroxicam] nonselective NSAID, COX-2 preferential NSAID or coxib) was between January 1999 and December 2003. For each patient, GI and CV risk profiles at index date were defined by a cumulative score derived from dispensing data (patient age, sex and history of medication use within 6 months of index date). Risk scores were categorized as low (score = 0), medium (1) or high (2+). Patients were recorded as switchers based on other NSAID use prior to the index date. Other information collected included the Chronic Disease Score (CDS). Crude odds ratios (ORs) were calculated for risk factors for each NSAID group versus first-line nonselective NSAID users as the reference cohort. The effect of calendar time was examined by plotting mean CV or GI risk score by quarter-year. Correlation between GI and CV scores was examined using the Pearson correlation coefficient (R). Data were stratified by patients' history of switching. The four cohorts comprised patients using: first-line nonselective NSAIDs (n = 42 750); second-line nonselective NSAIDs (n = 1771); COX-2 preferential NSAIDs (n = 3661) and coxibs (n = 4861) patients. New coxib users were most likely to have high GI and CV risk scores (OR 5.3 [95% CI 5.0, 5.6] and OR 2.2 [95% CI 2.1, 2.4], respectively). At the individual patient level, GI and CV risk profiles were moderately well correlated for all NSAID cohorts (R range 0.48 to 0.62). There was no remarkable change in mean GI or CV risk profile of patients over calendar time since the market introduction of coxibs. Of the four NSAID cohorts, new coxib users tended to have the highest numbers of GI and CV risk factors, with no obvious change over calendar time. There was also evidence of correlation between GI and CV risk scores. Thus, selective prescribing of coxibs applies to people with co-existing CV as well as GI risk factors. This is important when comparing the safety and/or efficacy of new therapies to existing therapies, and emphasizes the difficulties encountered by prescribers in assessing levels of risk when initiating coxib treatment.

Characterization of the interaction between fenamates and hippocampal neuron GABA A receptors

Fenamate NSAIDs have several central effects, including anti-epileptic and neuroprotective actions. The underlying mechanism(s) of these actions are not presently understood. In this study, the effects of five members of the fenamate NSAID group were investigated on native ligand-gated ion channels expressed in cultured rat hippocampal neurons. All fenamates tested (1–100 μM) dose-dependently potentiated GABA-evoked currents; mefenamic acid (MFA) was the most potent and efficacious and was found to shift the GABA dose–response curve to the left without effect on the maximum amplitude or the GABA Hill Slope. The modulation of GABA receptors by MFA was not reduced in the presence of the benzodiazepine antagonist, flumazenil (10 μM) and was moderately voltage-dependent. MFA at concentrations ≥10 μM evoked dose-dependent currents in the absence of GABA. These currents were potentiated by diazepam (1 μM) and blocked by bicuculline (10 μM). The MFA (50 μM) current–voltage relationship and reversal potential were similar to that evoked by GABA. MFA (1–100 μM) had no effects on sub-maximal glycine, glutamate or NMDA evoked currents. These data show that fenamate NSAIDs are a highly effective class of GABA A receptor modulator and activators.

Cardiovascular events associated with the use of four nonselective NSAIDs (Etodolac, Nabumetone, Ibuprofen, or Naproxen) Versus a Cyclooxygenase-2 Inhibitor (Celecoxib): A population-based analysis in taiwanese adults

Background: Serious cardiovascular events (CVEs) have been linked to the use of cyclooxygenase (COX)-2 inhibitors, a category of selective NSAIDs. However, few studies are available that have compared the risk for CVEs between COX-2 inhibitors and nonselective NSAIDs in adults undergoing long-term treatment. Objectives: The present study assessed (1) whether long-term use of nonselective NSAIDs (etodolac, nabumetone, ibuprofen, or naproxen) is associated with an increased risk for treatment-related CVEs (acute myocardial infarction [AMI], angina, cerebrovascular attack [CVA], and/or transient ischemic attack [TIA]) compared with long-term use of celecoxib and (2) which factors are associated with the risk for treatment-related CVEs in long-term users of nonselective NSAIDs in Taiwan. Methods: This population-based analysis used data from the Taiwanese Bureau of National Health Insurance (Taipei, Taiwan) database. Eligible patients were aged ≥18 years and had been receiving etodolac, nabumetone, ibuprofen, naproxen, or celecoxib for ≥180 days between January 1, 2001, and December 31, 2003. The primary outcomes measure was the prevalence of serious CVEs (AMI, angina, CVA, and/or TIA requiring hospitalization) after initiation of treatment. Analyses were performed on data from all eligible patients; person-time exposures to the drugs and hazard ratios (HRs) were calculated to determine the risk for CVEs with long-term use. Results: A total of 16,326 patients (8166 men, 8160 women; mean [SD] age, 61.83 [20.23] years) who had received long-term treatment with etodolac (2014 [12.34%]), nabumetone (2262 [13.86%]), ibuprofen (5239 [32.09%]), naproxen (3049 [18.68%]), or celecoxib (3762 [23.04%]) were identified. The overall prevalences of AMI, angina, CVA, and TIA were higher in long-term users with a history of cardiovascular disease (CVD) than in those without (AMI, 4.76% vs 0.99%; angina, 4.11% vs 0.43%; CVA, 7.74% vs 1.51%; and TIA, 4.03% vs 0.52%) (all, P < 0.01). The HRs for AMI, angina, CVA, and TIA were not significantly different between the NSAID and celecoxib groups. History of CVD played a significant role in recurrence during the period studied; the HRs (95% CIs) were 2.29 (1.22–4.32) for AMI, 6.19 (3.56–10.78) for angina, 3.56 (2.80–4.52) for CVA, and 6.60 (3.72–11.73) for TIA. Preexisting medical conditions (hypertension, dyslipidemia, diabetes mellitus, congestive heart failure, chronic renal disease) also significantly affected the risk for CVEs. Conclusions: In this cohort study of long-term (≥180 days) use of NSAIDs in Taiwanese adults, no significant differences in the risk for treatment-related CVEs were observed between groups prescribed 1 of 4 nonselective NSAIDs (etodolac, nabumetone, ibuprofen, or naproxen) or celecoxib. History of CVD was the most significant determinant of CVE risk. Patients with preexisting medical conditions appeared to have a significantly higher risk for CVEs associated with the use of NSAIDs and celecoxib compared with patients without these conditions.