Nonselective Nonsteroidal Anti-inflammatory Drugs Research Articles

Anti-Inflammatory Treatment in Chronic Back Pain

Objectives. To analyze the causes of the non-use of nonsteroidal anti-inflammatories (NSAID) and discontinuation of previously used NSAID treatment in patients with chronic nonspecific back pain (CBP). Materials and methods. Treatment was analyzed in 250 patients with CBP initially and at one and two years. Results and conclusions. A total of 52 CBP patients (20.8%) did not receive NSAID, 38 patients (15.2%) consistently received NSAID frequently (on four or more days per week), 44 patients (17.6%) received NSAID consistently at low frequency (on three or fewer days per week), 62 patients (24.8%) received courses of NSAID, and 54 (21.6%) received NSAID as needed. The absence of NSAID treatment in CBP was associated with older age, the presence of comorbid states, nonalcoholic fatty liver disease, and obesity. Discontinuation of previously used NSAID was equally linked with resolution of pain and the failure to respond to treatment, with excess body weight, and use of nonselective NSAID. Continuation of effective anti-inflammatory treatment was associated with the use of coxibs, use of Neurobion, normal body weight, and achievement of reductions in pain syndrome even if complete resolution was not attained. Increases in treatment compliance could be achieved by increasing efficacy by using NSAID (especially coxibs) in complex with group B vitamins (B1, B6, B12), normalization of body mass index, and effective control of liver function.

Cox-2 inhibitors in mandibular third molar surgery.

Pain control during and after any surgical procedure, is extremely essential for the comfort of patients. Pain killers used routinely act by inhibiting cyclooxygenase to control pain and inflammation. Cox-1 is constitutively expressed in most cell types, including platelets, whereas Cox-2 is absent from most healthy tissues but is induced by pro-inflammatory or proliferative stimuli. Cox-1 plays a role in the production of prostaglandins involved in protection of the gastric mucosal layer and thromboxanes (TX) in platelets. Cox-2 generally mediates elevations of prostaglandins associated with inflammation, pain, and pyresis. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen are generally nonselective inhibitors of Coxs. This lack of selectivity has been linked to their propensity to cause gastrointestinal side effects. The new Cox-2 selective inhibitors, or coxibs, show the same anti-inflammatory, analgesic, and antipyretic effects as nonselective NSAIDs but are supposed to have reduced side-effect profiles. This study evaluates whether rofecoxib (50 mg) given one hour pre-operatively or the same drug given one hour post-operatively is more effective in controlling the pain and swelling in mandibular third molar surgery.

MOLECULAR MECHANISMS OF POTENTIAL SYNERGI STIC EFFECT OF KETOPROFEN AND MELOX ICAM WITH CONVENTION AL CYTOSTATICS IN HUMAN CERVIX CANCER CELL LINE

Cyclooxygenases clearly appear to be implicated in carcinogenesis. It has been reported that COX-2 is active throughout the entire process of cancer development and progression. Various molecular mechanisms may be responsible for this. Epidemiological and experimental studies have revealed that nonselective non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors can reduce the risk of cancer. Inhibition of COX provides a plausible explanation of the data on NSAIDs and cancer. However, the molecular pathways of this effect are still unclear, more complex and likely involve multiple COX-2-dependent and independent mechanisms, where pro- and anti-apoptotic Bcl-2 family members may take part. We examined the effects of ketoprofen (KT), as nonselective COX-1/2, and meloxicam (MK), as selective COX-2 inhibitor, alone and combined with 5-fluorouarcil (FU) and cisplatin (CP), on the proliferation by MTT test and Bcl-2/Bax expression in HeLa cells (human cervical carcinoma cells). MC alone or combined with conventional anticancer drugs, FU and CP, showed better cytotoxic and antiproliferative effect than KT. The levels of Bcl-2 were decreased while the levels of Bax were increased dose-dependently by KT and MC. A significant increase in the expression of Bax protein in HeLa cells was more pronounced for MC. The synergy observed in the effects of ketoprofen and meloxicam with cisplatin and 5-fluorouracil on the cervical cancer cell line was generated by an enhancement of apoptosis. Therefore, ketoprofen and meloxicam may represent therapeutic candidates to improve access of cervical cancer chemoprevention and chemotherapy.

Cardiac toxicity of coxibs: mechanisms of development and their prevention

Development of highly selective COX-2 inhibitors – coxibs has proved a decreased risk of gastrointestinal toxicity, which was typical for non-selective NSAIDS, according to the evidence-based medicine. But such situation caused an imbalance in the impact on the synthesis of arachidonic acid metabolites: inhibition of COX-2 vasodilatatory prostacyclins and activation of thromboxane synthesis by platelets, which is accompanied by the increase in the frequency of thrombotic complications – myocardial infarctions and strokes. Some meta-analyses have proved this association: the higher is COX-2 inhibitors selectivity – the higher are CV-risks and cardiovascular toxicity of coxibs. Discontinuation or limitation of indications of coxibs, assessment of risk / benefit ratio is recommended in the conditions of comorbidity of CVS pathology, pain syndromes in rheumatology. Drugs of choice are moderately selective COX-2 inhibitors = meloxicam and nimesulide.

Gastrointestinal safety of coxibs: systematic review and meta-analysis of observational studies on selective inhibitors of cyclo-oxygenase 2.

Prior meta-analyses have shown a higher gastrointestinal risk of nonselective NSAIDs versus placebo and a lower gastrointestinal risk of coxibs versus nonselective NSAIDs. However, the available data about gastrointestinal risk for coxibs versus placebo are scarce. The aim of this study was to review the current evidence on the use of coxibs and to evaluate the risk of gastrointestinal adverse outcomes (GAO) associated with coxibs versus nonexposed. Search was conducted on PubMed and Embase databases. We selected cohort observational, case-control, nested case-control and case-crossover studies that reported the risk of GAO associated with coxibs versus nonexposed as relative risk (RR), odds ratio (OR), hazard ratio (HR) or incidence rate ratio (IRR). It was estimated the pooled RR and the 95% confidence interval (CI) for coxibs both individually and as a whole by the DerSimonian and Laird method. Twenty-eight studies met inclusion criteria. Overall, coxibs were associated with a significant increment in the risk of GAO [RR 1.64 (95% CI 1.44-1.86)]. The analysis by individual drugs showed that etoricoxib [RR 4.85 (95% CI 2.64-8.93)] presented the highest gastrointestinal risk, followed by rofecoxib [RR 2.02 (95% CI 1.56-2.61)] and celecoxib [RR 1.53 (95% CI 1.19-1.97)]. Gastrointestinal risk was also high for the subgroups aged <65years and low-dose coxibs. The use of coxibs is associated with a statistically significant increased risk of GAO, which would be high even for low-dose coxibs and <65-year-old subgroups. The risk would be higher for etoricoxib than for celecoxib and rofecoxib.

A narrative review of the cardiovascular risks associated with concomitant aspirin and NSAID use.

The concomitant use of low-dose aspirin for cardioprotection and non-steroidal anti-inflammatory agents for pain relief is prevalent, particularly in the elderly for whom cardiovascular disease and pain are common co-morbidities. Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) are known to interfere with the antiplatelet effect of aspirin through competitive binding with COX-1. While the clinical significance of this interference is still unclear, this review sought to assess the body of literature which has evaluated the potential attenuation of the anti-platelet effect of aspirin when dosed concomitantly with an NSAID. This review supports that the pharmacodynamic interaction between aspirin and non-selective NSAIDs occurs, but finds that the interaction varies amongst agents, and is highly dependent on numerous factors including: dose timing, dose of aspirin, and dose of the NSAID in question. Recent findings suggest that patient factors, such as body weight may also be indicators of aspirin's cardiovascular effectiveness. Ultimately, the clinical decision making for concomitant NSAID and low-dose aspirin regimens remains at the patient level.

A17904 Arterial hypertension and osteoarthritis as a comorbid duet

Objectives: Arterial hypertension (AH) and Osteoarthritis (OA) are related closely in elderly and associated with metabolic syndrome. They are regarded to be co-morbid, so have common aethiopathogenetic chains, coexist frequently, contribute to progression. In addition, treatment of one may also worsen course of other disease so it is vital to analyze modern literature as well as clinical, laboratory data related to course of AH and OA, estimate treatment results Methods: 138 patients with Ah with comorbid OA were examined. Full clinical investigation, ABPM, questionnatries related to life quality, VAS on symptoms degree, night sleep, life quality. blood chemistry, lipidogram, CRP level, adipokines level control were applied. Results: Hypocalcemia and hypercalciuria in AH influence mineral density of subchondral bone altering metabolic status of nearly located cartilage. Atherosclerotic lesions of arteries worsen ischemia state of synovial-cartilage complex and fail reparative mechanisms. Dysadipokinaemia that is worse in OA + AH increases oxidized LDL-induced increase of systemic production of reactive species of oxygen. Pain and inflammatory edema can mask manifestations of congestion in large circulation circuit in case of chronic heart failure. Hypodynamia that is result of pain facilitates development of obesity, which, in turn, switches on a lot of additional molecular interactions worsening course of basic pathology. Night symptoms of OA contribute into non-dipper profile change in OA and AH. Non-selective NSAIDs may increase blood pressure, selective - increase rate of heart-related acute events. Conclusion: AH and OA have multiple symptoms masking the course one of another. Search for effective metabolic, cardio- and chondroprotective remedies is actual.

Nonsteroidal Anti-Inflammatory Drugs and Risk of First Hospitalization for Heart Failure in Patients with No History of Heart Failure: A Population-Based Case-Crossover Study.

Traditional nonselective, nonsteroidal anti-inflammatory drugs (NSAIDs) are known to cause salt and fluid retention and should thus be used cautiously in patients with documented heart failure. Recent studies have found that some NSAIDs, including cyclooxygenase (COX)-2 inhibitors, are associated with an increased risk of incident heart failure regardless of the related medical history of the patient. This study aimed to investigate the potential link between NSAIDs (both COX-2 inhibitors and traditional nonselective NSAIDs) and heart failure in patients without a history of heart failure. We conducted a case-crossover study using the National Health Insurance Research Database (NHIRD) in Taiwan. A total of 5615 subjects with a first hospitalization for heart failure between 2005 and 2013 were identified from the NHIRD. Exposure to individual NSAIDs between the case period (1-30days before the index date) and control period (121-150days before the index date) were retrieved. Multivariable conditional logistic regression models were used to estimate the adjusted odds ratios (aORs) of the incident heart failure associated with NSAID use after adjustments for potential confounders. Multiple sensitivity analyses, including the case-time-control analysis, were performed to test the robustness of the study results. Overall, NSAID use was associated with a 1.58-fold risk [aOR 1.58; 95% confidence interval (CI) 1.40-1.79] of heart failure leading to hospitalization in the main analysis, and similar results were obtained in the case-time-control analysis [aOR 1.40 (95% CI 1.18-1.67)]. The increased risks of heart failure were comparable between traditional NSAIDs [aOR 1.53 (95% CI 1.35-1.74)] and COX-2 inhibitors [aOR 1.74 (95% CI 1.25-2.44)]. Among all NSAIDs, ketorolac was associated with the highest risk of heart failure [aOR 1.98 (95% CI 1.37-2.86)]. Both traditional NSAIDs and COX-2 inhibitors were associated with an increased risk of heart failure leading to hospitalization in patients without a related history of heart failure.

Cardiovascular Risk of Nonsteroidal Anti-inflammatory Drugs and Classical and Selective Cyclooxygenase-2 Inhibitors: A Meta-analysis of Observational Studies.

The purpose of this study was to review the published evidence on the clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) and to assess the cardiovascular risk (CVR) of cyclooxygenase-2 inhibitors (coxibs), excluding aspirin, by means of a meta-analytic procedure. A search was conducted on MEDLINE and EMBASE databases between October 1999 and June 2018. Cohort and case-control studies showing CVR as relative risk (RR), odds ratio, hazard ratio, or incidence rate ratio associated with NSAIDs versus no treatment were selected. We estimated the pooled RR and the 95% confidence interval (CI) for all NSAIDs as a whole and individually. Eighty-seven studies met the inclusion criteria. Overall, NSAIDs were found to be associated with a statistically significantly increased CVR (RR, 1.24 [95%CI, 1.19-1.28]). The risk was slightly higher for coxibs (RR, 1.22 [95%CI, 1.17-1.28]) as compared with nonselective NSAIDs (RR, 1.18 [95%CI, 1.12-1.24]). Data analysis by drug disclosed that rofecoxib (RR, 1.39 [95%CI, 1.31-1.47]), followed by diclofenac (RR, 1.34 [95%CI, 1.26-1.42]) and etoricoxib (RR, 1.27 [95%CI, 1.12-1.43]) were the NSAIDs associated with the highest CVR. Analysis by type of event showed that the highest risk corresponded to vascular events for both coxibs (RR, 2.18 [95%CI, 1.72-2.78]) and nonselective NSAIDs (RR, 2.46 [95%CI, 2.00-3.02]). The meta-analysis results suggest that the use of the marketed coxibs celecoxib and etoricoxib would be related to a statistically significant CVR increase. Etoricoxib CVR could be higher than that for celecoxib. This increment would be similar to classical NSAID CVR.

Defective bone repair in diclofenac treated C57Bl6 mice with and without lipopolysaccharide induced systemic inflammation.

Bone repair after trauma or surgical intervention involves a tightly regulated cascade of events that starts with hemostasis and an inflammatory response, which are critical for successful healing. Nonsteroidal anti-inflammatory drugs (NSAID) are routinely prescribed for pain relief despite their potential inhibitory effect on bone repair. The goal of this study was to determine the impact of administration of the non-selective NSAID diclofenac in the inflammatory phase of bone repair in mice with or without lipopolysaccharide-induced systemic inflammation. Repair of femoral window defects was characterized using micro computed tomography imaging and histological analyses at 2 weeks postoperative. The data indicate (a) impaired bone regeneration associated with reduced osteoblast, osteoclast, and macrophage activity; (b) changes in the number, activity, and distribution of mast cells in regenerating bone; and (c) impaired angiogenesis due to a direct toxic effect of diclofenac on vascular endothelial cells. The results of this study provide strong evidence to support the conjecture that administration of NSAIDs in the first 2 weeks after orthopaedic surgery disrupts the healing cascade and exacerbates the negative effects of systemic inflammation on the repair process.

Nonsteroidal anti-inflammatory drugs in chronic pain: implications of new data for clinical practice.

COX2-selective and nonselective (ns) nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for chronic pain management. There are marked differences in the risk of adverse gastrointestinal (GI) and cardiovascular (CV) events among different NSAIDs. In 2017, publication of two randomized controlled trials and an individual patient-data meta-analysis provided robust data on the relative GI and CV tolerability profiles of currently available NSAIDs. The PRECISION study showed similar CV-event rates with celecoxib vs naproxen and ibuprofen, but GI tolerability was better for celecoxib. In the CONCERN study of high-GI-risk patients, celecoxib was associated with fewer adverse GI-tract events than naproxen. The meta-analysis showed no significant difference between celecoxib and ns-NSAIDs in the rate of acute myocardial infarction, and celecoxib was the only COX2-selective NSAID with a lower risk of adverse CV and GI events vs ns-NSAIDs. These data add to the body of knowledge about the relative tolerability of different NSAIDs and were used to propose an updated treatment algorithm. The decision about whether to use an NSAID and which one should be based on a patient’s risk of developing adverse GI and CV events. Lower- and upper-GI-tract events need to be considered. Celecoxib has a better lower-GI-tract tolerability profile than ns-NSAIDs plus a proton-pump inhibitor. In addition, the latest data suggest that long-term use of celecoxib 200 mg/day may be appropriate for patients at increased CV risk.

In Vivo Brain Imaging, Biodistribution, and Radiation Dosimetry Estimation of [11C]Celecoxib, a COX-2 PET Ligand, in Nonhuman Primates.

COX-2 selective inhibitors (COXIBs) are non-steroidal anti-inflammatory drugs (NSAIDs), with fewer side effects compared with non-selective NSAIDs, and are used for the treatment of arthritis, headaches, and other inflammatory diseases of the brain and peripheral tissues. Radiolabeled COXIBs may permit positron emission tomography (PET) imaging of COX-2 localization and activity in diseases, enable monitoring of inflammatory processes, and determine target occupancy of COX-2 activity by NSAIDs, thus, accelerating the development of novel CIXIBs. We synthesized [11C]celecoxib, one of the COXIBs and a prescription drug, and here report its in vivo uptake in the brain, whole body biodistribution, and radiation dosimetry in baboons using PET. Brain imaging experiments were performed in one baboon and whole body PET scans were performed in triplicates in two male baboons using an ECAT ACCEL (Siemens Medical Solutions, Inc. Knoxville) under anesthetic conditions. PET studies in baboons show that [11C]celecoxib penetrates the blood brain barrier (BBB) and accumulates in the brain, followed by a washout of radioactivity. The liver has the highest residence time and the gallbladder is the critical organ for [11C]celecoxib. Organ Level Internal Dose Assessment (OLINDA) estimates indicate that the maximum permissible single study dosage of [11C]celecoxib in humans is 1110 MBq (30 mCi) for both males and females under the 21 CFR 361.1 dose limit for research subjects.

Selective COX-2 inhibitor versus non-selective COX-2 inhibitor for the prevention of heterotopic ossification after total hip arthroplasty: A meta-analysis.

Whether selective non-steroidal anti-inflammatory drugs (NSAIDs) has equally efficacy with non-selective NSAIDs in preventing heterotopic ossification (HO) after total hip arthroplasty (THA) was controversial. The purpose of this meta-analysis was to assess the efficacy and safety of selective NSAID versus non-selective NSAIDs for the prevention of HO after THA. PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, Google Search Engine, and China National Knowledge Infrastructure databases was searched for randomized controlled trials (RCTs) were comparing selective NSAID versus non-selective NSAIDs for preventing HO after THA. The primary outcomes were overall HO incidence, Brooker classification HO incidence, gastrointestinal side effects, the occurrence of excessive bleeding and discontinuation caused by gastrointestinal side effects (DGSE). Data were analyzed using Stata 12.0. A total of 8 RCTs involving 1636 patients were included in the meta-analysis. There was no significant difference between the nonselective NSAIDs group and the selective NSAIDs group in the overall incidence of HO (relative risk, RR = 0.91, 95% confidence intervals, CI 0.78-1.06, P = .203), Brooker I HO (RR = 1.02, 95% CI 0.85-1.23, P = .794), Brooker II HO (RR = 1.00, 95% CI 0.66-1.52, P = .996). Brooker III HO (RR = 0.98, 95% CI 0.37-2.62, P = .971). And the occurrence of excessive bleeding (RR = 0.67, 95% CI 0.24-1.92, P = .458). The selective NSAIDs group was associated with a significant decrease in gastrointestinal side effects (RR = 0.35, 95% CI 0.18-0.71, P = .004) and discontinuation caused by gastrointestinal side effects compared with the nonselective NSAIDs group (RR = 0.28, 95% CI 0.11-0.66, P = .004). The available evidence indicates selective NSAIDs were as effective as non-selective NSAIDs in preventing HO after THA. And selective NSAIDs were associated with less gastrointestinal side effects than non-selective NSAIDs. Considering the limitation of current meta-analysis, more RCTs need to identify the optimal NSAIDs drug for HO after THA.

Inappropriate use and overuse of PPIs: A strategy for discontinuation

Proton pump inhibitors (PPIs) have risks associated with long-term use, yet they are used chronically by more than 20 million Americans and account for more than $10 billion in health care spending.1https://apha.us/IMSInstituteGoogle Scholar Data on the effects of long-term PPI use are still emerging, but potential consequences include increased risk of vitamin and mineral deficiencies, bone fractures, changes in gut microbiota, Clostridium difficile–associated diarrhea, pneumonia, dementia, chronic kidney disease, gastric atrophy (higher risk among those with Helicobacter pylori infections), and gastric cancer. Overprescribing PPIs is common, with as many as 68.8% of patients being prescribed a PPI inappropriately at hospital discharge2J Manag Care Pharm. 2010; 16: 122-129PubMed Google Scholar and 36% to 39% of ambulatory patients lacking an indication for PPI use.3Am J Manag Care. 2010; 16: e228-e234PubMed Google Scholar, 4Am J Gastroenterol. 2003; 98: 51-58Crossref PubMed Scopus (113) Google Scholar As pharmacists, we can make an impact on inappropriate use and overuse of PPIs. At Central Pharmacy in Durham, NC, we initiated a service as part of a residency project to tackle the issue of PPI overuse. Our approach is to taper the PPI gradually while increasing the duration between each step to improve successful PPI discontinuation. The taper involves use of compounded omeprazole capsules, which allows the patient to decrease their PPI dose by 5 mg every 2 weeks. This regimen is also accompanied by lifestyle changes and supplements to support digestion and gastrointestinal (GI) health. Abrupt withdrawal of PPIs results in successful discontinuation in only 14% to 27% of patients who have used these medications for 8 weeks.5Eur J Gastroenterol Hepatol. 2010; 22: 1182-1188Crossref PubMed Scopus (26) Google Scholar, 6Int J Family Med. 2015; 2015: 175436Crossref PubMed Google Scholar Our goal is to have a higher success rate by tapering more gradually. Patients on step-down therapy with omeprazole 20 mg daily for 1 week, omeprazole 10 mg for 1 week, and omeprazole 10 mg every other day for 1 week saw slightly higher success rates, with 31% achieving discontinuation.7Aliment Pharmacol Ther. 2006; 24: 945-954Crossref PubMed Scopus (117) Google Scholar For our PPI discontinuation service, we first establish patient interest and eligibility. Patients ineligible for PPI discontinuation include those with Barret’s esophagus, Zollinger–Ellison disease, Los Angeles grade C or D erosive esophagitis, or idiopathic peptic ulcer disease. Other ineligible patients are those on nonselective NSAIDs at high risk of a GI bleed, those on COX-2 selective NSAIDs with a prior GI bleed, and those on antiplatelet therapy at high risk of a GI bleed. Once eligibility is determined, patients schedule a consult with a pharmacist to determine trigger foods and the potential need for supportive supplements on the basis of patient-specific symptoms. The patient’s daily PPI dose is converted to omeprazole equivalents to calculate the taper regimen that will be requested from the physician. If the patient receives 20 mg of omeprazole equivalent each day, their regimen will consist of omeprazole 15 mg for 2 weeks, omeprazole 10 mg for 2 weeks, and finally omeprazole 5 mg for 2 weeks. Patients are also provided with 5-mg capsules for breakthrough reflux symptoms. Follow-up with a pharmacist occurs by phone every 2 weeks to align with the time frame of the taper regimen. These phone calls assess patient symptoms and determine if any adjustments need to be made to the plan. We encourage patients to call the pharmacist whenever they need to report symptoms that are not responding to the breakthrough omeprazole. This project is under way, and as it progresses, we will collect metrics on frequency of rebound symptoms and success rate of discontinuation at 1, 3, and 6 months after conclusion of the PPI taper.

NSAID administration post colorectal surgery increases anastomotic leak rate: systematic review/meta-analysis.

Current enhanced recovery guidelines suggest that opioid sparing medications should be used for analgesia whenever possible following colorectal surgery. The present study aims to assess whether post-operative NSAID use is associated with an increased anastomotic leak rate after a colonic or rectal anastomosis. A systematic review was performed for studies investigating anastomotic leak rate following NSAID use vs control after colonic or rectal anastomosis. Meta-analysis was performed to assess for overall risk of anastomotic leak with NSAID use, as well as sub-group analysis to compare selective vs non-selective NSAIDs and drug-specific NSAID safety profiles. Seven studies were included in the final review. Use of an NSAID post-operatively was associated with an overall increased risk of anastomotic leakage [OR 1.58 (1.23, 2.03), P = 0.0003]. Non-selective NSAIDs were associated with an increased risk [OR 1.79 (1.47, 2.18), P < 0.00001], but selective NSAIDs were not. The non-selective NSAID diclofenac was associated with an increased leak rate [OR 2.79 (1.96, 3.96), P < 0.00001], but ketorolac was not [OR 1.36 (0.89, 2.06), P = 0.16]. Great caution must be taken when prescribing NSAIDs following colonic or rectal anastomotic creation. The safety profile varies within the NSAID class and further research is needed to clarify which NSAIDs are safe for use and which are not.

COX inhibitors and bone: A safer impact on osteoblasts by NO-releasing NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for the treatment of pain and inflammation. Although it is well known that NSAIDs can suppress bone growth, remodelling and repair, they are largely used post-operatively and post-traumatically to achieve analgesia and reduce inflammation in bone tissue. AimsThe impact of two NO-releasing, non-selective NSAIDs, NCX-4016 and HCT-3012 (NO-derivatives of Aspirin and Naproxen, respectively) on osteoblasts were evaluated and compared to the non-selective, parent chemicals and to the COX-2-selective inhibitor Celecoxib. Main methodsUsing MG-63 osteoblast-like cells, we considered proliferation, the early and late stage of differentiation, and the activity of proteinases thought to be involved in osteoid degradation, a preliminary fundamental event of bone remodelling. Key findingsUnlike Aspirin, Naproxen and Celecoxib, the two NO-NSAIDs did not alter proliferation and differentiation of osteoblasts. They also reduced the activity of plasminogen activator, metalloproteinases, and cathepsin B. Similar inhibitory effects against these proteinases were recapitulated by the NO-donor sodium nitroprusside, thereby suggesting a NO-mediated mechanism. SignificanceDue to a differential effect on cell proliferation and differentiation, the two NO-NSAIDs exhibit a safer impact on osteoblast metabolism compared to Celecoxib and their parent compounds. This suggests an advantageous option for these drugs in individuals with a need of COX-inhibiting treatment, in general. In addition, their capability of modulating the proteinases involved in osteoid degradation may specifically suggest an additional safer use in comorbidity conditions of inflammation or pain with bone disorders characterized by high rate of remodelling, such as high-turnover osteoporosis in post-menopausal women.

Non-steroidal anti-inflammatory drugs for heterotopic ossification prophylaxis after total hip arthroplasty: a systematic review and meta-analysis.

The aim of this study was to assess the efficacy of non-selective and selective non-steroidal anti-inflammatory drugs (NSAIDs) in preventing heterotopic ossification (HO) after total hip arthroplasty (THA). A thorough and systematic literature search was conducted and 29 studies were found that met inclusion criteria. Data were extracted and statistical analysis was carried out generating forest plots. Non-selective NSAIDs showed a significant decrease in the odds for forming HO after THA (odds ratio (OR) -1.35, confidence interval (CI) -1.83 to -0.86) when compared with placebo. Selective NSAIDs also showed a significant decrease in the odds for forming HO after THA when compared with placebo (OR -1.58, CI -2.41 to -0.75). When comparing non-selective NSAIDs with selective NSAIDs, there was no significant change in the odds for forming HO after THA (OR 0.22, CI -0.36 to 0.79). Our meta-analyses of all available data suggest that both non-selective and selective NSAIDs are effective HO prophylaxis and can be used routinely after THA for pain control as well as prevention of HO. Indomethacin may serve as the benchmark among non-selective NSAIDs and celecoxib among selective NSAIDs. There was no difference in the incidence of HO between non-selective and selective NSAIDs, allowing physicians to choose either based on the clinical scenario and patient-specific factors. Cite this article: Bone Joint J 2018;100-B:915-22.

Maintenance use of non-steroidal anti-inflammatory drugs and risk of gastrointestinal cancer in a nationwide population-based cohort study in Sweden

ObjectivesAspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are potential candidates for chemoprevention of gastrointestinal cancer. We aimed to assess the association between contemporary NSAID use (≥180 days) and gastrointestinal cancer.DesignNationwide...

The polysaccharide-rich tea of Ximenia americana barks prevents indomethacin-induced gastrointestinal damage via neutrophil inhibition

Ethnopharmacological relevanceBarks of Ximenia americana are used by the population to treat gastrointestinal inflammatory disorders. Indomethacin is a non-selective non-steroidal anti-inflammatory drug that induces marked gastrointestinal damage. Aims of the studiesTo evaluate the gastroprotective activity of total polysaccharides contained in the extract (TPL-Xa) or tea (Tea-Xa) of Ximenia americana barks in the mice gastric damage induced by indomethacin. Materials and methodsTPL-Xa was obtained by a combination of NaOH extraction and ethanol precipitation. Tea-Xa was prepared in distilled water boiled during 5 min. Animals received p.o. 0.9% NaCl (saline - control group), TPL-Xa (1–90 mg/kg) or Tea-Xa 1 h before gastritis induction by indomethacin (20 mg/kg). Mice were sacrificed 7 h after gastritis induction and analyzed for the following parameters: stomach lesions measurement; histological evaluation; myeloperoxidase (MPO) activity; nitrate/nitrite and cytokine levels; leukocyte adhesion and rolling by intravital microscopy. ResultsTPL-Xa reduced macroscopic and microscopic damage, MPO activity (59%), leukocyte rolling (86%) and adhesion (84%), nitrite/nitrate ratio (100%) and IL-8 (69%), but increased IL-4 (50%). Tea-Xa (12.8 yield; 39.3% carbohydrate, including 25.8% uronic acid; 4% protein) reduced macroscopic damage (62%) and MPO activity (50%). ConclusionTPL and Tea of Ximenia americana barks ameliorate the gastric injury induced by indomethacin in mice, an effect that was dependent on the reduction of neutrophil infiltration.

NSAIDs and the small bowel.

The review describes the effects of NSAID gastrointestinal toxicity on the small bowel, wherein injury is as prevalent as in the gastroduodenum. This is well documented by capsule endoscopy, which also provides an endoscopic endpoint for novel treatment strategies. Appreciation of the prevalence of NSAID enteropathy has grown with capsule endoscopy and the use of composite end points that include obscure haemoglobin decreases in clinical studies. Along with dual cyclo-oxygenase isoform inhibition, gram-negative antigen presentation plays a role in the pathogenesis of NSAID enteropathy. The concomitant use of proton pump inhibitor (PPI) agents with both selective and nonselective NSAIDs in gastroduodenal protection exacerbates endoscopic enteropathy, which is thought to be due to intestinal dysbiosis. Strategies for small bowel mucosal protection include prostaglandin repletion and augmenting the intestinal flora. NSAID- related enteropathy is common and often presents subclinically. The most common presentation is anaemia, which may be less common in those on cyclo-oxygenase (COX)-2 inhibitors than nonselective NSAIDs. PPI use worsens NSAID enteropathy with more occult bleeding and ulceration and has been linked to gram-negative intestinal dysbiosis. If NSAID cessation is not possible, COX-2 inhibition without PPI therapy should be considered in patients with upper gastrointestinal risk factors. Mucoprotective agents such as misoprostol and rebamipide show promise and probiotics may have a future role.