Multiple Nonsteroidal Anti-inflammatory Drugs Research Articles

Non-steroidal anti-inflammatory drugs, renin-angiotensin system blockade or diuretics and risk of acute kidney injury: A case-crossover study

BackgroundAging-related physiological changes, such as decline in renal function, not only exacerbates pre-existing comorbidities but also escalate the susceptibility to adverse events. Previous studies have shown that non-steroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of acute kidney injury (AKI), and the concomitant use of renin-angiotensin system blockade or diuretics may further potentiate the risk. However, studies evaluating the risk of AKI associated with NSAIDs (including routes, concomitant use of different NSAIDs, categories (traditional NSAIDs or COX-2 inhibitors), and cumulative doses of NSAIDs) are limited, particularly the risk of AKI associated with the dual or triple combination of NSAIDs with renin-angiotensin system blockade (RAS blockades) and/or diuretics. MethodsA case-crossover study utilized two sets of longitudinal data from Taiwan's National Health Insurance Research Database (NHIRD). Newly admitted patients with a primary AKI diagnosis were included, with the index date defined as the first admission date. The 1–7 days and 181–187 days prior to the index date served as the case and control periods. Exposure to NSAIDs and co-exposures of RAS blockade and/or diuretics were assessed in both periods. Multivariable conditional logistic regression models, adjusting for potential confounders, estimated adjusted odds ratios (aORs) and 95 % confidence intervals (CIs) for AKI associated with NSAIDs, dual, or triple combinations. Sensitivity analyses explored result robustness by varying case and control period lengths. ResultsThe study included 1,284 newly diagnosed AKI patients. NSAIDs showed a 3.55-fold increased risk of AKI (aOR: 3.55; 95 % CI 2.70–4.65), with similar risks for traditional NSAIDs and COX-2 inhibitors. Use of multiple NSAIDs, parenteral dosage forms, and higher cumulative doses increased AKI risk. Dual combination with either RAS blockade or diuretics resulted in a 2.90-fold (aOR: 2.90; 95 %CI 1.47–5.70) and 12.68-fold (aOR: 12.68; 95 %CI 6.15–26.12) risk, respectively. The highest risk occurred with triple combination (aOR: 29.22; 95 %CI 12.82–66.64). ConclusionsNSAIDs, including both non-selective NSAIDs and COX2 inhibitors, elevate the risk of AKI. Increased AKI risk is linked to using multiple NSAIDs, the parenteral dosage form, and higher cumulative doses. Dual combination of RAS blockade with NSAIDs or diuretics with NSAIDs, as well as triple therapy, heightens the risk, with the latter associated with the highest risk of AKI.

Global distribution of functionally important CYP2C9 alleles and their inferred metabolic consequences

BackgroundGenetic variability in the cytochrome P450 CYP2C9 constitutes an important predictor for efficacy and safety of various commonly prescribed drugs, including coumarin anticoagulants, phenytoin and multiple non-steroidal anti-inflammatory drugs (NSAIDs). A global map of CYP2C9 variability and its inferred functional consequences has been lacking.ResultsFrequencies of eight functionally relevant CYP2C9 alleles (*2, *3, *5, *6, *8, *11, *13 and *14) were analyzed. In total, 108 original articles were identified that included genotype data from a total of 81,662 unrelated individuals across 70 countries and 40 unique ethnic groups. The results revealed that CYP2C9*2 was most abundant in Europe and the Middle East, whereas CYP2C9*3 was the main reason for reduced CYP2C9 activity across South Asia. Our data show extensive variation within superpopulations with up to tenfold differences between geographically adjacent populations in Malaysia, Thailand and Vietnam. Translation of genetic CYP2C9 variability into functional consequences indicates that up to 40% of patients in Southern Europe and the Middle East might benefit from warfarin and phenytoin dose reductions, while 3% of patients in Southern Europe and Israel are recommended to reduce starting doses of NSAIDs.ConclusionsThis study provides a comprehensive map of the genetic and functional variability of CYP2C9 with high ethnogeographic resolution. The presented data can serve as a useful resource for CYP2C9 allele and phenotype frequencies and might guide the optimization of genotyping strategies, particularly for indigenous and founder populations with distinct genetic profiles.

Mastocytosis presenting with mast cell-mediator release-associated symptoms elicited by cyclo oxygenase inhibitors: prevalence, clinical, and laboratory features.

BackgroundNonsteroidal anti‐inflammatory drugs (NSAIDs) are frequently avoided in mastocytosis, because of a potential increased risk for drug hypersensitivity reactions (DHRs) due to inhibition of cyclo‐oxygenase (COX), subsequent depletion of prostaglandin E 2 and release of leukotrienes.ObjectivesHere, we aimed at determining the prevalence of mast cell (MC) mediator release symptoms triggered by NSAIDs in mastocytosis patients and the associated clinical and laboratory features of the disease.MethodsMedical records from 418 adults to 223 pediatric mastocytosis patients were retrospectively reviewed. Patients were classified according to tolerance patterns to NSAIDs and other COX inhibitors (COXi) and compared for epidemiological, clinical and laboratory findings.ResultsOverall, 87% of adults and 91% of pediatric patients tolerated NSAIDs and other COXi. Among adult and pediatric patients presenting DHRs, 5% and 0% reacted to multiple NSAIDs, 4% and 0.7% were single reactors, and 3% and 8% were single reactors with known tolerance to paracetamol but unknown tolerance to other COXi, respectively. Among adults, hypersensitivity to ≥2 drugs was more frequent among females (p = 0.009), patients with prior history of anaphylaxis to triggers other than NSAIDs or other COXi and Hymenoptera venom (p = 0.009), presence of baseline flushing (p = 0.02), baseline serum tryptase ≥48 ng/ml (p = 0.005) and multilineage KIT mutation (p = 0.02). In contrast, tolerance to NSAIDs and other COXi was more frequent among males (p = 0.02), in patients with anaphylaxis caused by Hymenoptera venom (p = 0.02), among individuals who had skin lesions due to mastocytosis (p = 0.01), and in cases that had no baseline pruritus (p = 0.006). Based on these parameters, a score model was designed to stratify mastocytosis patients who have never received NSAIDs or other COXi apart from paracetamol, according to their risk of DHR.ConclusionsOur results suggest that despite the frequency of MC mediator related symptoms elicited by NSAIDs and other COXi apart from paracetamol is increased among mastocytosis patients versus the general population, it is lower than previously estimated and associated with unique disease features. Patients that tolerated NSAIDs and other COXi following disease onset should keep using them. In turn, adults with unknown tolerance to such drugs and a positive score should be challenged with a preferential/selective COX‐2 inhibitor, while the remaining may be challenged with ibuprofen.

Non-steroidal anti-inflammatory drugs in equine orthopaedics.

SummaryOrthopaedic disorders are commonly encountered in equine veterinary medicine, and non‐steroidal anti‐inflammatory drugs (NSAIDs) play an important role in the management of many equine orthopaedic disorders. There are multiple NSAIDs available for use in horses, including both non‐selective and selective NSAIDS, and the body of literature evaluating the efficacy of these medications, their effects on normal and inflamed musculoskeletal tissues, and their side effects is broad. This review aims to summarise the current literature on the use of NSAIDs for equine orthopaedic disorders and examines new and future avenues for the management of inflammation in equine orthopaedics.

NSAID-Induced Enteropathy Affects Regulation of Hepatic Glucose Production by Decreasing GLP-1 Secretion.

Background/Aim: Given their widespread use and their notorious effects on the lining of gut cells, including the enteroendocrine cells, we explored if chronic exposure to non-steroidal anti-inflammatory drugs (NSAIDs) affects metabolic balance in a mouse model of NSAID-induced enteropathy. Method: We administered variable NSAIDs to C57Blk/6J mice through intragastric gavage and measured their energy balance, glucose hemostasis, and GLP-1 levels. We treated them with Exendin-9 and Exendin-4 and ran a euglycemic-hyperinsulinemic clamp. Results: Chronic administration of multiple NSAIDs to C57Blk/6J mice induces ileal ulcerations and weight loss in animals consuming a high-fat diet. Despite losing weight, NSAID-treated mice exhibit no improvement in their glucose tolerance. Furthermore, glucose-stimulated (glucagon-like peptide -1) GLP-1 is significantly attenuated in the NSAID-treated groups. In addition, Exendin-9—a GLP-1 receptor antagonist—worsens glucose tolerance in the control group but not in the NSAID-treated group. Finally, the hyper-insulinemic euglycemic clamp study shows that endogenous glucose production, total glucose disposal, and their associated insulin levels were similar among an ibuprofen-treated group and its control. Exendin-4, a GLP-1 receptor agonist, reduces insulin levels in the ibuprofen group compared to their controls for the same glucose exchange rates. Conclusions: Chronic NSAID use can induce small intestinal ulcerations, which can affect intestinal GLP-1 production, hepatic insulin sensitivity, and consequently, hepatic glucose production.

Nonsteroidal Anti-Inflammatory Drugs Reduce Second Cancer Risk in Patients With Breast Cancer: A Nationwide Population-Based Propensity Score-Matched Cohort Study in Taiwan.

Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce mortality in patients with cancer, especially breast cancer, but their influence on second cancer risk is uncertain. This study aimed to examine whether NSAID use is associated with second cancer risk in patients with breast cancer. This population-based propensity score-matched cohort study using Taiwan’s National Health Insurance Research Database enrolled patients with newly diagnosed breast cancer (n = 7356) with and without (n = 1839) NSAID therapy from 2000 to 2009. They were followed up until the diagnosis of second cancer, death, or end of 2011. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHR). The NSAID cohort had a lower incidence rate of second cancer than the non-NSAID cohort (5.57 vs. 9.19 per 1,000 person-years), with an aHR of 0.63 (95% confidence interval (CI) 0.46–0.87). When compared with the non-NSAID cohort, the second cancer incidence was lower in patients taking non-cyclooxygenase 2 inhibitors (aHR 0.67, 95% CI 0.47–0.94) and in those receiving multiple NSAIDs during follow-up (aHR 0.55, 95% CI 0.37–0.84). A dose–response relationship existed in NSAID cumulative days. The findings demonstrate that NSAID use reduces second cancer risk in a dose-dependent manner in patients with primary breast cancer.

Safety, Outcomes, and Recommendations for Two-Step Outpatient Nonsteroidal Anti-Inflammatory Drug Challenges

Nonsteroidal anti-inflammatory drug (NSAID) outpatient challenge protocols are not standardized. They vary in clinical practice and can be time- and resource-intensive to perform. To investigate the safety and outcomes of two-step outpatient NSAID challenges to evaluate patients with non-aspirin-exacerbated respiratory disease (AERD)-related NSAID hypersensitivity. We conducted a retrospective study of patients with a history of NSAID allergy who underwent outpatient NSAID challenges under allergist supervision. Individuals with AERD were excluded. Patient demographics, NSAID reaction history, and drug challenge details and outcomes were collected. A total of 249 patients (mean age, 51.6 years; 63.5% female) underwent 262 NSAID challenges. Of these, 224 challenges were negative (85.5%). Thirty challenges resulted in an immediate reaction during the challenge procedure (11.5%) and eight resulted in delayed reactions (3.1%). Three individuals with immediate reactions required treatment with intramuscular epinephrine. Factors associated with a positive NSAID challenge included a prior reaction occurring within 5 years of drug challenge (odds ratio [OR]= 3.66; 95% confidence interval [CI], 1.67-8.44), a prior immediate reaction within 3 hours of NSAID ingestion (OR= 2.45; 95% CI, 1.12-5.57), a history of cross-reactive NSAID hypersensitivity to multiple NSAIDs (OR= 2.97; 95% CI, 1.23-6.91), and the presence of comorbid chronic spontaneous urticaria (OR= 2.95; 95% CI, 1.35-6.41). More than 85% of two-step non-AERD NSAID drug challenges were negative for an immediate or delayed reaction, which allowed patients to use at least one clinically indicated NSAID. Challenge reactions were generally mild. Two-step NSAID challenge protocols can be safely performed in the outpatient setting.

Anticancer effects of non-steroidal anti-inflammatory drugs against cancer cells and cancer stem cells

Certain non-steroidal anti-inflammatory drugs (NSAIDs) are known to have anticancer effects. However, it is unclear whether all NSAIDs have anticancer effects, and thus far, very few studies have compared the antitumor effects among multiple NSAIDs. Therefore, we aimed to identify NSAIDs that enhance the anticancer effect of cisplatin (CDDP); the effects of 17 NSAIDs in lung cancer cells and their spheroids as cancer stem cells (CSCs) were evaluated. Some of the NSAIDs showed cytotoxic effects against A549 and SBC-3 cells and their CDDP-resistant cell lines (A549/DDP and SBC-3/DDP cells, respectively). In addition, co-addition of CDDP and celecoxib, which showed cytotoxic effects, increased the resistance to CDDP by increasing SLC7A11, which is one of the CDDP resistance mechanisms, in A549/DDP and SBC-3/DDP cells. On the other hand, celecoxib also showed antitumor effects on the spheroids of A549/DDP and SBC-3/DDP cells, and enhanced the antitumor effect of CDDP while increasing the mRNA levels of SLC7A11. Moreover, diclofenac was also cytotoxic and enhanced the cytotoxic effect of CDDP in cancer cells and CSCs. In conclusion, some NSAIDs including celecoxib and diclofenac may enhance the therapeutic efficacy of CDDP.

Cross-reactive hypersensitivity to NSAIDs: Experience of a Tunisian allergology center

BackgroundThe accurate diagnosis of cross-reactive reactions (CRR) to nonsteroidal anti-inflammatory drugs (NSAIDs) depends on a careful history and oral drug challenge. In this study, we report the result of a new procedure implemented in Tunisian allergology center to explore CRR to NASIDs in patients with immediate hypersensitivity (IHS) to NSAIDs. MethodsOur structured protocol using oral provocation tests (OPTs) was based on the latest advances in the literature. This protocol was tested in patients with a clinical history of IHS reactions to one or more NSAIDs and referred to the pharmacology department of Sfax (Tunisia) between 2012 and 2018. Patients were classified into 5 subgroups: an ASA subgroup, a multiple NSAIDs subgroup, a single non-selective NSAID subgroup, a paracetamol subgroup, and a celecoxib subgroup. ResultsA total of 34 patients were enrolled. Personal history of atopy was found in 26 (76.5%). A diagnosis of CRR to NSAIDs was made in 24 patients (70.6%): 6 patients in the ASA subgroup, 12 patients in the multiple NSAIDs subgroup, 4 patients in the single non-selective NSAID subgroup, 1 patient in the paracetamol subgroup and 1 patient in the celecoxib subgroup. Regarding safe alternatives in patients with CRR to NSAIDs (n=24), prevalence of cross-reactivity to paracetamol or celecoxib was found in 20% and 27.3% of patients with confirmed CRR to NSAIDs, respectively. ConclusionOur structured protocol based on standardized oral provocation tests helps physicians to prescribe a suitable drug in patients with a history of IHS reactions to NSAIDs.

Underutilization of gastrointestinal prophylaxis in high-risk chronic nonsteroidal anti-inflammatory drug users in Korea.

Background The increasing use of antithrombotic therapies in older patients has led to an increased risk of gastrointestinal (GI) bleeding in chronic nonsteroidal anti-inflammatory drug (NSAID) users. Therefore, there is a pressing need for GI prophylaxis in these high-risk patients. Objective To analyze prescribing patterns and factors associated with the use of gastroprotective agents (GPAs) among high-risk, chronic NSAID users. Setting National claims database including 20% of the total Korean population aged ≥ 65years. Method In this cross-sectional study, we identified older adults prescribed traditional NSAIDs for > 90days and classified them into high- and ultra-high-risk groups if they had one or two or more GI risk factors, respectively. Proton pump inhibitors or misoprostol prescribed for more than 80% of traditional NSAID treatment days was regarded as appropriate GI prophylaxis. Main outcome measure Prevalence and associated factors with appropriate GI prophylaxis. Results Among 69,992 chronic traditional NSAID users, 38.8% and 9.4% belonged to the high and ultra-high-risk groups; 13.2% and 19.9% received appropriate GI prophylaxis, respectively. The most frequently used GPA was histamine H2 antagonists. Multiple NSAID use, concomitant antiplatelets and anticoagulants, and prior GI ulcer history increased the likelihood of receiving appropriate GI prophylaxis. Advanced age (≥ 85years), indications other than arthritis, and neurology specialists negatively affected appropriate GI prophylaxis use. Conclusion Approximately one in five chronic NSAID users, considered ultra-high risk, are prescribed appropriate GI prophylaxis in Korea. Advanced age, indications, and specialties of the prescriber all need to be considered when selecting target populations for interventions.

Biphasic changes in TGF-β1 signaling drive NSAID-induced multi-organ damage

The clinical utility of non-steroidal anti-inflammatory drugs (NSAIDs), used extensively worldwide, is limited by adverse cardiac events resulting from chronic drug exposure. Here, we provide evidence identifying transforming growth factor β (TGF-β1), released from multiple tissues, as a critical driver of NSAID-induced multi-organ damage. Biphasic changes in TGF-β1 levels in liver and heart were accompanied by ROS generation, cell death, fibrotic remodeling, compromised cardiac contractility and elevated liver enzymes. Pharmacological inhibition of TGF-βRI signaling markedly improved heart and liver function and increased overall survival of animals exposed to multiple NSAIDs, effects likely mediated by reductions in NOX-dependent ROS generation. Notably, the beneficial impact of TGF-βRI blockade was confined to a critical window wherein consecutive, but not concurrent, inhibitor administration improved cardiac and hepatic endpoints. Remarkably, in addition to ameliorating indomethacin-mediated myofilament disruptions, cardiac TGF-βRI knockdown lead to drastic reductions in TGF-β1 production accompanied by lessening in intestinal lesioning underscoring the importance of endocrine TGF-β1 signaling in NSAID-driven tissue injury. Indeed, gastric ulceration was associated with a higher incidence of cardiac complications in a human cohort underscoring the critical importance of circulation-facilitated peripheral organ system interconnectedness in efforts seeking to mitigate the toxic side effects of chronic NSAID use.

Malabaricone C Attenuates Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Ulceration by Decreasing Oxidative/Nitrative Stress and Inflammation and Promoting Angiogenic Autohealing.

Aims: Nonsteroidal anti-inflammatory drugs (NSAIDs), among the most commonly used drugs worldwide, are associated with gastrointestinal (GI) complications that severely limit the clinical utility of this essential class of pain medications. Here, we mechanistically dissect the protective impact of a natural product, malabaricone C (Mal C), on NSAID-induced gastropathy. Results: Mal C dose dependently diminished erosion of the stomach lining and inflammation in mice treated with NSAIDs with the protective impact translating to improvement in survival. By decreasing oxidative and nitrative stress, Mal C treatment prevented NSAID-induced mitochondrial dysfunction and cell death; nuclear factor κ-light-chain enhancer of activated B cell induction, release of proinflammatory cytokines and neutrophil infiltration; and disruptions in the vascular endothelial growth factor/endostatin balance that contributes to mucosal autohealing. Importantly, Mal C failed to impact the therapeutic anti-inflammatory properties of multiple NSAIDs in a model of acute inflammation. In all assays tested, Mal C proved as or more efficacious than the current first-line therapy for NSAID-dependent GI complications, the proton pump inhibitor omeprazole. Innovation: Given that omeprazole-mediated prophylaxis is, itself, associated with a shift in NSAID-driven GI complications from the upper GI to the lower GI system, there is a clear and present need for novel therapeutics aimed at ameliorating NSAID-induced gastropathy. Mal C provided significant protection against NSAID-induced gastric ulcerations impacting multiple critical signaling cascades contributing to inflammation, cell loss, extracellular matrix degradation, and angiogenic autohealing. Conclusion: Thus, Mal C represents a viable lead compound for the development of novel gastroprotective agents.

Tolerability to paracetamol and preferential COX-2 inhibitors in patients with cross-reactive nonsteroidal anti-inflammatory drugs hypersensitivity.

BackgroundAcetylsalicylic acid/aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used drugs that may cause hypersensitivity reactions in a substantial proportion of patients. Physicians ought to be aware of these situations.ObjectiveWe aimed to present the clinical characteristics and rates of tolerability to cyclooxygenase (COX)-2 inhibitor analgesics in patients who had admitted due to multiple cross-reactive type of NSAID hypersensitivity.MethodsThe files of the patients who had admitted with multiple NSAIDs-induced symptoms were investigated retrospectively. Age, sex, underlying diseases, clinical manifestation, skin test results, and drug provocation test results were analyzed.ResultsIn 105 patients with multiple cross-reactive type of NSAID hypersensitivity, we found the rate of cross-reactivity to any of the relatively safe alternatives including paracetamol, meloxicam, and nimesulide to be 16.1%. The rate of cross-reactivity to these relatively safe drugs was significantly higher in patients with a history of anaphylaxis induced by NSAID intake (p = 0.006).ConclusionThe diagnosis of COX-1-mediated multiple NSAID hypersensitivity can be often established with a detailed history. Although rare, severe hypersensitivity reactions may be observed in these patients. Undesired situations for both patients and physicians may be avoided by testing relatively safe paracetamol and COX-2 inhibitors in experienced centers.

Postoperative Bleeding Associated with Ibuprofen Use after Tonsillectomy: A Meta-analysis.

To better quantify the risk of ibuprofen-associated posttonsillectomy hemorrhage (PTH). PUBMED/MEDLINE, Web of Science, and Cochrane Clinical Trials Database. Literature searches were performed for English-language publications containing the terms tonsillectomy, ibuprofen, and tonsillectomy from database inception to May 2017. Human clinical trials, prospective cohort studies, and retrospective cohort studies related to tonsillectomy, ibuprofen use, and posttonsillectomy hemorrhage among pediatric patients were selected. Electronic searches revealed 151 studies, of which 12 were deemed eligible for analysis. Studies were weighted according to level of evidence and risk of bias. Pooling of results across all studies showed a statistically significant increase in PTH among the patients taking ibuprofen (odds ratio, 1.38; 95% confidence interval, 1.11-1.72). The I2 statistic of 20.8% demonstrates overall low study heterogeneity and good comparability of the results. Our meta-analysis of available cohort studies and randomized controlled trials (RCTs) shows possible increased tendency to PTH with the use of ibuprofen. This has not been demonstrated in other studies and systematic reviews because their analyses were limited by use of multiple nonsteroidal anti-inflammatory drugs and inclusion of studies limited to the perioperative period and low sample size. However, the current analysis is limited due to inclusion of many retrospective cohort studies with unclear follow-up and no blinding. Further RCTs will be required to investigate this trend toward increased PTH.

Synthesis and preliminary assessment of the anticancer and Wnt/\u03b2-catenin inhibitory activity of small amide libraries of fenamates and profens

As part of an ongoing program to study the anticancer activity of non-steroidal anti-inflammatory drugs (NSAIDs) through generating diversity libraries of multiple NSAID scaffolds, we synthesized a series of NSAID amide derivatives and screened these sets against three cancer cell lines (prostate, colon and breast) and Wnt/β-catenin signaling. The evaluated amide analog libraries show significant anticancer activity/cell proliferation inhibition, and specific members of the sets show inhibition of Wnt/β-catenin signaling.

In Vitro Diagnosis of Hypersensitivity to Nonsteroidal Anti-Inflammatory Drugs (NSAID) Comparison of Two Methods

Objective: Current concept distinguishes between cross intolerance (non-immune) and single or multiple hypersensitivity based (immune) adverse reactions of non-steroidal anti-inflammatory drugs (NSAID) due to their potential to inhibit cyclooxygenase (COX) isoenzymes (COX-1, COX-2). Recently we described a rapid IL-6 release assay using blood mononuclear cells of patients with various clinical forms of drug hypersensitivity. Here we present data of a comprehensive analysis if the IL-6 release test and the classical IgE immuno-assay for their sensitivity in cases with adverse reactions to NSAIDs grouped according to the new clinical classification. Methods: Total and specific serum IgE against 9 different HSA coupled-NSAIDs were determined by manual ELISA tests (55 cases) and compared to drug-specific release from preformed IL-6 pool of PBMCs of patients sensitized to the same NSAIDs after short (20’) incubation of 4 standardized concentrations (51 cases and 9 controls) and IL-6 measurement from their cell free supernatants including positive and negative intraassay controls. Results: The ratio of cross intolerant to specific hypersensitive (HS) cases was higher in the IgE group (and total IgE too,) than in the IL-6 release tested ones. There was no difference, however, in the overall ratio of early and accelerated plus late onset adverse events based on individual histories. Nine NSAIDs were tested in both groups which represented all major COX-1 inhibitors. The positivity of validated test results was double within the IL-6 tested group (65.4% vs. 36.9%). In some cases non-drug components of NSAID formulations were responsible for the observed (mainly) anaphylactic reactions. Positive results in both groups were scattered amongst cross intolerant and single to multiple hypersensitive (HS) subgroups. To our knowledge no comprehensive analysis had been performed before either on clinical phenotypes dependent IgE immunoassays or on NSAID-induced “early” Tcell activation after those specified adverse events. Conclusion: Specific HS and multiple non cross-reactive NSAID sensitizations exceeded non- immune reactions in both in vitro tested groups. Some intolerant patients revealed detectable ASA antibodies of IgE type. Preformed IL-6 release by PBMC was more sensitive than specific IgE immunoassays as an in vitro diagnostic tool. The results indicate that checking of non-drug components should be considered in allergy workups. ASA in vivo provocations need further standardization.

Discrepancies in the diagnosis and classification of nonsteroidal anti-inflammatory drug hypersensitivity reactions in children

BackgroundHypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently encountered in daily clinical practice. The aim of this study was to determine the confirmation rates, risk factors of NSAID hypersensitivity in children and to try to classify them with a standardized diagnostic protocol. MethodsAll patients with a suspicion of NSAID-induced hypersensitivity were evaluated with European Network for drug Allergy (ENDA) recommendations. The children were classified as selective responders (SRs) or cross-intolerant (CI) depending on the drug provocation test (DPT) results. ResultsWe evaluated 106 children with a suspicion of NSAID hypersensitivity. NSAID hypersensitivity was confirmed with tests in 31 patients; 4 (12.9%) were diagnosed by skin tests and 27 (87.1%) by DPTs and two patients with a history of anaphylaxis by medical records. Eleven patients (33.3%) were classified as SRs, whereas twenty-two (66.6%) children as CIs. SRs and CIs were further classified as NSAID-induced urticaria/angioedema (n = 8), NSAID-exacerbated cutaneous disease (n = 6) and NSAID-exacerbated respiratory disease (n = 1) and single NSAID-induced urticaria/angioedema and/or anaphylaxis (n = 11). Eight (24.2%) patients could not be categorized according to ENDA/GA2LEN classification; one CI patient could not be classified based on pathomechanisms, seven CIs could not be categorized based on the underlying disease and clinical manifestations. A reaction within an hour of drug intake (aOR:3.0, 95% confidence interval: 1.18–7.67, p = 0.021), a history with multiple NSAIDs hypersensitivity (aOR:2.9, 95% confidence interval: 1.16–7.60, p = 0.022), and family history of atopy (aOR:4.0, 95% confidence interval: 1.50–10.82, p = 0.006) were found as the independent risk factors related to confirmed NSAID hypersensitivity. ConclusionsThis study suggests the presence of different phenotypes which do not fit into the current classifications in children with NSAID hypersensitivity.

Knowledge and perceptions of the risks of non-steroidal anti-inflammatory drugs among orthopaedic patients in Thailand.

Background There is a high incidence of adverse effects from non-steroidal antiinflammatory drugs (NSAIDs) in Thailand, but patients' perceptions and knowledge of NSAID risks is unknown. Objective This study aims to assess patients' perceptions and knowledge of NSAID risks and factors affecting them. Setting University hospital in North-East of Thailand. Method A Cross-sectional study conducted over 4months, using a self-administered questionnaire. Patients prescribed NSAIDs for at least one month duration from orthopaedic clinic were recruited using systematic random sampling. Main outcome measure Patients' perceptions on NSAID risks, knowledge on risk factors, and their associated factors. Results A total of 474 questionnaires were assessed. Overall perceptions of risks was low (scoring below five on a 0-10 visual analogue scale), with risks associated with the renal system scoring highest. Perceived risk of gastrointestinal problems differed between patients using non-selective and selective NSAIDs (3.47±2.75 vs 2.06±2.98; P<0.001). Receiving side effect information from a health professional was associated with higher risk perception. Most patients (80%) identified high doses, renal disease and gastrointestinal ulcer increased risks of NSAIDs, but fewer than half recognized that use in the elderly, multiple NSAID use, drinking, hypertension and cardiovascular disease also increased risk of adverse events. Having underlying diseases and receiving side effect information were associated with 1.6-2.0 fold increased knowledge of NSAID risks. Conclusion Perceptions and knowledge concerning NSAID risks was generally low in Thai patients, but higher in those who had received side effect information. Risk-related information should be widely provided, especially in high-risk patients.

Microextraction by packed sorbent and HPLC–PDA quantification of multiple anti-inflammatory drugs and fluoroquinolones in human plasma and urine

We developed and validated an analytical method based on microextraction packed sorbent (MEPS) and high-performance liquid chromatography (HPLC) coupled to photodiode array (PDA) detector to simultaneously quantify multiple nonsteroidal anti-inflammatory drugs (NSAIDs) and fluoroquinolones (FLQs), which may provide as combination several adverse reactions in nephrology and neurology. The linearity range from LOQs (0.1 μg/mL) to 10 μg/mL, and LODs values were 0.03 μg/mL for both NSAIDs and FLQs. The validation was performed according to international guidelines and the accuracy was tested measuring the precision, intermediate precision and trueness. The drugs stability was tested under different storage conditions (+4 °C and −20 °C) and after three different cycles of freezing and thawing. The method can be a suitable tool to simultaneously detect a possible association of drugs in human biological samples and provide several potentialities for clinical applications, bioequivalence studies, pharmacodynamics and toxicodynamics of different pharmaceutical dosage forms showing NSAIDs and FLQs.

Multiple nonsteroidal anti-inflammatory drug hypersensitivity without hypersensitivity to aspirin

Multiple nonsteroidal anti-inflammatory drug hypersensitivity without hypersensitivity to aspirin