Alternative Nonsteroidal Anti-inflammatory Drugs Research Articles

Alternative Drug Safety in Children with Nonsteroidal Anti-Inflammatory Drug Hypersensitivity

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used in the pediatric age group as pain relievers, antipyretics and anti-inflammatory drugs. Since NSAIDs are used in many medical conditions, there is a need for alternative NSAIDs to be used safely in people with hypersensitivity reactions. Selective and partially selective COX-2 inhibitors and weak COX-1 inhibitors are generally used as safe alternative drugs. The aim of this study was to evaluate safe NSAIDs determined by oral provocation tests (OPTs) according to phenotypes in children with NSAID hypersensitivity reactions. Methods: The results of the oral provocation test performed with alternative NSAIDs (paracetamol, meloxicam, nimesulide, celecoxib) in patients followed up with the diagnosis of NSAID hypersensitivity reaction in the Pediatric Immunology and Allergy Department between January 2015 and February 2023 were evaluated retrospectively. Results: During the study period, 91 patients underwent OPTs with 109 alternative drugs 48 (52.7%) of whom were girls, with a median age of 15 years. 91 patients had a history of reactions to 117 drugs. As an alternative NSAID; OPT was performed with paracetamol in 58 patients, meloxicam in 44 patients, nimesulide in 5 patients, and celecoxib in 2 patients. Since 15 patients used paracetamol safely at home, no tests were performed with paracetamol. Reactions were observed in 3 of the 73 patients (4.1%) who underwent OPT with paracetamol and in 2 of the 44 (4.5%) who underwent OPT with meloxicam. Reactions to nimesulide were also observed in the latter 2 patients (2/5, 40%), but they appeared to tolerate celecoxib. No reaction was observed in the 2 patients who were tested with celecoxib. Conclusion: Paracetamol, meloxicam, and nimesulide can be used as safe alternative drugs in most children with NSAID hypersensitivity. Selective COX-2 inhibitors should be tried as an alternative in patients who cannot tolerate them.

For adults with acute postoperative pain, how does single-dose intravenous (IV) ketorolac compare with alternative non-steroidal anti-inflammatory drugs (NSAIDs) or opioids?

For adults with acute postoperative pain, how does single-dose intravenous (IV) ketorolac compare with alternative non-steroidal anti-inflammatory drugs (NSAIDs) or opioids?

Meloxicam and/or Etoricoxib Could Be Administered Safely in Two Equal Doses during an Open Oral Challenge in Patients with Nonsteroidal Anti-Inflammatory Drug Hypersensitivity

Background: Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) are common. These patients require an effective and safe analgesic alternative. Objective: The aim of the study was to demonstrate the safety of meloxicam and etoricoxib administered by open oral challenge in 2 equal steps in patients with NSAID hypersensitivity. Methods: A cross-sectional, descriptive study of patients with a diagnosis of NSAID hypersensitivity who underwent an oral drug provocation test (DPT) with meloxicam or etoricoxib between January 2011 and August 2017 was conducted. The analysis was performed from a database in BD Clinic. Results: Two hundred and twenty-eight oral provocations were performed with an alternative NSAID (203 with meloxicam and 25 with etoricoxib) in 217 patients with hypersensitivity to NSAIDs. The median age was 38 years. Ninety-eight percent of meloxicam and 100% of etoricoxib DPTs were performed in 2 steps (without previous placebo), and 52% and 64% of meloxicam and etoricoxib DPTs, respectively, were performed with 50% of the therapeutic dose in each step. Tolerance to meloxicam was demonstrated in 192 patients (94.5%) and in 100% of patients receiving etoricoxib. Conclusions: Open oral provocation with meloxicam and etoricoxib carried out in 2 steps without placebo seems to be safe and implies less costs and less time expenditure. Also, it could be performed with 2 equal doses.

Behind the scene: Paracetamol hypersensitivity in children

Paracetamol, a non-steroidal anti-inflammatory drug, is commonly being used for fever and pain relief worldwide. The aim of this study was to evaluate children with a suspected history of paracetamol hypersensitivity. Sixty patients who were referred to our clinic in between January 2015 and December 2018 with a suspected history of paracetamol hypersensitivity were included. Reactions were classified according to the European Network for Drug Allergy (ENDA)/Global Allergy and Asthma European Network classification and European Academy of Allergy and Clinical Immunology (EAACI)/ENDA Position Paper. Diagnoses were confirmed by skin tests and oral challenge tests (OCTs). In those with verified paracetamol hypersensitivity, an OCT with a strong COX-1 inhibitor was performed to classify the type of the reaction to refer as either selective or cross-intolerance hypersensitivity. A subsequent OCT with a selective COX-2 inhibitor was performed in those cross-intolerant patients to find out a safe alternative drug. Sixty OCTs with paracetamol were performed to patients with a median age of 8.5 years, and hypersensitivity to paracetamol was verified in 8 patients. Four children were classified as selective responders, and 3 were classified as cross-intolerant after OCT with a COX-1 inhibitor. Overall, skin test positivity for paracetamol was detected in only one patient, in whom OCT with paracetamol was negative. In all 3 cross-intolerant patients, a safe alternative non-steroidal anti-inflammatory drug was identified after an OCT with a selective COX-2 inhibitor. OCT stands as the gold-standard procedure in verifying the diagnosis of patients with paracetamol-induced drug hypersensitivity, as well as, in defining the type of reactions and finding out safe alternative drugs.

Hypersensitivity reactions to non-steroidal anti-inflammatory drugs: results of an Austrian cohort study

Summary Background Hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) is the second most common cause of drug hypersensitivity. Despite the importance of NSAIDs in routine analgesia only few studies have systematically addressed the question of tolerability in hypersensitive patients. Methods The authors retrospectively analysed 398 patients that were treated at the Department of Dermatology, Kepler University Hospital Linz, Austria, in the period 2012–2016 with a clinical history of NSAID hypersensitivity. Skin tests (skin prick and intracutaneous tests) to common NSAIDs were performed, followed by single-blinded, placebo-controlled drug challenge with either the culprit drug or an alternative NSAID. Results A total of 361 patients were subjected to skin testing. Of these, 25 patients (6.3%) showed a positive reaction to the culprit drug. According to the severity of the reaction in the medical history, 87 patients were exposed orally to the culprit drug (oral provocation test, OPT) after negative skin test and 255 patients received OPT with alternative NSAIDs according to established protocols. OPT with the culprit drug resulted in hypersensitivity reactions in 12 patients (13.79%). In terms of alternative NSAID testing, the three most commonly tested drugs were lornoxicam (192 OPTs), acetaminophen (156 OPTs) and celecoxib (133 OPTs) with tolerability rates in respectively 88.54% (hypersensitivity reactions, 11.46%), 92.31% (hypersensitivity reactions, 7.69%) and 91.73% (hypersensitivity reactions, 8.27%) of cases. Conclusion OPT with alternative NSAIDs are useful in patients with NSAID hypersensitivity as tolerability varies between the individual substances.

Clinical Control of CSU with Antihistamines Allows for Tolerance of NSAID-Exacerbated Cutaneous Disease

Many patients with chronic spontaneous urticaria (CSU) experience exacerbations after the administration of nonsteroidal anti-inflammatory drugs (NSAIDs), with clinical implications for the selection of therapeutic options for pain management. Case reports suggest that antihistamines could prevent these reactions. To determine whether antihistamines can prevent NSAID-exacerbated reactions in patients with CSU. Data on 121 patients with CSU and a history of NSAID exacerbations were evaluated. Two types of challenge with NSAIDs were performed using the NSAIDs reported in the medical record (a diagnostic challenge test without the use of antihistamines and a challenge test using antihistamines). The order in which the tests were performed in each patient was dependent on the treating physician. Patients with a positive first diagnostic challenge underwent a second challenge using H1-antihistamines (anti-H1), patients with a negative first challenge using anti-H1 underwent a second diagnostic challenge without the use of anti-H1, and patients with a negative first diagnostic challenge or a positive first challenge using anti-H1 did not undergo a second challenge. In some patients, additional challenges were performed with an alternative NSAID before performing the diagnostic challenge test or the challenge test using anti-H1. In the diagnostic challenge test, 96 patients tested positive. Seventy-two (75%) of these patients tolerated the NSAIDs involved in the reaction when they used antihistamines. NSAID restrictions create many inconveniences for patients with CSU. Clinical control of CSU with the use of antihistamines can prevent further exacerbations due to NSAID intake in many patients to help them avoid unnecessary restrictions.

An Indolent Cause of Recurrent Anaphylaxis with NSAIDs: Systemic Mastocytosis

Systemic Mastocytosis (SM) is one of the subtypes of mast cell disorders. Patients with SM suffer from flushing, abdominal cramps and hypotension. It may also cause unexplained and recurrent anaphylactic episodes sometimes. The secretion of mediators can be triggered by various factors. Non-steroidal anti-inflammatory drugs (NSAIDs) are extensively used for their analgesic, antipyretic and anti-inflammatory properties, and they are one of the most commonly prescribed drugs in the world. On the other hand, they may cause a group of adverse reactions, ranging from mild reactions like gastritis to life-threatening allergic reactions like anaphylaxis. In this paper, we report a patient who had multiple severe adverse reactions against NSAIDs and was referred to our clinic to find a safe alternative NSAID. She was eventually diagnosed with Indolent SM (ISM) when she was evaluated with all of her systemic complaints and symptoms.

H1-Antihistamine Premedication in NSAID-Associated Urticaria

Therapeutic options for pain management are restricted in patients with nonsteroidal anti-inflammatory drug (NSAID)-induced or NSAID-exacerbated urticaria because strong cyclooxygenase (COX)-I inhibiting NSAID cannot be used. Alternative NSAID such as weak COX-I inhibitors or selective COX-II inhibitors are sometimes not sufficiently effective or have potentially troublesome adverse effects. To date, prophylactic premedication with H1-antihistamines is rarely practiced in patients concurrently suffering from recurrent pain and NSAID-associated urticaria. Our data analysis aims to clarify whether prophylactic premedication before the intake of NSAID is effective, safe, and practicable. Data of 21 patients with NSAID-induced or NSAID-exacerbated urticaria who underwent single dose NSAID provocation 30 minutes after premedication with 5 mg desloratadine were retrospectively evaluated. After H1-antihistamine premedication, 17 patients tolerated 16 single dose provocation tests with strong COX-I inhibitors and 2 tests with weak COX-I inhibitors. Despite H1-antihistamine premedication, 2 patients developed acute urticaria after intake of 400 mg ibuprofen. Another 2 patients with acute urticaria after intake of 800 mg ibuprofen tolerated 400 mg ibuprofen and 1000 mg paracetamol, respectively. In the majority of patients with NSAID-induced or NSAID-exacerbated urticaria concurrently suffering from intermittent pain, a premedication regimen with 5 mg desloratadine 30 minutes before intake of a strong COX-I inhibitor seems to be effective, safe, and practicable.

Gastrointestinal injury associated with NSAID use: a case study and review of risk factors and preventative strategies.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective anti-inflammatory and analgesic agents and are among the most commonly used classes of medications worldwide. However, their use has been associated with potentially serious dose-dependent gastrointestinal (GI) complications such as upper GI bleeding. GI complications resulting from NSAID use are among the most common drug side effects in the United States, due to the widespread use of NSAIDs. The risk of upper GI complications can occur even with short-term NSAID use, and the rate of events is linear over time with continued use. Although gastroprotective therapies are available, they are underused, and patient and physician awareness and recognition of some of the factors influencing the development of NSAID-related upper GI complications are limited. Herein, we present a case report of a patient experiencing a gastric ulcer following NSAID use and examine some of the risk factors and potential strategies for prevention of upper GI mucosal injuries and associated bleeding following NSAID use. These risk factors include advanced age, previous history of GI injury, and concurrent use of medications such as anticoagulants, aspirin, corticosteroids, and selective serotonin reuptake inhibitors. Strategies for prevention of GI injuries include anti-secretory agents, gastroprotective agents, alternative NSAID formulations, and nonpharmacologic therapies. Greater awareness of the risk factors and potential therapies for GI complications resulting from NSAID use could help improve outcomes for patients requiring NSAID treatment.

COX-Independent Mechanisms of Cancer Chemoprevention by Anti-Inflammatory Drugs

Epidemiological and clinical studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase (COX)-2 selective inhibitors, reduce the risk of developing cancer. Experimental studies in human cancer cell lines and rodent models of carcinogenesis support these observations by providing strong evidence for the antineoplastic properties of NSAIDs. The involvement of COX-2 in tumorigenesis and its overexpression in various cancer tissues suggest that inhibition of COX-2 is responsible for the chemopreventive efficacy of these agents. However, the precise mechanisms by which NSAIDs exert their antiproliferative effects are still a matter of debate. Numerous other studies have shown that NSAIDs can act through COX-independent mechanisms. This review provides a detailed description of the major COX-independent molecular targets of NSAIDs and discusses how these targets may be involved in their anticancer effects. Toxicities resulting from COX inhibition and the suppression of prostaglandin synthesis preclude the long-term use of NSAIDs for cancer chemoprevention. Furthermore, chemopreventive efficacy is incomplete and treatment often leads to the development of resistance. Identification of alternative NSAID targets and elucidation of the biochemical processes by which they inhibit tumor growth could lead to the development of safer and more efficacious drugs for cancer chemoprevention.

Possible Link between History of Hypersensitivity to a Specific Non-steroidal Anti-inflammatory Drug (NSAID) and Positive Results Following Challenge Test to Alternative NSAIDs

In subjects with hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs), the choice of suitable alternative drugs with the lowest risk of reaction is imperative for therapeutic management. A safe method to exclude drug hypersensitivity is to perform a challenge test for an alternative drug. The present study was conducted to: obtain more information about the safety of NSAIDs; assess the risk of reaction following the administration of a selective or nonselective cyclooxygenase 2 (COX-2) inhibitor in patients with a history of adverse reactions to NSAIDs; investigate if age and/or gender play a role in the susceptibility to develop adverse reactions to NSAIDs. This retrospective study includes 524 patients with a history of hypersensitivity to NSAIDs admitted to undergo challenge test to an alternative anti-inflammatory drug. Statistical significance was achieved when odds ratio (OR) and risk ratio (RR) values were >1. 8.39% of patients with hypersensitivity reactions to NSAIDs showed a positive challenge test for the alternative drug. Challenge tests for nonselective COX-2 inhibitors were positive in 16.2% of patients with previous reaction to a same drug class and in 12.9% of patients with a history of reaction to selective COX-2 inhibitors. No positive challenge test to a non-selective COX-2 inhibitor was found in patients with a history of hypersensitivity to nimesulide (CAS 51803-78-2). Challenge tests for selective COX-2 inhibitors were positive in 4.6% of patients with a previous reaction to nonselective COX-2 inhibitors and in 7.2% of patients with a history of reaction to selective COX-2 inhibitors. The RR of a positive challenge test to a non-selective COX-2 inhibitor was significant in patients who had a history of reaction to an analogous compound (P 0.21, OR 1.31, RR 1.26). In this study, selective COX-2 inhibitors represented the class of NSAIDs less frequently reported as responsible of adverse reaction. These data underline that there is a higher risk to find a positive challenge test to a non-selective COX-2 inhibitor than to a selective one in patients with previous adverse reactions to a non-selective COX-2 inhibitor. Moreover, the data evidence that females could have a higher risk compared to males to develop an adverse reaction to selective COX-2 inhibitors. In conclusion, it appears necessary to pay attention to the kind of NSAIDs reported as the cause of hypersensitivity in anamnesis, because it must be considered a successful guide in choosing the alternative drug to administer to the patient during the challenge test.

Response to a selective COX‐2 inhibitor in patients with urticaria/angioedema induced by nonsteroidal anti‐inflammatory drugs

In subjects with hypersensitivity reactions with cross-intolerance to nonsteroidal anti-inflammatory drugs (NSAIDs), tolerance to selective COX-2 inhibitors has not been evaluated in large series of well-phenotyped cases. We evaluated 252 patients with urticaria and/or angioedema caused by hypersensitivity owing to cross-intolerance to NSAIDs. In addition to the clinical history, diagnosis was confirmed by provocation to an alternative NSAID. Two groups were considered: (A) patients with cross-intolerance to NSAIDs and intolerance to paracetamol and (B) patients with cross-intolerance to NSAIDs and good tolerance to paracetamol. Etoricoxib was administered to Group A patients and to a representative sample of Group B patients. In the event of a positive response, serum tryptase levels were determined and skin biopsy was performed in five patients in each group. Ibuprofen was the most commonly implicated drug, followed by acetylsalicylic acid (ASA). Urticaria was the most common manifestation, followed by angioedema. Most of the patients developed symptoms within 1 h. Twenty-five percent in Group A (n = 47) and 6% in Group B (n = 50) were intolerant to etoricoxib. Skin biopsy showed mast cell activation with the release of tryptase to the extracellular space but without the increase in serum tryptase levels. Selective COX-2 inhibitors may be unsafe in subjects with urticaria and/or angioedema caused by hypersensitivity reactions to NSAIDs with cross-intolerance if they are intolerant to paracetamol. A quarter of patients who were intolerant to this drug were also intolerant to etoricoxib. In subjects with hypersensitivity to NSAIDs and intolerance to paracetamol, selective COX-2 inhibitors should be administered as a controlled, incremental dose provocation test to assess tolerance.

Evaluating the negative predictive value of provocation tests with nonsteroidal anti‐inflammatory drugs

The nonsteroidal anti-inflammatory drugs (NSAIDs) hypersensitivity work-up is based on clinical history, skin tests, and drug provocation tests. The negative predictive value (NPV) of the latter is not established. A cohort study was conducted in the Allergy Department in Montpellier to evaluate the NPV of the provocation test with NSAIDs in patients with clinical presentation suggestive of hypersensitivity, and negatively tested. Patients were contacted at least 6 months after the work-up. Patients who took NSAID and reacted were proposed a new allergy work-up, which included a provocation test with the culprit drug. Among the 393 patients contacted, 279 (71.0%) were followed up. Two hundred and sixty (93.2%) patients had taken a NSAID at least once: 139 (53.5%) the same drug as the one tested and 215 (82.7%) an alternative (94, 33.7% taking both the tested NSAID and an alternative). Eight patients (3.1%) reported a reaction (five with the negatively tested NSAID and three with another NSAID). All the reactions occurred immediately after the first administration and were not severe. Among the five patients who reacted with the negatively tested NSAID, only three accepted a re-challenge, negative in two cases and positive in one, representing a NPV of 97.8% (95% CI: 95.4-100%). Three patients (3/215) reported a reaction when an alternative NSAID was taken, representing a NPV of 98.6% (95% CI: 97-100%). The NPV of NSAIDs drug provocation test is high. This should reassure physicians who might hesitate to prescribe NSAIDs, especially in patients with negative allergic work-ups.

Predictive Value of Autologous Plasma Skin Test for Multiple Nonsteroidal Anti-Inflammatory Drug Intolerance

Background: Recent studies show that patients with multiple nonsteroidal anti-inflammatory drug (NSAID) intolerance are frequently characterized by autoreactivity; this can be detected by autologous serum skin test (ASST). Objective: To assess whether the autologous plasma skin test (APST), a test that was recently shown to be more sensitive than ASST, may be usefully employed as a predictive test for multiple NSAID intolerance in patients with a history of single NSAID intolerance. Methods: Thirty otherwise normal adults with a history of acute urticaria following the ingestion of one single NSAID underwent an APST before being challenged with a COX-1-inhibiting NSAID other than the offending drug. Results: Sixteen patients experienced urticaria following the ingestion of the alternative NSAID and were therefore classified as multiple NSAID reactors; all 16 (100%) scored positive on APST. In contrast only 3/14 patients finally classified as single NSAID reactors were positive on APST (p < 0.001). The positive and negative predictive value of APST for multiple NSAID intolerance were 86 and 100%, respectively. Conclusion: In patients with a history of acute urticaria induced by a single NSAID APST can be usefully employed to detect patients that are prone to react to NSAID other than the original offending one.

Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions

Alzheimer's disease (AD) and cardiovascular disease (CVD) are syndromes of aging that share analogous lesions and risk factors, involving lipoproteins, oxidative damage and inflammation. Unlike in CVD, in AD, sensitive biomarkers are unknown, and high-risk groups are understudied. To identify potential prevention strategies in AD, we have focused on pre-clinical models (transgenic and amyloid infusion models), testing dietary/lifestyle factors strongly implicated in reducing risk in epidemiological studies. Initially, we reported the impact of non-steroidal anti-inflammatory drugs (NSAIDs), notably ibuprofen, which reduced amyloid accumulation, but suppressed few inflammatory markers and without reducing oxidative damage. Safety concerns with chronic NSAIDs led to a screen of alternative NSAIDs and identification of the phenolic anti-inflammatory/anti-oxidant compound curcumin, the yellow pigment in turmeric that we found targeted multiple AD pathogenic cascades. The dietary omega-3 fatty acid, docosahexaenoic acid (DHA), also limited amyloid, oxidative damage and synaptic and cognitive deficits in a transgenic mouse model. Both DHA and curcumin have favorable safety profiles, epidemiology and efficacy, and may exert general anti-aging benefits (anti-cancer and cardioprotective.)

Oral aspirin challenges in patients with a history of intolerance to single non‐steroidal anti‐inflammatory drugs

Summary Background In the clinical practice patients with a history of acute urticaria induced by a single non-steroidal anti-inflammatory drug (NSAID) and seeking for safe alternative drugs generally undergo tolerance tests with alternative NSAIDs that have little or no cyclooxygenase-1 (COX-1) enzyme inhibitory activity. This practice does not allow for the detection of single NSAID reactors and may lead to unnecessary avoidance of many potentially useful NSAIDs. Evaluate aspirin challenge as a means to distinguish single from multiple NSAID intolerance in patients with a clinical history of acute urticaria induced by a single NSAID. Methods One hundred and seventeen otherwise normal subjects with a history of acute urticaria following the ingestion of a single NSAID (pyrazolones (n=58), nimesulide (n=17), propionic acid derivatives (n=13), aryl acetic acid derivatives (n=14), acetaminophen (n=9), piroxicam (n=5), and indometacin (n=1)) underwent single-blind placebo-controlled oral challenges with aspirin. Aspirin-intolerant subjects underwent further tolerance tests drugs exerting little or no inhibitory activity on COX-1 enzyme (including paracetamol, nimesulide, rofecoxib, tramadol, and floctafenine). Results Aspirin induced urticaria in 28/117 (24%) patients. Five out of 28 (18%) aspirin reactors did not tolerate alternative NSAID on subsequent oral challenges. Conclusion In subjects with a history of urticaria induced by a single NSAID (other than aspirin) the diagnostic workup should start with an aspirin challenge in order to detect single/multiple NSAID reactors.

Intolerance to nonsteroidal anti-inflammatory drugs might precede by years the onset of chronic urticaria

Background: Recent studies have found that most otherwise normal subjects with a history of acute urticaria induced by several nonsteroidal anti-inflammatory drugs (NSAIDs) show a wheal-and-flare reaction on intradermal injection of autologous serum. This phenomenon has been previously observed in patients with chronic urticaria (CU) and suggests a possible common background in CU and NSAID-induced urticaria. A relationship between these 2 conditions is further suggested by the fact that up to 30% of patients with CU have a worsening of their skin disorders after the ingestion of chemically unrelated NSAIDs. Objective: I sought to assess whether otherwise normal subjects with multiple or single NSAID intolerance show a propensity to have CU. Methods: Two hundred eighty otherwise normal patients with an unequivocal history of acute urticaria induced by NSAIDs seen during the last 10 years were studied. On the basis of both clinical history and oral challenge tests with at least 2 alternative NSAIDs, the patients were classified as having single or multiple NSAID intolerance. All the patients were re-evaluated within the end of 2002, 1 to 10 years after the first visit, to assess the onset of CU. One hundred allergic adults without a history of CU and of drug allergy followed up for 1 to 10 years were used as control subjects. Results: One hundred fifty-nine and 121 patients were finally considered as having single or multiple NSAID intolerance, respectively. At the follow-up visit, 93 (33%) of 280 patients had CU. The prevalence of CU was very similar in subjects with single or multiple NSAID intolerance (48/159 [30%] vs 45/121 [37%], respectively; P = not significant). Only 1 (1%) of 100 atopic control subjects had CU during the follow-up period (P < .001). Among single NSAID reactors, patients who had CU had a significantly higher prevalence of intolerance to aspirin than those who did not have CU (36/48 [75%] vs 41/111 [37%], P < .001), whereas the latter had a markedly higher prevalence of intolerance to pyrazolone drugs (52/111 [47%] vs 10/48 [21%], P < .01). Altogether, only 12 (15%) of 82 patients intolerant to drugs other than aspirin versus 36 (47%) of 77 aspirin reactors had CU (P < .001). Conclusion: NSAID intolerance might precede the onset of CU by years. Both multiple and single NSAID reactors with a history of aspirin-induced urticaria seem at higher risk for CU than patients with a history of single intolerance to NSAIDs other than aspirin. (J Allergy Clin Immunol 2003;111:1095-8.)

Update on sensitivity to nonsteroidal antiinflammatory drugs.

Non steroidal antiinflammatory drugs (NSAIDs) are among the most frequently prescribed medications worldwide. These drugs are effective for the treatment of a wide spectrum of diseases: musculoskeletal disorders, headhache, fever, pain, and others. Their widespread use explains the very high incidence of intolerance; reactions range from asthma, rhinitis, to urticaria/angioedema, various skin eruptions and anaphylactic shock. The pathogenesis of intolerance is still unclear: immune-mediated reactions have been reported following the use of pyrazolone derivatives and, less commonly aspirin, anthranilic-acid derivatives and diclofenac. It has been suggested that NSAIDs may induce pseudoallergic reactions, while in case of bronchial asthma the inhibition of cyclooxigenase by NSAIDs has been proposed as a pathogenetic mechanism. The diagnosis of NSAIDs sensitivity can usually be established by history; in fact skin prick tests with NSAIDs have not been successful and no reliable in vitro tests are available. The only definitive diagnostic test is oral test dosing. To identify an alternative NSAIDs in a sensitive patient a tolerance test is performed. Here we review the current state of knowledge concerning NSAIDs sensitivity, including personal data to increase awareness on this issue.

The Curry Spice Curcumin Reduces Oxidative Damage and Amyloid Pathology in an Alzheimer Transgenic Mouse

Inflammation in Alzheimer's disease (AD) patients is characterized by increased cytokines and activated microglia. Epidemiological studies suggest reduced AD risk associates with long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs). Whereas chronic ibuprofen suppressed inflammation and plaque-related pathology in an Alzheimer transgenic APPSw mouse model (Tg2576), excessive use of NSAIDs targeting cyclooxygenase I can cause gastrointestinal, liver, and renal toxicity. One alternative NSAID is curcumin, derived from the curry spice turmeric. Curcumin has an extensive history as a food additive and herbal medicine in India and is also a potent polyphenolic antioxidant. To evaluate whether it could affect Alzheimer-like pathology in the APPSw mice, we tested a low (160 ppm) and a high dose of dietary curcumin (5000 ppm) on inflammation, oxidative damage, and plaque pathology. Low and high doses of curcumin significantly lowered oxidized proteins and interleukin-1beta, a proinflammatory cytokine elevated in the brains of these mice. With low-dose but not high-dose curcumin treatment, the astrocytic marker GFAP was reduced, and insoluble beta-amyloid (Abeta), soluble Abeta, and plaque burden were significantly decreased by 43-50%. However, levels of amyloid precursor (APP) in the membrane fraction were not reduced. Microgliosis was also suppressed in neuronal layers but not adjacent to plaques. In view of its efficacy and apparent low toxicity, this Indian spice component shows promise for the prevention of Alzheimer's disease.

NSAIDs and blood pressure. Clinical importance for older patients.

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) and antihypertensive medication increases with age to 26% and > 50%, respectively, among the elderly. Overall, 12 to 15% of elderly individuals take at least 1 NSAID and an antihypertensive medication concurrently. A large case-control study of older individuals demonstrated that recent users of NSAIDs had a 1.7-fold increase in risk of initiating antihypertensive therapy compared with non-users. A community-based epidemiological study revealed that NSAID use significantly predicted the presence of hypertension (odds ratio 1.4, 95% confidence interval 1.1 to 1.7) in the elderly. Furthermore, among those taking antihypertensive agents in the 65+ Rural Health Study, in Iowa, US, individuals also taking NSAIDs had a mean systolic blood pressure (BP) 4.9 mm Hg higher than non-users of NSAIDs. The hypertensive effect of NSAIDs varies depending on the specific NSAID used and the type of antihypertensive agent, if they are taken concurrently. While the results of randomised, controlled trials in the elderly have been conflicting, 2 meta-analyses involving younger adults have revealed that NSAID use produces a clinically significant increment in mean BP of 5.0 mm Hg, which is most marked in patients with controlled hypertension. Stratification by NSAID type has revealed that piroxicam and indomethacin had the greatest, and sulindac the least, pressor effect. While the mechanisms) of the pressor effect remain speculative, salt and water retention, caused by several factors operating in parallel, coupled with an increased total peripheral vascular resistance via increased renal endothelin-1 synthesis, are potentially important. A 5 to 6 mm Hg increase in diastolic BP maintained over a few years may be associated with a 67% increase in total stroke occurrence and a 15% increase in events associated with coronary heart disease. Clinicians should strive to avoid excessive use of NSAID treatment and consider alternative, well-tolerated therapeutic options, including simple analgesics and physical therapy. For patients who require concomitant NSAID and antihypertensive treatment, clinicians should be aware of the greater hypertensive effect of indomethacin and piroxicam compared with alternative NSAIDs, and the potential for relatively greater antagonism by NSAIDs of the BP-lowering effect of beta-blockers compared with other antihypertensives. Finally, the progress of each patient should be monitored by careful BP measurement particularly during the initiation of NSAID therapy.