Effective Ibuprofen Desensitization in a Patient with Myopericarditis.

To date, aspirin desensitization is employed with patients with nonsteroidal anti-inflammatory drugs (NSAIDs) exacerbated respiratory diseases (NERD) or with aspirin or NSAIDs hypersensitive patients needing a stent procedure for coronary artery disease. On the other hand, few data exist regarding aspirin desensitization in other cardiological features and particularly we haven't data on different NSAIDs desensitization. Only for NERD patients we have data on ketorolac use. We report an efficacious desensitization procedure for ibuprofen in urticaria/angioedema patient with pericarditis and myocarditis associated.

Non-steroidal anti-inflammatory drug hypersensitivity in children.

INTRODUCTION: There are rather few publications about hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAID) in the paediatric age. In this study, we aimed to assess the frequency of confirmed NSAID hypersensitivity in children with a previous reported reaction to NSAID in order to investigate the role of the drug provocation test (DPT) in the diagnostic workup and to explore the factors associated with confirmed NSAID hypersensitivity. METHODS: We conducted a retrospective analysis of the clinical files from every patient under 18 years old who attended two Portuguese paediatric allergy outpatient clinics, from January 2009 to August 2014, due to a suspected NSAID hypersensitivity. RESULTS: We included 119 patients, with a median age of nine years (P25-P75: 5-14). Ibuprofen was the commonest implicated NSAID in the patients' reports (n=94-79%). After DPT, NSAID hypersensitivity was confirmed in nine (7.6%) patients, excluded in 93 (78.2%) and was inconclusive in 17 (14.3%). In the majority (n=95-79.8%), the reaction occurred in the first 24h after intake. Eighty-four patients (70.6%) reported only cutaneous manifestations and 18 (15.1%) had systemic symptoms. Anaphylaxis represented a relative risk to NSAID hypersensitivity confirmation. No association was found for atopy and the number of previous reactions. CONCLUSION: In our study, NSAID hypersensitivity was confirmed in a small proportion of the patients with a previous reported reaction. Ibuprofen was the most implicated drug with urticaria/angio-oedema as the commonest manifestation. Anaphylaxis was associated with confirmed drug hypersensitivity. The drug provocation test was essential to establish the diagnosis.

Differential effects of chlorogenic acid on various immunological parameters relevant to rheumatoid arthritis.

Despite chlorogenic acid (CGA) being widely present in nature, particularly in the human diet, there is very little information regarding its pharmacological activities. The present investigation was carried out to investigate the antiarthritic activities of this compound in adjuvant induced-arthritis in male Wistar rats, and to explore the underlying mechanisms of actions in view of immunological responses. We observed that CGA effectively controlled the total (CD3) and differentiated (CD4 and CD8) T cells count at the dose of 40 mg/kg. We also assessed the effect on co-stimulatory molecules (CD28, CD80/86) and found that CGA efficiently suppressed CD80/86 but failed to bring any changes in the CD28 count, whereas ibuprofen (standard drug) resulted in highly significant inhibition of both. We next examined the effect on CD4⁺ T cells specific Th1/Th2 cytokines by flow cytometry and observed that CGA suppressed the Th1 cytokines in a highly significant manner but elevated Th2 cytokines with dose dependence. Results of the present investigation suggest that CGA is a potent antiarthritic agent.

[Acute eosinophilic pneumonia caused by several drugs including ibuprofen].

A 41-year-old woman took an EVE-A tablet, which contained ibuprofen, because of pyrexia over 39 degrees C. Due to continued pyrexia, she visited a physician and received cefcapene and acetaminophen under a diagnosis of cold. However, next day, she was admitted to our hospital with severe hypoxemia and pulmonary infiltrates on chest radiograph. Analysis of bronchoalveolar lavage fluid disclosed an increased proportion of 66% eosinophils. All of the lymphocyte stimulation tests for EVE-A tablet, cefcapene and acetaminophen showed positive. After the cessation of these drugs, she was successfully treated with steroids. This case was diagnosed as eosinophilic pneumonia caused by several drugs, and to our knowledge, this is the first report in Japan of ibuprofen (EVE-A tablet)-induced pneumonia.

Enantioselective immunorecognition of protein modification with optically active ibuprofen using polyclonal antibody.

Formation of covalently bound protein adducts with 2-arylpropionic acids (2-APAs) has been proposed as a possible explanation for hypersensitivity and toxic responses to chiral carboxylic acid drugs. To identify the cellular proteins chemically modified with optically active (S)-ibuprofen, we generate polyclonal antibodies by immunizing rabbits with immunogen coupled to bovine serum albumin (BSA) via the spacer of 4-aminobutyric acid. The resulting antibodies largely cross-reacted with N-alpha-(t-butoxycarbonyl)--(S)-ibuprofenyl lysine as well as with the conjuguated (S)-ibuprofen with glycine and taurine and unconjugated (S)-ibuprofen, enabling enantioselective detection of (S)-ibuprofen residues anchored on ovalbumin molecules, introduced by the reaction of the ibuprofen p-nitrophenyl ester. Furthermore, immunoblotting with an antibody allows the enantioselective detection of (S)-ibuprofen-introduced glutathione-S-transferase (GST). These results indicate that the developed method will be useful for monitoring the generation and localization of protein covalently bound with (S)-ibuprofen, which may be the cause of ibuprofen-induced toxicity.

Effect of endotoxin on ventilation and breath variability: role of cyclooxygenase pathway.

To evaluate the effects of endotoxemia on respiratory controller function, 12 subjects were randomized to receive endotoxin or saline; six also received ibuprofen, a cyclooxygenase inhibitor, and six received placebo. Administration of endotoxin produced fever, increased respiratory frequency, decreased inspiratory time, and widened alveolar-arterial oxygen tension gradient (all p < or = 0.001); these responses were blocked by ibuprofen. Independent of ibuprofen, endotoxin produced dyspnea, and it increased fractional inspiratory time, minute ventilation, and mean inspiratory flow (all p < or = 0.025). Endotoxin altered the autocorrelative behavior of respiratory frequency by increasing its autocorrelation coefficient at a lag of one breath, the number of breath lags with significant serial correlations, and its correlated fraction (all p < 0.05); these responses were blocked by ibuprofen. Changes in correlated behavior of respiratory frequency were related to changes in arterial carbon dioxide tension (r = 0.86; p < 0.03). Endotoxin decreased the oscillatory fraction of inspiratory time in both the placebo (p < 0.05) and ibuprofen groups (p = 0.06). In conclusion, endotoxin produced increases in respiratory motor output and dyspnea independent of fever and symptoms, and it curtailed the freedom to vary respiratory timing-a response that appears to be mediated by the cyclooxygenase pathway.

Development and validation of an indirect enzyme-linked immunosorbent assay (ELISA) for the nonsteroidal anti-inflammatory drug S-ibuprofen.

An indirect enzyme-linked immunosorbent assay (ELISA) was developed for the nonsteroidal anti-inflammatory drug (NSAID) S-ibuprofen. Conjugates for immunization were prepared by linking S-ibuprofen via the spacer 4-aminobutyric acid to bovine serum albumin as well as to a novel synthetic lipopeptide using the N-hydroxysuccinimide/dicyclohexylcarbodiimide method. Immunization with these immunogens was carried out in New Zealand rabbits. A poly-L-lysine-S-ibuprofen conjugate was used as a hapten-carrier for coating the surface of the microtiter plates with the hapten. Horse-radish peroxidase labeled anti-rabbit IgG served as secondary antibody using hydrogen peroxide and ABTS as substrates. The characterization of the polyclonal antiserum with compounds of analogous structure demonstrated that the antiserum possesses a very high specificity for S-ibuprofen (cross-reactivity < 0.14-1.4%). Additional cross-reactivity experiments using R-ibuprofen (cross-reactivity 50.5%), ibufenac (58%) and isopropylphenylacetic acid (6.4%) were carried out to obtain more detailed information about the antigenic recognition concerning the chiral center. The results indicated that the polyclonal antiserum possesses an additional antibody population, whose antigenic recognition did not contain the chiral center. The upper and lower limits of quantification of the developed ELISA were defined as 362 and 3.62 ng S-ibuprofen/ml, respectively, based on a 90% confidence interval.

Oral aspirin and ibuprofen increase cytokine-induced synthesis of IL-1 beta and of tumour necrosis factor-alpha ex vivo.

We investigated the effect of oral aspirin and ibuprofen on the ex vivo synthesis of interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-6, tumour necrosis factor-alpha (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) by stimulated peripheral blood mononuclear cells (PBMC) from healthy volunteers. Seven volunteers took 325 mg of aspirin daily for 14 days. Three weeks after ending aspirin medication, ex vivo IL-1 beta and TNF synthesis induced by exogenous IL-1 alpha was elevated threefold compared to the pre-aspirin value (P = 0.01 and P = 0.005, respectively). Using lipopolysaccharide (LPS) as a stimulus, no influence of oral aspirin was observed. The increase in cytokine synthesis did not parallel decreased synthesis of prostaglandin E2 (PGE2). Seven weeks after discontinuation of aspirin, cytokine and PGE-2 production returned to pre-aspirin levels. Another seven volunteers took 200 mg of ibuprofen daily for 12 days. Again, there was no effect on LPS- or Staphylococcus epidermidis-induced cytokine synthesis. However, IL-1 alpha-induced synthesis of IL-1 beta was elevated to a mean individual increase of 538% (P < 0.001) and synthesis of TNF was elevated to 270% (P < 0.001) at the end of ibuprofen medication and 2 weeks after discontinuation of ibuprofen. There were parallel increases in PGE2 and both returned to their pre-ibuprofen levels 5 weeks after stopping. Although inhibitors of cyclo-oxygenase blunt PGE2-mediated symptoms such as fever and pain, we conclude that short term use of either aspirin or ibuprofen results in a 'rebound' increase in cytokine-induced cytokine synthesis that is not observed in LPS-induced cytokines.

Lymphocyte reactivity to ex-vivo drug antigens in drug-induced hepatitis.

The diagnosis of drug-induced hepatitis is usually based on clinical criteria, with emphasis on both the temporal relationship between drug intake and liver injury and the exclusion of alternative causes. In vitro tests of lymphocyte sensitization to drugs are considered to have a low sensitivity. We investigated the possibility of detecting lymphocyte reactivity to drugs in drug-induced hepatitis by analyzing the lymphocyte proliferative responses to ex-vivo drug or metabolite antigens to improve the sensitivity of the in vitro test. Lymphocyte proliferative responses to five different concentrations of the drug and to ex-vivo drug antigens (serum collected from normal subjects after the ingestion of the drugs) were analyzed in 25 patients with a clinical diagnosis of drug-induced hepatitis, 27 healthy subjects and 10 individuals with a recent exposure to the same drugs without development of adverse drug reactions. In seven of the 25 patients, lymphocyte reactivity to drugs was detected (28%). The use of sera collected from healthy volunteers after drug intake (ex-vivo drug antigens) and the addition of a prostaglandin inhibitor to the cultures allowed the detection of lymphocyte sensitization in seven additional cases, increasing the detection ability from 28% to 56%. We suggest that the use of ex-vivo drug antigens may represent a significant contribution to the identification of the drug involved in cases of drug-induced hepatitis.

Immunologic safety of ibuprofen in rheumatoid arthritis: preliminary evidence.

Some evidence indicates that ibuprofen and other prostaglandin synthetase inhibitors may have the potential for cellular immune enhancement in addition to their anti-inflammatory activity. If this is true, treatment of rheumatoid arthritis, a disorder of presumed autoimmune pathogenesis, would present a dilemma. These agents are widely used in rheumatoid arthritis for their anti-inflammatory effects. If they are found to enhance cellular immune function, however, the disease might be stimulated over the long term, rather than suppressed. Preliminary evidence from four patients with rheumatoid arthritis show that oral ibuprofen had no significant immunologic effect during sequential "on" and "off" cycles, as assessed by the following measures: delayed hypersensitivity skin testing; lymphocyte transformation to mitogen (phytohemagglutinin) or specific antigen (Candida albicans); T-cell subsets, as determined by monoclonal antibody techniques; or production of the lymphokine, human immune interferon, in response to phytohemagglutinin or to staphylococcal enterotoxin A. Early evidence, therefore, suggests that oral ibuprofen therapy may be 'immunologically safe' in patients with rheumatoid arthritis, but investigations of large series of patients also assessing local immune reaction in diseased joints may be necessary for confirmation.

Acute adverse reactions to ibuprofen in systemic lupus erythematosus.

Three young women with systemic lupus erythematosus who were given ibuprofen for arthritis voluntarily discontinued taking the drug. On reinstitution of therapy, profound hypotension, fever, and headaches developed within hours, without other identifiable cause. A possible relationship to salicylate intolerance was considered. Because of these apparent side effects, we stress caution in the use of ibuprofen in systemic lupus erythematosus, particularly if there is any history of salicylate intolerance.

Cross-reactivity between aspirin and ibuprofen in an asthmatic--a case report.

A case of an adverse reaction occurring in a 53-year-old, aspirin-sensitive asthmatic male with nasal polyps following administration of a 400-mg ibuprofen tablet is reported. Symptoms of the adverse reaction included an urticarial rash, labored breathing, laryngeal edema and tightness of the chest. Treatment consisted of isoproterenol inhalant (self-administered), subcutaneous epinephrine 0.25 mg, intramuscular diphenhydramine hydrochloride 50 mg and intravenous hydrocortisone 250 mg. The pathogenesis of the patient's adverse reaction and the possible fole of aspirin, of other analgesics and of tartrazine in its development are discussed. The adverse reaction was not mediated immunologically but rather resulted from the prostaglandin synthetase (PGS)-inhibitor activity shared by aspirin, ibuprofen and other analgesics. Selection of an analgesic for an aspirin-sensitive patient should be based on the analgesic's PGS-inhibitor activity.