A 1-Day, 90-Minute Aspirin Challenge and Desensitization Protocol in Aspirin-Exacerbated Respiratory Disease.

BACKGROUND: Aspirin challenge and desensitization remains the criterion standard in diagnosis and treatment for patients with aspirin-exacerbated respiratory disease (AERD), but the protocols can be time and resource intensive. OBJECTIVE: To provide evidence that oral aspirin challenge and desensitization can be safely performed in an outpatient setting in 1 day. METHODS: Forty-four patients with a confirmed diagnosis of AERD, stable asthma, and baseline FEV1 value greater than or equal to 70% of predicted completed an oral aspirin challenge and desensitization protocol. The starting dose was 40.5 mg with escalating doses of aspirin (81, 162.5, 325 mg) at 90-minute intervals until symptoms were provoked. Desensitization was defined as tolerating a repeated administration of the provocative aspirin dose and at least 1 subsequent dose, bringing the total aspirin ingested during the in-clinic desensitization to 325 mg or more. RESULTS: Ninety-three percent of patients completed the challenge and desensitization in 1 day, with an average protocol completion time of 9 hours and 29 minutes. Two patients (4.6%) chose to complete the protocol over 2 days. One patient (2.3%) was discontinued from the protocol because of ongoing abdominal discomfort and diarrhea. No patient required epinephrine, emergency department visit, or hospitalization. CONCLUSIONS: Patients with AERD on a stable asthma regimen and with a baseline FEV1 value greater than or equal to 70% can be safely desensitized to aspirin using a 90-minute dose escalation protocol, starting at a dose of 40.5 mg, and defining desensitization as tolerance of the repeated provocation dose and at least 1 subsequent aspirin dose, bringing total cumulative daily dose to 325 mg or more. This protocol can routinely be completed in 1 day.

Blockade of the renin-angiotensin system prevents acute and immunologically relevant colitis in murine models.

BACKGROUND: Blockade of the renin-angiotensin system (RAS) has been shown to alleviate inflammatory processes in the gastrointestinal tract. The aim of this study was to determine if blockade of the RAS would be effective in an immunologically relevant colitis model, and to compare outcome with an acute colitis model. METHODS: A losartan analog, CCG-203025 (C23H26ClN3O5S) containing a highly polar sulfonic acid moiety that we expected would allow localized mucosal antagonism with minimal systemic absorption was selected as an angiotensin II type 1a receptor antagonist (AT1aR-A). Two colitis models were studied: (1) Acute colitis was induced in 8- to 10-week-old C57BL/6J mice by 2.5 % dextran sodium sulfate (DSS, in drinking water) for 7 days. (2) IL10-/-colitis Piroxicam (200 ppm) was administered orally in feed to 5-week-old IL-10-/-mice (C57BL/6J background) for 14 days followed by enalaprilat (ACE-I), CCG-203025 or PBS administered transanally for 14 days. RESULTS: In the DSS model, weight loss and histologic score for CCG-203025 were better than with placebo. In the IL10-/-model, ACE-I suppressed histologic damage better than CCG-203025. Both ACE-I and CCG-203025 reduced pro-inflammatory cytokines and chemokines. CONCLUSIONS: This study demonstrated the therapeutic efficacy of both ACE-I and AT1aR-A for preventing the development of both acute and immunologically relevant colitis.

Immunopathogenesis of tuberculosis and novel mechanisms of vaccine activity.

The 4th Global Forum on TB Vaccines, convened in Shanghai, China, from 21 - 24 April 2015, brought together a wide and diverse community involved in tuberculosis vaccine research and development to discuss the current status of, and future directions for this critical effort. This paper summarizes the sessions on Immunopathogenesis of Tuberculosis, and Immunopathogenesis and Novel Mechanisms of Vaccine Activity. Summaries of all sessions from the 4th Global Forum are compiled in a special supplement of Tuberculosis.

Aspirin sensitivity and coronary artery disease: implications for the practicing cardiologist.

Aspirin is the most commonly used antiplatelet agent in patients with coronary artery disease (CAD). It continues to play a key role as an antiplatelet agent given its long-term safety, efficacy and low cost. Aspirin or NSAID hypersensitivity is not an uncommon occurrence and can vary from generalized urticaria and angioedema to exacerbation of upper and lower respiratory tract reactions. It is not uncommon for clinicians to avoid using aspirin and alternative agents when encountering aspirin hypersensitivity among CAD patients. However, given the critical role of aspirin in CAD patients, particularly among those who receive the drug-eluting stents, aspirin desensitization can be useful. This article highlights the importance of aspirin desensitization, the mechanism and the process involved. We draw attention to recently described rapid desensitization protocols and how they can be more useful than the old procedure.

Safety of parecoxib in patients with nonsteroidal anti-inflammatory drug-induced urticaria or angioedema.

BACKGROUND: Parecoxib is the first injectable cyclooxygenase 2 selective inhibitor indicated for the treatment of acute postoperative pain. OBJECTIVE: To describe the results of a challenge with parecoxib in patients with a history of urticaria or angioedema to 1 or more nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: The study was performed from October 1, 2006, through March 31, 2007, with 79 patients who historically had experienced urticaria or angioedema after use of NSAIDs. The patients underwent a single-blind challenge with parecoxib, 40 mg. RESULTS: No reaction to placebo was observed in any patient. Similarly, no reaction to parecoxib was observed in any patients in the single-class or multiple-class intolerance group. CONCLUSION: Our report demonstrates that parecoxib does not induce cross-reactivity in patients with a history of urticaria or angioedema. Hence, this finding suggests that this drug could be safely proposed as an alternative (but only after a prior challenge) in patients with previous hypersensitive reactions to NSAIDs, even if there are added risk factors such as atopy and antimicrobial allergy, who require an analgesic drug perioperatively.

The effects of non-steroidal anti-inflammatory drug application on incisional wound healing in rats.

OBJECTIVE: There is evidence that non-steroidal anti-inflammatory drugs (NSAIDs) delay both epithelialisation and angiogenesis in the early phases of wound healing because of an antiproliferative effect. We investigated the influence of diclofenac, a non-selective NSAID, on incisional wound healing. METHOD: Ten male Wistar rats were given 5 mg diclofenac per kg bodyweight per day; 10 rats were given placebo pellets. After 10 days, unimpaired healing occurred independently of drug treatment both macroscopically and microscopically. Histomorphometry revealed a significant reduction (p = 0.006) in fibroblasts after diclofenac application (median 3 166 cells per mm2) compared with the placebo group (median 3940 cells per mm2). Epidermal thickness was not statistically different between the two groups. RESULTS: Diclofenac diminished the amount of fibroblasts in connective tissue, reflecting the known antiproliferative effect of NSAIDs on fibroblasts. Clinical healing was not affected. CONCLUSION: We recommend short-term diclofenac application for post-surgical and post-traumatic patients with wounds who would benefit from its antiphlogistic and analgesic effect. However, if wound healing is disturbed, the negative effect of diclofenac on fibroblasts should be considered. This is particularly relevant for patients with chronic wounds or conditions such as diabetes which can delay wound healing.

Etoricoxib tolerability in patients with hypersensitivity to nonsteroidal anti-inflammatory drugs.

BACKGROUND: Adverse reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly observed, particularly among patients with chronic urticaria or asthma. The identification of a safe and reliable alternative is a frequent problem in clinical practice. Our aim was to investigate the clinical tolerability of etoricoxib, a new selective cyclooxygenase-2 inhibitor, in a group of patients with well-established NSAID hypersensitivity. METHODS: We assessed 31 adults (21 women and 10 men) who reported one or more adverse reactions to NSAIDs, manifested as cutaneous, respiratory or anaphylactic symptoms. Sixteen of them reported reactions to a single NSAID (single reactors) and 15 to more than one NSAID (multiple reactors); the most frequently involved drug was acetylsalicylic acid. First, each patient underwent allergologic tests (skin and/or oral challenge tests) with culprit NSAIDs and then tolerability tests with increasing doses of etoricoxib up to 120 mg. All challenges were performed under single-blind, placebo-controlled conditions. RESULTS: NSAID hypersensitivity was diagnosed in all 31 patients: 3 displayed positive results to pyrazolone skin tests and the other 28 to challenges with culprit NSAIDs. None reacted to either placebos or etoricoxib. CONCLUSIONS: Etoricoxib seems to be a safe alternative for patients with well-demonstrated NSAID hypersensitivity.

Clinical and pathologic perspectives on aspirin sensitivity and asthma.

Aspirin and other nonsteroidal anti-inflammatory drugs that inhibit COX-1 induce unique nonallergic reactions, consisting of attacks of rhinitis and asthma. These hypersensitivity reactions occur in a subset of asthmatic subjects, thus identifying them as having this exclusive clinical presentation. We refer to these patients as having aspirin-exacerbated respiratory disease, a disease process that produces devastating eosinophilic inflammation of both the upper and lower respiratory tracts. This review focuses on a description of patients with aspirin-exacerbated respiratory disease, methods available to diagnose their condition, the unique ability of all nonsteroidal anti-inflammatory drugs that inhibit COX-1 to cross-react with aspirin, an update on pathogenesis, and current thoughts about treatment.

A combination of a transforming growth factor-beta antagonist and an inhibitor of cyclooxygenase is an effective treatment for murine pulmonary tuberculosis.

Transforming growth factor-beta (TGF-beta) and prostaglandins (PG) regulate the cell-mediated immune response, so it has been proposed that they affect the progression of pulmonary tuberculosis. Here we report that the administration of soluble betaglycan, a potent TGF-beta antagonist, and niflumic acid, a PG synthesis inhibitor, during the chronic phase of experimental murine tuberculosis enhanced Th1 and decreased Th2 cytokines, increased the expression of iNOS and reduced pulmonary inflammation, fibrosis and bacillary load. This immunotherapeutic approach resulted in significant control of the disease comparable to that achieved by anti-microbial treatment alone. Importantly, the combination of immunotherapy and anti-microbials resulted in an accelerated clearance of bacilli from the lung. These results confirm that TGF-beta and PG have a central pathophysiological role in the progression of pulmonary tuberculosis in the mouse and suggest that the addition of immunotherapy to conventional anti-microbial drugs might result in improved treatment of the disease.

Short-term tolerability of etoricoxib in patients with cutaneous hypersensitivity reactions to nonsteroidal anti-inflammatory drugs.

BACKGROUND: Etoricoxib is a novel cyclooxygenase 2 selective inhibitor. Until now, there has not been information in the literature about its tolerability in patients with a history of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs). OBJECTIVE: To determine the short-term tolerability of etoricoxib in patients with a history of cutaneous adverse reactions to NSAIDs. METHODS: Single-blind challenge testing was performed on 2 different days using placebo (talc) and etoricoxib. On the first day, 2 placebo capsules were administered 1 hour apart; 7 days later, each patient received divided doses of the total therapeutic dose of 90 mg of etoricoxib: 22.5 mg initially and 67.5 mg 1 hour later if no reactive symptoms were noted. RESULTS: Of 141 patients who underwent challenge testing with etoricoxib, only 2 (1.4%) had positive test results; both developed wheals on the extremities. These 2 patients were treated with chlorpheniramine maleate (10 mg intravenously), and the symptoms completely resolved within 2 hours. None of the patients experienced adverse reactions to the placebo challenge. CONCLUSION: The low rate of adverse reactions to etoricoxib, tested by oral challenge, suggests that patients with previous cutaneous hypersensitivity reactions to NSAIDs (primarily urticaria and angioedema) may tolerate this drug.

Prostanoids as friends, not foes: further evidence from the interference by cycloxygenase-inhibitory drugs when inducing tolerance to experimental arthritigens in rats.

Pharmacologists have generally been prejudiced against prostanoids, uncritically accepting their suppression as desirable therapy, especially for 'quick-fix' analgesia. This myopic perception for a long time ignored (a) the essentiality of prostanoid precursors in nutrition, (b) the physiological protective functions of natural prostaglandins (PGs) (vasculature, stomach, kidney), (c) resolution of inflammation after the expression of COX-2 and (d) increasing therapeutic use of either synthetic PGs (for erectile dysfunction, ophthalmic disorders, inducing parturition, etc) or their natural precursors, e.g., omega3-rich polyunsaturated oils, to treat arthritis. Experimental studies in rats have indicated that prostaglandins (E series) are (i) useful, perhaps auto-regulators of established immunoreactivity and (ii) able to amplify (or even induce) anti-inflammatory activity with other agents. Furthermore, anti-prostanoid therapy (APT) can be arthritigenic!!, interfering with the acquisition of tolerance to some arthritigens. For patients with rheumatoid arthritis this additional side-effect of APT, barely recognised to date, may actually perpetuate their arthritis by impairing prostanoid-mediated remission processes. Hopefully, recent adverse publicity about COX-2 inhibitory drugs might stimulate serious re-assessment of some traditional anti-inflammatory therapies with low APT activity for the management of both acute pain (non-addictive cannabinoids, celery seed, etc.) and chronic inflammation, e.g., Lyprinol (a mussel lipid extract).

The effects of Celecoxib on inflammation and synovial microcirculation in murine antigen-induced arthritis.

OBJECTIVE: There is controversy about the effects of cyclooxygenase-2 (COX-2) on adhesion molecules and the microvasculature in inflamed tissue. Thus, the aim of this study was to assess COX-2-expression in Antigen-induced Arthritis (AiA) and to investigate the effects of selective COX-2 inhibition by Celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide) (CXB), on synovial microcirculation and adhesion molecule expression in arthritic as well as healthy mice. METHODS: Balb/c mice were allocated to 4 groups; 2 control groups with saline or CXB and 2 groups with AiA which also received saline or CXB (30 mg/kg BW in 0.3 ml solution). The severity of arthritis was assessed by changes in the transverse joint diameter On day 14 after AiA-induction, the patella tendon of the left knee joint was microsurgically resected and intravital fluorescence microscopy on synovial tissue was performed. Finally, the knee joint was removed for histology and immunohistochmistry. RESULTS: COX-2-expression in the inflamed synovium was demonstrated by immunohistochemistry. Application of Celecoxib resulted in a significant reduction in the rolling leukocyte fraction as well as in the number of leukocytes adherent to the endothelium (0.25 +/- 0. 1 and 96 +/- 34 cells/mm2 respectively) in comparison to the untreated animals with AiA (0.44 +/- 0.03 and 206 +/- 22 cells/mm2 respectively). Additionally, CXB-treated arthritic animals showed significantly less knee joint swelling and reduced adhesion molecule expression. CONCLUSION: In the present study, COX-2 expression in the synovial tissue of mice with AiA could be demonstrated. Selective COX-2 inhibition with CXB resulted in reduced leucocyte-endothelial cell interactions and decreased adhesion molecule expression. Evidence for a protective role of COX-2 in mouse AiA was not found.

Aspirin sensitivity: implications for patients with coronary artery disease.

CONTEXT: Although acetylsalicylic acid (aspirin) is commonly used for patients with chronic cardiovascular disease, a minority of patients have a sensitivity to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs. OBJECTIVE: To provide a diagnostic strategy for evaluating and treating patients with aspirin sensitivity, with additional consideration for issues specific to patients with coronary artery disease (CAD). EVIDENCE ACQUISITION: Published articles were identified through a search of MEDLINE and the Cochrane databases using the dates 1966 to June 2004 and the search terms aspirin allergy, coronary artery disease, aspirin desensitization, and aspirin sensitivity. References of retrieved articles were also reviewed for pertinent studies. Articles were included in this review if they were controlled studies, published in the English language, and appeared in a peer-reviewed journal. EVIDENCE SYNTHESIS: The prevalence of aspirin-exacerbated respiratory tract disease is approximately 10% and for aspirin-induced urticaria the prevalence varies from 0.07% to 0.2% of the general population. Aspirin sensitivity is most often manifested as rhinitis and asthma or urticaria/angioedema induced by cross-reacting nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase 1. The primary mechanism of sensitivity is less often related to drug-specific IgE antibody production leading to urticaria/angioedema and rarely to anaphylaxis. Most patients with acetylsalicylic acid sensitivity are able to undergo desensitization therapy safely and successfully except in cases of chronic idiopathic urticaria. However, there have not been any randomized trials that specifically focus on the efficacy of aspirin desensitization. Furthermore, experience with acetylsalicylic acid desensitization in patients with CAD is very limited. After successful desensitization, acetylsalicylic acid therapy must be indefinitely continued to prevent resensitization. CONCLUSIONS: Acetylsalicylic acid sensitivity is common and desensitization can be performed safely in many patients. Large-scale trials are warranted to determine the safety and efficacy of acetylsalicylic acid desensitization therapy in patients with concomitant CAD because data are currently limited to small case series.

Immune tolerance to drugs. (II).: Long-term tolerability of nimesulide in patients with NSAID hypersensitivity.

Nimesulide is well-tolerated as an alternative to nonsteroidal antiinflammatory drugs (NSAIDs) in patients with a previous adverse reaction to other classes of NSAIDs. However, there is little information in the literature about its long-term tolerability. The study was carried out on 625 patients who had experienced adverse reactions to one or more NSAIDs. All patients received and tolerated peroral challenges with nimesulide. On the first day, patients were given an equivalent number of placebo doses to the planned number of nimesulide doses. In a successive session, the test was administered by means of increasing doses of nimesulide at 30 min intervals until the common daily therapeutic dose of 100 mg was reached (10 mg-20 mg-30 mg-40 mg). A questionnaire was distributed to all subjects. In particular, they were asked to clarify any reactive symptoms they had developed after ingestion of the drug. It was found that only 2.1% (4/192) of subjects who were given this drug experienced urticaria during treatment. We have identified three significant risk factors: a history of chronic urticaria, a history of antibiotic hypersensitivity and a history of hypersensitivity to more than one class of NSAIDs. In patients with the above risk factors, a prior tolerance test with a selective COX2 antagonist should be administered.

Synergistic anti-inflammatory activity of omega-3 lipid and rofecoxib pretreatment on macrophage proinflammatory cytokine production occurs via divergent NF-kappaB activation.

UNLABELLED: Omega-3 lipid pretreatment significantly decreases TNF-alpha production in LPS-stimulated Mphis; however, this response is only a partial inhibition, suggesting that other nonsubstrate- (lipid) dependent mechanisms are involved. The cyclooxygenase (COX)-2 enzyme is principally responsible for lipid metabolism; thus, a selective COX-2 inhibitor (Rofecoxib) would clarify if it is an omega-3 lipid direct effect or a COX-2 enzyme-associated modulated reduction in TNF-alpha. Moreover, potential synergy between omega-3 lipids and selective COX-2 inhibition is postulated. HYPOTHESIS: Through divergent regulatory mechanisms, omega-3 lipids in combination with Rofecoxib will synergistically decrease the LPS-stimulated Mphi inflammatory response. METHODS: RAW 264.7 cells were pretreated with omega-3 lipids, Rofecoxib, or combination treatment and then washed and exposed to LPS. Supernatants were collected for ELISA, total proteins were obtained to determine COX-2 protein expression by Western blot, and nuclear extracts were isolated to determine NF-kappaB activation by electromobility shift assay. RESULTS: TNF-alpha and PGE2 production was significantly decreased with omega-3 and Rofecoxib pretreatment, and with combination treatment a further decrease in TNF-alpha production was observed. COX-2 protein expression was demonstrated to increase in omega-3, Rofecoxib, and combination groups stimulated with LPS. No alteration in NF-kappaB activation was observed with Rofecoxib or combination pretreatment compared with LPS-stimulated control cells. Repletion of prostaglandin (PGE2) in the Mphi model significantly decreased TNF-alpha in all groups. CONCLUSIONS: Omega-3 lipids and Rofecoxib independently decrease TNF-alpha and PGE2 production in LPS-stimulated Mphi, yet in combination a synergistic reduction in TNF-alpha production is observed. Although the anti-inflammatory effects observed from omega-3 lipids are known to occur partially through decreasing NF-kappaB activation, we demonstrated that Rofecoxib or even a combination of omega-3 and Rofecoxib does not alter NF-kappaB activation, as seen with omega-3 lipids alone. These data support that combination treatment may result in decreased Mphi inflammation, yet this occurs via divergent mechanisms.