leukotriene-b4 and Drug-Hypersensitivity

Topics: Animals; Anti-Inflammatory Agents; Aspirin; Central Nervous System Diseases; Cyclic AMP; Drug Hypersensitivity; Female; Gastrointestinal Diseases; Glucocorticoids; Hemostasis; Humans; Kidney; Leukotriene B4; Liver; Mice; Nutrition Disorders; Pregnancy; Prostaglandins; Puerperal Disorders; Thrombosis; Thromboxanes

Although the mechanism of aspirin-induced asthma and rhinitis is unknown, it has been suggested that adverse nasal and bronchial reactions are caused by an increased production of lipoxygenase products. In examining this hypothesis we have measured the release of peptide leukotrienes (PeptLTs), 15-HETE, and prostaglandins in nasal fluids obtained by nasal lavages after instillation of acetylsalycilic acid (ASA) and placebo (saline). Ten ASA-sensitive asthmatics, 10 ASA-insensitive asthmatics, and seven healthy subjects were challenged in a double-blind study with normal saline and 12 mg of ASA. Twelve mg were administered based on the results of a previous study that showed that this dose caused minor to moderate symptoms in ASA-sensitive patients. PeptLTs, LTB4, 15-HETE, PGE2, PGF2 alpha, and PGD2 were measured by radioimmunoassay methods. Significant levels of PeptLTs were detected in sensitive asthmatic patients 60 min after nasal challenge. This change was associated with a significant increase in symptoms. No increase in PeptLTs levels were found, however, in either insensitive patients or healthy subjects. Inhibition of PGE2 and PGF2 alpha release was detected in the three groups after ASA administration. ASA also inhibited PGD2 release in insensitive asthmatic patients but not in both sensitive patients and healthy subjects. These results suggest that an abnormal release of PeptLTs in ASA-sensitive asthmatic patients contributes to nasal and bronchial adverse reactions. The lack of effects on PGD2 release suggests that mast cells from ASA-insensitive patients are more sensitive to ASA than those from sensitive asthmatic patients and healthy subjects.

Topics: Administration, Intranasal; Adult; Albumins; Aspirin; Asthma; Dinoprost; Dinoprostone; Drug Hypersensitivity; Female; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Leukotrienes; Male; Middle Aged; Nasal Mucosa; Prostaglandin D2

Aspirin-exacerbated respiratory disease (AERD) is characterized by severe, sometimes life-threatening reactions to nonsteroidal anti-inflammatory drugs (NSAIDs). Mechanisms driving the disease include overproduction of leukotrienes and loss of anti-inflammatory prostaglandin E. To investigate the capacity of aspirin and NSAIDs to drive eosinophil activation and the ability of PGE. Eosinophils were purified from blood of healthy individuals without AERD and stimulated with lysine aspirin, ketorolac, or sodium salicylate. The role of PGE. Stimulation of eosinophils with lysine aspirin, ketorolac, or sodium salicylate resulted in secretion of CysLTs and LTB. Eosinophils can be directly activated by NSAIDs via cyclooxygenase-independent pathways to produce CysLTs and LTB

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cells, Cultured; Cysteine; Dinoprostone; Drug Hypersensitivity; Eosinophils; Humans; Ketorolac; Leukotriene B4; Leukotrienes; Lysine; Sodium Salicylate

A diagnosis of aspirin-intolerant asthma requires aspirin provocation in specialist clinics. Urinary leukotriene E(4) (LTE(4)) is increased in aspirin-intolerant asthma. A study was undertaken to investigate new biomarkers of aspirin intolerance by comparing basal levels of cysteinyl-leukotrienes (CysLTs) and leukotriene B(4) (LTB(4)) in saliva, sputum and ex vivo stimulated blood in subjects with aspirin-intolerant and aspirin-tolerant asthma. The effects of aspirin- and allergen-induced bronchoconstriction on leukotriene levels in saliva and ex vivo stimulated blood were also compared with the effects of the provocations on urinary mediators.. Induced sputum, saliva, urine and blood were obtained at baseline from 21 subjects with asthma. At a separate visit, 11 subjects showed a positive response to lysine-aspirin inhalation and 10 were aspirin tolerant. Saliva, blood and urine were also collected on the provocation day. Analyses of CysLTs and LTB(4) and the prostaglandin D(2) metabolite 9alpha,11beta-prostaglandin F(2) were performed and the fraction of exhaled nitric oxide was measured.. Subjects with aspirin-intolerant asthma had higher exhaled nitric oxide levels and higher baseline levels of CysLTs in saliva, sputum, blood ex vivo and urine than subjects with aspirin-tolerant asthma. There were no differences in LTB(4) levels between the groups. Levels of urinary LTE(4) and 9alpha,11beta-prostaglandin F(2) increased after aspirin provocation whereas leukotriene levels in saliva and ex vivo stimulated blood did not increase.. These findings support a global and specific increase in CysLT production in aspirin-intolerant asthma. Measurement of CysLTs in saliva has the potential to be a new and convenient non-invasive biomarker of aspirin-intolerant asthma.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Biomarkers; Cysteine; Dinoprost; Drug Hypersensitivity; Female; Humans; Leukotriene B4; Leukotrienes; Male; Middle Aged; Saliva; Sputum; Uteroglobin

Immunoallergological studies were carried out to clarify the differences between 24 patients with drug-induced asthma (DIA) and 240 with non-drug-induced asthma (non-DIA). The mean values of age, skin reaction to Candida albicans (C. albicans), serum IgE levels, specific IgE antibodies to house dust (HD) and C. albicans, bronchial sensitivity and leukotriene B4 (LTB4) synthesis from peripheral venous blood in patients with DIA were not significantly different from those in patients with non-DIA. In contrast, the frequency of positive skin reaction to HD and histamine release from peripheral basophils by anti-IgE were significantly lower in DIA than in non-DIA. These results agree with the reports that DIA was often observed in non-atopic asthma. But, the mean value of serum IgE was very high in DIA as well as in non-DIA. This result suggests that IgE mediated reaction in DIA is important. Furthermore, the proportion of neutrophils in bronchoalveolar lavage fluid (BALF) was significantly lower in DIA than in non-DIA. Our findings suggest that a decrease of intrapulmonary neutrophils might play an important role in the pathophysiology of DIA.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies; Asthma; Bronchi; Bronchoalveolar Lavage Fluid; Candida albicans; Child; Child, Preschool; Drug Hypersensitivity; Dust; Female; Histamine Release; Humans; Immunoglobulin E; Immunoglobulin M; Leukotriene B4; Male; Methacholine Chloride; Middle Aged; Radioallergosorbent Test; Retrospective Studies; Skin Tests

The levels of leukotriene C4 (LTC4), leukotriene B4 (LTB4), prostaglandin E2 (PGE2), and histamine were measured in nasal lavage fluids obtained from aspirin-sensitive, desensitized aspirin-sensitive, and aspirin-insensitive asthmatics and normal volunteers before and after ingestion of aspirin. Increased levels of LTC4 and histamine were associated with significant decreases in the FEV1 for 3 of 4 aspirin-sensitive asthmatics who had both naso-ocular and bronchospastic reactions to aspirin. In contrast, no increase in LTC4 or histamine release was detected in aspirin-sensitive asthmatics who had only bronchospastic reactions to aspirin. No significant decreases in PGE2 levels or increases in LTB4 levels were detected during these reactions to relatively low doses of aspirin regardless of the clinical symptoms, nor was any increase in mediator release apparent in lavage fluids from normal donors, aspirin-insensitive asthmatics, and desensitized aspirin-sensitive subjects before or after various doses of aspirin. Levels of PGE2 decreased in nasal secretions from normal volunteers, aspirin-insensitive asthmatics, and desensitized aspirin-sensitive subjects after ingestion of 650 mg of aspirin. These decreases were not associated with increased LTC4 or LTB4 or with histamine release, decreased FEV1, or naso-ocular symptoms. In addition, reductions of PGE2 release were similar for normal and desensitized aspirin-sensitive volunteers (63 +/- 11 versus 61 +/- 10%, respectively). The data demonstrate that LTC4 and histamine are released into nasal secretions of aspirin-sensitive asthmatics with naso-ocular and bronchospastic reactions after ingestion of low doses of aspirin without a decrease in the levels of PGE2 and suggest that LTC4 and histamine contribute to the naso-ocular and bronchospastic symptoms characteristic of reactions to aspirin.

Topics: Adult; Aspirin; Asthma; Dinoprostone; Drug Hypersensitivity; Female; Forced Expiratory Volume; Histamine Release; Humans; Leukotriene B4; Male; Middle Aged; Nasal Mucosa; Prostaglandins E; Reference Values; SRS-A

A constant enigma has been the ability of aspirin and other structurally unrelated nonsteroidal anti-inflammatory drugs to induce non-IgE mediated allergic reactions. These reactions range from mild hypersensitivity to fatal anaphylaxis. Recent biochemical and pharmacologic studies involving the oxidative metabolism of arachidonic acid in different cells and tissues have provided insights into how this could conceivably occur. The products of cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism and their interactions may provide an approach, if not the solution, to the problem of aspirin intolerance.

Topics: Anti-Inflammatory Agents; Arachidonic Acid; Arachidonic Acids; Aspirin; Blood Platelets; Cyclooxygenase Inhibitors; Drug Hypersensitivity; Drug Tolerance; Humans; Hydroxyeicosatetraenoic Acids; Leukocytes; Leukotriene B4; Leukotrienes; Lipoxygenase; Prostaglandin-Endoperoxide Synthases; SRS-A

Intradermal injections of 1-50 pmol leukotriene B4, C4, D4 and E4, (LTB4, LTC4, LTD4 and LTE4) were performed in healthy subjects and patients with recurrent urticaria. A wheal and erythema were seen 15 minutes after injection and were most marked after LTC4 and LTD4. LTE4 also produced a wheal whereas the reaction to LTB4 did not significantly differ from the saline control. When mixed with histamine no potentiation of the wheals was noted and no significant difference in reaction was observed between the healthy controls and those with urticaria.

Topics: Drug Hypersensitivity; Erythema; Histamine; Humans; Intradermal Tests; Leukotriene B4; Leukotriene E4; Male; Skin; SRS-A; Urticaria