dinoprost and Drug-Hypersensitivity

Drugs can interfere with the immune system in two basically different ways: (1) they may interact with the specific recognition mechanisms of the immune system and thus induce an allergic response that is specific for the offending agent; (2) drugs may exert pharmacological effects on the immune systems which result in a response that is independent of its recognition structures or they may activate effector and amplification mechanisms that are normally triggered by specific immune processes. Allergic reactions to drugs are different from reactions that exhibit the same clinical symptoms but lack the specificity of an allergic reaction to the offending agent. It has been suggested that those non-specific reactions which mimic the signs and symptoms of allergic reactions should be classified as pseudo-allergic reactions (PAR). PAR are characterized by the following properties which differentiate them from allergic reactions. (1) The symptoms of PAR are qualitatively different from the pharmacological response of a drug and are not related to adverse reactions connected with its pharmacological and toxicological profile. (2) PAR are not specific with regard to the chemical structure of the triggering agent. (3) PAR lack transferability to other subjects of the same species. (4) In contrast to the allergic reactivity, the pseudo-allergic reactivity is not acquired but genetically predetermined. (5) Pseudo-allergic reactivity is often expressed upon the first contact with an eliciting agent. PAR are thus an expression of a pharmacological interaction of drugs or their metabolites in genetically predisposed individuals.

Topics: Anaphylaxis; Aspirin; Complement Activation; Complement System Proteins; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Drug Hypersensitivity; Epitopes; Female; Histamine; Histamine Release; Humans; Immunosuppression Therapy; Lupus Erythematosus, Systemic; Prostaglandins E; Prostaglandins F

Topics: Adolescent; Anaphylaxis; Anti-Inflammatory Agents, Non-Steroidal; Dinoprost; Drug Hypersensitivity; Female; Humans; Leukotriene E4; Prostaglandin D2; Salicylamides

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can precipitate adverse reactions in two apparently different clinical conditions: bronchial asthma and chronic idiopathic urticaria (CIU). Recent evidence indicates that the reactions are triggered by the drugs that inhibit cyclooxygenase-1 but not cyclooxygenase-2.. To assess whether patients with CIU and aspirin sensitivity share common eicosanoid alterations with patients who have aspirin-sensitive asthma.. Seventy-four patients with CIU and a history of sensitivity to aspirin and NSAIDs underwent placebo-controlled oral aspirin challenge tests. Concentrations of urinary leukotriene E4 (uLTE4) were measured by ELISA and plasma stable prostaglandin D2 metabolite, 9alpha,11beta prostaglandin F(2) by GC/MS. All measurements were carried out at baseline and after aspirin dosing. Patients were genotyped for the leukotriene C4 synthase (LTC4S) promoter single nucleotide polymorphism.. In 30 of 74 patients, the aspirin challenge was positive, resulting in urticaria/angioedema. In these 30 patients, baseline uLTE4 levels were higher than in nonresponders and the healthy control subjects and increased further (significantly) after the onset of clinical reaction. No such increase occurred in subjects with negative aspirin challenge. Baseline uLTE4 levels correlated with severity of skin reactions. Plasma 9alpha,11beta prostaglandin F(2) levels rose significantly in both aspirin responders and nonresponders, although in the latter group the increase occurred later than in the former. In patients who reacted to aspirin, frequency of (-444)C allele of LTC4S was significantly higher than in patients who did not react.. CIU with aspirin sensitivity is characterized by the eicosanoid alterations, which are similar to those present in aspirin-induced asthma.

Topics: Adult; Alleles; Aspirin; Asthma; Dinoprost; Drug Hypersensitivity; Eicosanoids; Female; Genotype; Glutathione Transferase; Humans; Leukotriene E4; Male; Middle Aged; Polymorphism, Single Nucleotide; Single-Blind Method; Urticaria

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

The role of arachidonic acid metabolites in NSAID-induced hypersensitivity has been studied in depth for NSAID-exacerbated respiratory disease (NERD) and NSAID-exacerbated cutaneous disease (NECD). However, no information is available for NSAID-induced urticarial/angioedema (NIUA), despite it being the most frequent clinical entity induced by NSAID hypersensitivity. We evaluated changes in leukotriene and prostaglandin metabolites for NIUA patients, using patients with NECD and single-NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA) for comparison.. Urine samples were taken from patients with confirmed NSAID-induced urticaria and healthy controls, at baseline and at various time intervals after ASA administration. Eicosanoid measurement was performed using high-performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry.. No differences were found between groups at baseline. Following ASA administration, LTE4 and 9α,11β-PGF2 levels were increased in both NIUA and NECD patients compared to baseline, rising initially, before decreasing toward initial levels. In addition, the levels of these metabolites were higher in NIUA and NECD when compared with the SNIUAA and control groups after ASA administration. No changes were found with respect to baseline values for SNIUAA and control groups.. We present for the first time data regarding the role of COX-1 inhibition in NIUA. Patients with this entity show a similar pattern eicosanoid levels following ASA challenge to those with NECD. Further studies will help ascertain the cell populations involved and the underlying molecular mechanisms.

Topics: Administration, Oral; Adolescent; Adult; Anaphylaxis; Angioedema; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Dinoprost; Drug Hypersensitivity; Eicosanoids; Female; Humans; Leukotriene E4; Male; Middle Aged; Phenotype; Young Adult

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

Topics: Adult; Aspirin; Asthma; Dinoprost; Drug Hypersensitivity; Female; Humans; Hypergammaglobulinemia; Immunoglobulin E; Male; Middle Aged; Prostaglandins E; Prostaglandins F

Six out of eight patients with a history of aspirin-provoked urticaria/angioedema responded with adverse reactions, including urticaria and bronchospasm, to provoking doses of oral aspirin from 30-515 mg. The other two patients did not react to 1.2 g of aspirin on three occasions. Five of the six patients who had reacted became desensitized after their initial aspirin reaction, tolerating 650 mg on the second day. They then took 650 mg day-1 of aspirin for three weeks, during which time the ingestion of foods which had previously caused a variety of moderate or severe reactions caused no symptoms. The resting plasma PGF2 alpha in ten 'aspirin-sensitive' urticaria patients (24.89 +/- 2.79 pg m-1) was significantly higher than the levels in ten normal subjects (6.75 +/- 1.1 pg ml-1) (P less than 0.01). In the patient group the lowest levels of PGF2 alpha were found in the two patients who subsequently did not experience a positive reaction after aspirin provocation. The PGF2 alpha/PGE2 ratio in 'aspirin-sensitive' urticaria patients (1.83 +/- 0.026) was significantly higher than that in normal subjects (0.63 +/- 0.14) (P less than 0.01).

Topics: Adolescent; Adult; Aspirin; Dinoprost; Dinoprostone; Drug Hypersensitivity; Female; Food Hypersensitivity; Humans; Male; Middle Aged; Prostaglandins E; Prostaglandins F; Urticaria

Aspirin and many other analgesics may be hazardous for some patients with asthma. These patients, numbering approximately 10% to 15% of all asthmatics, have a clinical course that has been well characterized. The diagnosis is usually made from the history, but sometimes it requires analgesic challenge tests. The pathogenesis remains controversial. It appears that the analgesics responsible for the syndrome inhibit prostaglandin synthesis, and this action in turn causes the release of potent bronchoconstrictors such as SRS-A, histamine, or kinins. Usually, recognition of the syndrome and careful avoidance of prostaglandin synthesis inhibitors in affected patients are the two steps needed for effective management. Persistent symptoms, however, may require aminophylline, corticosteroids, and disodium cromoglycate as well. Recent developments may allow these patients to use substituted aspirin analogues or even aspirin itself under certain conditions. Further investigation of the prostaglandins may promote a better understanding of asthma.

Topics: Alprostadil; Analgesics; Aspirin; Asthma; Dinoprost; Dinoprostone; Drug Hypersensitivity; Humans; Prostaglandins; Prostaglandins E; Prostaglandins F; SRS-A

The introduction of dinoprost tromethamine (Prostin F2 Alpha) as an abortifacient in the second trimester of pregnancy represents the first clinical use of a prostaglandin. Various synthetic analogues of the naturally occurring derivatives are being employed investigationally in the treatment of peptic ulcer, hypertension, asthma, and hypercalcemia. In the United States, dinoprost tromethamine is primarily administered intra-amniotically. Despite the fact that a substantial number of patients experience allergic reactions, hypertension, bronchospasm, nausea, vomiting, cramps, and diarrhea, the efficacy and relative safety of dinoprost tromethamine establish it as superior to intra-amniotic instillation of hypertonic saline. Cervical laceration, laceration or rupture of the lower uterine segment, retention of the placenta, and hemorrhage in part reflect the intensity of uterine contraction induced by dinoprost. Experience in administration improves the therapeutic response and diminishes adverse reactions.

Topics: Abortifacient Agents; Bronchial Spasm; Diarrhea; Dinoprost; Dose-Response Relationship, Drug; Drug Evaluation; Drug Hypersensitivity; Female; Humans; Hypertension; Injections; Muscle Contraction; Myometrium; Nausea; Pregnancy; Pregnancy Trimester, Second; Prostaglandins F; Vomiting