misoprostol and Asthma

Prostaglandin E2 is a potent immunomodulator that inhibits the early and late bronchoconstriction to inhaled allergen, as well as inhibiting the acute allergen-induced release of mediators into the human airway. To determine if the stable prostaglandin E agonist misoprostol could alter the late allergic formation of mediators we measured the appearance of eosinophils and key cytokines in the bronchoalveolar lavage fluid 24 h after allergen instillation.. Six atopic asthmatics underwent bronchoscopy, alveolar lavage and antigen instillation followed 24 h later by bronchoalveolar lavage. Eosinophil counts were done, together with measurements of IL-4, IL-5, eotaxin, RANTES and cysteinyl leukotrienes by immunoassay. The study was done in randomized blinded fashion while the volunteers took placebo or 600 microg of misoprostol four times a day (QID).. Misoprostol significantly decreased the appearance of IL-5 late after allergen challenge. Eotaxin levels were reduced, but not statistically significantly. Eosinophil number, RANTES, eosinophil cationic protein and cysteinyl leukotrienes were not altered by misoprostol.. Misoprostol reduces the formation of IL-5 late after allergen challenge, perhaps by inhibiting eosinophil, mast cell, and/or T lymphocyte production of IL-5. Despite decreases in IL-5 and eotaxin, eosinophils were recruited and activated by allergen.

Topics: Adult; Asthma; Blood Proteins; Bronchoalveolar Lavage Fluid; Chemokine CCL11; Chemokines, CC; Eosinophil Granule Proteins; Eosinophils; Humans; Hypersensitivity, Immediate; Interleukin-5; Leukotriene D4; Middle Aged; Misoprostol; Ribonucleases

Prostaglandins of the E series and misoprostol (a stable analogue of prostaglandin E(1)) prevent bronchoconstriction following aspirin ingestion or inhalation in subjects with aspirin sensitive asthma. A study was undertaken to investigate the influence of misoprostol on the course of aspirin induced asthma.. A double blind, crossover, randomised, placebo controlled study was performed in 17 patients with aspirin sensitive asthma (13 women) aged 26-68 years. All subjects had aspirin sensitivity confirmed by means of oral aspirin or inhaled lysine aspirin challenge. Misoprostol (Cytotec, Searle, 800 or 1600 microg daily according to individual tolerance) or placebo were administered over a period of six weeks. Morning and evening peak expiratory flow rate (PEFR), beta(2) agonist use, asthma and rhinitis severity scores, and defaecation score were measured daily. At the beginning and end of each treatment period spirometric tests were performed and blood was taken for eosinophil count. Eight subjects took misoprostol at a dose of 800 microg and nine subjects at a dose of 1600 microg daily.. No differences were seen in asthma control between misoprostol and placebo except for the rhinorrhoea score which was lower on misoprostol during the period of the study.. Misoprostol in a daily dose of 800 or 1600 microg does not significantly improve asthma control in subjects with aspirin sensitive asthma.

Topics: Adult; Aged; Anti-Asthmatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Cross-Over Studies; Dinoprostone; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Misoprostol; Peak Expiratory Flow Rate; Prostaglandins E

Misoprostol, a synthetic prostaglandin E1 analogue, has been reported to have antibronchoconstricive and antiinflammatory effects in animal studies. We investigated the effect of misoprostol on FEV1 and bronchial hyperresponsiveness (BHR) to histamine in mildly asthmatics. 14 mildly asthmatic patients were given 400 mg/day oral misoprostol. Four patients had to left the study either due to the side effects. The remaining 10 patients (all women and mean age was 33.2 +/- 3.3) underwent the histamine challenge test before and after the treatment with misoprostol. Mean values of FEV1 obtained before and after the treatment were as follows respectively: 2.79 +/- 0.17 L; 2.78 +/- 0.18 L. Mean log PC20 values were as follows respectively: 0.60 +/- 0.23 mg/ml; 0.60 +/- 0.14 mg/ml. There was no difference either in FEV1 and log PC20 values before and after the treatment with misoprostol (p > 0.05). As a result administered misoprostol has no favorable effect on expiratory flow rates and BHR in asthmatic patients.

Topics: Adult; Anti-Allergic Agents; Asthma; Bronchial Hyperreactivity; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Misoprostol; Treatment Failure

We performed a double-blind, two-phase study on protective and bronchodilator effects of prostaglandins E2 and E1 (PGE2, PGE1) and salbutamol in patients with aspirin-induced asthma (AIA). In phase 1 we assessed the effects of pretreatment with PGE2, salbutamol, or the PGE1-analogue, misoprostol, on bronchoconstriction precipitated by inhalation of L-lysine aspirin in 11 patients with AIA. PGE2 and salbutamol were inhaled at equimolar concentrations of 0.25 mumol, 5 min before the aspirin challenge, while 400 micrograms misoprostol was administered orally 1 h before challenge. PGE2 attenuated the bronchoconstrictive reactions in 10 patients, salbutamol in eight, and misoprostol in seven. The mean provocative dose of aspirin causing a 20% fall in FEV1 (PD20) decreased after PGE2 (p = 0.04) and salbutamol (p = 0.06), but only marginally after misoprostol (p = 0.25). There was a positive correlation between magnitude of the protection offered by the three compounds in individual subjects. In phase 2, we examined bronchial response to inhaled PGE2, PGE1, salbutamol, and 2% ethanol in 12 AIA patients compared with 10 aspirin-tolerant patients with asthma. AIA subjects were characterized by less pronounced and shorter bronchodilator responses. There was no correlation between the protective and bronchodilator actions of the compounds used in individual patients. Thus, inhaled PGE2 and salbutamol protect against aspirin-induced attacks of asthma through mechanisms unrelated to their bronchodilator properties. Airways of aspirin-sensitive patients with asthma demonstrate distinct bronchial reactivity.

Topics: Administration, Inhalation; Administration, Oral; Adult; Albuterol; Alprostadil; Aspirin; Asthma; Bronchi; Bronchodilator Agents; Dinoprostone; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Misoprostol; Prostaglandins E

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Caspases, Initiator; Cells, Cultured; Dinoprostone; Drug Synergism; Female; Humans; Indomethacin; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Misoprostol; Pyroptosis

Prostaglandin E₁ (PGE₁) is commonly used in obstetric practice for labor induction and cervical ripening and in treating postpartum hemorrhage; however, its use in pregnant asthmatic patients has not been studied to date. The package insert states there is an unknown causal side effect for dyspnea and bronchospasm. Other pharmacological publications have stated that bronchoconstriction may occur with the use of PGE₁. The study objective was to examine peripartum pregnant asthmatic patients who received prostaglandin E₁.. Every patient who was administered PGE₁ from January 2010 through December 2013 was prospectively recorded. The charts were retrospectively reviewed. Peripartum patients with asthma were identified and further analyzed for any evidence of an asthma exacerbation following administration of the drug.. A total of 234 of 2629 patients (8.9%) who received PGE₁ were identified as having asthma. None of the patients had any evidence of an asthma exacerbation (0 of 234; 95% confidence interval, 0-0.017). Of the 234 patients, 104 (44%) had active asthma and were receiving daily medication, and the remaining 130 patients had a medical history of asthma for which they used an inhaler on an as-needed basis. A total of 98 patients (42%) received greater than 400 μg of total dose. A post hoc statistical assessment was performed, and the study was sufficiently powered to detect any clinically meaningful increase in asthma exacerbation with PGE₁ usage, if such a risk existed.. Based on the 95% confidence interval of these data, the maximum risk for an asthma exacerbation following the use of prostaglandin E₁ is less than 2%. Although all medications administered to asthmatic patients in the peripartum period should be carefully selected, this information supports the use of prostaglandin E₁ in obstetric patients with asthma, if clinically indicated.

Topics: Administration, Intravaginal; Administration, Oral; Administration, Rectal; Adult; Asthma; Disease Progression; Drug Administration Schedule; Female; Humans; Misoprostol; Oxytocics; Patient Outcome Assessment; Peripartum Period; Pregnancy; Pregnancy Complications; Retrospective Studies; Risk Factors

Endogenous prostanoids have been suggested to modulate sensitization during experimental allergic asthma, but the specific role of prostaglandin (PG) E₂ or of specific E prostanoid (EP) receptors is not known.. Here we tested the role of EP2 signaling in allergic asthma.. Wild-type (WT) and EP2(-/-) mice were subjected to ovalbumin sensitization and acute airway challenge. The PGE2 analog misoprostol was administered during sensitization in both genotypes. In vitro culture of splenocytes and flow-sorted dendritic cells and T cells defined the mechanism by which EP2 exerted its protective effect. Adoptive transfer of WT and EP2(-/-) CD4 T cells was used to validate the importance of EP2 expression on T cells.. Compared with WT mice, EP2(-/-) mice had exaggerated airway inflammation in this model. Splenocytes and lung lymph node cells from sensitized EP2(-/-) mice produced more IL-13 than did WT cells, suggesting increased sensitization. In WT but not EP2(-/-) mice, subcutaneous administration of misoprostol during sensitization inhibited allergic inflammation. PGE₂ decreased cytokine production and inhibited signal transducer and activator of transcription 6 phosphorylation by CD3/CD28-stimulated CD4(+) T cells. Coculture of flow cytometry-sorted splenic CD4(+) T cells and CD11c(+) dendritic cells from WT or EP2(-/-) mice suggested that the increased IL-13 production in EP2(-/-) mice was due to the lack of EP2 specifically on T cells. Adoptive transfer of CD4(+) EP2(-/-) T cells caused greater cytokine production in the lungs of WT mice than did transfer of WT CD4(+) T cells.. We conclude that the PGE2-EP2 axis is an important endogenous brake on allergic airway inflammation and primarily targets T cells and that its agonism represents a potential novel therapeutic approach to asthma.

Topics: Adoptive Transfer; Allergens; Animals; Asthma; Bronchoalveolar Lavage Fluid; CD4-Positive T-Lymphocytes; Cells, Cultured; Cytokines; Dendritic Cells; Dinoprostone; Lymph Nodes; Male; Mice; Mice, Knockout; Misoprostol; Ovalbumin; Pneumonia; Receptors, Prostaglandin E, EP2 Subtype; Spleen

Topics: Abortifacient Agents, Nonsteroidal; Anti-Ulcer Agents; Asthma; Contraindications; Humans; Misoprostol

The mechanism of aspirin (acetylsalicylic acid: ASA) hypersensitivity in asthmatic patients is related to arachidonic acid metabolism abnormalities, and specific triggering by ASA of 15-hydroxyeicosatetraenoic acid (15-HETE) generation was observed in leucocytes from aspirin-sensitive (AS) but not from aspirin-tolerant (AT) asthmatics.. The aim of this study was to identify the enzymatic pathway involved in ASA-induced 15-HETE generation in AS asthmatics and to assess the regulatory role of prostaglandin EP receptors.. Peripheral blood leucocytes (PBLs) were isolated from AS (n=18) and AT (n=20) asthmatics and challenged with ASA, with and without pre-incubation with caffeic acid (CA) [15-lipoxygenase (15-LO) inhibitor] or prostaglandin receptor non-specific (misoprostol, sulprostone) and specific EP1-4 receptors agonists. Eicosanoids were measured in supernatants using specific immunoassays.. Aspirin triggered 15-HETE generation in PBLs of AS asthmatics (mean increase 292%) but not in AT asthmatics and inhibited prostaglandin(2) (PGE(2)) generation in both groups of patients to the same degree. Leucocytes from AS patients produced less PGE(2), both before and after ASA incubation. Pre-incubation of PBLs with CA decreased basal 15-HETE production in all patients and completely inhibited ASA-induced 15-HETE generation in AS asthmatics. CA did not change basal PGE(2) production but enhanced induced by ASA inhibition of PGE(2). Non-specific agonists of EP receptors (misoprostol and sulprostone) did not affect basal 15-HETE production but inhibited in a dose-dependent manner the ASA-induced increase of 15-HETE generation in AS asthmatics. On the contrary, in AT asthmatics, pre-incubation of PBLs with misoprostol or sulprostone resulted in a significant increase in 15-HETE generation after addition of ASA (200 microm). EP1-3 receptor agonists inhibited (range 72-94%) the ASA-induced 15-HETE production significantly.. Our study demonstrated that ASA-triggered 15-HETE generation involves the activation of 15-LO and is modulated by prostaglandin EP1-3 receptors. The relevance of these observations to the mechanism of in vivo ASA-induced asthmatic attack remains to be established.

Topics: Adolescent; Adult; Aged; Arachidonate 15-Lipoxygenase; Aspirin; Asthma; Caffeic Acids; Dinoprostone; Drug Hypersensitivity; Female; Humans; Hydroxyeicosatetraenoic Acids; Leukocytes; Lipoxygenase Inhibitors; Male; Middle Aged; Misoprostol; Receptors, Prostaglandin E

Although the mechanisms of aspirin-induced rhinosinusitis-asthma appear to be related to arachidonic acid abnormalities, only recently has a specific aspirin-triggered enhancement of 15-hydroxyeicosatetraenoic acid (15-HETE) generation in nasal polyp epithelial cells from aspirin-sensitive patients been demonstrated.. The aim of this study was to assess generation of 15-HETE and other eicosanoids by peripheral blood leukocytes (PBLs) from aspirin-sensitive and aspirin-tolerant asthmatic patients and modulation of 15-HETE generation by a prostaglandin (PG) E(1) analogue (misoprostol).. Twenty-four aspirin-sensitive patients with asthma-rhinosinusitis and 18 aspirin-tolerant asthmatic patients were studied, and eicosanoids released from PBLs were assessed by means of enzyme immunoassays.. Unstimulated PBLs from aspirin-sensitive and aspirin-tolerant patients generated similar amounts of PGE(2), leukotriene C(4), and 15-HETE, but lipoxin A(4) release was significantly less in aspirin-sensitive patients (300 +/- 70 pg/mL) in comparison with that seen in aspirin-tolerant patients (690 +/- 100 pg/mL, P <.05). Cell incubation with 2, 20, or 200 micromol/L aspirin resulted in a dose-dependent increase in 15-HETE generation (mean change of +85%, +189%, and +284% at each aspirin concentration, respectively) only in aspirin-sensitive asthmatic patients. Naproxen stimulated 15-HETE generation in aspirin-sensitive asthmatic patients, but indomethacin or specific COX-2 inhibitors (NS-398 and celecoxib) did not affect 15-HETE release. A synthetic PGE(1) analogue (misoprostol) inhibited aspirin-induced 15-HETE release but enhanced 15-HETE generation by aspirin in leukocytes from aspirin-tolerant patients. After preincubation with misoprostol, aspirin induced a dose-dependent production of lipoxin A(4) in both groups.. PBLs from patients with aspirin-sensitive rhinosinusitis-asthma might be specifically triggered by aspirin to generate 15-HETE. Metabolism of 15-HETE is differentially regulated by misoprostol in aspirin-tolerant and aspirin-sensitive asthmatic patients.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Dinoprostone; Drug Tolerance; Eicosanoids; Female; Humans; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Ionophores; Leukocytes; Leukotriene C4; Lipoxins; Male; Middle Aged; Misoprostol

Inhaled E-type prostaglandins (PGE) have been shown to modulate responses to both allergic and nonallergic provocation. Misoprostol, a PGE1 analog, was developed as an antiulcer agent because it prevents gastrointestinal ulceration. Little is known about the effect inhaled misoprostol has on the airway and whether its potential antiasthmatic activity would be similar to other PGEs. Nebulizied solutions of misoprostol and PGE2 effectively blocked the acute bronchospasm caused by a subsequent inhaled antigen challenge in actively sensitized guinea pigs. The minimal concentration to result in a significant reduction in specific airway resistance was 3 and 30 micrograms/ml for misoprostol and PGE2, respectively. Exposure to a 300 micrograms/ml nebulized misoprostol solution provided significant protection for 2 h. Eosinophil recovery in bronchoalveolar lavage performed 24 h after antigen challenge was significantly reduced by 72%. In a chronic model of antigen-induced airway inflammation in which guinea pigs are given multiple antigen exposures over a 3-wk period, both misoprostol and its free acid-active metabolite 5C-30695 significantly reduced bronchoalveolar lavage eosinophils by 50 to 55%. Treatment with TRFK5, a monoclonal antibody to interleukin-5, resulted in a 76% decrease in eosinophil recovery. The combination of antibronchoconstrictive and anti-inflammatory effects suggests that inhaled misoprostol may be an effective treatment for the acute and chronic symptoms of asthma.

Topics: Administration, Inhalation; Aerosols; Airway Resistance; Animals; Anti-Asthmatic Agents; Antibodies, Monoclonal; Asthma; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Dinoprostone; Eosinophils; Guinea Pigs; Interleukin-5; Male; Misoprostol; Respiratory Hypersensitivity

It is believed that aspirin (ASA) and other nonsteroidal antiinflammatory drugs elicit dysponea in ASA sensitive asthmatics by blocking the cyclooxygenase. It is unclear whether this bronchospasm is due to shunting of arachidonic acid into the lipooxygenase pathway or removal of cyclooxygenase product which prevent bronchospasm. Diminished tissue concentration of PGE may cause bronchoconstriction. PGE play also modulatory function to mast call decreasing the release of mediators of anaphylaxis. There are some evidences concerning the mast cell degranulation in postaspirin reaction in ASA sensitive asthmatics. The authors investigated the influence of synthetic analogue of PGE1--misoprostol (Cototec, Searle) on the postaspirin bronchoconstriction in seven ASA sensitive asthmatics aged 33-62. Aspirin threshold doses ranged from 10 to 150 mg. Postaspirin bronchoconstriction begun usually within 1-2 hrs after digestion of ASA and 200 micrograms were additionally given 2 h later. Seven days later misoprostol (400 micrograms) was administered together with previously determined dose of ASA. One the other day the bronchodilating effect of misoprostol alone was examined. In all but one patients we observed the protective influence of misoprostol on ASA induced bronchoconstriction. Max. fall in FEV1 in % after ASA in each of the patients was 40, 25, 24, 33, 47 and 54, and after ASA with misoprostol, respectively 10, 9, 4, (+8), 10, (+2) and 45. Misoprostol given together with ASA attenuated aspirin-induced bronchoconstriction reaching statistical significance at 3 and 3.5 h, and also diminished extrapulmonary symptoms. The authors discuss the possible mechanism of protective influence of misoprostol.

Topics: Adult; Aspirin; Asthma; Bronchoconstriction; Bronchodilator Agents; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Misoprostol