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A Szczeklik - One of the best experts on this subject based on the ideXlab platform.
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hypersensitivity to aspirin common eicosanoid alterations in urticaria and Asthma
The Journal of Allergy and Clinical Immunology, 2004Co-Authors: Lucyna Mastalerz, Marek Sanak, Malgorzta Setkowicz, A SzczeklikAbstract:Abstract Rationale To assess whether patients with chronic idiopathic urticaria (CIU) and aspirin sensitivity share common eicosanoid alterations with patients suffering from aspirin-sensitive Asthma. Methods 74 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, 9α,11βPGF2, by GC/MS. All measurements were carried out at base, and after aspirin dosing. Patients were genotyped for the leukotriene C4 synthase (LTC4S) promoter single nucleotide polymorphism. Results In 30 of 74 patients the aspirin challenge was positive, resulting in urticaria/angioedema. In these 30 patients baseline uLTE4 were higher than in non-responders and healthy controls, 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 9α,11βPGF2 levels rose significantly in both aspirin-responders and non-responders, although in the latter group the increase occurred later than in the former. In patients who reacted to aspirin, frequency of −444C allele of LTC4S was significantly higher than in patients who did not react. Conclusions CIU with aspirin sensitivity is characterized by the eicosanoid alterations which are similar to those present in Aspirin-Induced Asthma.
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cyclooxygenase 2 gene polymorphism g 765c and prostaglandin synthesis in patients with bronchial Asthma
The Journal of Allergy and Clinical Immunology, 2004Co-Authors: Wojciech Szczeklik, Marek Sanak, A SzczeklikAbstract:Abstract Rationale Promoter polymorphism of COX-2 gene (G −765 C), recently described by Papafili et al., lowered transcriptional activity of the gene by 30% in cultured fibroblasts (Arterioscler Thromb Vasc Biol. 22; 2002; 1631). The goal of the study was to investigate the genetic association and function of the polymorphism in adult patients with bronchial Asthma. Methods COX-2 promoter region for G −765 C SNP was genotyped by PCR-based RFLP. Three groups were studied: 1) a random sample from Cracow (n=549;M/F=237/312); 2) Patients with Aspirin-Induced Asthma (AIA) (n=117;M/F=41/76); 3) Asthmatics tolerating aspirin (ATA) (n=217;M/F=73/144). We studied ex vivo production of prostaglandins (PGs) by monocytes isolated from blood of Asthmatic patients with GG (n=6) and CC (n=9) genotypes. Results In Asthmatic patients the −765 C allele frequency was similar (AIA=0.16; ATA=0.186), to the controls (Con=0.16). All groups followed Hardy-Weinberg equilibrium. Variant allele homozygotes (CC) were detected only in Asthmatic women (p=0.004). In controls, distribution of CC genotypes did not differ between men and women. The baseline monocyte PGs production was nearly tenfold higher in CC homozygotes than in GG group (p=0.0003). Response to stimulation with LPS gave similar increase of PGs in both groups. Conclusions We demonstrated a functional effect of COX-2 −765 C homozygocity resulting in increased PGs production by monocytes. However, genetic association with COX-2 was detected only in women patients.
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a controlled study of 9α 11β pgf2 a prostaglandin d2 metabolite in plasma and urine of patients with bronchial Asthma and healthy controls after aspirin challenge
The Journal of Allergy and Clinical Immunology, 2003Co-Authors: Grazyna Bochenek, E Nizankowska, Krzysztof Nagraba, A SzczeklikAbstract:BACKGROUND: Prostaglandin D(2) (PGD(2)) is the predominant cyclooxygenase product of mast cells, the number of which is increased in bronchial Asthma. Release of PGD(2) might reflect mast cell activation and disordered function of the Asthmatic lung. OBJECTIVE: We sought to determine blood and urinary levels of 9alpha,11beta-PGF(2), a major stable PGD(2) metabolite in 2 well-defined phenotypes of Asthma, Aspirin-Induced Asthma (AIA) and aspirin-tolerant Asthma (ATA), and in healthy control subjects and to study the effects of aspirin on PGD(2) release. METHODS: Using gas chromatography/mass spectrometry, we determined plasma and urinary concentrations of 9alpha,11beta-PGF(2) at baseline in 131 stable Asthmatic patients, 65 of whom had AIA and 66 of whom had ATA. Fifty healthy nonatopic subjects served as the control group. The measurements were also performed after an aspirin challenge in 26 of 65 patients with AIA and in 24 of 50 control subjects. RESULTS: At baseline, patients with AIA had significantly higher plasma levels of 9alpha,11beta-PGF(2) than either patients with ATA or healthy subjects. A similar significant elevation of serum tryptase was observed in patients with AIA compared with patients with ATA and control subjects. Mean urinary 9alpha,11beta-PGF(2) values did not differ among the 3 groups. In patients with AIA, as opposed to healthy subjects, aspirin challenge invariably precipitated a clinical reaction, accompanied in most patients by a further rise in plasma levels of PGD(2) metabolite and tryptase. CONCLUSIONS: In stable AIA, though not in ATA, there is a steady release of PGD(2) into the blood, accompanied by the release of tryptase. Aspirin enhances this reaction in most patients. Release of bronchoconstrictive PGD(2) might contribute to the severe clinical course of AIA.
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genetics of aspirin induced Asthma
Thorax, 2000Co-Authors: Marek Sanak, A SzczeklikAbstract:Aspirin induced Asthma (AIA) is more common in women than in men. The first symptoms of the disease are often a viral respiratory infection which is followed by a prolonged and perennial rhinitis.1 Nasal congestion, anosmia, and rhinorrhoea are accompanied by nasal polyps which are found on physical examination in about half the patients. Within a few years bronchial Asthma develops, characterised by aspirin intolerance. Aspirin precipitates life threatening attacks of Asthma accompanied by rhinorrhoea, conjunctive congestion, and facial and neck flushing. The trait of aspirin sensitivity, despite avoidance of non-steroidal anti-inflammatory drugs to which patients usually have cross sensitivity, frequently remains for the patient's lifetime. Although Asthma, nasal polyps, and aspirin intolerance are considered as an inherited disease in the catalogue of Mendelian Inheritance in Man ,2reports on familial occurrence of AIA are rather scarce. Miller described a pair of sisters with the trait.3 In one of the families described by Lockey et al 4 consanguinity of the parents suggested a recessive inheritance pattern. In the other family a late onset of AIA and discordance between identical twins raised the possibility of an interaction between environmental and genetic factors. Another multiple family with mild Asthma sensitive aspirin and dominant inheritance of the trait was described by von Maur et al .5 An early onset of Asthma in most affected members of the family and a lack of symptoms of sinusitis or nasal polyposis distinguished this familial variant of AIA. In almost 400 patients studied in the European Network on Aspirin Induced Asthma6 familial occurrence of aspirin hypersensitivity was reported in 5.1%. In families with multiple cases of AIA, affected individuals were usually siblings. The course of their disease was characterised by an intense rhinitis and was more severe, as scored by the number …
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oral and bronchial provocation tests with aspirin for diagnosis of aspirin induced Asthma
European Respiratory Journal, 2000Co-Authors: E Nizankowska, A Bestynskakrypel, A Cmiel, A SzczeklikAbstract:In 35 Asthmatic patients with acetylsalicylic acid (aspirin; ASA) intolerance (AIA) and 15 Asthmatics tolerating ASA well, the authors compared the diagnostic value of the placebo-controlled oral ASA versus inhaled L-lysine (L) ASA challenges. All AIA subjects gave a history of Asthmatic attacks following ingestion of ASA and in all of them the intolerance was confirmed by oral challenge test over the past 10 yrs. Doses of ASA increasing in geometric progression were used in oral tests 10-312 mg (cumulative dose 500 mg); in bronchial tests 0.18-115 mg (cumulative dose 182 mg). Either challenge was considered as positive, if forced expiratory volume in one second (FEV1) dropped at least 20% from the baseline value and/or strong extrabronchial symptoms of intolerance occurred. Urinary leukotriene E4 excretion was determined at baseline and following the challenges. In 24 out of 35 patients the oral test was positive, based on a 20% decrease in FEV1. When including extrabronchial symptoms this was positive in 31 cases. Bronchial L-ASA challenge led to > or =20% fall FEV1 in 21 out of 35 cases, and in 27 cases when including extrabronchial symptoms. No correlation was observed between ASA provocative dose causing a 20% fall in FEV1, determined by the oral route compared to the inhalation route. Urinary LTE4 increased after both challenges the rise being higher following oral as compared to inhalation provocation (p=0.0001). It is concluded that both tests had similar specificity whilst the oral test showed a tendency to higher sensitivity for the clinical diagnosis of acetylsalicylic acid intolerance. The inclusion of extrabronchial symptoms into the criteria of test positivity enhanced the diagnostic value of both procedures. In both tests the highest leukotriene E4 increases were found in the presence of extrabronchial symptoms, suggesting the participation of tissues other than the lung in aspirin induced leukotriene E4 release to urine.
E Nizankowska - One of the best experts on this subject based on the ideXlab platform.
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a controlled study of 9α 11β pgf2 a prostaglandin d2 metabolite in plasma and urine of patients with bronchial Asthma and healthy controls after aspirin challenge
The Journal of Allergy and Clinical Immunology, 2003Co-Authors: Grazyna Bochenek, E Nizankowska, Krzysztof Nagraba, A SzczeklikAbstract:BACKGROUND: Prostaglandin D(2) (PGD(2)) is the predominant cyclooxygenase product of mast cells, the number of which is increased in bronchial Asthma. Release of PGD(2) might reflect mast cell activation and disordered function of the Asthmatic lung. OBJECTIVE: We sought to determine blood and urinary levels of 9alpha,11beta-PGF(2), a major stable PGD(2) metabolite in 2 well-defined phenotypes of Asthma, Aspirin-Induced Asthma (AIA) and aspirin-tolerant Asthma (ATA), and in healthy control subjects and to study the effects of aspirin on PGD(2) release. METHODS: Using gas chromatography/mass spectrometry, we determined plasma and urinary concentrations of 9alpha,11beta-PGF(2) at baseline in 131 stable Asthmatic patients, 65 of whom had AIA and 66 of whom had ATA. Fifty healthy nonatopic subjects served as the control group. The measurements were also performed after an aspirin challenge in 26 of 65 patients with AIA and in 24 of 50 control subjects. RESULTS: At baseline, patients with AIA had significantly higher plasma levels of 9alpha,11beta-PGF(2) than either patients with ATA or healthy subjects. A similar significant elevation of serum tryptase was observed in patients with AIA compared with patients with ATA and control subjects. Mean urinary 9alpha,11beta-PGF(2) values did not differ among the 3 groups. In patients with AIA, as opposed to healthy subjects, aspirin challenge invariably precipitated a clinical reaction, accompanied in most patients by a further rise in plasma levels of PGD(2) metabolite and tryptase. CONCLUSIONS: In stable AIA, though not in ATA, there is a steady release of PGD(2) into the blood, accompanied by the release of tryptase. Aspirin enhances this reaction in most patients. Release of bronchoconstrictive PGD(2) might contribute to the severe clinical course of AIA.
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oral and bronchial provocation tests with aspirin for diagnosis of aspirin induced Asthma
European Respiratory Journal, 2000Co-Authors: E Nizankowska, A Bestynskakrypel, A Cmiel, A SzczeklikAbstract:In 35 Asthmatic patients with acetylsalicylic acid (aspirin; ASA) intolerance (AIA) and 15 Asthmatics tolerating ASA well, the authors compared the diagnostic value of the placebo-controlled oral ASA versus inhaled L-lysine (L) ASA challenges. All AIA subjects gave a history of Asthmatic attacks following ingestion of ASA and in all of them the intolerance was confirmed by oral challenge test over the past 10 yrs. Doses of ASA increasing in geometric progression were used in oral tests 10-312 mg (cumulative dose 500 mg); in bronchial tests 0.18-115 mg (cumulative dose 182 mg). Either challenge was considered as positive, if forced expiratory volume in one second (FEV1) dropped at least 20% from the baseline value and/or strong extrabronchial symptoms of intolerance occurred. Urinary leukotriene E4 excretion was determined at baseline and following the challenges. In 24 out of 35 patients the oral test was positive, based on a 20% decrease in FEV1. When including extrabronchial symptoms this was positive in 31 cases. Bronchial L-ASA challenge led to > or =20% fall FEV1 in 21 out of 35 cases, and in 27 cases when including extrabronchial symptoms. No correlation was observed between ASA provocative dose causing a 20% fall in FEV1, determined by the oral route compared to the inhalation route. Urinary LTE4 increased after both challenges the rise being higher following oral as compared to inhalation provocation (p=0.0001). It is concluded that both tests had similar specificity whilst the oral test showed a tendency to higher sensitivity for the clinical diagnosis of acetylsalicylic acid intolerance. The inclusion of extrabronchial symptoms into the criteria of test positivity enhanced the diagnostic value of both procedures. In both tests the highest leukotriene E4 increases were found in the presence of extrabronchial symptoms, suggesting the participation of tissues other than the lung in aspirin induced leukotriene E4 release to urine.
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nasal provocation test with lysine aspirin for diagnosis of aspirin sensitive Asthma
The Journal of Allergy and Clinical Immunology, 1998Co-Authors: Mamert Milewski, Lucyna Mastalerz, E Nizankowska, A SzczeklikAbstract:Nasal provocation tests (NPTs) with lysine-aspirin (L-ASA) have been recently introduced for assessment of Aspirin-Induced Asthma (AIA). They differ in dose and means of aspirin instillation, duration of observation period, and criteria for positivity. Thus far they have not become a routine part of clinical diagnosis. Fifty-one patients with AIA, confirmed by oral challenge test, were recruited to undergo diagnostic NPTs with L-ASA. In 10 of these patients (19.6%), NPTs could not be performed because of total obstruction of at least one nostril or marked fluctuations in nasal flows, leaving 41 patients with AIA for the study. Control groups consisted of 13 aspirin-tolerant Asthmatic patients and 10 healthy subjects. L-ASA at a total dose of 16 mg of acetylsalicylic acid applied bilaterally into the inferior nasal conchae caused significant fall in inspiratory nasal flow in at least one nostril (>40%), which was measured by anterior rhinomanometry, and clinical symptoms of watery discharge and nasal blockage in 35 of 41 patients with AIA, one of 10 healthy subjects, and none of 13 aspirin-tolerant Asthmatic patients. No relationship was found between the baseline nasal flow values and the intensity of response to L-ASA. No systemic reactions, including bronchospasm, were noticed, even in patients whose initial FEV1 was lower than 70% of predicted value. This test is highly specific (95.7%) and sensitive (86.7%), but negative results do not exclude possible intolerance to aspirin (predictive value of a negative result 78.6%). In conclusion, the NPT described is a simple, safe, and quick test for diagnosis of AIA. It can be used in patients with unstable Asthma. It may be a method of choice to confirm hypersensitivity to aspirin manifested only by symptoms from the upper respiratory tract. Patients suspected of aspirin intolerance who have negative NPT results should undergo bronchial or oral challenge tests with aspirin.
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bronchial aspirin challenge causes specific eicosanoid response in aspirin sensitive Asthmatics
American Journal of Respiratory and Critical Care Medicine, 1996Co-Authors: A Szczeklik, Krzysztof Sladek, Ryszard Dworski, Jerzy Soja, James R Sheller, E Nizankowska, John A OatesAbstract:We have shown that inhalation of lysine aspirin enhances leukotriene production in the lungs of patients with Aspirin-Induced Asthma (AIA). To assess the specificity of this reaction, we compared two well-matched groups of patients: eleven with AIA versus 14 Asthmatics tolerant to aspirin (ATA). All subjects underwent bronchoalveolar lavage (BAL) with saline followed immediately by instillation of 10 mg of lysine aspirin, into a right middle lobe segmental bronchus, which was lavaged 15 min later. At baseline the two groups did not differ with respect to BAL fluid concentrations of cyclooxygenase products, peptido-leukotrienes, histamine, tryptase, interleukin-5 (IL-5), eosinophil cationic protein (ECP), or eosinophil number. Fifteen minutes after aspirin instillation, there was a statistically significant rise in peptido-leukotrienes, IL-5, and eosinophil number in AIA, but not in ATA, but not in ATA patients. In the former, but not in the latter group, mean histamine concentrations rose in response to aspirin, approaching the level of statistical significance. Tryptase and ECP levels showed no significant change. Aspirin significantly depressed PGE2 and thromboxane B2 (TXB2) in both groups, however PGD2, PGF2 alpha, and 9 alpha, 11 beta-PGF2 decreased only in ATA patients. A characteristic disturbance in eicosanoid balance, produced by aspirin in patients intolerant to this drug, might explain precipitation of Asthma attacks.
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eicosanoids in bronchoalveolar lavage fluid of aspirin intolerant patients with Asthma after aspirin challenge
American Journal of Respiratory and Critical Care Medicine, 1994Co-Authors: Krzysztof Sladek, Ryszard Dworski, Jerzy Soja, James R Sheller, E Nizankowska, John A Oates, A SzczeklikAbstract:We have recently shown that oral aspirin provocation leads to an increase in LTE4 and a reduction in 11-dehydro-TXB2 levels in urine of patients with aspirin induced-Asthma (AIA). To test the hypothesis that cyclooxygenase inhibition and an enhancement of cysteinyl-leukotriene production occurs in the lungs of patients with AIA, we examined the eicosanoid levels in bronchoalveolar lavage fluid obtained 30 min after lysine-aspirin or placebo inhalation in 10 patients with AIA. Eosinophil cationic protein (ECP) levels were determined to evaluate eosinophil activation. Six Asthmatics nonsensitive to aspirin (NA) underwent challenge with placebo. The dose of lysine-aspirin inhaled by patients with AIA was equal to that which had produced > or = 20% fall in FEV1. Compared with NA, patients with AIA had: (1) eicosanoid levels, particularly PGE2 and TXB2, elevated and (2) higher number of eosinophils and ECP. The overproduction of eicosanoids could be related to a distinct eosinophilic inflammation in airways of...
Kazuo Akiyama - One of the best experts on this subject based on the ideXlab platform.
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Japanese Guideline for Adult Asthma 2014
Allergology International, 2014Co-Authors: Ken Ohta, Masakazu Ichinose, Hiroyuki Nagase, Masao Yamaguchi, Hisatoshi Sugiura, Yuji Tohda, Kohei Yamauchi, Mitsuru Adachi, Kazuo AkiyamaAbstract:Adult bronchial Asthma (hereinafter, Asthma) is characterized by chronic airway inflammation, reversible airway narrowing, and airway hyperresponsiveness. Long-standing Asthma induces airway remodeling to cause intractable Asthma. The number of patients with Asthma has increased, and that of patients who die from Asthma has decreased (1.5 per 100,000 patients in 2012). The aim of Asthma treatment is to enable patients with Asthma to lead a normal life without any symptoms. A good relationship between physicians and patients is indispensable for appropriate treatment. Long-term management with antiAsthmatic agents and elimination of the causes and risk factors of Asthma are fundamental to its treatment. Four steps in pharmacotherapy differentiate between mild and intensive treatments; each step includes an appropriate daily dose of an inhaled corticosteroid, varying from low to high. Long-acting 02-agonists, leukotriene receptor antagonists, and sustained-release theophylline are recommended as concomitant drugs, while anti-immunoglobulin E antibody therapy has been recently developed for the most severe and persistent Asthma involving allergic reactions. Inhaled 02-agonists, aminophylline, corticosteroids, adrenaline, oxygen therapy, and others are used as needed in acute exacerbations by choosing treatment steps for Asthma exacerbations depending on the severity of attacks. Allergic rhinitis, chronic obstructive pulmonary disease, Aspirin-Induced Asthma, pregnancy, Asthma in athletes, and coughvariant Asthma are also important issues that need to be considered.
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urinary 3 bromotyrosine and 3 chlorotyrosine concentrations in Asthmatic patients lack of increase in 3 bromotyrosine concentration in urine and plasma proteins in aspirin induced Asthma after intravenous aspirin challenge
Clinical & Experimental Allergy, 2004Co-Authors: Haruhisa Mita, Noritaka Higashi, Masami Taniguchi, Ai Higashi, Yukio Kawagishi, Kazuo AkiyamaAbstract:Summary Background Eosinophil peroxidase and myeloperoxidase halogenate tyrosine residues in plasma proteins and generate 3-bromotyrosine (BY) and 3-chlorotyrosine (CY), respectively. Objectives (1) To estimate urinary concentrations of BY and CY in Asthmatic patients. (2) To investigate BY concentration in relation to urinary leukotriene E4 (LTE4) concentration in order to evaluate the activation of eosinophils in patients with Aspirin-Induced Asthma (AIA). Methods BY and CY were quantified with a gas chromatograph-mass spectrometer using 13C-labelled compounds as internal standards. Results (1) Activation of eosinophils and neutrophils by immobilized IgG1 induced preferential formation of BY and CY, respectively. (2) A significantly higher concentration of BY was observed in the urine from Asthmatic patients than in that from healthy control subjects (45±21.7 vs. 22.6±10.8 ng/mg-creatinine, P<0.01). CY concentration was also elevated in the urine from Asthmatic patients (4.4±3.2 vs. 1.5±1.0 ng/mg-creatinine, P<0.01). (3) After intravenous aspirin challenge of Aspirin-Induced Asthmatic patients, the concentration of BY in urine did not significantly change. No significant change was also observed in the ratio of BY concentration to total tyrosine concentration in plasma proteins. In contrast, the concentration of urinary LTE4 significantly increased after the intravenous aspirin challenge. Conclusion Determination of BY and CY concentrations may be useful for monitoring the activation of eosinophils and neutrophils in Asthmatic patients, respectively. After aspirin challenge of AIA patients, the increased concentration of urinary LTE4 did not accompany changes in BY concentration in both urine and plasma proteins. These results may preclude the activation of eosinophils after aspirin challenge in patients with AIA.
Marek Sanak - One of the best experts on this subject based on the ideXlab platform.
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Aspirin desensitization in patients with Aspirin-Induced and aspirin-tolerant Asthma: A double-blind study
The Journal of Allergy and Clinical Immunology, 2014Co-Authors: Monika Świerczyńska-krępa, Grazyna Bochenek, Adam Ćmiel, Hanna Plutecka, Andrzej Szczeklik, Paweł Brzęk, Marek Sanak, Anna Gielicz, Ewa Nizankowska-mogilnickaAbstract:Background Numerous open trials have demonstrated the beneficial clinical effects of aspirin desensitization (AD) in patients with Aspirin-Induced Asthma (AIA). These beneficial effects might be attributable to aspirin's potent anti-inflammatory properties, but that supposition requires further corroboration. Objective We sought to compare the clinical and biochemical responses to chronic oral AD in 20 patients with AIA and 14 patients with aspirin-tolerant Asthma (ATA). All of the patients had chronic rhinosinusitis and nasal polyposis, and these responses were investigated in a pilot, double-blind, placebo-controlled study. Methods Twelve patients with AIA and 6 patients with ATA were randomly assigned to receive 624 mg of aspirin, and 8 patients with AIA and 8 patients with ATA received placebo. Both aspirin and placebo were administered once daily for 6 months. Nasal symptoms, Sino-Nasal Outcome Test (SNOT20) scores, peak nasal inspiratory flows, Asthma Control Questionnaire scores, spirometric parameters, peak expiratory flows, blood eosinophilia, and corticosteroid doses were assessed on a monthly basis. Levels of urinary leukotriene E 4 and the stable plasma prostaglandin (PG) D 2 metabolite 9α,11β-PGF2 were evaluated at baseline and after 1, 3, 5, and 6 months. Results Only the patients with AIA subjected to AD reported improvements in smell and reductions in sneezing and nasal blockade. The SNOT20 and Asthma Control Questionnaire scores of these patients decreased, and their peak nasal inspiratory flows increased. The dosages of inhaled corticosteroids were reduced. There were no changes in leukotriene E 4 or 9α,11β-PGF 2 levels after AD. Conclusion The clinically beneficial effects of AD on nasal and bronchial symptoms occurred only in the patients with AIA.
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hypersensitivity to aspirin common eicosanoid alterations in urticaria and Asthma
The Journal of Allergy and Clinical Immunology, 2004Co-Authors: Lucyna Mastalerz, Marek Sanak, Malgorzta Setkowicz, A SzczeklikAbstract:Abstract Rationale To assess whether patients with chronic idiopathic urticaria (CIU) and aspirin sensitivity share common eicosanoid alterations with patients suffering from aspirin-sensitive Asthma. Methods 74 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, 9α,11βPGF2, by GC/MS. All measurements were carried out at base, and after aspirin dosing. Patients were genotyped for the leukotriene C4 synthase (LTC4S) promoter single nucleotide polymorphism. Results In 30 of 74 patients the aspirin challenge was positive, resulting in urticaria/angioedema. In these 30 patients baseline uLTE4 were higher than in non-responders and healthy controls, 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 9α,11βPGF2 levels rose significantly in both aspirin-responders and non-responders, although in the latter group the increase occurred later than in the former. In patients who reacted to aspirin, frequency of −444C allele of LTC4S was significantly higher than in patients who did not react. Conclusions CIU with aspirin sensitivity is characterized by the eicosanoid alterations which are similar to those present in Aspirin-Induced Asthma.
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cyclooxygenase 2 gene polymorphism g 765c and prostaglandin synthesis in patients with bronchial Asthma
The Journal of Allergy and Clinical Immunology, 2004Co-Authors: Wojciech Szczeklik, Marek Sanak, A SzczeklikAbstract:Abstract Rationale Promoter polymorphism of COX-2 gene (G −765 C), recently described by Papafili et al., lowered transcriptional activity of the gene by 30% in cultured fibroblasts (Arterioscler Thromb Vasc Biol. 22; 2002; 1631). The goal of the study was to investigate the genetic association and function of the polymorphism in adult patients with bronchial Asthma. Methods COX-2 promoter region for G −765 C SNP was genotyped by PCR-based RFLP. Three groups were studied: 1) a random sample from Cracow (n=549;M/F=237/312); 2) Patients with Aspirin-Induced Asthma (AIA) (n=117;M/F=41/76); 3) Asthmatics tolerating aspirin (ATA) (n=217;M/F=73/144). We studied ex vivo production of prostaglandins (PGs) by monocytes isolated from blood of Asthmatic patients with GG (n=6) and CC (n=9) genotypes. Results In Asthmatic patients the −765 C allele frequency was similar (AIA=0.16; ATA=0.186), to the controls (Con=0.16). All groups followed Hardy-Weinberg equilibrium. Variant allele homozygotes (CC) were detected only in Asthmatic women (p=0.004). In controls, distribution of CC genotypes did not differ between men and women. The baseline monocyte PGs production was nearly tenfold higher in CC homozygotes than in GG group (p=0.0003). Response to stimulation with LPS gave similar increase of PGs in both groups. Conclusions We demonstrated a functional effect of COX-2 −765 C homozygocity resulting in increased PGs production by monocytes. However, genetic association with COX-2 was detected only in women patients.
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genetics of aspirin induced Asthma
Thorax, 2000Co-Authors: Marek Sanak, A SzczeklikAbstract:Aspirin induced Asthma (AIA) is more common in women than in men. The first symptoms of the disease are often a viral respiratory infection which is followed by a prolonged and perennial rhinitis.1 Nasal congestion, anosmia, and rhinorrhoea are accompanied by nasal polyps which are found on physical examination in about half the patients. Within a few years bronchial Asthma develops, characterised by aspirin intolerance. Aspirin precipitates life threatening attacks of Asthma accompanied by rhinorrhoea, conjunctive congestion, and facial and neck flushing. The trait of aspirin sensitivity, despite avoidance of non-steroidal anti-inflammatory drugs to which patients usually have cross sensitivity, frequently remains for the patient's lifetime. Although Asthma, nasal polyps, and aspirin intolerance are considered as an inherited disease in the catalogue of Mendelian Inheritance in Man ,2reports on familial occurrence of AIA are rather scarce. Miller described a pair of sisters with the trait.3 In one of the families described by Lockey et al 4 consanguinity of the parents suggested a recessive inheritance pattern. In the other family a late onset of AIA and discordance between identical twins raised the possibility of an interaction between environmental and genetic factors. Another multiple family with mild Asthma sensitive aspirin and dominant inheritance of the trait was described by von Maur et al .5 An early onset of Asthma in most affected members of the family and a lack of symptoms of sinusitis or nasal polyposis distinguished this familial variant of AIA. In almost 400 patients studied in the European Network on Aspirin Induced Asthma6 familial occurrence of aspirin hypersensitivity was reported in 5.1%. In families with multiple cases of AIA, affected individuals were usually siblings. The course of their disease was characterised by an intense rhinitis and was more severe, as scored by the number …
M Robuschi - One of the best experts on this subject based on the ideXlab platform.
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attenuation of aspirin induced bronchoconstriction by sodium cromoglycate and nedocromil sodium
American Journal of Respiratory and Critical Care Medicine, 1997Co-Authors: M Robuschi, G Gambaro, Piersante Sestini, Maria Pieroni, Rosa Metella Refini, Adriano Vaghi, S BiancoAbstract:The protective activity of nedocromil sodium and of sodium cromoglycate against Aspirin-Induced Asthma has never been investigated in controlled studies. Because it has been reported that Aspirin-Induced platelet-mediated cytotoxic activity in vitro is inhibited after treatment in vivo with nedocromil but not with cromoglycate, we investigated whether these compounds also exhibit a different protective activity against Aspirin-Induced bronchoconstriction. Ten patients with Aspirin-Induced Asthma underwent three bronchial challenges with a single dose of lysine acetylsalicylate (LASA) that caused a decrease in FEV1 of 25% or more in a preliminary dose-response test 30 min after inhalation of 4 mg nedocromil sodium, 10 mg sodium cromoglycate, or placebo. FEV1 and SRaw were recorded at intervals for 195 min. After placebo, LASA caused a maximal decrease in FEV1 of 42 +/- 4% of baseline. After cromoglycate and nedocromil the maximal decrease in FEV1 was reduced to 20 +/- 3% and 18 +/- 4%, respectively (p < 0.01 versus placebo for both treatments), without significant differences between the two treatments. Similar results were observed with SRaw. We conclude that, at the recommended therapeutic doses, sodium cromoglycate and nedocromil sodium are equally effective in attenuating Aspirin-Induced bronchoconstriction and that it is unlikely that platelet activation participates in the pathogenesis of Aspirin-Induced Asthma.
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inhaled pge2 prevents aspirin induced bronchoconstriction and urinary lte4 excretion in aspirin sensitive Asthma
American Journal of Respiratory and Critical Care Medicine, 1996Co-Authors: Piersante Sestini, G Gambaro, Maria Pieroni, Rosa Metella Refini, Adriano Vaghi, S Bianco, L Armetti, Angelo Sala, Gc Folco, M RobuschiAbstract:Bronchial overproduction of leukotrienes and inhibition of prostaglandin synthesis are involved in the pathogenesis of Aspirin-Induced Asthma. We investigated whether inhaled prostaglandin E2 (PGE2) attenuates the response to bronchial challenge with lysine acetylsalicylate (LASA) and the associated increase in urinary leukotriene E4 (u-LTE4) in seven aspirin-sensitive subjects with Asthma. Each subject performed two challenges with a single dose of LASA that caused a decrease in FEV1 of 20% or more in a preliminary test, immediately after inhaling 100 micrograms PGE2 in 4 ml saline or placebo, according to a randomized double-blind protocol. FEV1 was recorded at 30-min intervals for 4 h. u-LTE4 was measured by combined high-performance liquid chromatography enzyme immunoassay at 2-h intervals. After placebo, LASA caused an obstructive reaction in all patients, with a maximum decrease in FEV1 of 35 +/- 5% with respect to baseline. u-LTE4 rose from 911 +/- 261 picograms (pg)/mg creatinine at baseline to a ...
