Effect of thromboxane A2-receptor antagonist on bradykinin-induced bronchoconstriction in asthma

1996 ◽  
Vol 80 (6) ◽  
pp. 1973-1977 ◽  
Author(s):  
K. Rajakulasingam ◽  
S. L. Johnston ◽  
J. Ducey ◽  
W. Ritter ◽  
P. H. Howarth ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Geometric Mean ◽  
Thromboxane A2 ◽  
Forced Expiratory Volume ◽  
Significant Inhibition ◽  
Prostaglandin D2 ◽  
Double Blind ◽  
Bronchial Responsiveness ◽  
Significant Difference ◽  
Txa2 Receptor

The role of the thromboxane A2 (TxA2) receptor in bradykinin-induced bronchial responses was investigated in this study by using a selective and potent TxA2-receptor antagonist BAY u 3405. Eleven asthmatic subjects were randomized to receive 50 mg of BAY u 3405 or matched placebo in a crossover and double-blind fashion. Ninety minutes after dosing, serum was taken for drug assay, and subjects underwent provocation with bradykinin or prostaglandin D2 (PGD2) to determine bronchial responsiveness [provocative concentration of agonist required to produce a 20% fall in forced expiratory volume in 1 s from the postdiluent baseline (PC20)]. Pretreatment with BAY u 3405 caused a twofold doubling-dilution reduction in bronchial reactivity to PGD2; the geometric mean PC20 values were 0.132 (0.015-0.871) and 0.034 (0.008-0.095) mg/ml, respectively, for active and placebo days (P = 0.001). There was, however, no significant difference in PC20 values for bradykinin between active and placebo treatment days. We have demonstrated that BAY u 3405 caused a significant inhibition of bronchconstriction induced by inhaled PGD2 but had no influence on bronchial responsiveness to inhaled bradykinin. This study suggests therefore that TxA2 receptors do not play a role in bradykinin-induced bronchoconstriction in asthma.

Modification of bronchial reactivity by physiological concentrations of plasma epinephrine

1992 ◽  
Vol 73 (3) ◽  
pp. 1004-1007 ◽  
Author(s):  
A. J. Knox ◽  
H. Campos-Gongora ◽  
A. Wisniewski ◽  
I. A. MacDonald ◽  
A. E. Tattersfield
Keyword(s):  
Geometric Mean ◽  
Plasma Concentrations ◽  
Challenge Test ◽  
Forced Expiratory Volume ◽  
Bronchial Reactivity ◽  
Plasma Epinephrine ◽  
Double Blind ◽  
Bronchial Responsiveness ◽  
Mean Values ◽  
Epinephrine Concentration

Circulating epinephrine concentrations are altered in certain pathophysiological states, but whether such changes in epinephrine concentrations can alter bronchial responsiveness in subjects with asthma has not been studied. We studied 10 subjects with asthma in a double-blind crossover study on 4 nonconsecutive days. After measurement of baseline forced expiratory volume in 1 s (FEV1) and plasma epinephrine concentration, subjects were given placebo or 4, 16, or 64 ng.kg-1.min-1 epinephrine by intravenous infusion for 45 min. Blood was taken for plasma epinephrine concentration before the infusion and at 30 min, when a histamine challenge test was performed. Mean plasma epinephrine concentrations ranged from 0.37 nmol/l on placebo to 3.76 nmol/l with the 64-ng/kg infusion. FEV1 increased progressively with increasing concentrations of infused epinephrine, the mean change ranging from -0.051 on placebo to 0.331 after the highest concentration of epinephrine. The provocative dose of histamine causing a 20% fall in FEV1 increased progressively with increasing concentrations of infused epinephrine, geometric mean values ranging from 0.61 mumol with placebo to 1.7 mumol after the highest dose of epinephrine. Thus epinephrine, at physiological plasma concentrations, can modify bronchial reactivity.

scholarly journals A phase 1 study of single and repeat oral doses of GSK3439171A, a highly selective H-PGDS inhibitor, in healthy adult participants

2021 ◽  
Author(s):  
Thomas Haws ◽  
Nilay Thakkar ◽  
Summer Goodson ◽  
Caroline Sychterz ◽  
Nisha George ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Drug Hypersensitivity ◽  
Phase 1 ◽  
Geometric Mean ◽  
Human Study ◽  
Study Drug ◽  
Prostaglandin D2 ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Oral Doses

Aim: Prostaglandin D2 (PGD2) is implicated in the pathophysiology of inflammatory diseases. GSK3439171A is a potent, reversible, and highly selective azetidine urea inhibitor of haematopoietic prostaglandin D synthase (H-PGDS, a key promoter of PGD2 production in several inflammatory cell types). Based on favourable preclinical data, we performed a first-time-in-human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK3439171A, and the effect of food on these parameters. Methods: This was a phase 1, randomized, double-blind, placebo-controlled, dose-escalation study. Single and repeat oral doses of GSK3439171A were administered to healthy males aged 18–65 years. Levels of inflammatory markers including tetranor-prostaglandin D metabolite (tPGDM) were measured in urine samples. Results: Sixty-six participants were enrolled, with 57 receiving GSK3439171A. Single doses (5–180 mg) and repeat once-daily doses (5 and 11 mg for 14 days; 40 mg for 7 days) were administered. Seven participants (12%) had adverse events (AEs) related to study drug, mainly drug hypersensitivity (n=4 [7%]; non-serious, transient skin rash). There were no serious AEs (SAEs) or clinically significant changes in vital signs, electrocardiogram, or laboratory parameters. Dose-proportional increases in Cmax and AUC(0–inf) were observed, and the geometric mean half-life of GSK3439171A was up to 12 hours. Results were similar when GSK3439171A was taken with or without food. No consistent suppression of tPGDM levels was observed. Conclusion: GSK3439171A was well tolerated in healthy participants and there were no SAEs. Selective inhibition of H-PGDS offers therapeutic potential for muscle-related disorders (e.g. Duchenne Muscular Dystrophy) and muscular recovery following injury.

scholarly journals Effects of the Toll-like receptor 7 (TLR7) agonist, AZD8848, on allergen-induced responses in patients with mild asthma: a double-blind, randomised, parallel-group study

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Brian R. Leaker ◽  
Dave Singh ◽  
Sam Lindgren ◽  
Gun Almqvist ◽  
Leif Eriksson ◽  
...  
Keyword(s):  
Immune System ◽  
Allergic Asthma ◽  
Allergen Challenge ◽  
Forced Expiratory Volume ◽  
Post Treatment ◽  
Double Blind ◽  
Parallel Group Study ◽  
Parallel Group ◽  
Significant Difference ◽  
Th2 Responses

Abstract Background Although allergic asthma is a complex area with many interacting factors involved, the ‘hygiene hypothesis’ proposes that a lack of exposure to infection during childhood may polarise the immune system towards allergen-reactive Th2-type responses in genetically susceptible individuals. Toll-like receptors (TLRs) play a key role within the innate immune system and TLR7 agonists have previously been shown to up-regulate Th1 responses and down-regulate Th2 responses to allergens in murine models of allergic or chronic asthma. This study aimed to examine the efficacy and safety of the novel TRL7 agonist AZD8848, which has been developed as an antedrug. Methods In this double-blind, randomised, parallel-group study, AZD8848 60 μg or placebo was administered intranasally once-weekly for 8 weeks in patients with mild-to-moderate allergic asthma (NCT00999466). Efficacy assessments were performed at 1 and 4 weeks after the last dose. The primary outcome was the late asthmatic response (LAR) fall in forced expiratory volume in 1 s (FEV1) after allergen challenge at 1-week post-treatment. Results AZD8848 significantly reduced average LAR fall in FEV1 by 27% vs. placebo at 1 week after treatment (p = 0.035). This effect was sustained at 4 weeks post-treatment; however, it did not reach clinical significance. AZD8848 reduced post-allergen challenge methacholine-induced airway hyper-responsiveness (AHR) vs. placebo at 1 week post-dosing (treatment ratio: 2.20, p = 0.024), with no effect at 4 weeks. There was no significant difference between the two groups in plasma cytokine, sputum Th2 cytokine or eosinophil responses post-allergen challenge at 1 week after treatment. The incidence of adverse events was similar in the two groups. AZD8848 was generally well tolerated. Conclusions and clinical relevance In patients with allergic asthma, TLR7 agonists could potentially reduce allergen responsiveness by stimulating Type 1 interferon responses to down-regulate the dominant Th2 responses. Trial registration clinicaltrials.gov identifier NCT00999466.

Prevention of cisplatin-induced emesis: a double-blind multicenter randomized crossover study comparing ondansetron and ondansetron plus dexamethasone.

1991 ◽  
Vol 9 (4) ◽  
pp. 675-678 ◽  
Author(s):  
F Roila ◽  
M Tonato ◽  
F Cognetti ◽  
E Cortesi ◽  
G Favalli ◽  
...  
Keyword(s):  
Side Effects ◽  
Crossover Study ◽  
Receptor Antagonist ◽  
Treatment Preference ◽  
Complete Protection ◽  
Double Blind ◽  
Significant Difference ◽  
Antiemetic Activity ◽  
To Receive ◽  
Randomized Crossover Study

Ondansetron (OND) is a new 5-HT3 receptor antagonist that give complete protection from emesis/nausea in approximately 50% of cisplatin (CDDP)-treated patients. To evaluate if dexamethasone (DEX) added to OND increases antiemetic efficacy, we carried out a double-blind randomized crossover study to compare the antiemetic activity of OND with OND plus DEX. One hundred two chemotherapy-naive patients (44 women and 58 men) scheduled to receive CDDP chemotherapy at doses greater than or equal to 50 mg/m2 entered the study. Eighty-nine patients completed both cycles with the following results: complete protection from emesis/nausea was obtained in 57/59 patients (64.0%/66.3%) with OND and in 81/79 (91.0%/88.8%) with OND plus DEX (P = .0005/P = .0021). At the end of the study, 53% of the patients expressed a treatment preference, and of these, 74% chose OND plus DEX compared with 26% who preferred OND alone, a statistically significant difference (P less than .003). Side effects were very mild and not significantly different between the two treatments. We conclude that OND plus DEX is more efficacious than OND in protecting patients from CDDP-induced emesis and nausea.

scholarly journals Formoterol Thrice Weekly Does Not Result in the Development of Tolerance to Bronchoprotection

2003 ◽  
Vol 10 (1) ◽  
pp. 23-26 ◽  
Author(s):  
Beth E Davis ◽  
John K Reid ◽  
Donald W Cockcroft
Keyword(s):  
Crossover Trial ◽  
Positive Control ◽  
Forced Expiratory Volume ◽  
Weekly Administration ◽  
Double Blind ◽  
Once Daily ◽  
Regular Treatment ◽  
Significant Difference ◽  
Direct Acting ◽  
Development Of Tolerance

BACKGROUND: Loss of bronchoprotection routinely follows regular treatment with beta2-agonists. There are no data on the effects on bronchoprotection for thrice weekly use of a beta2-agonist.METHODS: A double-blind, randomized, placebo controlled crossover trial was conducted to investigate the effects of thrice weekly administration of 12 μg of formoterol versus placebo on bronchoprotection against methacholine. As an expected positive control, formoterol 12 μg once daily was also evaluated.RESULTS: There was no significant difference versus placebo in the bronchoprotective effects of 12 μg of formoterol administered on day 8, following daily treatment for seven days or treatment every other day (analysis of variance P=0.34). However, a nonsignificant trend towards lower concentration of methacholine that caused a 20% fall in forced expiratory volume in 1 s developed only following the daily formoterol dosing.CONCLUSIONS: Thrice weekly dosing does not result in the development of tolerance to bronchoprotection against the direct acting stimulus methacholine.

Does baseline airway caliber affect measurements of airway responsiveness to histamine

1993 ◽  
Vol 74 (6) ◽  
pp. 3034-3039 ◽  
Author(s):  
O. P. Twentyman ◽  
S. V. Hood ◽  
S. T. Holgate
Keyword(s):  
Time Course ◽  
Geometric Mean ◽  
Forced Expiratory Volume ◽  
Airway Responsiveness ◽  
Bronchial Responsiveness ◽  
Subsequent Response ◽  
Airway Caliber ◽  
Before And After ◽  
Airway Response ◽  
Considerable Controversy

Considerable controversy exists over the influence of baseline airway caliber on indexes of bronchial responsiveness in asthma. To directly investigate this, we used inhaled methacholine to alter baseline airway caliber to determine whether this altered the airway response to subsequent bronchoprovocation with inhaled histamine. Seventeen stable asthmatic subjects were studied; their median age was 22 yr, baseline forced expiratory volume in 1 s (FEV1) was 101.5 +/- 3.7% (SE) predicted, and geometric mean provocative concentration of inhaled methacholine causing a 20% fall in FEV1 (PC20) was 0.87 mg/ml. Initially the time course of bronchoconstriction to inhaled methacholine was determined. Subsequently the airway response to inhaled histamine administered as a single concentration was determined, both before and after reductions in baseline FEV1 by saline or methacholine of 0, 15, 25, and 35%, on 4 separate days. Altering baseline airway caliber had no effect on the subsequent response of the airways to inhaled histamine when calculated as percent fall from the new baseline. The power of the study to detect an effect of altering baseline FEV1 on the measured PC20 histamine of 0.5 doubling dilutions was > 55%, and the power to detect an effect of 1.0 doubling dilutions was > 98%.

scholarly journals 0487 Effects of Suvorexant on Sleep Architecture in Patients with Alzheimer’s Disease and Insomnia

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A187-A187
Author(s):  
V Svetnik ◽  
T Wang ◽  
P Ceesay ◽  
O Ceren ◽  
E Snyder ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Clinical Response ◽  
Total Sleep Time ◽  
Sleep Time ◽  
Sleep Architecture ◽  
Sleep Laboratory ◽  
Double Blind ◽  
Moderate Severity ◽  
Competitive Antagonism ◽  
Significant Difference

Abstract Introduction Suvorexant, an orexin receptor antagonist that enables sleep to occur via competitive antagonism of wake-promoting orexins, improved total sleep time (TST) in a sleep laboratory polysomnography (PSG) study of patients with AD and insomnia. Here we report on the effects of suvorexant on sleep architecture in the study. Methods This was a randomized, double-blind, 4-week trial (ClinicalTrials.gov NCT02750306). Participants who met diagnostic criteria for both probable AD dementia (of mild to moderate severity) and insomnia were randomized to suvorexant 10mg (could be increased to 20mg based on clinical response) or matching placebo. Overnight sleep laboratory PSG was performed on 3 nights: screening, baseline, and Night-29 (last night of dosing). Suvorexant differences from placebo in changes-from-baseline at Night-29 for sleep architecture were analyzed as exploratory endpoints. Results A total of 274 participants were included in the analysis (suvorexant N=135, placebo N=139). At Night-29, suvorexant improved TST by 28 minutes versus placebo (p=0.001). There were no significant differences between suvorexant and placebo in the % of TST spent in REM (1.3%, 95% CI: -0.5, 3.0), N1 (0.6%, 95% CI: -1.2, 2.5), N2 (-1.0%, 95% CI: -3.2, 1.2), or N3 (-0.6%, 95% CI: -1.8, 0.6). There was no significant difference between suvorexant and placebo in latency to REM (-5.4 minutes, 95% CI: -23.4, 12.7). Conclusion Suvorexant improves TST without altering the underlying sleep architecture in AD patients with insomnia. Support Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

scholarly journals Randomised, double-blind, placebo-controlled pilot trial of omeprazole in idiopathic pulmonary fibrosis

Thorax ◽  
2019 ◽  
Vol 74 (4) ◽  
pp. 346-353 ◽  
Author(s):  
Prosenjit Dutta ◽  
Wendy Funston ◽  
Helen Mossop ◽  
Vicky Ryan ◽  
Rhys Jones ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Controlled Trial ◽  
Geometric Mean ◽  
Pilot Trial ◽  
Acid Reflux ◽  
Forced Expiratory Volume ◽  
Double Blind ◽  
Cough Frequency ◽  
Randomised Controlled

BackgroundCough is a common, disabling symptom of idiopathic pulmonary fibrosis (IPF), which may be exacerbated by acid reflux. Inhibiting gastric acid secretion could potentially reduce cough. This study aimed to determine the feasibility of a larger, multicentre trial of omeprazole for cough in IPF, to assess safety and to quantify cough.MethodsSingle-centre, double-blind, randomised, placebo-controlled pilot trial of the proton pump inhibitor (PPI) omeprazole (20 mg twice daily for 3 months) in patients with IPF. Primary objectives were to assess feasibility and acceptability of trial procedures. The primary clinical outcome was cough frequency.ResultsForty-five participants were randomised (23 to omeprazole, 22 to placebo), with 40 (20 in each group) having cough monitoring before and after treatment. 280 patients were screened to yield these numbers, with barriers to discontinuing antacids the single biggest reason for non-recruitment. Recruitment averaged 1.5 participants per month. Geometric mean cough frequency at the end of treatment, adjusted for baseline, was 39.1% lower (95% CI 66.0% lower to 9.3% higher) in the omeprazole group compared with placebo. Omeprazole was well tolerated and adverse event profiles were similar in both groups, although there was a small excess of lower respiratory tract infection and a small fall in forced expiratory volume and forced vital capacity associated with omeprazole.ConclusionsA large randomised controlled trial of PPIs for cough in IPF appears feasible and justified but should address barriers to randomisation and incorporate safety assessments in relation to respiratory infection and changes in lung function.

Adverse Pulmonary Responses to Aspirin and Acetaminophen in Chronic Childhood Asthma

PEDIATRICS ◽  
1983 ◽  
Vol 71 (3) ◽  
pp. 313-318
Author(s):  
Thomas J. Fischer ◽  
Timothy D. Guilfoile ◽  
Hemant H. Kesarwala ◽  
John G. Winant ◽  
Gregory L. Kearns ◽  
...  
Keyword(s):  
Pulmonary Function ◽  
Flow Rate ◽  
Past History ◽  
Forced Expiratory Volume ◽  
Base Line ◽  
Double Blind ◽  
Asthmatic Children ◽  
Significant Difference ◽  
History Of ◽  
Expiratory Flow

Because aspirin (ASA) is often reported to have an adverse effect on pulmonary function in children with chronic asthma, acetaminophen is commonly used as an ASA substitute in these children. To study acetaminophen effects on pulmonary functions, double-blind, oral challenges of ASA (600 mg), acetaminophen (600 mg), or lactose were administered on separate days to 25 chronic asthmatics, ten boys and 15 girls, ranging in age from 8 to 18 years (mean age ± 1 SD: 12.5 ± 2.8 years). No patient had a past history of adverse reactions to either drug. Forced expiratory volume in 1 second (FEV1), peak expiratory flow rate (PEFR), maximal mid-expiratory flow rate (FEF25-75), forced vital capacity (FVC), maximal voluntary ventilation (MVV), and flow volume curves were measured at base line and ½, 1, 2, 3, and 4 hours after ingestion of drug or placebo. Persistent decreases from base line FEV1 (> 20%) or FEF25-75 (> 30%) occurred in four ASA- and two acetaminophen-challenged patients. One ASA-sensitive patient was placebo intolerant; another reacted to acetaminophen. The acetaminophen responses were of less intensity than the ASA responses. Analysis of group mean pulmonary function responses to ASA, acetaminophen, and lactose showed no significant difference among the three agents at any time. Aspirin should be used cautiously in asthmatic children. Acetaminophen appears to be an adequate, although not completely, innocuous ASA substitute.

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