The effect of tezepelumab on airway hyperresponsiveness to mannitol in asthma (UPSTREAM)

Rationale and objectivesThymic stromal lymphopoietin (TSLP), an epithelial upstream cytokine, initiates production of type-2 (T2) cytokines with eosinophilia and possibly airway hyperresponsiveness (AHR) in asthma.This study aimed to determine whether tezepelumab (a human monoclonal antibody targeting TSLP) decreases AHR and airway inflammation in patients with symptomatic asthma on maintenance treatment with inhaled corticosteroids.Methods and measurementsIn this double-blind, placebo-controlled randomised trial adult patients with asthma and AHR to mannitol received either 700 mg tezepelumab or placebo intravenously at 4-week intervals for 12 weeks. AHR to mannitol was assessed, and a bronchoscopy was performed at baseline and after 12 weeks. The primary outcome was the change in AHR from baseline to week-12 and secondary outcomes were changes in airway inflammation.ResultsForty patients were randomised to receive either tezepelumab (n=20) or placebo (n=20). The mean change in PD15 with tezepelumab was 1.9 DD (95% CI 1.2 to 2.5) versus 1·0 (95% CI 0.3 to 1.6) with placebo; p=0.06. Nine (45%) tezepelumab and three (16%) placebo patients had a negative PD15 test at week-12, p=0.04. Airway tissue and BAL eosinophils decreased by 74% (95% CI −53 to −86) and 75% (95% CI −53 to −86) respectively with tezepelumab compared with an increase of 28% (95% CI −39 to 270) and a decrease of 7% (95% CI −49 to 72) respectively with placebo, p=0.004 and p=0.01.ConclusionsInhibiting TSLP-signalling with tezepelumab reduced the proportion of patients with AHR and decreased eosinophilic inflammation in BAL and airway tissue.

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The Antiaggressive Action of Combined Haloperidol-Propranolol Treatment in Schizophrenia

European Psychologist ◽

10.1027//1016-9040.5.4.312 ◽

2000 ◽

Vol 5 (4) ◽

pp. 312-325 ◽

Cited By ~ 9

Author(s):

Gadi Maoz ◽

Daniel Stein ◽

Sorin Meged ◽

Larisa Kurzman ◽

Joseph Levine ◽

...

Keyword(s):

Rating Scales ◽

Double Blind ◽

Propranolol Group ◽

Schizophrenic Patients ◽

Propranolol Treatment ◽

Simultaneous Decrease ◽

The Mean ◽

Haloperidol Treatment ◽

To Receive ◽

Drug Free

Psychopharmacological interventions for managing aggression in schizophrenia have thus far yielded inconsistent results. This study evaluates the antiaggressive efficacy of combined haloperidol-propranolol treatment. Thirty-four newly admitted schizophrenic patients were studied in a controlled double-blind trial. Following a 3-day drug-free period and 7 days of haloperidol treatment, patients were randomly assigned to receive either haloperidol-propranolol or haloperidol-placebo for eight consecutive weeks. Doses of medications were adjusted as necessary; biperiden was administered if required. Rating scales were applied to assess aggression, anger, psychosis, depression, anxiety and extrapyramidal symptoms. The mean daily dose of haloperidol was 21 mg (SD = 6.4) in the research group and 29 mg (SD = 6.9) in the controls. Mean and maximal daily doses of propranolol were 159 mg (SD = 61) and 192 mg (SD = 83), and of placebo, 145 mg (SD = 50) and 180 mg (SD = 70), respectively. Compared with the controls, the scores for the research patients decreased significantly from baseline, particularly after 4 weeks of treatment, for some dimensions of anger, psychosis, anxiety, and neuroleptic-induced parkinsonism. A tendency for reduced aggression was shown in the combined haloperidol-propranolol group for some dimensions but not others. These patients also required significantly less biperiden. The tendency toward elevated antiaggressive effect of combined haloperidol-propranolol treatment compared to haloperidol alone may be explained by a simultaneous decrease in aggression, psychotic symptomatology, and anxiety.

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Contrasting roles for the receptor for advanced glycation end-products on structural cells in allergic airway inflammation vs. airway hyperresponsiveness

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00087.2015 ◽

2015 ◽

Vol 309 (8) ◽

pp. L789-L800 ◽

Cited By ~ 13

Author(s):

Akihiko Taniguchi ◽

Nobuaki Miyahara ◽

Koichi Waseda ◽

Etsuko Kurimoto ◽

Utako Fujii ◽

...

Keyword(s):

Airway Inflammation ◽

Airway Hyperresponsiveness ◽

Allergic Airway Inflammation ◽

T Helper ◽

Advanced Glycation ◽

Glycation End Products ◽

End Products ◽

Group 2 ◽

Airway Responses

The receptor for advanced glycation end-products (RAGE) is a multiligand receptor that belongs to the immunoglobulin superfamily. RAGE is reported to be involved in various inflammatory disorders; however, studies that address the role of RAGE in allergic airway disease are inconclusive. RAGE-sufficient (RAGE+/+) and RAGE-deficient (RAGE−/−) mice were sensitized to ovalbumin, and airway responses were monitored after ovalbumin challenge. RAGE−/− mice showed reduced eosinophilic inflammation and goblet cell metaplasia, lower T helper type 2 (Th2) cytokine production from spleen and peribronchial lymph node mononuclear cells, and lower numbers of group 2 innate lymphoid cells in the lung compared with RAGE+/+ mice following sensitization and challenge. Experiments using irradiated, chimeric mice showed that the mice expressing RAGE on radio-resistant structural cells but not hematopoietic cells developed allergic airway inflammation; however, the mice expressing RAGE on hematopoietic cells but not structural cells showed reduced airway inflammation. In contrast, absence of RAGE expression on structural cells enhanced innate airway hyperresponsiveness (AHR). In the absence of RAGE, increased interleukin (IL)-33 levels in the lung were detected, and blockade of IL-33 receptor ST2 suppressed innate AHR in RAGE−/− mice. These data identify the importance of RAGE expressed on lung structural cells in the development of allergic airway inflammation, T helper type 2 cell activation, and group 2 innate lymphoid cell accumulation in the airways. RAGE on lung structural cells also regulated innate AHR, likely through the IL-33-ST2 pathway. Thus manipulating RAGE represents a novel therapeutic target in controlling allergic airway responses.

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A Parallel-Group Comparison of Astemizole and Loratadine for the Treatment of Perennial Allergic Rhinitis

Journal of International Medical Research ◽

10.1177/030006059702500401 ◽

1997 ◽

Vol 25 (4) ◽

pp. 175-181 ◽

Cited By ~ 66

Author(s):

H Al-Muhaimeed

Keyword(s):

Allergic Rhinitis ◽

Statistical Significance ◽

Double Blind Study ◽

Perennial Allergic Rhinitis ◽

Double Blind ◽

Once Daily ◽

Runny Nose ◽

Parallel Group ◽

The Mean ◽

To Receive

The efficacy and safety of the two antihistamines, astemizole and loratadine, were compared in a double-blind study of 84 patients with perennial allergic rhinitis. Patients were randomized to receive orally either astemizole 10 mg once daily ( n = 40) or loratadine 10 mg once daily ( n = 44) for 1 week. No other antirhinitis medication was allowed during the study. By day 7 the mean daily symptom scores, recorded on diary cards, were lower in patients receiving astemizole than in those receiving loratadine for runny nose, itchy nose and sneezing, although not for blocked nose, and treatment differences only reached statistical significance for runny nose. After 7 days, 53.75% of patients on astemizole and 38.6% on loratadine were free of symptoms, and 87% of patients on astemizole described the treatment as good or excellent compared with 62% on loratadine. The present results suggest that astemizole may be more effective than loratadine in controlling symptoms of perennial allergic rhinitis.

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High-Dose Adrenaline in Adult In-Hospital Asystolic Cardiopulmonary Resuscitation: A Double-Blind Randomised Trial

Anaesthesia and Intensive Care ◽

10.1177/0310057x9302100210 ◽

1993 ◽

Vol 21 (2) ◽

pp. 192-196 ◽

Cited By ~ 38

Author(s):

J. Lipman ◽

W. Wilson ◽

S. Kobilski ◽

J. Scribante ◽

C. Lee ◽

...

Keyword(s):

Intensive Care Unit ◽

Cardiac Arrest ◽

Intensive Care ◽

Side Effects ◽

Cardiopulmonary Resuscitation ◽

Standard Dose ◽

Randomised Trial ◽

High Dose ◽

Double Blind ◽

To Receive

Forty intensive care unit patients requiring cardiopulmonary resuscitation were randomised to receive either the standard dose of adrenaline (1 mg every five minutes) or high-dose adrenaline (10 mg every five minutes). In the majority of patients, overwhelming sepsis was the major contributing factor leading to cardiac arrest. In this group of patients no difference could be detected in response to high-dose adrenaline compared with the standard dose. Although no side-effects were noted with this high dose of adrenaline, more investigation is required prior to its routine use in cardiopulmonary resuscitation.

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Efficacy of umeclidinium/vilanterol versus umeclidinium and salmeterol monotherapies in symptomatic patients with COPD not receiving inhaled corticosteroids: the EMAX randomised trial

Respiratory Research ◽

10.1186/s12931-019-1193-9 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 9

Author(s):

François Maltais ◽

Leif Bjermer ◽

Edward M. Kerwin ◽

Paul W. Jones ◽

Michael L. Watkins ◽

...

Keyword(s):

Treatment Failure ◽

Inhaled Corticosteroids ◽

Randomised Trial ◽

Forced Expiratory Volume ◽

Chronic Obstructive ◽

Short Term ◽

Double Blind ◽

Once Daily ◽

Clinically Important Deterioration ◽

Exacerbation Risk

Abstract Background Prospective evidence is lacking regarding incremental benefits of long-acting dual- versus mono-bronchodilation in improving symptoms and preventing short-term disease worsening/treatment failure in low exacerbation risk patients with chronic obstructive pulmonary disease (COPD) not receiving inhaled corticosteroids. Methods The 24-week, double-blind, double-dummy, parallel-group Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised patients at low exacerbation risk not receiving inhaled corticosteroids, to umeclidinium/vilanterol 62.5/25 μg once-daily, umeclidinium 62.5 μg once-daily or salmeterol 50 μg twice-daily. The primary endpoint was trough forced expiratory volume in 1 s (FEV1) at Week 24. The study was also powered for the secondary endpoint of Transition Dyspnoea Index at Week 24. Other efficacy assessments included spirometry, symptoms, heath status and short-term disease worsening measured by the composite endpoint of clinically important deterioration using three definitions. Results Change from baseline in trough FEV1 at Week 24 was 66 mL (95% confidence interval [CI]: 43, 89) and 141 mL (95% CI: 118, 164) greater with umeclidinium/vilanterol versus umeclidinium and salmeterol, respectively (both p < 0.001). Umeclidinium/vilanterol demonstrated consistent improvements in Transition Dyspnoea Index versus both monotherapies at Week 24 (vs umeclidinium: 0.37 [95% CI: 0.06, 0.68], p = 0.018; vs salmeterol: 0.45 [95% CI: 0.15, 0.76], p = 0.004) and all other symptom measures at all time points. Regardless of the clinically important deterioration definition considered, umeclidinium/vilanterol significantly reduced the risk of a first clinically important deterioration compared with umeclidinium (by 16–25% [p < 0.01]) and salmeterol (by 26–41% [p < 0.001]). Safety profiles were similar between treatments. Conclusions Umeclidinium/vilanterol consistently provides early and sustained improvements in lung function and symptoms and reduces the risk of deterioration/treatment failure versus umeclidinium or salmeterol in symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids. These findings suggest a potential for early use of dual bronchodilators to help optimise therapy in this patient group.

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A Double-Blind Randomized Prospective Study Comparing Ondansetron with Droperidol in the Prevention of Emesis following Strabismus Surgery

Anaesthesia and Intensive Care ◽

10.1177/0310057x9502300404 ◽

1995 ◽

Vol 23 (4) ◽

pp. 438-443 ◽

Cited By ~ 25

Author(s):

A. Davis ◽

S. Krige ◽

D. Moyes

Keyword(s):

Recovery Time ◽

Strabismus Surgery ◽

Double Blind Study ◽

Double Blind ◽

Oral Fluids ◽

Group A ◽

The Mean ◽

Group B ◽

To Receive ◽

Mean Time

A prospective double-blind study was conducted to compare the anti-emetic efficacy of ondansetron and droperidol in preventing postoperative emesis following strabismus surgery. A sample size of 213 patients was divided into three equal groups to receive ondansetron 150 μg/kg (Group A), ondansetron 75 μg/kg (Group B), or droperidol 75 fig/kg (Group C). All patients received a standardized anaesthetic technique. All episodes of emesis, recovery time, and time to tolerating oral fluids were recorded. The incidence of emesis during 24 hours was Groups A and B 19.7%, and Group C 28.2%. The lower incidence of emesis recorded by the ondansetron groups compared with the droperidol group was not statistically significant. Ondansetron at 75 μg/kg was as effective as 150 μg/kg in reducing emesis when compared with droperidol. Mean time to discharge from the recovery room was 75.3 minutes (Group A), 44.4 minutes (Group B), and 41.0 minutes (Group C). The mean time to tolerating oral fluids was 356.5 minutes (Group A), 402.8 minutes (Group B), and 378.1 minutes (Group C). There was no statistical difference in discharge times from recovery or time to tolerating oral fluids in any of the three groups.

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