Effects of the Oral Angiotensin II Type 2 Receptor Agonist C21 in Sugen-Hypoxia Induced Pulmonary Hypertension in Rats

Substantial evidence supports the involvement of the renin-angiotensin system in pulmonary hypertension (PH), and the angiotensin II type 2 receptor (AT2R) is known to exert tissue protective actions. The effect of the selective AT2R agonist C21 (also known as Compound 21 or buloxibutid) was evaluated in the rat Sugen-hypoxia PH model. After a single injection of Sugen 5416 and hypoxia for 21 days, C21 (2 or 20 mg/kg) or vehicle was administered perorally twice daily from Day 21 to Day 55. On Day 56, hemodynamic assessments were performed, and lung and heart tissue were prepared for quantification of cardiac and vascular remodeling and fibrosis. Treatment with C21 20 mg/kg improved cardiac output and stroke volume and decreased right ventricular hypertrophy (all p 100 μm (all p < 0.05). There were no significant differences between the two C21 doses on any parameter, and post hoc analyses comparing the merged C21 groups with the vehicle group showed that C21 treatment reduced vascular remodeling (reduced endothelial proliferation and thickening of the vascular wall) in vessels of all sizes; moreover, the diastolic pulmonary artery pressure and right ventricular pressure were reduced along with reduction of right ventricular hypertrophy. Sugen 5416 and hypoxia increased pulmonary collagen deposition, which was counteracted by C21 20 mg/kg. In conclusion, the effects of C21 on vascular remodeling, hemodynamic alterations, and fibrosis suggest that AT2R agonists may have a role in Group 1 and 3 PH treatment

A phase 2 trial investigating the efficacy and safety of the mPGES-1 inhibitor vipoglanstat in systemic sclerosis-related Raynaud's

OBJECTIVE: Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP.METHODS: Patients with systemic sclerosis (SSc) and ≥7 RP attacks during the last screening week prior to a baseline visit were randomised to four weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud's Condition Score, with change in RP attacks/week as primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory endpoints included patients' and physicians' global impression of change, Assessment of Scleroderma-associated Raynaud's Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites.RESULTS: Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). Mean weekly number of RP attacks (baseline; vipoglanstat 14.4[SD 6.7], placebo 18.2[12.6]) decreased by 3.4[95% CI -5.8;-1.0] and 4.2[-6.5;-2.0] attacks per week (p= 0.628) respectively. All patient reported outcomes improved, with no difference between the groups. Mean change in recovery of peripheral blood flow after cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in urine. Vipoglanstat was safe and well tolerated.CONCLUSION: Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role.</p

A phase 2 trial investigating the efficacy and safety of the mPGES-1 inhibitor vipoglanstat in systemic sclerosis-related Raynaud's

OBJECTIVE: Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP.METHODS: Patients with systemic sclerosis (SSc) and ≥7 RP attacks during the last screening week prior to a baseline visit were randomised to four weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud's Condition Score, with change in RP attacks/week as primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory endpoints included patients' and physicians' global impression of change, Assessment of Scleroderma-associated Raynaud's Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites.RESULTS: Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). Mean weekly number of RP attacks (baseline; vipoglanstat 14.4[SD 6.7], placebo 18.2[12.6]) decreased by 3.4[95% CI -5.8;-1.0] and 4.2[-6.5;-2.0] attacks per week (p= 0.628) respectively. All patient reported outcomes improved, with no difference between the groups. Mean change in recovery of peripheral blood flow after cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in urine. Vipoglanstat was safe and well tolerated.CONCLUSION: Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role.</p

Cell Recovery in Bronchoalveolar Lavage Fluid in Smokers Is Dependent on Cumulative Smoking History

Background: Smoking is a risk factor for various lung diseases in which BAL may be used as a part of a clinical investigation. Interpretation of BAL fluid cellularity is however difficult due to high variability, in particular among smokers. In this study we aimed to evaluate the effect of smoking on BAL cellular components in asymptomatic smokers. The effects of smoking cessation, age and gender were also investigated in groups of smokers and exsmokers. Methods: We performed a retrospective review of BAL findings, to our knowledge the largest single center investigation, in our department from 1999 to 2009. One hundred thirty two current smokers (48 males and 84 females) and 44 ex-smokers (16 males and 28 females) were included. A group of 295 (132 males and 163 females) never-smokers served as reference. Result: The median [5–95 pctl] total number of cells and cell concentration in current smokers were 63.4 [28.6–132.1]610 6 and 382.1 [189.7–864.3]610 6 /L respectively and correlated positively to the cumulative smoking history. Macrophages were the predominant cell type (96.7 % [90.4–99.0]) followed by lymphocytes (2 % [0.8–7.7]) and neutrophils (0.6 % [0–2.9]). The concentration of all inflammatory cells was increased in smokers compared to never smokers and ex-smokers. BAL fluid recovery was negatively correlated with age (p,0.001). Smoking men had a lower BAL fluid recovery than smoking women. Conclusion: Smoking has a profound effect on BAL fluid cellularity, which is dependent on smoking history. Our results performed on a large group of current smokers and ex-smokers in a well standardized way, can contribute to bette

Environmental correlates of impaired lung function in non-smokers with severe alpha 1-antitrypsin deficiency (PiZZ)

BACKGROUND: Active smoking is the most important risk factor for pulmonary emphysema in subjects with severe alpha 1-antitrypsin (AAT) deficiency. The aim of this study was to analyse the effects of environmental risk factors other than active smoking on lung function and on respiratory symptoms in non-smoking PiZZ individuals. METHODS: Lifetime exposure to passive smoking, domiciliary use of a kerosene (paraffin) heater or gas cooker, and all occupations since leaving school were reported by 205 non-smoking PiZZ individuals (95 men and 110 women) included in the Swedish AAT deficiency register. Lung function test results and histories of respiratory symptoms (chronic bronchitis, recurrent wheezing, and exertional dyspnoea) were elicited from the AAT register records. RESULTS: After adjustment for age, agricultural employment and domiciliary kerosene heater usage, but not gas cooker usage or passive smoking, were both associated with significantly decreased lung function. Multiple linear regression analysis showed age, sex, kerosene heater usage, and agricultural employment to be independent determinants of lung function impairment. Age and passive smoking for 10 years or more, both at home and at the work place, were associated with the presence of chronic bronchitis. Age and agricultural employment for > or = 10 years were associated with recurrent wheezing and exertional dyspnoea. CONCLUSIONS: Domiciliary kerosene heater usage and an agricultural occupation therefore appear to be environmental factors associated with decreased lung function in non-smoking PiZZ individuals, and passive smoking is associated with an increased frequency of chronic bronchitis, but not with impaired lung function

Two phase ii randomized trials on the CRTh2 antagonist AZD1981 in adults with asthma

Background: Chemoattractant receptor-homologous molecule expressed on T helper type 2 (Th2) cell (CRTh2) receptor antagonists is being investigated for asthma. Objectives: The aim of this study was to assess the effects of the CRTh2 receptor antagonist, AZD1981 (with/without inhaled corticosteroids [ICSs]), on lung function and asthma control. Patients and methods: Adults aged 18–60 years were enrolled in two randomized, placebo-controlled, parallel-group trials (protocol number: D9830C00003 [study 1, n=209] and protocol number: D9830C00004 [study 2, n=510]). In study 1, patients with stable asthma (forced expiratory volume in 1 second [FEV1]: 65%−110%) were withdrawn from ICS (<400 μg/d) and randomized to AZD1981 1,000 mg twice daily (bid) or placebo. In study 2, patients with uncontrolled asthma (FEV1: 40%−85%) despite ICS therapy (≥500 μg/d) were randomized to 50 mg, 400 mg, or 1,000 mg bid AZD1981 or placebo. The primary efficacy variable for both trials was the change in morning peak expiratory flow after 4 weeks of treatment. Secondary variables included Asthma Control Questionnaire (ACQ-5) scores, FEV1 assessments, safety, and tolerability. In study 2, efficacy was also assessed according to atopic status. Results: Following 4 weeks of treatment, there was a nonsignificant increase in morning peak expiratory flow on AZD1981 1,000 mg bid (9.5 L/min vs placebo, P=0.086 [study 1] and 12 L/min vs placebo, P=0.16 [study 2]). In study 2, all doses of AZD1981 provided significant improvements in ACQ-5 scores (0.26–0.3 units vs placebo, P=0.010–0.022); however, there was no dose–response relationship. Improved ACQ-5 scores and FEV1 were observed in the majority of atopic patients treated with AZD1981. AZD1981 was well tolerated across treatment groups. Conclusion: Further research may be warranted in atopic patients to fully evaluate the clinical efficacy of AZD1981

Effect of age and occupational exposure to airway irritants on lung function in non-smoking individuals with alpha 1-antitrypsin deficiency (PiZZ)

BACKGROUND: Severe alpha 1-antitrypsin (AAT) deficiency (PiZZ) is associated with an increased risk of lung emphysema, especially in smokers. The aim of this study was to identify risk factors other than smoking for declining lung function. METHODS: Lung function was studied in 225 self-reported never-smoking PiZZ individuals included in the Swedish AAT deficiency register. RESULTS: Lung function was poorer in men than in women (mean (SD) forced expiratory volume in one second (FEV1) 80 (30) versus 88 (17)% predicted) despite the fact that the men were younger (mean (SD) age 45 (18) versus 51 (17) years), and poorer in those aged 50 or older than in those aged under 50 (mean (SD) FEV1 70 (30) versus 98 (16)% predicted). Self-reported occupational exposure to gas, fumes, or dust occurred more frequently in men than in women. In those aged 50 or older lung function was lower in individuals exposed to airway irritants than those who were not exposed (mean (SD) FEV1 63 (29) versus 76 (31)% predicted). Male sex, increasing age, and previous symptoms of wheezing were independent risk factors for lung function impairment, and male sex, wheeziness, and occupational exposure to airway irritants were independent risk factors in the subjects aged 50 years or more. CONCLUSIONS: In non-smoking PiZZ individuals lung function declines with increasing age, especially after 50. Men are at greater risk of lung function deterioration than women. Asthmatic symptoms and occupational exposure to airway irritants appear to constitute additional risk factors

Effects of the Oral Angiotensin II Type 2 Receptor Agonist C21 in Sugen-Hypoxia Induced Pulmonary Hypertension in Rats

Substantial evidence supports the involvement of the renin-angiotensin system in pulmonary hypertension (PH), and the angiotensin II type 2 receptor (AT2R) is known to exert tissue protective actions. The effect of the selective AT2R agonist C21 (also known as Compound 21 or buloxibutid) was evaluated in the rat Sugen-hypoxia PH model. After a single injection of Sugen 5416 and hypoxia for 21 days, C21 (2 or 20 mg/kg) or vehicle was administered perorally twice daily from Day 21 to Day 55. On Day 56, hemodynamic assessments were performed, and lung and heart tissue were prepared for quantification of cardiac and vascular remodeling and fibrosis. Treatment with C21 20 mg/kg improved cardiac output and stroke volume and decreased right ventricular hypertrophy (all p 100 μm (all p 2R agonists may have a role in Group 1 and 3 PH treatment

Bronchoalveolar lavage results are independent of season, age, gender and collection site.

BACKGROUND: Clinical interpretation of bronchoalveolar lavage fluid results is dependent on the availability of reference values for healthy individuals. Only a few studies have published such reference values and the applicability of results is restricted by small sample sizes and the limited representativeness of the study population. We aim to investigate the influence of age, gender, collection site and season on bronchoalveolar lavage fluid results and to establish reference values for use in clinical practice. METHODOLOGY/PRINCIPAL FINDINGS: Bronchoalveolar lavage fluid data from 295 healthy never-smoking volunteers, investigated during 1990-2009, were analyzed retrospectively. 47 volunteers had 2-5 repeat lavages during the course of several years. Fluid recovery, total number of cells, cell concentration, and differential cell counts on cytospin prepared slides were recorded. Reference values, as represented by the 5(th) to the 95(th) percentile, were 72-96% for macrophages, 2-26% for lymphocytes, 0-4% for neutrophils and 0-1% for eosinophils. Basophils and mast cells were rare. When repeat lavages were performed, there was a relatively large intra-individual variability, mainly for macrophages and lymphocytes. An age dependent decrease of lavage fluid return was present, but there was no age dependent correlation with any of the other BALF parameters. The BALF cell parameters were independent of gender, season and site (lingula vs. middle lobe). CONCLUSIONS/SIGNIFICANCE: Our data show that bronchoalveolar lavage fluid cell differential count is independent of age, gender, season and collection site (RML or lingua). It therefore seems acceptable to use the same reference values for all never-smoking individuals