Vip Call Girls Anna Salai Chennai 👉 8250192130 ❣️💯 Top Class Girls Available
Effects of an anti tslp antibody on allergen-induced asthmatic
1. Effects of an Anti-TSLP(Anti
Thymic stromal lymphopoietin
antibody) on Allergen-Induced
Asthmatic Responses
DR JAWAD ALI
PGR MEDICINE KRL HOSPITAL ISLAMABAD
5. BACKGROUND
Thymic stromal lymphopoietin (TSLP) is an
epithelial-cell–derived protein belonging to cytokine
family that is implicated in allergic inflammation.
It is known to play an important role in the maturation
of T cell populations through activation of antigen
presenting cells.
6. BACKGROUND
TSLP signals through a hetero dimeric receptor
complex composed of the thymic stromal
lymphopoietin receptor CRLF2 and the IL-7R alpha
chain.
After binding STAT5 phosphorylation is induced
resulting in the expression of upstream transcription
factors
7.
8. BACKGROUND
Levels of human TSLP messenger RNA and protein
are increased in the airways of patients with asthma, as
compared with controls, and the magnitude of this
expression correlates with the severity of disease.
targeting TSLP may inhibit multiple biologic pathways
involved in asthma.
AMG 157 is a human anti-TSLP monoclonal
immunoglobulin G2λ that binds human TSLP and
prevents receptor interaction.
9. METHODS
ELIGIBLE PATIENTS
nonsmoking men and women
18 to 60 years of age
(FEV1) of 70% or more of the predicted value
all patients had no other lung disease.
No asthma-controller treatments were allowed during
the study although the use of inhaled short-acting
β2-agonists as rescue treatment administered fewer
than 2 days per week was permitted
All other asthma medications were discontinued at
least 4 weeks before enrollment.
10. EXCLUSION CRITERIA
Patients were excluded from the study
if they had worsening of asthma,
respiratory-related visits to the emergency department
within 6 weeks before study enrollment,
previous use of AMG 157
known sensitivity to any AMG 157 excipients
11. STUDY DESIGN
proof-of-concept,
Randomized double-blind
placebo-controlled study at five centers in Canada.
Patients were randomly assigned, in a 1:1 ratio, by
means of an interactive voice-response system to
receive 700 mg of AMG 157 or placebo in a 1-hour
intravenous infusion on study days 1, 29, and 57
12. STUDY ENDPOINTS
The primary end point was the late asthmatic
response, as measured 3 to 7 hours after the allergen
challenge.
The primary outcome measures USED maximum
percentage decrease in FEV1 and the area under the
curve (AUC) of the time-adjusted percent decrease in
FEV1.
13. STUDY ENDPOINTS
The secondary end points were the late response,
as measured by the minimum FEV1 and
the AUC of the time-adjusted minimum FEV1;
the early asthmatic response, as measured within
2 hours after the allergen challenge; and the
safety, side-effect profile, and immunogenicity
of AMG 157
14. STUDY ENDPOINTS
Exploratory end points included
levels of sputum and blood eosinophils
the fraction of exhaled nitric oxide
levels of type 2helper T (Th2) cells in the blood,
the ratio of Th2 cells to type 1 helper T (Th1) cells in
theblood,
total IgE levels in blood,
the provocative concentration of methacholine required to
reduce the FEV1 by 20% (methacholine PC20)
15.
16. LABAROTORY PROCEDURES
The allergen for inhalation was selected on the basis of
SKIN PRICK TESTING
early asthmatic response (0 to 2 hours after allergen
challenge)
late asthmatic response (3 to 7 hours after allergen
challenge).
Venous blood was sampled for determination of levels
of leukocytes, total IgE, and cytokines, and airway
eosinophils were sampled from induced sputum with
the use of a standard method.
17. STATISTICAL ANALYSIS
On the basis of evidence from previous studies
IT was determined that with 15 patients in each
group, the study would have a power of 80% to detect
an absolute between-group difference of 10 percentage
points in the maximum percent decrease in the FEV1
during the late response.
Included In the analysis for each end point all patients
who received at least one dose of AMG 157 or placebo.
18. RESULTS
STUDY POPULATION
From October 31, 2011, to April 5, 2013,
31 patients were enrolled (16 in the AMG-157 group and
15 in the placebo group).
All the patients received at least one dose of a study
drug in accordance with the randomization schedule.
A total of 28 patients (90%) completed the full
intervention period, and 27 (87%) completed the study
Of the 4 patients who did not complete the study, 3
were lost to follow-up
19.
20. STUDY ENDPOINTS
EARLY AND LATE ASTHMATIC RESPONSES
Treatment with AMG 157, as compared with placebo,
partially attenuated both the late response early response
at days 42 and 84.
The maximum percentage decrease in the FEV1 during the
late response was 34.0% smaller in the AMG-157 group than
in the placebo group
on day 42 (P = 0.09) and 45.9% smaller (a decrease of 11.7%
vs. 21.6%) on day 84 (P = 0.02).
21. STUDY ENDPOINTS
Patients in the AMG 157 ,COMPARED WITH THOSE
IN PLACEBO had a significant
increase in the minimum FEV1 (P = 0.01) and in the
AUC of the time-adjusted minimum FEV1 (P = 0.02)
during the late response on day 42 and in the
minimum FEV1 (P = 0.01) on day 84.
22.
23. BLOOD EOSINOPHILS
On day 29, the mean baseline blood eosinophil counts
decreased from 296.5±40.2 TO 121.9±14.7 per cubic
millimeter in theAMG-157 group
as compared with a decrease from 281.1±57.2 per cubic
millimeter to 224.1±36.5 per cubic millimeter in the
placebo group
Blood eosinophil counts increased on days 43 and 85, 1
day after the allergen challenges
the levels were significantly lower in the AMG 157
group than in the placebo group (P = 0.004).
25. SPUTUM EOSINOPHILS
Treatment with AMG 157 decreased levels of sputum
eosinophils before and after allergen challenge.
on day 83. As compared with placebo, AMG
157significantly reduced sputum eosinophil levels
before allergen challenge over the course of the study
(P = 0.02) and significantly attenuated allergen-
induced changes 24 hours after challenge (P = 0.004).
27. EXHALED NITRIC OXIDE
The fraction of exhaled nitric oxide was elevated in the
two study groups under baseline conditions.
treatment with AMG 157 significantly decreased the
fraction of exhaled nitric oxide throughout the study (P
= 0.002) and significantly attenuated allergen-induced
changes 24 hours after challenge (P = 0.02)
29. ADVERSE EVENTS
Treatment with AMG 157 was not associated with
changes in measured laboratory values, temperature,
blood pressure, pulse, or respiration.
There were NO ADVERSE EVENTS OR DEATHS .
30. CONCLUSION
All currently available asthma treatments attenuate
components of allergen-induced airway responses.
However only inhaled glucocorticoids attenuate
baseline airway levels of the fraction of exhaled nitric
oxide and eosinophils.
This early proof-of-concept study indicates that
targeting TSLP can reduce the fraction of exhaled
nitric oxide and blood and airway eosinophils
31. CONCLUSION
treatment for 12 weeks with AMG 157 reduced the
fraction of exhaled nitric oxide and blood and sputum
eosinophils in patients with allergic asthma.
This treatment also attenuated allergen-induced
changes in these inflammatory measures, as well as
the early and late asthmatic responses.
These results support further work on mechanisms of
action and investigation of the clinical benefit of AMG
157 in patients with poorly controlled asthma.