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KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma.

Abstract Mast cells are present in the airways of patients who have severe asthma despite glucocorticoid treatment; these cells are associated with disease characteristics including poor quality of life and inadequate asthma control. Stem cell factor and its receptor, KIT, are central to mast-cell homeostasis. We conducted a proof-of-principle trial to evaluate the effect of imatinib, a KIT inhibitor, on airway hyperresponsiveness, a physiological marker of severe asthma, as well as on airway mast-cell numbers and activation in patients with severe asthma.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title the new england journal of medicine
Publication Year Start




PMID- 28514613
OWN - NLM
STAT- MEDLINE
DA  - 20170517
DCOM- 20170522
LR  - 20170522
IS  - 1533-4406 (Electronic)
IS  - 0028-4793 (Linking)
VI  - 376
IP  - 20
DP  - 2017 May 18
TI  - KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma.
PG  - 1911-1920
LID - 10.1056/NEJMoa1613125 [doi]
AB  - BACKGROUND: Mast cells are present in the airways of patients who have severe
      asthma despite glucocorticoid treatment; these cells are associated with disease 
      characteristics including poor quality of life and inadequate asthma control.
      Stem cell factor and its receptor, KIT, are central to mast-cell homeostasis. We 
      conducted a proof-of-principle trial to evaluate the effect of imatinib, a KIT
      inhibitor, on airway hyperresponsiveness, a physiological marker of severe
      asthma, as well as on airway mast-cell numbers and activation in patients with
      severe asthma. METHODS: We conducted a randomized, double-blind,
      placebo-controlled, 24-week trial of imatinib in patients with poorly controlled 
      severe asthma who had airway hyperresponsiveness despite receiving maximal
      medical therapy. The primary end point was the change in airway
      hyperresponsiveness, measured as the concentration of methacholine required to
      decrease the forced expiratory volume in 1 second by 20% (PC20). Patients also
      underwent bronchoscopy. RESULTS: Among the 62 patients who underwent
      randomization, imatinib treatment reduced airway hyperresponsiveness to a greater
      extent than did placebo. At 6 months, the methacholine PC20 increased by a mean
      (+/-SD) of 1.73+/-0.60 doubling doses in the imatinib group, as compared with
      1.07+/-0.60 doubling doses in the placebo group (P=0.048). Imatinib also reduced 
      levels of serum tryptase, a marker of mast-cell activation, to a greater extent
      than did placebo (decrease of 2.02+/-2.32 vs. 0.56+/-1.39 ng per milliliter,
      P=0.02). Airway mast-cell counts declined in both groups. Muscle cramps and
      hypophosphatemia were more common in the imatinib group than in the placebo
      group. CONCLUSIONS: In patients with severe asthma, imatinib decreased airway
      hyperresponsiveness, mast-cell counts, and tryptase release. These results
      suggest that KIT-dependent processes and mast cells contribute to the
      pathobiologic basis of severe asthma. (Funded by the National Institutes of
      Health and others; ClinicalTrials.gov number, NCT01097694 .).
FAU - Cahill, Katherine N
AU  - Cahill KN
AD  - From Brigham and Women's Hospital, Harvard Medical School, Boston (K.N.C.,
      H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes
      for BioMedical Research, Cambridge (S.K.) - both in Massachusetts; Washington
      University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia
      University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.);
      University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University,
      Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) - both
      in Pennsylvania; and National Jewish Health, Denver (M.E.W.).
FAU - Katz, Howard R
AU  - Katz HR
AD  - From Brigham and Women's Hospital, Harvard Medical School, Boston (K.N.C.,
      H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes
      for BioMedical Research, Cambridge (S.K.) - both in Massachusetts; Washington
      University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia
      University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.);
      University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University,
      Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) - both
      in Pennsylvania; and National Jewish Health, Denver (M.E.W.).
FAU - Cui, Jing
AU  - Cui J
AD  - From Brigham and Women's Hospital, Harvard Medical School, Boston (K.N.C.,
      H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes
      for BioMedical Research, Cambridge (S.K.) - both in Massachusetts; Washington
      University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia
      University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.);
      University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University,
      Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) - both
      in Pennsylvania; and National Jewish Health, Denver (M.E.W.).
FAU - Lai, Juying
AU  - Lai J
AD  - From Brigham and Women's Hospital, Harvard Medical School, Boston (K.N.C.,
      H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes
      for BioMedical Research, Cambridge (S.K.) - both in Massachusetts; Washington
      University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia
      University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.);
      University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University,
      Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) - both
      in Pennsylvania; and National Jewish Health, Denver (M.E.W.).
FAU - Kazani, Shamsah
AU  - Kazani S
AD  - From Brigham and Women's Hospital, Harvard Medical School, Boston (K.N.C.,
      H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes
      for BioMedical Research, Cambridge (S.K.) - both in Massachusetts; Washington
      University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia
      University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.);
      University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University,
      Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) - both
      in Pennsylvania; and National Jewish Health, Denver (M.E.W.).
FAU - Crosby-Thompson, Allison
AU  - Crosby-Thompson A
AD  - From Brigham and Women's Hospital, Harvard Medical School, Boston (K.N.C.,
      H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes
      for BioMedical Research, Cambridge (S.K.) - both in Massachusetts; Washington
      University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia
      University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.);
      University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University,
      Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) - both
      in Pennsylvania; and National Jewish Health, Denver (M.E.W.).
FAU - Garofalo, Denise
AU  - Garofalo D
AD  - From Brigham and Women's Hospital, Harvard Medical School, Boston (K.N.C.,
      H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes
      for BioMedical Research, Cambridge (S.K.) - both in Massachusetts; Washington
      University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia
      University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.);
      University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University,
      Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) - both
      in Pennsylvania; and National Jewish Health, Denver (M.E.W.).
FAU - Castro, Mario
AU  - Castro M
AD  - From Brigham and Women's Hospital, Harvard Medical School, Boston (K.N.C.,
      H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes
      for BioMedical Research, Cambridge (S.K.) - both in Massachusetts; Washington
      University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia
      University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.);
      University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University,
      Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) - both
      in Pennsylvania; and National Jewish Health, Denver (M.E.W.).
FAU - Jarjour, Nizar
AU  - Jarjour N
AD  - From Brigham and Women's Hospital, Harvard Medical School, Boston (K.N.C.,
      H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes
      for BioMedical Research, Cambridge (S.K.) - both in Massachusetts; Washington
      University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia
      University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.);
      University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University,
      Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) - both
      in Pennsylvania; and National Jewish Health, Denver (M.E.W.).
FAU - DiMango, Emily
AU  - DiMango E
AD  - From Brigham and Women's Hospital, Harvard Medical School, Boston (K.N.C.,
      H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes
      for BioMedical Research, Cambridge (S.K.) - both in Massachusetts; Washington
      University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia
      University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.);
      University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University,
      Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) - both
      in Pennsylvania; and National Jewish Health, Denver (M.E.W.).
FAU - Erzurum, Serpil
AU  - Erzurum S
AD  - From Brigham and Women's Hospital, Harvard Medical School, Boston (K.N.C.,
      H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes
      for BioMedical Research, Cambridge (S.K.) - both in Massachusetts; Washington
      University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia
      University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.);
      University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University,
      Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) - both
      in Pennsylvania; and National Jewish Health, Denver (M.E.W.).
FAU - Trevor, Jennifer L
AU  - Trevor JL
AD  - From Brigham and Women's Hospital, Harvard Medical School, Boston (K.N.C.,
      H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes
      for BioMedical Research, Cambridge (S.K.) - both in Massachusetts; Washington
      University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia
      University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.);
      University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University,
      Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) - both
      in Pennsylvania; and National Jewish Health, Denver (M.E.W.).
FAU - Shenoy, Kartik
AU  - Shenoy K
AD  - From Brigham and Women's Hospital, Harvard Medical School, Boston (K.N.C.,
      H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes
      for BioMedical Research, Cambridge (S.K.) - both in Massachusetts; Washington
      University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia
      University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.);
      University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University,
      Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) - both
      in Pennsylvania; and National Jewish Health, Denver (M.E.W.).
FAU - Chinchilli, Vernon M
AU  - Chinchilli VM
AD  - From Brigham and Women's Hospital, Harvard Medical School, Boston (K.N.C.,
      H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes
      for BioMedical Research, Cambridge (S.K.) - both in Massachusetts; Washington
      University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia
      University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.);
      University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University,
      Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) - both
      in Pennsylvania; and National Jewish Health, Denver (M.E.W.).
FAU - Wechsler, Michael E
AU  - Wechsler ME
AD  - From Brigham and Women's Hospital, Harvard Medical School, Boston (K.N.C.,
      H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes
      for BioMedical Research, Cambridge (S.K.) - both in Massachusetts; Washington
      University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia
      University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.);
      University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University,
      Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) - both
      in Pennsylvania; and National Jewish Health, Denver (M.E.W.).
FAU - Laidlaw, Tanya M
AU  - Laidlaw TM
AD  - From Brigham and Women's Hospital, Harvard Medical School, Boston (K.N.C.,
      H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes
      for BioMedical Research, Cambridge (S.K.) - both in Massachusetts; Washington
      University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia
      University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.);
      University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University,
      Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) - both
      in Pennsylvania; and National Jewish Health, Denver (M.E.W.).
FAU - Boyce, Joshua A
AU  - Boyce JA
AD  - From Brigham and Women's Hospital, Harvard Medical School, Boston (K.N.C.,
      H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes
      for BioMedical Research, Cambridge (S.K.) - both in Massachusetts; Washington
      University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia
      University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.);
      University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University,
      Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) - both
      in Pennsylvania; and National Jewish Health, Denver (M.E.W.).
FAU - Israel, Elliot
AU  - Israel E
AD  - From Brigham and Women's Hospital, Harvard Medical School, Boston (K.N.C.,
      H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes
      for BioMedical Research, Cambridge (S.K.) - both in Massachusetts; Washington
      University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia
      University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.);
      University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University,
      Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) - both
      in Pennsylvania; and National Jewish Health, Denver (M.E.W.).
LA  - eng
SI  - ClinicalTrials.gov/NCT01097694
GR  - U01 HL102225/HL/NHLBI NIH HHS/United States
GR  - R01 HL117945/HL/NHLBI NIH HHS/United States
GR  - R01 AI078908/AI/NIAID NIH HHS/United States
GR  - R37 AI052353/AI/NIAID NIH HHS/United States
GR  - T32 AI007306/AI/NIAID NIH HHS/United States
GR  - K23 AI118804/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PL  - United States
TA  - N Engl J Med
JT  - The New England journal of medicine
JID - 0255562
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0W5ETF9M2K (Methacholine Chloride)
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - EC 3.4.21.59 (Tryptases)
SB  - AIM
SB  - IM
CIN - N Engl J Med. 2017 May 18;376(20):1983-1984. PMID: 28514622
MH  - Adult
MH  - Asthma/*drug therapy/immunology/physiopathology
MH  - Bronchial Hyperreactivity/drug therapy
MH  - Bronchial Provocation Tests
MH  - Cell Count
MH  - Double-Blind Method
MH  - Female
MH  - Forced Expiratory Volume/drug effects
MH  - Humans
MH  - Imatinib Mesylate/adverse effects/*therapeutic use
MH  - Male
MH  - Mast Cells/*metabolism
MH  - Methacholine Chloride
MH  - Middle Aged
MH  - Protein Kinase Inhibitors/adverse effects/*therapeutic use
MH  - Quality of Life
MH  - Tryptases/blood/secretion
EDAT- 2017/05/18 06:00
MHDA- 2017/05/23 06:00
CRDT- 2017/05/18 06:00
AID - 10.1056/NEJMoa1613125 [doi]
PST - ppublish
SO  - N Engl J Med. 2017 May 18;376(20):1911-1920. doi: 10.1056/NEJMoa1613125.

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