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Antioxidant Hope For Pulmonary Fibrosis
Antioxidant Hope For Pulmonary Fibrosis
"Increase in desferrioxamine-chelatable iron levels"
Public release date: 20-May-2008
Contact: Keely Savoie
ksavoie@thoracic.org
212-315-8620
American Thoracic Society
New treatment gives hope for pulmonary fibrosis patients
ATS 2008, TORONTO=E2=80=94Patients with idiopathic pulmonary fibrosis (IPF)
may have a new treatment option, according to researchers in Japan.
In a Phase III, double-blind, placebo-controlled clinical trial, the
investigators discovered that a daily dose of pirfenidone could slow
the progression of IPF, reducing the loss of lung capacity. The
results will be announced at the American Thoracic Society=E2=80=99s 2008
International Conference in Toronto on Tuesday, May 20.
=E2=80=9CThe most common treatment for IPF is anti-inflammatory agents such =
as
steroids,=E2=80=9D said lead researcher Takashi Ogura, M.D., of Kanagawa
Cardiovascular and Respiratory Center in Yokohama, Japan. =E2=80=9CHowever o=
ur
study confirmed that pirfenidone, the main action of which is thought
to be antifibrotic, achieved a therapeutic effect on IPF. I expect
that our study will serve as a guide to develop a new therapy for IPF
in the future.=E2=80=9D
The researchers recruited a total of 275 Japanese patients with mild
to moderate IPF and randomized them to a high dose pirfenidone (1,800
mg/day) group, a low dose pirfenidone group (1,200 mg/day) and a
placebo group. They measured lung capacity (vital capacity or VC) and
progression-free survival, defined as a period without death or a
greater than 10 percent decrease in VC, to determine the effectiveness
of the regimens.
At the end of one year, they found that patients who had been
randomized to the high dose regimen had significantly lower loss of VC
than the placebo group. Furthermore, pirfenidone slowed the overall
deterioration of IPF compared to the placebo.
=E2=80=9CTaken altogether, our study demonstrated positive clinical effects =
of
pirfenidone that suppresses the progress of IPF and potentially
contributes to improving the outcomes of patients with IPF,=E2=80=9D said Dr=
.
Ogura.
Pirfenidone represents new hope, not only for IPF patients who
currently have no curative treatment options, but because it is
thought to be an antifibrotic agent, it may be able to treat other
fibrotic lung diseases, such as interstitial pneumonia with collagen
vascular disease and extrapulmonary fibrosis.
=E2=80=9CWe will continue the follow-up of the patient cohort included in th=
is
study to identify whether pirfenidone can contribute to prolonged
survival in patients with IPF,=E2=80=9D said Dr. Ogura. =E2=80=9COther clini=
cal
studies of pirfenidone are also being conducted in the U.S. and
Europe, and we hope that our results will be replicated there.=E2=80=9D
###
Press Conference: Tuesday, May 20, 7:15 a.m., Room 101, North
Building, Metro Toronto Convention Centre
The research was funded by: Shionogi & Co., Ltd.
----------------------------------------------------------------------------=
----
Description
Pirfenidone is an orally active small molecule drug that may inhibit
collagen synthesis, down regulate production of multiple cytokines and
block fibroblast proliferation and stimulation in response to
cytokines. Pirfenidone has demonstrated activity in multiple fibrotic
conditions, including those of the lung, kidney and liver.
Investigational Activity
Pirfenidone for idiopathic pulmonary fibrosis (IPF) has been studied
in multiple Phase 2 clinical trials.
We completed enrollment for CAPACITY, a Phase 3 clinical program
evaluating pirfenidone in patients with IPF, in May 2007.
Investigational, not an FDA approved product.
-------------------------
NEW HOPE FOR IPF PATIENTS? PIRFENIDONE SHOWS PROMISE IN CLINICAL
TRIALS
Key Point
The novel anti-inflammatory, antioxidant, and antifibrotic agent
pirfenidone may reduce exacerbations and improve lung function in IPF
patients.
TOKYO=E2=80=94New research suggests that pirfenidone, a novel agent with ant=
i-
inflammatory, antioxidant, and antifibrotic properties, may improve
lung function and reduce the number of acute exacerbations in patients
with idiopathic pulmonary fibrosis (IPF). In fact, the study was
terminated early because the reduction in exacerbations was so
significant that the review board wanted to allow all participants to
take the drug.1
STEM CELLS TESTED
Ganesh Raghu, MD, and colleagues randomized 107 corticosteroid-na=C3=AFve
IPF patients to receive treatment with pirfenidone or placebo; follow-
up lasted nine months. All patients were on a dose-titration schedule
of 200 mg three times a day for the first two days, 400 mg three times
a day for the next two days, and 600 mg three times a day (maximum
dose) for the last three days. The maximum dose was maintained
throughout the study in patients who tolerated it. Patients not
tolerating the maximum dose received a reduced dose. Primary end
points included the difference in the change of the lowest oxygen
saturation by pulse oximetry during two six-minute exercise tests
administered at baseline and again at six months. Secondary end points
included lung function (vital capacity [VC]) and episodes of acute IPF
exacerbation. According to the authors, =E2=80=9CThe most striking and
clinically important findings noted were that the episodes of acute
exacerbation of IPF manifested exclusively in the placebo group and
there was a lesser decline in change in VC in patients receiving
pirfenidone.=E2=80=9D
SECONDARY END POINTS IMPROVE
There were no statistically significant differences between groups in
the change in oxygen saturation during the six-minute exercise test
(the primary end point), though the pirfenidone group did show an
increase from baseline, versus a decrease in the placebo group. The
patients in the pirfenidone group, however, experienced significant
improvements in the secondary end points. At nine months, the
difference in decline of VC between groups was =E2=80=930.13 L in the placeb=
o
group and =E2=80=930.03 L in the treatment group. Ground-glass and reticular=
opacities on high-resolution CTs were reduced in 15% of pirfenidone
patients versus 7% of placebo patients.
Most importantly, none of the pirfenidone recipients experienced an
acute IPF exacerbation during nine months. In contrast, 14% of placebo
recipients had an exacerbation (one of whom died). Because of these
data, the study was aborted and the drug was given to placebo
patients. =E2=80=9CThe implication of the prevention of acute exacerbation b=
y
pirfenidone is potentially crucial for the prognosis of IPF, as these
episodes often have a fatal outcome despite aggressive levels of
supportive care in the [ICU],=E2=80=9D stressed the authors.
Compliance rates at both six and nine months were similar between
groups: About 85% of pirfenidone and 81% of placebo patients were
compliant at six months, and 78% of both groups were adherent at nine
months. Pirfenidone, however, was not without adverse effects; in
fact, about half of the patients were taking a reduced dose at nine
months due to side effects. The most common of these were
photosensitivity, vomiting, fever, and hepatic dysfunction. Most of
these symptoms disappeared once the medication was decreased or
stopped.
WHAT DOES THE FUTURE HOLD?
=E2=80=9CAn efficacious treatment regimen for IPF is long overdue,=E2=80=9D =
wrote the
authors. In an accompanying editorial, Roland M. du Bois, MD, cited
some dismal results for trials of interferon-=CE=B3 and mentioned that
studies involving antitumor necrosis factor-=CE=B1 and antiendothelin dual-
receptor antagonists are on the horizon.2 Although the pirfenidone
study looks promising, Dr. du Bois cited the end point issue and
asked, =E2=80=9CWhat is the most appropriate measure of change to be used in=
clinical trials?=E2=80=9D The study authors acknowledge that their primary e=
nd
point needs to be validated, and the clinical relevance of other
outcome measures must be determined in order for treatments to be
tested effectively. =E2=80=9CIPF has a mortality greater than some cancers,=
=E2=80=9D
maintained Dr. du Bois. =E2=80=9CWe need to follow the model of cancer trial=
s:
comparison of current =E2=80=98best therapy=E2=80=99 with novel drugs,=E2=80=
=9D in large
trials that are powered to provide answers.
=E2=80=94Tamara Gibb
References
1. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-
controlled trial of pirfenidone in patients with idiopathic pulmonary
fibrosis. Am J Respir Crit Care Med. 2005;171:1040-1047.
2. du Bois RM. Is idiopathic pulmonary fibrosis now treatable? Am J
Respir Crit Care Med. 2005;171:939-940.
-------------------------
"Increase in desferrioxamine-chelatable iron levels"
Am J Respir Crit Care Med 1996 Jun;153(6 Pt 1):1918-23
Serum indicators of free radical activity in idiopathic pulmonary
fibrosis.
Jack CI, Jackson MJ, Johnston ID, Hind CR
The University Department of Medicine, University of Liverpool,
United
Kingdom.
Serum levels of free radical activity were measured in 37 patients
with idiopathic pulmonary fibrosis (IPF) and 16 control subjects.
Three assays used were (1) simultaneously measured levels of the 9,11-
diene conjugate of linoleic acid and 9,12-linoleic acid expressed as a
percent molar ratio (%MR), a measure of free-radical-mediated lipid
peroxidation; (2) thiobarbituric acid reactive substances (TBARS), one
of which is malondialdehyde; (3) desferrioxamine-chelatable iron
assay, a measure of the
potential iron available to catalyze free radical generation.
Mean %MR, TBARS and desferrioxamine-chelatable iron were all elevated
initially in patients with IPF compared with control subjects (%MR, p
< 0.0001; TBARS, p =3D 0.0013; desferrioxamine-chelatable iron, p =3D
0.0029).
Furthermore, the serum %MR was higher in a subset of patients with
clinically worsening IPF than in those patients with clinically stable
disease (p =3D 0.002).
Treatment did not appear to affect the three different serum
indicators of free radical activity.
Thus, lipid peroxidation appears to be increased in patients with IPF
and is associated with an increase in desferrioxamine-chelatable iron
levels.
Serum % MR levels appeared to correlate with clinical disease
activity, and they may have a role in monitoring disease activity.
PMID: 8665056, UI: 96279783
---------------------------------------------------------------------------=
=C2=AD-
----
Who loves ya.
Tom
Jesus Was A Vegetarian!
http :// tinyurl,com /2r2nkh
Man Is A Herbivore!
http :// tinyurl,com /a3cc3
DEAD PEOPLE WALKING
http :// tinyurl,com /zk9fk
"Increase in desferrioxamine-chelatable iron levels"
Public release date: 20-May-2008
Contact: Keely Savoie
ksavoie@thoracic.org
212-315-8620
American Thoracic Society
New treatment gives hope for pulmonary fibrosis patients
ATS 2008, TORONTO=E2=80=94Patients with idiopathic pulmonary fibrosis (IPF)
may have a new treatment option, according to researchers in Japan.
In a Phase III, double-blind, placebo-controlled clinical trial, the
investigators discovered that a daily dose of pirfenidone could slow
the progression of IPF, reducing the loss of lung capacity. The
results will be announced at the American Thoracic Society=E2=80=99s 2008
International Conference in Toronto on Tuesday, May 20.
=E2=80=9CThe most common treatment for IPF is anti-inflammatory agents such =
as
steroids,=E2=80=9D said lead researcher Takashi Ogura, M.D., of Kanagawa
Cardiovascular and Respiratory Center in Yokohama, Japan. =E2=80=9CHowever o=
ur
study confirmed that pirfenidone, the main action of which is thought
to be antifibrotic, achieved a therapeutic effect on IPF. I expect
that our study will serve as a guide to develop a new therapy for IPF
in the future.=E2=80=9D
The researchers recruited a total of 275 Japanese patients with mild
to moderate IPF and randomized them to a high dose pirfenidone (1,800
mg/day) group, a low dose pirfenidone group (1,200 mg/day) and a
placebo group. They measured lung capacity (vital capacity or VC) and
progression-free survival, defined as a period without death or a
greater than 10 percent decrease in VC, to determine the effectiveness
of the regimens.
At the end of one year, they found that patients who had been
randomized to the high dose regimen had significantly lower loss of VC
than the placebo group. Furthermore, pirfenidone slowed the overall
deterioration of IPF compared to the placebo.
=E2=80=9CTaken altogether, our study demonstrated positive clinical effects =
of
pirfenidone that suppresses the progress of IPF and potentially
contributes to improving the outcomes of patients with IPF,=E2=80=9D said Dr=
.
Ogura.
Pirfenidone represents new hope, not only for IPF patients who
currently have no curative treatment options, but because it is
thought to be an antifibrotic agent, it may be able to treat other
fibrotic lung diseases, such as interstitial pneumonia with collagen
vascular disease and extrapulmonary fibrosis.
=E2=80=9CWe will continue the follow-up of the patient cohort included in th=
is
study to identify whether pirfenidone can contribute to prolonged
survival in patients with IPF,=E2=80=9D said Dr. Ogura. =E2=80=9COther clini=
cal
studies of pirfenidone are also being conducted in the U.S. and
Europe, and we hope that our results will be replicated there.=E2=80=9D
###
Press Conference: Tuesday, May 20, 7:15 a.m., Room 101, North
Building, Metro Toronto Convention Centre
The research was funded by: Shionogi & Co., Ltd.
----------------------------------------------------------------------------=
----
Description
Pirfenidone is an orally active small molecule drug that may inhibit
collagen synthesis, down regulate production of multiple cytokines and
block fibroblast proliferation and stimulation in response to
cytokines. Pirfenidone has demonstrated activity in multiple fibrotic
conditions, including those of the lung, kidney and liver.
Investigational Activity
Pirfenidone for idiopathic pulmonary fibrosis (IPF) has been studied
in multiple Phase 2 clinical trials.
We completed enrollment for CAPACITY, a Phase 3 clinical program
evaluating pirfenidone in patients with IPF, in May 2007.
Investigational, not an FDA approved product.
-------------------------
NEW HOPE FOR IPF PATIENTS? PIRFENIDONE SHOWS PROMISE IN CLINICAL
TRIALS
Key Point
The novel anti-inflammatory, antioxidant, and antifibrotic agent
pirfenidone may reduce exacerbations and improve lung function in IPF
patients.
TOKYO=E2=80=94New research suggests that pirfenidone, a novel agent with ant=
i-
inflammatory, antioxidant, and antifibrotic properties, may improve
lung function and reduce the number of acute exacerbations in patients
with idiopathic pulmonary fibrosis (IPF). In fact, the study was
terminated early because the reduction in exacerbations was so
significant that the review board wanted to allow all participants to
take the drug.1
STEM CELLS TESTED
Ganesh Raghu, MD, and colleagues randomized 107 corticosteroid-na=C3=AFve
IPF patients to receive treatment with pirfenidone or placebo; follow-
up lasted nine months. All patients were on a dose-titration schedule
of 200 mg three times a day for the first two days, 400 mg three times
a day for the next two days, and 600 mg three times a day (maximum
dose) for the last three days. The maximum dose was maintained
throughout the study in patients who tolerated it. Patients not
tolerating the maximum dose received a reduced dose. Primary end
points included the difference in the change of the lowest oxygen
saturation by pulse oximetry during two six-minute exercise tests
administered at baseline and again at six months. Secondary end points
included lung function (vital capacity [VC]) and episodes of acute IPF
exacerbation. According to the authors, =E2=80=9CThe most striking and
clinically important findings noted were that the episodes of acute
exacerbation of IPF manifested exclusively in the placebo group and
there was a lesser decline in change in VC in patients receiving
pirfenidone.=E2=80=9D
SECONDARY END POINTS IMPROVE
There were no statistically significant differences between groups in
the change in oxygen saturation during the six-minute exercise test
(the primary end point), though the pirfenidone group did show an
increase from baseline, versus a decrease in the placebo group. The
patients in the pirfenidone group, however, experienced significant
improvements in the secondary end points. At nine months, the
difference in decline of VC between groups was =E2=80=930.13 L in the placeb=
o
group and =E2=80=930.03 L in the treatment group. Ground-glass and reticular=
opacities on high-resolution CTs were reduced in 15% of pirfenidone
patients versus 7% of placebo patients.
Most importantly, none of the pirfenidone recipients experienced an
acute IPF exacerbation during nine months. In contrast, 14% of placebo
recipients had an exacerbation (one of whom died). Because of these
data, the study was aborted and the drug was given to placebo
patients. =E2=80=9CThe implication of the prevention of acute exacerbation b=
y
pirfenidone is potentially crucial for the prognosis of IPF, as these
episodes often have a fatal outcome despite aggressive levels of
supportive care in the [ICU],=E2=80=9D stressed the authors.
Compliance rates at both six and nine months were similar between
groups: About 85% of pirfenidone and 81% of placebo patients were
compliant at six months, and 78% of both groups were adherent at nine
months. Pirfenidone, however, was not without adverse effects; in
fact, about half of the patients were taking a reduced dose at nine
months due to side effects. The most common of these were
photosensitivity, vomiting, fever, and hepatic dysfunction. Most of
these symptoms disappeared once the medication was decreased or
stopped.
WHAT DOES THE FUTURE HOLD?
=E2=80=9CAn efficacious treatment regimen for IPF is long overdue,=E2=80=9D =
wrote the
authors. In an accompanying editorial, Roland M. du Bois, MD, cited
some dismal results for trials of interferon-=CE=B3 and mentioned that
studies involving antitumor necrosis factor-=CE=B1 and antiendothelin dual-
receptor antagonists are on the horizon.2 Although the pirfenidone
study looks promising, Dr. du Bois cited the end point issue and
asked, =E2=80=9CWhat is the most appropriate measure of change to be used in=
clinical trials?=E2=80=9D The study authors acknowledge that their primary e=
nd
point needs to be validated, and the clinical relevance of other
outcome measures must be determined in order for treatments to be
tested effectively. =E2=80=9CIPF has a mortality greater than some cancers,=
=E2=80=9D
maintained Dr. du Bois. =E2=80=9CWe need to follow the model of cancer trial=
s:
comparison of current =E2=80=98best therapy=E2=80=99 with novel drugs,=E2=80=
=9D in large
trials that are powered to provide answers.
=E2=80=94Tamara Gibb
References
1. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-
controlled trial of pirfenidone in patients with idiopathic pulmonary
fibrosis. Am J Respir Crit Care Med. 2005;171:1040-1047.
2. du Bois RM. Is idiopathic pulmonary fibrosis now treatable? Am J
Respir Crit Care Med. 2005;171:939-940.
-------------------------
"Increase in desferrioxamine-chelatable iron levels"
Am J Respir Crit Care Med 1996 Jun;153(6 Pt 1):1918-23
Serum indicators of free radical activity in idiopathic pulmonary
fibrosis.
Jack CI, Jackson MJ, Johnston ID, Hind CR
The University Department of Medicine, University of Liverpool,
United
Kingdom.
Serum levels of free radical activity were measured in 37 patients
with idiopathic pulmonary fibrosis (IPF) and 16 control subjects.
Three assays used were (1) simultaneously measured levels of the 9,11-
diene conjugate of linoleic acid and 9,12-linoleic acid expressed as a
percent molar ratio (%MR), a measure of free-radical-mediated lipid
peroxidation; (2) thiobarbituric acid reactive substances (TBARS), one
of which is malondialdehyde; (3) desferrioxamine-chelatable iron
assay, a measure of the
potential iron available to catalyze free radical generation.
Mean %MR, TBARS and desferrioxamine-chelatable iron were all elevated
initially in patients with IPF compared with control subjects (%MR, p
< 0.0001; TBARS, p =3D 0.0013; desferrioxamine-chelatable iron, p =3D
0.0029).
Furthermore, the serum %MR was higher in a subset of patients with
clinically worsening IPF than in those patients with clinically stable
disease (p =3D 0.002).
Treatment did not appear to affect the three different serum
indicators of free radical activity.
Thus, lipid peroxidation appears to be increased in patients with IPF
and is associated with an increase in desferrioxamine-chelatable iron
levels.
Serum % MR levels appeared to correlate with clinical disease
activity, and they may have a role in monitoring disease activity.
PMID: 8665056, UI: 96279783
---------------------------------------------------------------------------=
=C2=AD-
----
Who loves ya.
Tom
Jesus Was A Vegetarian!
http :// tinyurl,com /2r2nkh
Man Is A Herbivore!
http :// tinyurl,com /a3cc3
DEAD PEOPLE WALKING
http :// tinyurl,com /zk9fk
