ironjustice
2011-03-26 14:49:47 UTC
Asthma Drug Could Help Control Or Treat Alzheimer’s Disease
Released: 3/25/2011 11:35 AM EDT
Source: Temple University
Newswise — A drug used to treat asthma has been shown to help reduce
the formation of amyloid beta, a peptide in the brain that is
implicated in the development of Alzheimer’s disease, according to
researchers at Temple University’s School of Medicine.
The researchers published their findings, “Pharmacologic Blockade of 5-
Lipoxygenase Improves the Amyloidotic Phenotype of an AD Transgenic
Mouse Model,” in the American Journal of Pathology.
In previous studies, the Temple researchers discovered that 5-
lipoxygenase, an enzyme long known to exist in the brain, controls the
activation state of gamma secretase, another enzyme that is necessary
and responsible for the final production of amyloid beta. When
produced in excess, amyloid beta causes neuronal death and forms
plaques in the brain. The amount of these amyloid plaques in the brain
is used as a measurement of the severity of Alzheimer's.
In their current study, led by Domenico Praticò, an associate
professor of pharmacology in Temple’s School of Medicine, the
researchers tested the drug Zileuton, an inhibitor of 5-lipoxygenase
typically used to treat asthma, in a transgenic mouse model of
Alzheimer’s disease. At the end of the treatment they found that this
drug, by blocking the 5-lipoxygenase, reduced gamma secretase’s
production of amyloid beta and the subsequent build up of amyloid
plaques in the brain by more than 50 percent.
Praticò said that gamma secretase is present throughout the body and,
despite its role in the development of amyloid plaques, plays a
significant role in numerous important functions. Direct inhibitors of
gamma secretase are known, he said, but blocking the enzyme completely
may cause problems such as the development of cancer. Unlike classical
gamma secretase inhibitors, Zileuton only modulates the protein
expression levels, which keeps some of its vital functions in tact
while blocking many of its bad effects, which in this case is the
development of the amyloid plaques.
Praticò and his colleagues have begun working with researchers in
Temple’s Moulder Center for Drug Discovery Research to create more
potent inhibitors that can target 5-lipoxygenase in the brain and
increase the ability to reduce amyloid plaque formation and the
development of Alzheimer’s. Because Zileuton is already FDA approved,
it is known that 5-lipoxygenase inhibition is an acceptable target
that is not associated with overt toxicity and therefore not harmful
to patients. The new drug derivative might be expected to advance to
clinical trials relatively easily.
“This drug is already on the market and, most importantly, is already
FDA-approved, so you don’t need to go through an intense drug
discovery process,” said Praticò. “So we could quickly begin a
clinical trial to determine if there is a new application for this
drug against a disease where there is currently nothing.”
The study was funded by the National Institutes of Health and the
Alzheimer’s Association.
Copies of this study are available to working journalists and may be
obtained by contacting Preston M. Moretz in Temple’s Office of
University Communications at ***@temple.edu.
----------
Neuropharmacology and Analgesia
CJ-13610, an orally active inhibitor of 5-lipoxygenase is
efficacious in preclinical models of pain
Luz A. Cortes-Burgos, a, , Ben S. Zweifela,
Steven L. Settlea, Robert A. Pufahla,
Gary D. Andersona, Medora M. Hardya,
Dana E. Weira, George Hua, Fernando A. Happaa,
Zachary Stewarta, Shanmugam Muthiana,
Matthew J. Granetoa and Jaime L. Masferrera
aPfizer Global Research & Development,
St. Louis Laboratories, Pfizer Inc, St. Louis, MO 63017
Received 27 April 2009; revised 18 June 2009;
accepted 22 June 2009. Available online 4 July 2009.
Abstract
Zileuton, a redox and iron chelator 5-lipoxygenase (5-LOX) inhibitor
and, leukotriene receptor antagonists are presently used clinically
in the long term treatment of asthma.
Recent data implicate 5-LOX pathway in pain signaling.
We report 5-LOX expression in the central nervous system (CNS)
and analyze the pain efficacy of a new class of non redox, non
iron chelating 5-LOX inhibitor.
CJ-13610, 4-(3-(4-(2-methyl-1H-imidazol-1-yl) phenylthio)
phenyl)-tetrahydro-2H-pyran-4-carboxamide, demonstrated
antihyperalgesic activity in inflammatory pain models including the
acute carrageenan model and the chronic inflammatory model using
complete Freund's adjuvant.
Following complete Freund's adjuvant stimulus leukotrieneB4
concentration in the brain was elevated (9 ± 1 ng/g, Mean ± S.E.M.)
by about 3 times that of the control group (3 ± 0.11, Mean ± S.E.M.).
Hyperalgesia and leukotrieneB4 concentration were both reversed
following CJ-13610 treatment.
Furthermore, we demonstrate CJ-13610 efficacy against osteoarthritis
like pain using the rat medial meniscal transection model.
CJ-13610 at oral doses of 0.6, 2 and 6 mg/kg/day reversed two
modalities of pain in this model; tactile allodynia and weight
bearing differential.
Taken together, these data suggest that 5-LOX pathway and the
leukotriene products are important mediators of pain.
Inflammation; Analgesia; Behavioral pharmacology
Corresponding author. 700 Chesterfield Parkway West,
BB-591C, Saint Louis, MO 63017. Tel.: +1 636 247
PMID: 18923838
doi:10.1016/j.ejphar.2009.06.058
Copyright © 2009 Published by Elsevier B.V.
Who loves ya.
Tom
Jesus Was A Vegetarian!
http://tinyurl.com/634q5a
Man Is A Herbivore!
http://tinyurl.com/4rq595
DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk
Released: 3/25/2011 11:35 AM EDT
Source: Temple University
Newswise — A drug used to treat asthma has been shown to help reduce
the formation of amyloid beta, a peptide in the brain that is
implicated in the development of Alzheimer’s disease, according to
researchers at Temple University’s School of Medicine.
The researchers published their findings, “Pharmacologic Blockade of 5-
Lipoxygenase Improves the Amyloidotic Phenotype of an AD Transgenic
Mouse Model,” in the American Journal of Pathology.
In previous studies, the Temple researchers discovered that 5-
lipoxygenase, an enzyme long known to exist in the brain, controls the
activation state of gamma secretase, another enzyme that is necessary
and responsible for the final production of amyloid beta. When
produced in excess, amyloid beta causes neuronal death and forms
plaques in the brain. The amount of these amyloid plaques in the brain
is used as a measurement of the severity of Alzheimer's.
In their current study, led by Domenico Praticò, an associate
professor of pharmacology in Temple’s School of Medicine, the
researchers tested the drug Zileuton, an inhibitor of 5-lipoxygenase
typically used to treat asthma, in a transgenic mouse model of
Alzheimer’s disease. At the end of the treatment they found that this
drug, by blocking the 5-lipoxygenase, reduced gamma secretase’s
production of amyloid beta and the subsequent build up of amyloid
plaques in the brain by more than 50 percent.
Praticò said that gamma secretase is present throughout the body and,
despite its role in the development of amyloid plaques, plays a
significant role in numerous important functions. Direct inhibitors of
gamma secretase are known, he said, but blocking the enzyme completely
may cause problems such as the development of cancer. Unlike classical
gamma secretase inhibitors, Zileuton only modulates the protein
expression levels, which keeps some of its vital functions in tact
while blocking many of its bad effects, which in this case is the
development of the amyloid plaques.
Praticò and his colleagues have begun working with researchers in
Temple’s Moulder Center for Drug Discovery Research to create more
potent inhibitors that can target 5-lipoxygenase in the brain and
increase the ability to reduce amyloid plaque formation and the
development of Alzheimer’s. Because Zileuton is already FDA approved,
it is known that 5-lipoxygenase inhibition is an acceptable target
that is not associated with overt toxicity and therefore not harmful
to patients. The new drug derivative might be expected to advance to
clinical trials relatively easily.
“This drug is already on the market and, most importantly, is already
FDA-approved, so you don’t need to go through an intense drug
discovery process,” said Praticò. “So we could quickly begin a
clinical trial to determine if there is a new application for this
drug against a disease where there is currently nothing.”
The study was funded by the National Institutes of Health and the
Alzheimer’s Association.
Copies of this study are available to working journalists and may be
obtained by contacting Preston M. Moretz in Temple’s Office of
University Communications at ***@temple.edu.
----------
Neuropharmacology and Analgesia
CJ-13610, an orally active inhibitor of 5-lipoxygenase is
efficacious in preclinical models of pain
Luz A. Cortes-Burgos, a, , Ben S. Zweifela,
Steven L. Settlea, Robert A. Pufahla,
Gary D. Andersona, Medora M. Hardya,
Dana E. Weira, George Hua, Fernando A. Happaa,
Zachary Stewarta, Shanmugam Muthiana,
Matthew J. Granetoa and Jaime L. Masferrera
aPfizer Global Research & Development,
St. Louis Laboratories, Pfizer Inc, St. Louis, MO 63017
Received 27 April 2009; revised 18 June 2009;
accepted 22 June 2009. Available online 4 July 2009.
Abstract
Zileuton, a redox and iron chelator 5-lipoxygenase (5-LOX) inhibitor
and, leukotriene receptor antagonists are presently used clinically
in the long term treatment of asthma.
Recent data implicate 5-LOX pathway in pain signaling.
We report 5-LOX expression in the central nervous system (CNS)
and analyze the pain efficacy of a new class of non redox, non
iron chelating 5-LOX inhibitor.
CJ-13610, 4-(3-(4-(2-methyl-1H-imidazol-1-yl) phenylthio)
phenyl)-tetrahydro-2H-pyran-4-carboxamide, demonstrated
antihyperalgesic activity in inflammatory pain models including the
acute carrageenan model and the chronic inflammatory model using
complete Freund's adjuvant.
Following complete Freund's adjuvant stimulus leukotrieneB4
concentration in the brain was elevated (9 ± 1 ng/g, Mean ± S.E.M.)
by about 3 times that of the control group (3 ± 0.11, Mean ± S.E.M.).
Hyperalgesia and leukotrieneB4 concentration were both reversed
following CJ-13610 treatment.
Furthermore, we demonstrate CJ-13610 efficacy against osteoarthritis
like pain using the rat medial meniscal transection model.
CJ-13610 at oral doses of 0.6, 2 and 6 mg/kg/day reversed two
modalities of pain in this model; tactile allodynia and weight
bearing differential.
Taken together, these data suggest that 5-LOX pathway and the
leukotriene products are important mediators of pain.
Inflammation; Analgesia; Behavioral pharmacology
Corresponding author. 700 Chesterfield Parkway West,
BB-591C, Saint Louis, MO 63017. Tel.: +1 636 247
PMID: 18923838
doi:10.1016/j.ejphar.2009.06.058
Copyright © 2009 Published by Elsevier B.V.
Who loves ya.
Tom
Jesus Was A Vegetarian!
http://tinyurl.com/634q5a
Man Is A Herbivore!
http://tinyurl.com/4rq595
DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk