Zileuton An Iron Chelator

[ironjustice]

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.: [phone]


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

[ad hominem]

Stay in your mama's basement with your gay porn and cum drenched
keyboard. You need to go into rehab for your crack cocaine addiction.
You are an illiterate spamming tosser with no hope of redemption. You
would have more luck of finding redemption with Allah. You use the
internet as your personal weapon of mass destruction. You copy and
paste research that is frequently flawed. The research often does NOT
relate to the subject line. Just because a piece of research is found
on PubMed it does not mean it is not flawed. I will always cut your
spam when posting a reply to your tripe. At first I found it hilarious
to see someone so delusional, illiterate (that was sad), and a veiled
attempt to extrapolate a conclusion from research that even the
primary researchers had no intention of doing. Tom you think you are
God sent (a delusion), intelligent (another delusion) and you think
people respect your opinion (another delusion). Three strikes you’re
out. So fuck off Tom you crack head queer.

Tom the crack head poofter even has a webpage devoted to him at
http://kook.us/tom-hennessy.htm

[Happy Oyster]

On Sun, 5 Jul 2009 20:33:19 -0700 (PDT), ironjustice <***@hotmail.com>
wrote:

[...]

Post by ironjustice
Jesus Was A Vegetarian!

[...]

Post by ironjustice
Man Is A Herbivore!

[...]

Post by ironjustice
DEAD PEOPLE WALKING

[...]

3x wrong.

[ironjustice]

On Jul 6, 7:13 am, Happy Oyster <***@ariplex.com> wrote:snip
<<

Predator you do not understand ..

Predators cannot be heard over the sound
of how awesome I am.

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.: [phone]


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

[ad hominem]

Stay in your mama's basement with your gay porn and cum drenched
keyboard. You need to go into rehab for your crack cocaine addiction.
You are an illiterate spamming tosser with no hope of redemption. You
would have more luck of finding redemption with Allah. You use the
internet as your personal weapon of mass destruction. You copy and
paste research that is frequently flawed. The research often does NOT
relate to the subject line. Just because a piece of research is found
on PubMed it does not mean it is not flawed. I will always cut your
spam when posting a reply to your tripe. At first I found it hilarious
to see someone so delusional, illiterate (that was sad), and a veiled
attempt to extrapolate a conclusion from research that even the
primary researchers had no intention of doing. Tom you think you are
God sent (a delusion), intelligent (another delusion) and you think
people respect your opinion (another delusion). Three strikes you’re
out. So fuck off Tom you crack head queer.

Tom the crack head pillow biter even has a webpage devoted to him at
http://kook.us/tom-hennessy.htm

[ironjustice]

On Jul 6, 1:12 pm, ad hominem <***@gmail.com>
wrote:snip
<<

Predators cannot be heard over the sound
of how awesome I am.


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.: [phone]


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

[Happy Oyster]

Post by ironjustice
Predator you do not understand ..
Predators cannot be heard over the sound
of how awesome I am.

Ah, the very same gramophone record with a crack...

Strange habits people have...

[ironjustice]

On Jul 6, 5:08 pm, Happy Oyster <***@ariplex.com> wrote:snip
<<

Predators cannot be heard over the sound
of how awesome I am.


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.: [phone]


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

[Happy Oyster]

Post by ironjustice
Predators cannot be heard over the sound
of how awesome I am.

Better read the bible!

I quote:

"'Euch segne Vater, Sohn und Geist.'
(Apostel nach Diktat verreist.)"

;O)

[ironjustice]

On Jul 7, 3:43 am, Happy Oyster <***@ariplex.com> wrote:snip
<<

Predators cannot be heard over the sound
of how awesome I am.


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.: [phone]


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

[ironjustice]

On Jul 7, 4:45 am, ironjustice <***@hotmail.com> wrote:
inhibitor of 5-lipoxygenase <<

Hyperforin is a novel type of 5-lipoxygenase inhibitor
with high efficacy in vivo.
Cell Mol Life Sci. 2009 Jul 5.
Feißt C, Pergola C, Rakonjac M, Rossi A, Koeberle A,
Dodt G, Hoffmann M, Hoernig C, Fischer L, Steinhilber D,
Franke L, Schneider G, Rådmark O, Sautebin L, Werz O.
Institute of Pharmaceutical Chemistry, University of Frankfurt,
Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.

We previously showed that, in vitro, hyperforin from St. John's
wort (Hypericum perforatum) inhibits 5-lipoxygenase (5-LO),
the key enzyme in leukotriene biosynthesis.
Here, we demonstrate that hyperforin possesses a novel and unique
molecular pharmacological profile as a 5-LO inhibitor with remarkable
efficacy in vivo.
Hyperforin (4 mg/kg, i.p.) significantly suppressed leukotriene B(4)
formation in pleural exudates of carrageenan-treated rats associated
with potent anti-inflammatory effectiveness.
Inhibition of 5-LO by hyperforin, but not by the iron-ligand type
5-LO inhibitor BWA4C or the nonredox-type inhibitor ZM230487, was
abolished in the presence of phosphatidylcholine and strongly reduced
by mutation (W13A-W75A-W102A) of the 5-LO C2-like domain.
Moreover, hyperforin impaired the interaction of 5-LO with
coactosin-like protein and abrogated 5-LO nuclear membrane
translocation in ionomycin-stimulated neutrophils, processes that
are typically mediated via the regulatory 5-LO C2-like domain.
Together, hyperforin is a novel type of 5-LO inhibitor apparently
acting by interference with the C2-like domain, with high
effectiveness
in vivo.

PMID: 19579006


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

Post by ironjustice
<<
Predators cannot be heard over the sound
of how awesome I am.
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.: [phone]
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 WALKINGhttp://tinyurl.com/zk9fk

[Ken]

Stay in your mama's basement with your gay porn and cum drenched
keyboard. You need to go into rehab for your crack cocaine addiction.
You are an illiterate spamming tosser with no hope of redemption. You
would have more luck of finding redemption with Allah. You use the
internet as your personal weapon of mass destruction. You copy and
paste research that is frequently flawed. The research often does
NOT
relate to the subject line. Just because a piece of research is found
on PubMed it does not mean it is not flawed. I will always cut your
spam when posting a reply to your tripe. At first I found it
hilarious
to see someone so delusional, illiterate (that was sad), and a veiled
attempt to extrapolate a conclusion from research that even the
primary researchers had no intention of doing. Tom you think you are
God sent (a delusion), intelligent (another delusion) and you think
people respect your opinion (another delusion

[Happy Oyster]

Post by ironjustice
Predators cannot be heard over the sound
of how awesome I am.

Read the bible!

"Kein Einz'ger blieb am Leben,
dann raubten sie das Vieh,
der Herr hat es gegeben,
es scheint, er liebte sie."

[ironjustice]

On Jul 7, 11:12 am, Happy Oyster <***@ariplex.com>
wrote:Hyperforin is a novel type of 5-lipoxygenase inhibitor
with high efficacy in vivo.
Cell Mol Life Sci. 2009 Jul 5.
Feißt C, Pergola C, Rakonjac M, Rossi A, Koeberle A,
Dodt G, Hoffmann M, Hoernig C, Fischer L, Steinhilber D,
Franke L, Schneider G, Rådmark O, Sautebin L, Werz O.
Institute of Pharmaceutical Chemistry, University of Frankfurt,
Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.


We previously showed that, in vitro, hyperforin from St. John's
wort (Hypericum perforatum) inhibits 5-lipoxygenase (5-LO),
the key enzyme in leukotriene biosynthesis.
Here, we demonstrate that hyperforin possesses a novel and unique
molecular pharmacological profile as a 5-LO inhibitor with remarkable
efficacy in vivo.
Hyperforin (4 mg/kg, i.p.) significantly suppressed leukotriene B(4)
formation in pleural exudates of carrageenan-treated rats associated
with potent anti-inflammatory effectiveness.
Inhibition of 5-LO by hyperforin, but not by the iron-ligand type
5-LO inhibitor BWA4C or the nonredox-type inhibitor ZM230487, was
abolished in the presence of phosphatidylcholine and strongly reduced
by mutation (W13A-W75A-W102A) of the 5-LO C2-like domain.
Moreover, hyperforin impaired the interaction of 5-LO with
coactosin-like protein and abrogated 5-LO nuclear membrane
translocation in ionomycin-stimulated neutrophils, processes that
are typically mediated via the regulatory 5-LO C2-like domain.
Together, hyperforin is a novel type of 5-LO inhibitor apparently
acting by interference with the C2-like domain, with high
effectiveness
in vivo.


PMID: 19579006

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.: [phone]


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

[Happy Oyster]

Post by ironjustice
wrote:Hyperforin is a novel type of 5-lipoxygenase inhibitor
with high efficacy in vivo.

Nope. You are a forger.

[ironjustice]

On Jul 8, 8:33 pm, Happy Oyster <***@ariplex.com> wrote: snip
<<

I'm sorry predators cannot be heard over the sound of how
awesome I am.


Hyperforin is a novel type of 5-lipoxygenase inhibitor
with high efficacy in vivo.
Cell Mol Life Sci. 2009 Jul 5.
Feißt C, Pergola C, Rakonjac M, Rossi A, Koeberle A,
Dodt G, Hoffmann M, Hoernig C, Fischer L, Steinhilber D,
Franke L, Schneider G, Rådmark O, Sautebin L, Werz O.
Institute of Pharmaceutical Chemistry, University of Frankfurt,
Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.

We previously showed that, in vitro, hyperforin from St. John's
wort (Hypericum perforatum) inhibits 5-lipoxygenase (5-LO),
the key enzyme in leukotriene biosynthesis.
Here, we demonstrate that hyperforin possesses a novel and unique
molecular pharmacological profile as a 5-LO inhibitor with remarkable
efficacy in vivo.
Hyperforin (4 mg/kg, i.p.) significantly suppressed leukotriene B(4)
formation in pleural exudates of carrageenan-treated rats associated
with potent anti-inflammatory effectiveness.
Inhibition of 5-LO by hyperforin, but not by the iron-ligand type
5-LO inhibitor BWA4C or the nonredox-type inhibitor ZM230487, was
abolished in the presence of phosphatidylcholine and strongly reduced
by mutation (W13A-W75A-W102A) of the 5-LO C2-like domain.
Moreover, hyperforin impaired the interaction of 5-LO with
coactosin-like protein and abrogated 5-LO nuclear membrane
translocation in ionomycin-stimulated neutrophils, processes that
are typically mediated via the regulatory 5-LO C2-like domain.
Together, hyperforin is a novel type of 5-LO inhibitor apparently
acting by interference with the C2-like domain, with high
effectiveness
in vivo.


PMID: 19579006


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.: [phone]


PMID: 18923838


doi:10.1016/j.ejphar.2009.06.058


Copyright © 2009 Published by Elsevier B.V


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