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Anti-inflammatory effects of willow bark extract

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Anti-inflammatory effects of willow bark extract To the Editor: By using in vitro assays, Wagner et al1 showed that a Salix extract inhibits cytokine and prostaglandin E2 (PGE2) release in vitro, which is in line with recent data from our group.2 Furthermore, they presented data showing that in a wholeblood assay from 3 Salix-treated volunteers (single dose of 1575 mg Salix extract, corresponding to 240 mg salicin) lipopolysaccharide-induced release of cytokines and PGE2 was not affected by willow bark extract treatment. From this experiment, they concluded that Salix does not interfere with the arachidonic acid cascade or cytokine release in vivo. In our opinion, this hypothesis is not necessarily supported by the experimental setup. The authors’ single-dose setup assumption is based on the fact that blood levels of salicylic acid (the major metabolite of salicin) peaked at 2 hours after oral intake of Salix extract.3 However, Schmid et al3 concluded that given the low bioavailability of salicylic acid it is unlikely that an analgesic or antirheumatic effect of willow bark can be attributed to salicylic acid alone. This conclusion is confirmed by our study, showing that neither salicin nor salicylic acid alone is responsible for the anti-inflammatory effects of Salix extracts.2 Whereas Salix extract potently prevented PGE2 and cytokine release in a dose of 100 microg/mL, similar doses of salicin and salicylic acid showed no or slight inhibitory effects, suggesting other constituents to be responsible for the effectiveness of the extract, which might have completely different pharmacokinetic profiles than salicylic acid. This hypothesis is strongly supported by the fact that there is no evidence of the therapeutic effectiveness of a single-dose Salix therapy. Therefore an extended treatment with willow bark may be necessary before relevant blood levels are reached. For example, ex vivo–in vitro whole-blood assays after Urtica extract treatment revealed that inhibition of lipopolysaccharide-induced release of the cytokines tumor necrosis factor alpha and interleukin 1beta correlated with the duration of drug intake after 7 and 21 days.4 Until we establish the active constituents of Salix, we are not able to predict the pharmacokinetics and thus the effectiveness of Salix therapy in vivo on the molecular level, such as with regard to the inhibition of cytokines and prostaglandins. To prove whether Salix is (or is not) interfering with cytokines or the arachidonic acid cascade in vivo, we need more information about the active principles and the pharmacokinetics, and a more physiologic
Anti-inflammatory effects of willow bark extract
To the Editor:
By using in vitro assays, Wagner et al
1
showed that a Salix
extract inhibits cytokine and prostaglandin E
2
(PGE
2
) release
in vitro, which is in line with recent data from our group.
2
Furthermore, they presented data showing that in a whole-
blood assay from 3 Salix-treated volunteers (single dose of
1575 mg Salix extract, corresponding to 240 mg salicin)
lipopolysaccharide-induced release of cytokines and PGE
2
was not affected by willow bark extract treatment. From this
experiment, they concluded that Salix does not interfere with
the arachidonic acid cascade or cytokine release in vivo.
In our opinion, this hypothesis is not necessarily supported
by the experimental setup. The authorssingle-dose setup
assumption is based on the fact that blood levels of salicylic
acid (the major metabolite of salicin) peaked at 2 hours after
oral intake of Salix extract.
3
However, Schmid et al
3
con-
cluded that given the low bioavailability of salicylic acid it is
unlikely that an analgesic or antirheumatic effect of willow
bark can be attributed to salicylic acid alone.
This conclusion is conrmed by our study, showing that
neither salicin nor salicylic acid alone is responsible for the
anti-inammatory effects of Salix extracts.
2
Whereas Salix
extract potently prevented PGE
2
and cytokine release in a
dose of 100 g/mL, similar doses of salicin and salicylic acid
showed no or slight inhibitory effects, suggesting other con-
stituents to be responsible for the effectiveness of the extract,
which might have completely different pharmacokinetic pro-
les than salicylic acid. This hypothesis is strongly supported
by the fact that there is no evidence of the therapeutic effec-
tiveness of a single-dose Salix therapy. Therefore an extended
treatment with willow bark may be necessary before relevant
blood levels are reached. For example, ex vivoin vitro
whole-blood assays after Urtica extract treatment revealed
that inhibition of lipopolysaccharide-induced release of the
cytokines tumor necrosis factor and interleukin 1corre-
lated with the duration of drug intake after 7 and 21 days.
4
Until we establish the active constituents of Salix, we are not
able to predict the pharmacokinetics and thus the effective-
ness of Salix therapy in vivo on the molecular level, such as
with regard to the inhibition of cytokines and prostaglandins.
To prove whether Salix is (or is not) interfering with
cytokines or the arachidonic acid cascade in vivo, we need
more information about the active principles and the pharma-
cokinetics, and a more physiologic ex vivoin vitro setup is
probably needed.
Bernd L. Fiebich, PhD
Department of Psychiatry and Psychotherapy
University of Freiburg Medical School
Freiburg, Germany
Kurt Appel, PhD
VivaCell Biotechnology
Freiburg, Germany
References
1. Wagner I, Greim C, Laufer S, Heide L, Gleiter CH. Inuence of
willow bark extract on cyclooxygenase activity and on tumor
necrosis factor or interleukin 1release in vitro and ex vivo
[letter]. Clin Pharmacol Ther 2003;73:272-4.
2. Fiebich B, Chrubasik S. Effects of an ethanolic Salix extract on
the release of selected inammatory mediators in vitro. Phyto-
medicine. In press 2003.
3. Schmid H, Ko¨tter L, Heide I. Pharmacokinetics of salicin after
oral administration of a standardised willow bark extract. Eur
J Clin Pharmacol 2001;57:387-91.
4. Teucher T, Obertreis B, Ruttkowski T, Schmitz H. Cytokine
secretion in whole blood of healthy subjects following oral ad-
ministration of Urtica dioica L plant extract [in German]. Arz-
neimittelforschung 1996;46:906-10 .
doi:10.1016/S0009-9236(03)00116-4
Reply: Effects of willow bark extract
To the Editor:
Our study showed that a standardized extract of willow
bark inhibited cyclooxygenase (COX) 1 and COX-2 activity
and, to a lesser degree, the release of tumor necrosis factor
(TNF) and interleukin (IL) 1, in whole-blood assays in
vitro. However, the formation of none of these mediators was
signicantly inhibited after oral ingestion of a therapeutic
dose of the same willow bark extract by human volunteers.
Apparently, the constituents responsible for the effect ob-
served in vitro did not reach therapeutic blood levels, pre-
sumably as a result of either (or both) their low amount or
pharmacokinetic factors such as low absorption rate or met-
abolic inactivation.
Fiebich and Chrubasik
1
also investigated the effects of
willow bark extract on the release of inammatory mediators
but apparently only in vitro.
We have used a single dose of willow bark and did not
assess its effect in the steady state, after several days or weeks
of medication. In their letter, Fiebich and Appel point out that
extended treatment with willow bark may be necessary to
inuence inammatory parameters. However, experiments
with diclofenac,
2
nimesulide,
3
and even the long-acting
meloxicam
2
suggest that at least the effects of these COX
inhibitors are not more pronounced at steady state than after
a single dose. The study on Urtica (stinging nettle), cited in
both Fiebich and Appels letter and Chrubasiks letter, re-
ported only moderate inhibitions of TNF-and IL-1release
after 7 and 21 days of treatment, and the clinical relevance of
these ndings is doubtful. Chrubasik points out several other
lines of evidence that suggest an analgesic or anti-
inammatory activity of willow bark extract. Some of this
evidence is convincing, and some of it is not, as we discussed
in a recent review article.
4
We share with Chrubasik, as well as Fiebich and Appel,
the hope that a pharmacologic mechanism of action for wil-
low bark may be identied. On the basis of our ndings,
however, we propose that it should no longer be claimed that
CLINICAL PHARMACOLOGY & THERAPEUTICS
96 Letters to the Editor JULY 2003
... However, willow bark is an important bitter tonic with marked astringent properties in humans, making it useful in chronic hypersecretory states, such as mucus discharges, passive hemorrhage, leucorrhea, humid asthma, diarrhea, and dysentery [80]. The effects of willow bark attributed to the salicin compounds include analgesic [78], anti-inflammatory [32,81,82], antipyretic [83,84], and antiplatelet activity [80]. These activities are also well known for supporting the body's response to normal physiological stress [85]. ...
... Polyphenols have been reported to act as inhibitors of NF-κB [147,148]. Few studies showed that the antiinflammatory properties of willow bark are associated with the inhibition of cyclooxygenases and pro-inflammatory cytokines [81,149]. ...
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... However, willow bark is an important bitter tonic with marked astringent properties in humans, making it useful in chronic hypersecretory states, such as mucus discharges, passive hemorrhage, leucorrhea, humid asthma, diarrhea and dysentery [77]. The effects of willow bark attributed to the salicin compounds include analgesic [75], anti-inflammatory [29,78,79], antipyretic [80,81] and antiplatelet activity [77]. These activities are also well known for supporting the body's response to normal physiological stress [82]. ...
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Over the last decade, there has been a growing interest in the use of a wide range of phytoadditives to counteract the harmful effects of heat stress in poultry. Willow (Salix spp.) is a tree with a long history. Among various forms, willow bark is an important natural source of salicin, β-O-glucoside of saligenin, but also of polyphenols (flavonoids and condensed tannins) with antioxidant, antimicrobial and anti-inflammatory activity. In light of this, the current review presents some literature data aiming to: (1) describe the relationship between heat stress and oxidative stress in broilers, (2) present or summarize literature data on the chemical composition of Salix species, (3) summarize the mechanisms of action of willow bark in heat-stressed broilers, (4) present different biological effects of the extract of Salix species in different experimental models.
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