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Anti-inflammatory effects of willow bark extract

DOI:10.1016/S0009-9236(03)00116-4
Authors:
Bernd L. Fiebich at University Medical Center Freiburg
Bernd L. Fiebich
Kurt Appel at Vivacell Biotechnology GmbH
Kurt Appel
  • Vivacell Biotechnology GmbH
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Abstract

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
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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 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 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 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 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-
files 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 vivo–in vitro
whole-blood assays after Urtica extract treatment revealed
that inhibition of lipopolysaccharide-induced release of the
cytokines tumor necrosis factor ␣and interleukin 1␤corre-
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 vivo–in 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. Influence of
willow bark extract on cyclooxygenase activity and on tumor
necrosis factor ␣or interleukin 1␤release 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 inflammatory 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
significantly 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 inflammatory 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
influence inflammatory 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 Appel’s letter and Chrubasik’s letter, re-
ported only moderate inhibitions of TNF-␣and IL-1␤release
after 7 and 21 days of treatment, and the clinical relevance of
these findings is doubtful. Chrubasik points out several other
lines of evidence that suggest an analgesic or anti-
inflammatory 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 identified. On the basis of our findings,
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]. ...
Heat Stress in Broiler Chickens and the Effect of Dietary Polyphenols, with Special Reference to Willow (Salix spp.) Bark Supplements—A Review
Article
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  • Apr 2021
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, and (4) present different biological effects of the extract of Salix species in different experimental models.
... 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]. ...
... Polyphenols have been reported to act as inhibitors of NF-κB [142,143]. Few studies showed that the anti-inflammatory properties of willow bark are associated with the inhibition of cyclooxygenases and pro-inflammatory cytokines [78,144]. ...
Heat Stress in Broiler Chickens and the Effect of Dietary Polyphenols, with Special Reference to Willow (Salix spp.) Bark Supplements - A Review
Preprint
  • Apr 2021
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.
... Willow bark is regarded as a successful example of a modern drug developed from an herbal remedy, which was first described 200 years ago. Salicin (SA) is the main chemically standardized willow bark extract; its chemical oxidation resulted in a new substance termed "salicylic acid", and the acetylated derivative was finally turned into the famous drug called "aspirin" 4,5 . SA is metabolized into salicylic acid after oral ingestion and plays roles in the treatment of pain, headaches, and inflammatory conditions 5,6 . ...
The natural product salicin alleviates osteoarthritis progression by binding to IRE1α and inhibiting endoplasmic reticulum stress through the IRE1α-IκBα-p65 signaling pathway
Article
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Despite the high prevalence of osteoarthritis (OA) in older populations, disease-modifying OA drugs (DMOADs) are still lacking. This study was performed to investigate the effects and mechanisms of the small molecular drug salicin (SA) on OA progression. Primary rat chondrocytes were stimulated with TNF-α and treated with or without SA. Inflammatory factors, cartilage matrix degeneration markers, and cell proliferation and apoptosis markers were detected at the mRNA and protein levels. Cell proliferation and apoptosis were evaluated by EdU assays or flow cytometric analysis. RNA sequencing, molecular docking and drug affinity-responsive target stability analyses were used to clarify the mechanisms. The rat OA model was used to evaluate the effect of intra-articular injection of SA on OA progression. We found that SA rescued TNF-α-induced degeneration of the cartilage matrix, inhibition of chondrocyte proliferation, and promotion of chondrocyte apoptosis. Mechanistically, SA directly binds to IRE1α and occupies the IRE1α phosphorylation site, preventing IRE1α phosphorylation and regulating IRE1α-mediated endoplasmic reticulum (ER) stress by IRE1α-IκBα-p65 signaling. Finally, intra-articular injection of SA-loaded lactic-co-glycolic acid (PLGA) ameliorated OA progression by inhibiting IRE1α-mediated ER stress in the OA model. In conclusion, SA alleviates OA by directly binding to the ER stress regulator IRE1α and inhibits IRE1α-mediated ER stress via IRE1α-IκBα-p65 signaling. Topical use of the small molecular drug SA shows potential to modify OA progression.
... Known for its alleviating effect on fever, pain, and inflammation, willow bark has been referred to as "nature's Aspirin." In preclinical and clinical studies, willow bark has been reported to be effective in pain management and anti-inflammation [8,9]. Salicin is the major component of willow bark extract. ...
Vascular protection of salicin on IL-1β-induced endothelial inflammatory response and damages in retinal endothelial cells
Article
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  • Dec 2019
Retinal endothelial cells (RECs) are involved in many ocular diseases such as age-related macular degeneration (AMD) and diabetic retinopathy. Salicin is the major ingredient of willow bark extract, and it has been shown to be a potent anti-inflammatory agent. We aim to explore whether salicin has a vascular protective effect in RECs. Our data indicate that the presence of salicin in RECs culture media ameliorates interleukin-1β (IL-1β)-induced cellular reactive oxygen species (ROS) production and NADPH oxidase 4 (NOX-4) expression. At the cellular level, salicin attenuates IL-1β-induced mitochondrial injury as revealed by its preservation on mitochondrial membrane potential (MMP). Furthermore, salicin inhibits IL-1β-induced production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1), vascular adhesion molecules such as intercellular cell adhesion molecule-1 (iCAM-1) and vascular cell adhesion molecule 1 (VCAM-1), and high-mobility group protein 1 (HMGB-1). On the other hand, salicin recovers IL-1β-induced reduction of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) release. The presence of salicin significantly reduces the IL-1β-induced release of lactate dehydrogenase (LDH), indicating that it mitigates cytokine caused cytotoxicity. Mechanistically, we show that salicin suppresses IL-1β-induced activation of the nuclear factor-kappa B (NF-κB) signaling as revealed by its suppression on nuclear p65 protein and transfected NF-κB promoter. Collectively, our study demonstrates by multiple facets of its mechanisms that salicin is a protective agent in retinal endothelial cells. These results imply its potential use in therapeutic usage of retinal disease.
... Apparently, the constituents responsible for the effect observed in vitro did not reach therapeutic levels in the body. Fiebich and Appel (2003) suggest that therapeutic levels are not achieved by a single dosing protocol, and propose multiple day treatment protocols instead. This hypothesis is supported by Chrubasik et al. (2000;2003b), who emphasize that the beneficial effects of most phytotherapeutics gradually peak after several weeks of treatment. ...
Anti-inflammatory phytotherapeutics: A valuable alternative to NSAID treatment in horses?
Article
Full-text available
In equine practice, phytotherapy is meeting the increasing demand of horse owners for "natural", safe treatment methods. Long-term use of NSAIDs can cause severe adverse effects, hence the growing popularity of anti-inflammatory phytotherapeutics. At the current time, several different herbal mixes are being commercialized, which makes it difficult for horse owners and veterinarians alike to make a well-founded choice. Harpagophytum procumbens (devil's claw), Salix spp. (willow) and Ribes nigrum (blackcurrant), three plants that are often used in these mixes, have been evaluated both in vitro and in vivo. Based on published studies and the evaluation of these studies, for example by the Cochrane Collaboration, there seems to be some evidence for Harpagophytum procumbens and Salix spp. having a stronger analgesic and anti-inflammatory effect than placebos in humans. In horses, however, only one limited clinical study on Harpagophytum has been performed up until now, while no studies were found on the use of Salix in horses. More research is needed before any claims concerning efficacy or safety can be made regarding the use of these plants in treating horses. It has also been claimed that Ribes nigrum leaves have an anti-inflammatory effect, though this has not yet been clinically proven either in humans or in horses. Although veterinary phytotherapy is as old as animal husbandry itself, little scientific proof can be found regarding its uses. More research is needed before phytotherapy can be advertised as a valuable and safe alternative to the more conventional treatment protocols.
... The active substance of the common white willow, a glycoside of salicylic acid known as salicin, was isolated in 1829 by Leroux, who also demonstrated its antipyretic properties (Chrubasik and Shvartzman 1999). The effects of willow bark attributed to the salicin compounds include analgesic , anti-inflammatory, antipyretic, and antiplatelet activity (Fiebich and Apel 2003). ...
Effects of Willow Bark (Salix alba) and Its Salicylates on Blood Coagulant
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  • Jun 2013
The herb white willow (Salix alba), also known as willow bark, is used to treat pain and fever. It is also used for myalgias, osteoarthritis, dysmenorrheal, gouty arthritis, rheumatoid arthritis, gout, common cold, influenza, and weight loss. White willow contains a substance (salicine) that is converted by the body into a salicylate similar to the blood-thinner aspirin. Over the last twenty years, another use for aspirin has emerged connected with the discovery of its anti-thrombotic action.
... Willow bark (Salix alba) is a CAM which may play a role in the relief of pain and inflammation [168,248,249]. Although salicin, an active component, is metabolized in vivo to salicylic acid, studies have suggested that the analgesic and anti-inflammatory effects of willow bark may not be due to either salicin or salicylic acid alone [250,251]. Willow bark is reported to have antiplatelet effects in humans but to a lesser extent than acetylsalicylate (aspirin) [167], and has been associated with an increased risk of selfreported bleeding [75]. It manifests an interaction with warfarin and may potentiate an increased risk of bleeding [76]. ...
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  • Dec 2010
Complementary and alternative medicines (CAMs), in particular herbal medicines, are commonly used by cancer patients in conjunction with chemotherapy treatment for their anticancer properties and supportive care. However, the effects of many of these herbs are not well-documented due to limited studies done on them. Severe herb-drug interactions (HDIs) have been recorded in some cases, and failure to recognize these harmful HDIs can lead to dire consequences in cancer patients. This study discusses clinically-relevant interactions between anticancer drugs (ACDs) and herbs classified into 7 categories: cancer treatment and prevention, immune-system-related, alopecia, nausea and vomiting, peripheral neuropathy and pain, inflammation, and fatigue. Some promising patents which contain these herbs and thus may manifest these interactions are also presented in this article. Pharmacokinetic interactions involved mainly induction or inhibition of the cytochrome P450 isozymes and p-glycoprotein, while pharmacodynamic interactions were related to increased risks of central nervous system-related effects, hepatotoxicity and bleeding, among others. Clinicians should be vigilant when treating cancer patients who take CAMs with concurrent chemotherapy since they face a high risk of HDIs. These HDIs can be minimized or avoided by selecting herb-drug pairs which are less likely to interact. Furthermore, close monitoring of pharmacological effects and plasma drug levels should be carried out to avoid toxicity and ensure adequate chemotherapeutic coverage in patients with cancer.
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Reactive oxygen species such as OH, peroxynitrite and the non-radical, hypochlorous acid, play outstanding roles in many disease. The formation of OH (Fenton)-type radicals is catalyzed by enzymes such as xanthine oxidase (XOD) via one-electron reduction of molecular oxygen producing superoxide radical anions (O2). Subsequent transfer of one electron to hydrogen peroxide by Fe2+ or Cu+ -ions yields OH-radicals measurable as ethene release from 1-keto-4-methylthiobutyrate (KMB). Xanthine oxidase or activated neutrophils are prominent sources of this strong oxidant produced at inflammatory sites. Many natural compounds such as salicylates or flavonoids interfere either with the production of these activated oxygen species or function as radical scavengers and thus as antioxidants. Extracts from willow-bark (Salix spec.) and also other species such as ash-tree (Fraxinus spec.) or poplar (Populus spec.) have been used as antiinflammatory drugs since a long time. In this communication we wish to report on model reactions to demonstrate a) the radical scavenging activities of such plant extracts inhibiting ethene release from KMB induced by Fenton-type oxidants and b) the inhibition of the formation of nitrogen monoxide (NO) from hydroxylamine including XOD either in the presence or absence of myoglobin (MYO) measurable as nitrite formation: In the absence of MYO, superoxide dismutase is an excellent inhibitor of nitrite formation but is inactive in its presence. Extracts from the willow-bark or the drug Phytodolar however, are inhibitory both in the presence and absence of MYO. As active principle, the flavonoid rutin included in these extracts is likely to function as one inhibitor of the XOD-mediated reaction.
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Objective: To assess the clinical efficacy of a chemically standardized willow bark extract in the treatment of osteoarthritis. Methods: Willow bark extract, in a dose corresponding to 240mg salicin/day, was compared to placebo in a 2-week, double-blind, randomized controlled trial. The primary outcome measure was the pain dimension of the WOMAC Osteoarthritis Index. Secondary outcome measures included the stiffness and physical function dimensions of the WOMAC, daily visual analogue scales (VAS) on pain and physical function, and final overall assessment by both patients and investigators. Results: 78 patients (39 willow bark extract, 39 placebo) participated in the trial. A statistically significant difference between active treatment and placebo group was observed in the WOMAC pain dimension (d=6.5mm, 95%¶C.I.=0.2–12.7mm, p=0.047); the WOMAC pain score was reduced by 14% from baseline level after two weeks of active treatment, compared to an increase of 2% in the placebo group. Patient diary VAS confirmed this result, and likewise the final overall assessments showed superiority of willow bark extract over placebo ¶(patients assessment, p=0.0002; investigators assessment, p=0.0073). Conclusion: Willow bark extract shows a moderate analgesic effect in osteoarthritis.
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Cytokine secretion in whole blood of healthy subjects following oral administration of Urtica dioica L. plant extract [Zytokin-Sekretion im Vollblut gesunder Probanden nach oraler Einnahme eines Urtica dioica L.-Blattextraktes]
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Twenty healthy volunteers ingested for 21 days 2 capsules b.i.d. of an IDS 23/1 containing nettle leaf extract (Rheuma-Hek). Before and after 7 and 21 days the basal and the lipopolysaccharide (LPS) stimulated tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) concentrations were measured ex vivo. In vitro the effects of IDS 23/1 on the release of these cytokines were determined. Additionally basal interleukin-4 (IL-4) and interleukin-10 (IL-10) levels were recorded. Orally taken the test drug has ex vivo no effect on basal levels of TNF-alpha, IL-1 beta, IL-4, IL-6 or IL-10 which were always below detection limits. After 7 and 21 days ingestion ex vivo a decrease of LPS stimulated TNF-alpha release of 14.6 and 24.0%, respectively, was observed. IL-1 beta was reduced for 19.2 and 39.3%. In vitro IDS 23/1 added to whole blood resulted in an exceeded inhibition of LPS stimulated TNF-alpha and IL-1 beta secretion which correlated with the duration of the drug ingestion. Using the highest tested IDS 23/1 concentration the inhibition reached 50.5 (day 0) to 79.5% (day 21) for TNF-alpha and 90.0 (day 0) to 99.2% (day 21) for IL-1 beta, respectively. IDS 23/1 induced a pronounced release of IL-6 in absence of LPS only in vitro. The detected IL-6 concentrations were comparable to those after LPS stimulation, additive effects could not be observed. The absence of detectable IL-6 concentrations in whole blood ex vivo after oral ingestion of the tested drug as well as the differences in the inhibition patterns for TNF-alpha and IL-1 beta ex vivo and ex vivo in vitro suggest that the extract contains different pharmacological effective compounds with varying bioavailabilities.
Ex vivo assay to determine the cyclooxygenase selectivity of non-steroidal anti-inflammatory drugs
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In this study we describe experiments to establish ex vivo the selectivity of non-steroidal anti-inflammatory drugs (NSAIDs) given in vivo. Anaesthetised (Inactin, 120 mg kg−1) male Wistar rats (220–250 g) received an i.v. dose of one of the following compounds (dose mg kg−1): aspirin (20), diclofenac (3), L-745,337 (30), nimesulide (15), salicylate (20), sulindac (10). Blood samples were taken before and up to 6 h after dosing and the plasma obtained from it was tested for its ability to inhibit prostanoid formation in IL-1β-treated A549 cells (COX-2 system) and human washed platelets (COX-1 system). For control the same compounds were also added directly to the assay systems. All drugs, except sodium salicylate, inhibited COX-1 and COX-2 when added directly to the test systems. Plasma from aspirin-treated rats was without effect on either COX-1 or COX-2, consistent with the rapid in vivo metabolism to salicylate. Conversely, plasma from sulindac-treated rats inhibited COX-1 and COX-2 with potencies according with in vivo metabolism to sulindac sulphide. Diclofenac was COX-1/2 non-selective when tested in vitro, but a slightly preferential inhibitor of COX-2 when tested ex vivo. Nimesulide was confirmed as preferential inhibitor of COX-2 both in vitro and ex vivo. L-745,337 was a selective COX-2 inhibitor when tested in vitro or ex vivo. In conclusion, our experiments show clearly (a) NSAIDs inactivation, (b) activation of pro-drugs, and (c) NSAIDs selectivity. Our assay provides useful information about the selectivity of NSAIDs that could be extended by the analysis of plasma samples taken from humans similarly treated with test drugs. British Journal of Pharmacology (1999) 126, 1824–1830; doi:10.1038/sj.bjp.0702518
The Role of Cytokines as Inflammatory Mediators in Osteoarthritis: Lessons from Animal Models
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  • Feb 1999
Studies in animal models of osteoarthritis (OA) have been used extensively to gain insight into the pathogenesis of OA, but early studies largely ignored inflammation except as a secondary phenomenon. Synovitis has often been noted as a feature in experimental OA, and more recent work has established a central role for inflammatory cytokines as biochemical signals which stimulate chondrocytes to release cartilage-degrading proteinases. Thus, proteinase inhibitors, cytokine antagonists and receptor blocking antibodies, and growth/differentiation factors have been considered as potential therapeutic agents and targets for gene therapy. Although there is some disagreement, it is generally accepted that IL-1 is the pivotal cytokine at early and late stages, while TNF-alpha is involved primarily in the onset of arthritis. Other cytokines released during the inflammatory process in the OA joint may be regulatory (IL-6, IL-8) or inhibitory (IL-4, IL-10, IL-13, IFN-gamma). Furthermore, studies in animal models have illustrated the potentially beneficial effects of anticytokine therapy with monoclonal antibodies or receptor antagonists, although local rather than systemic delivery would be necessary for the largely localized OA in humans. Transgenic or knockout mice have also provided insights into general mechanisms of cytokine-induced cartilage degradation but have not directly addressed OA pathogenesis. Similarly, animals with spontaneous or transgenic modifications in cartilage matrix components, growth/differentiation factors, or developmentally regulated transcription factors have provided information about potential gene defects that predispose to OA without addressing the role of inflammatory mediators in cartilage destruction. Although the multiple etiologies of human OA indicate that it is more complex than any animal model, the use of appropriate, well-defined animal models will establish the feasibility of novel forms of therapy.
Treatment of low back pain exacerbations with willow bark extract: a randomized double-blind study* 1
Article
Herbal medicines are widely used for the treatment of pain, although there is not much information on their effectiveness. This study was designed to evaluate the effectiveness of willow (Salix) bark extract, which is widely used in Europe, for the treatment of low back pain. We enrolled 210 patients with an exacerbation of chronic low back pain who reported current pain of 5 or more (out of 10) on a visual analog scale. They were randomly assigned to receive an oral willow bark extract with either 120 mg (low dose) or 240 mg (high dose) of salicin, or placebo, with tramadol as the sole rescue medication, in a 4-week blinded trial. The principal outcome measure was the proportion of patients who were pain-free without tramadol for at least 5 days during the final week of the study. The treatment and placebo groups were similar at baseline in 114 of 120 clinical features. A total of 191 patients completed the study. The numbers of pain-free patients in the last week of treatment were 27 (39%) of 65 in the group receiving high-dose extract, 15 (21%) of 67 in the group receiving low-dose extract, and 4 (6%) of 59 in the placebo group (P <0.001). The response in the high-dose group was evident after only 1 week of treatment. Significantly more patients in the placebo group required tramadol (P <0.001) during each week of the study. One patient suffered a severe allergic reaction, perhaps to the extract. Willow bark extract may be a useful and safe treatment for low back pain.