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Herbal Medicinal Products in the Treatment of Osteoarthritis

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Abstract

Osteoarthritis (OA) is the most common form of arthritis, which represents a substantial economic burden for society and significantly affects patients' quality of life. Current conventional treatments of OA may be insufficiently effective and unsafe. In an attempt to overcome these limitations, many patients use herbal medicinal products (HMPs) and dietary supplements. A considerable number of herbal drugs and preparations (e.g., willow bark, Salicis cortex; devil's claw root, Harpagophyti radix; blackcurrant leaf, Ribis nigri folium; nettle leaf/herb, Urticae folium/herba; meadowsweet/meadowsweet flower, Filipendulae ulmariae herba/flos; rosemary leaf/oil, Rosmarini folium/aetheroleum; and juniper oil, Juniperi aetheroleum) are traditionally employed to relieve minor articular pain. Active constituents (e.g., sesquiterpene lactones, triterpenic acids, diarylheptanoids, iridoid glycosides, phenolic glycosides, procyanidins, and alkaloids) are not often fully known. Experimental studies suggest that herbal extracts/compounds are able to suppress inflammation, inhibit catabolic processes, and stimulate anabolic processes relevant to OA. Therapeutic benefit of most HMPs is expected solely from the experience of their long-standing traditional use. Efficacy and safety of several HMPs were assessed in clinical trials. The growing body of preclinical and clinical evidence provides rationale for the use of herbal products in the treatment of OA. However, at present, they cannot be recommended to patients with confidence.
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Chapter
Herbal Medicinal Products in the
Treatment of Osteoarthritis
Zoran Maksimovićand Stevan Samardžić
Abstract
Osteoarthritis (OA) is the most common form of arthritis, which represents a
substantial economic burden for society and significantly affects patientsquality of
life. Current conventional treatments of OA may be insufficiently effective and
unsafe. In an attempt to overcome these limitations, many patients use herbal
medicinal products (HMPs) and dietary supplements. A considerable number of
herbal drugs and preparations (e.g., willow bark, Salicis cortex; devils claw root,
Harpagophyti radix; blackcurrant leaf, Ribis nigri folium; nettle leaf/herb, Urticae
folium/herba; meadowsweet/meadowsweet flower, Filipendulae ulmariae herba/flos;
rosemary leaf/oil, Rosmarini folium/aetheroleum; and juniper oil, Juniperi
aetheroleum) are traditionally employed to relieve minor articular pain. Active
constituents (e.g., sesquiterpene lactones, triterpenic acids, diarylheptanoids,
iridoid glycosides, phenolic glycosides, procyanidins, and alkaloids) are not often
fully known. Experimental studies suggest that herbal extracts/compounds are able
to suppress inflammation, inhibit catabolic processes, and stimulate anabolic
processes relevant to OA. Therapeutic benefit of most HMPs is expected solely from
the experience of their long-standing traditional use. Efficacy and safety of several
HMPs were assessed in clinical trials. The growing body of preclinical and clinical
evidence provides rationale for the use of herbal products in the treatment of OA.
However, at present, they cannot be recommended to patients with confidence.
Keywords: osteoarthritis, herbal medicinal products, medicinal plants, mechanism
of action, active constituents, clinical efficacy
1. Introduction
Osteoarthritis (OA) is the most common form of arthritis and the main cause of
disability in elderly. Due to the aging population and obesity (major risk factors), its
prevalence increases. It is estimated that symptomatic OA of knee affects
approximately 12% of the older population (60 years). Symptomatic OA of hand
(6.8%, 26 years) and hip (9.2%, 45 years) is also frequent. OA can influence
patientsquality of life significantly, as it is usually accompanied with the pain and
loss of physical function. OA often affects knees, hips, hands (distal and proximal
interphalangeal joints and the base of thumb), cervical and lumbosacral spine, and
feet (first metatarsal phalangeal joint). It is characterized by failure of all joint
structures. Articular cartilage loss is the most prominent feature of the disease, but
subchondral bone, synovial membrane, associated muscles, and ligaments are also
affected. On cellular level, catabolic function of chondrocytes prevails over their
1
anabolic activity. This imbalance is promoted by pro-inflammatory cytokines,
which stimulate chondrocytes to produce enzymes (collagenases and aggrecanases)
able to degrade extracellular matrix composed of collagen type II and
proteoglycans. Several mediators (e.g., TNF-α, IL-1β, NO, and PGE
2
) play an
important role in the pathogenesis and progression of OA [1, 2].
Conventional treatment of OA encompasses non-pharmacotherapeutic
approach (e.g., physiotherapy, correction of malalignment, weight control, and
patient education), pharmacotherapy, and surgery. Nonsteroidal anti-inflammatory
drugs (NSAIDs) are medicines used most often for the relief of osteoarthritic
symptoms. Although NSAIDs are relatively efficient, their prolonged use or their
use in susceptible individuals can cause serious side effects such as gastrointestinal
toxicity, cardiovascular events, edema development, reversible renal insufficiency,
and modest increase of blood pressure. Topical formulations of NSAIDs are slightly
less efficient than the oral ones, but their advantage lies in better safety profile.
However, irritation of the skin often occurs at the application area [1].
Some patients experiencing unsatisfactory efficacy and side effects of conven-
tional therapy try to overcome current treatment deficiencies by using modalities
of complementary and alternative medicine. In that regard, herbal medicinal
products (HMPs) and dietary supplements have become considerably popular for
alleviation of OA symptoms [3]. Besides expected direct effects, important indi-
rect benefit of their use may be the decrease of required doses of concomitantly
administered conventional drugs, as this may result in reduced side effects. At
present, available scientific data are insufficient to support the use of these
products in clinical management of OA. The aim of this review is therefore to
present current knowledge on herbal treatment options in the therapy of OA, i.e.,
active constituents of plants and mechanisms of their action relevant to OA,
advice for patients using herbal products, and results of clinical trials, if available.
2. Herbal medicinal products for oral use in the treatment of
osteoarthritis
Willow bark (Salicis cortex)is whole or fragmented dried bark of young
branches or whole dried pieces of current-year twigs of various species of genus
Salix including S. purpurea L., S. daphnoides Vill., and S. fragilis L. [4]. Herbal teas
(infusion and decoction), powder, dry aqueous extracts, liquid hydroalcoholic
extract, and tincture of willow bark are traditionally used for minor articular pain
relief. Duration of the treatment is restricted to 4 weeks. In the case of hypersensi-
tivity (to the willow bark, salicylates, or the other NSAIDs), asthma due to hyper-
sensitivity to salicylates, active peptic ulcer disease, third trimester of pregnancy,
glucose-6-phosphate dehydrogenase deficiency, children and adolescents younger
than 18 (risk of Reyes syndrome), severe liver or renal dysfunction and coagulation
disorders, the use of Salicis cortex-based HMPs is contraindicated. Concomitant
application of salicylates and other NSAIDs is not recommended, unless advised by
the physician. Willow bark preparations may interact with anticoagulants. Their use
is not recommended in the first and second trimester of pregnancy, as well as
during lactation. Side effects include allergic reactions and gastrointestinal symp-
toms [5]. The main constituents of willow bark with respect to the pharmacological
action are phenolic glycosides (e.g., salicin, salicortin, 2-O-acetylsalicortin, and/or
tremulacin) [6, 7] although the other secondary metabolites (e.g., polyphenolic
compounds) may also participate in the total anti-inflammatory activity [8].
Phenolic glycosides are considered as prodrug compounds that are metabolized to
salicylic acid in gastrointestinal tract and liver. Beneficial effect is a result of
2
Osteoarthritis
cyclooxygenase inhibition and diminished production of prostaglandins [9]. Two
randomized controlled clinical trials provided low-quality evidence that short-term
treatment with standardized willow bark extracts (daily doses corresponded to
240 mg of salicin) was not efficient in reduction of pain and improvement of
physical function in patients with OA of hip and knee [3, 10]. Additional well-
designed sufficiently powered studies are needed in order to estimate willow bark
clinical effect.
Devils claw root (Harpagophyti radix)consists of cut and dried, tuberous
secondary roots of Harpagophytum procumbens DC. and/or Harpagophytum zeyheri
Decne. [4]. Herbal tea and liquid or solid dosage forms containing different devils
claw root preparations (e.g., dry aqueous or hydroalcoholic extracts, liquid or soft
hydroalcoholic extracts, tincture, powder) are used for the relief of minor articular
pain, exclusively based upon long-standing traditional use. Patients with known
hypersensitivity to devils claw root or active gastric/duodenal ulcer must not use
these products. Additionally, in cases of gallstones, a physician should be consulted
prior to use of devils claw root preparations. Undesirable effects include
hypersensitivity, as well as adverse reactions of the central nervous system and
gastrointestinal tract [11]. Harpagophyti radix contains bitter iridoid glycosides
(harpagide and harpagoside), triterpenoids, polyphenolic acids, phenylethyl
glycosides, and flavonoids [7]. Devils claw root preparations exhibited anti-
inflammatory activity in vitro by decreasing production of pro-inflammatory
cytokines (TNF-α, IL-1β, and IL-6) and PGE
2
in LPS-stimulated human monocytes
[12] and by reducing levels of matrix metalloproteinases (MMP-1, MMP-3, MMP-9)
in IL-1β-stimulated human chondrocytes [13]. Aqueous extract of H. procumbens
downregulated expression of COX-2 and iNOS in the mouse fibroblasts and, as a
result, decreased PGE
2
and NO generation [14]. Harpagoside, similarly to devils
claw root extracts, suppressed expression of IL-6 and MMP-13 in human
chondrocytes, probably via the inhibition of transcription factor activator protein-1
(AP-1) activity [15]. Antiosteoarthritic properties of three devils claw root prepa-
rations were the subject of four randomized controlled clinical trials. In two studies
investigating Flexiloges
®
(ethanolic (60%) extract, DER 4.55.5:1, daily dose
960 mg), there was no improvement in pain scores. However, the pain-relieving
activity of Arthrotabs
®
(aqueous extract, DER 1.52.5:1, daily dose 2400 mg) was
noticed in another study. Finally, one study indicated that Harpadol
®
(cryoground
powder, daily dose 2610 mg) was comparable to diacerhein in reducing pain [10].
Blackcurrant leaf (Ribis nigri folium)is a dried leaf of Ribes nigrum L. [4].
Phytochemical analysis showed that it contains polyphenolic compounds (flavo-
noids, proanthocyanidins, hydroxycinnamic acid derivatives) and traces of essential
oil [6]. Blackcurrant leaf is used in traditional medicine to reduce minor articular
pain [16]. Hydroalcoholic extract of this herbal drug exerted beneficial effects in
carrageenan-induced acute inflammation, cotton pellet granuloma, and Freunds
adjuvant-induced arthritis in rats. It also acted as an antinociceptive agent in the
acetic acid-induced writhing test in mice [17]. Prodelphinidins (Ribis nigri folium
constituents) stimulated synthesis of type II collagen and proteoglycans, and
decreased the generation of PGE
2
in human chondrocytes [18]. Documented anti-
inflammatory, analgesic, and anabolic effects give credence to reported folkloric use.
Meadowsweet herb (Filipendulae ulmariae herbawhole or cut, dried
flowering tops) and meadowsweet flower (Filipendulae ulmariae flos, syn. Spiraeae
flosdried flowers) are herbal drugs obtained from Filipendula ulmaria (L.)
Maxim. (syn. Spiraea ulmaria L.), which are traditionally used in treatment of
minor articular pain [4, 1921]. They are characterized by high content of
polyphenols, particularly flavonoids and ellagitannins. Phenolic glycosides and
salicylic acid are also present [6, 22]. In vitro anti-inflammatory action of
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Herbal Medicinal Products in the Treatment of Osteoarthritis
DOI: http://dx.doi.org/10.5772/intechopen.80593
meadowsweet preparations was mediated by inhibition of complement activation,
reduction of the production of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6)
and, to a certain degree, inhibition of cyclooxygenase and PGE
2
generation [6, 23,
24]. In animal model of carrageenan-induced acute inflammation, lyophilized
flower infusion of F. ulmaria exerted analgesic activity [25]. There is no literature
data related to clinical effects of meadowsweet in OA.
Nettle leaf (Urticae folium)is whole or a cut dried leaf of Urtica dioica L., Urtica
urens L., or their mixture [4], whereas nettle herb (Urticae herba) is dried cut or
fragmented aerial part of Urtica dioica L., Urtica urens L., their hybrids or mixtures,
collected or harvested during the flowering period [26]. Both herbal drugs are
employed in folkloric medicine for alleviation of minor articular pain. Side effects
include gastrointestinal and allergic reactions [26, 27]. Constituents of nettle leaf and/
or herb are caffeic acid esters, flavonoids, minerals, free amino acids, etc. [6]. Reputed
benefit of nettle preparations in the treatment of OA complaints is supported by
experimental findings that they suppressed activation of transcription factor NF-κB
and inhibited IL-1β-stimulated production of MMP-1, MMP-3, and MMP-9 in human
chondrocytes [28, 29]. Furthermore, oral intake of nettle leaf extract by healthy
volunteers, during a three-week period, reduced production of pro-inflammatory
cytokines (TNF-α,IL-1β) in whole blood ex vivo after LPS challenge [30].
Ash leaf (Fraxini folium)is by definition a dried leaf of Fraxinus excelsior L. or
Fraxinus angustifolia Vahl (syn. Fraxinus oxyphylla M. Bieb), or of hybrids of these
two species or of a mixture [4]. It is employed in ethnomedicine as herbal tea
(infusion or decoction) to reduce minor articular pain [31]. Constituents occurring
in ash leaf are coumarins, iridoids, secoiridoids, flavonoids, lignans, simple phenolic
compounds, etc. [32]. Evidence from pharmacological studies that could explain
recorded traditional use is scarce. Certain support was provided by experimental
observation that esculin, a coumarin present in both species, decreased NO pro-
duction in macrophages by inhibition of transcription factor NF-κB activation.
Additionally, esculin was able to suppress inflammatory response (reduce levels of
TNF-αand IL-6) induced by injecting LPS to mice [33].
Mixture of avocado and soybean unsaponifiables. Antiosteoarthritic proper-
ties of a mixture of avocado and soybean unsaponifiables (ASU) were extensively
examined in the past. Phytochemical analysis of its composition revealed the pres-
ence of phytosterols (β-sitosterol, campesterol, and stigmasterol), fat-soluble
vitamins, triterpene alcohols, and possibly furan fatty acids. Experimental studies
provided significant evidence of ASU anabolic and anticatabolic action in cartilage.
ASU stimulated the synthesis of extracellular matrix components (collagen and
aggrecan) and inhibited production of pro-inflammatory molecules (TNF-α, IL-1β,
IL-6, IL-8, MIP-1β, NO, and PGE
2
) probably by interfering with signaling of
transcription factor NF-κB. Cartilage degradation may be decreased as a result of
ASU ability to inhibit matrix metalloproteinases (MMP-2, MMP-3, and MMP-13)
and stimulate expression of tissue inhibitor of metalloproteinases-1. Beneficial
activity may also be related to the capacity of ASU to affect levels of transforming
growth factor-βand vascular endothelial growth factor [34]. Four randomized
controlled clinical studies recruiting 651 participants provided moderate-quality
evidence that ASU proprietary product Piascledine
®
(mixture of unsaponifiable
fractions of fatty oils of Persea gratissima (P) and Glycine max (G), 1/3 P + 2/3 G;
daily dose 300 mg) generated small improvement in osteoarthritic symptoms with
questionable clinical significance, after a treatment lasting 312 months. Adverse
events of herbal intervention were not probably increased compared to the placebo
group. Moderate-quality evidence showed that Piascledine
®
in higher daily dose
(600 mg) also reduced OA symptoms. Available data did not support assumption
4
Osteoarthritis
that it significantly improved joint structure. There is limited evidence that it
prevented joint space narrowing [10].
Indian frankincense (Olibanum indicum)is an air-dried gum-resin exudate,
obtained by incision of the stem or branches of Boswellia serrata Roxb. ex Colebr. [4],
which is used in the treatment of OA [35]. To assure optimal absorption, it is
recommended to use Indian frankincense preparations with food. Cases of neutrope-
nia were documented after long-term use of dry extract in a daily dose of up to 10 g.
It contains pentacyclic triterpenic acids, i.e., β-boswellic acid (BA), 11-keto-
β-boswellic acid (KBA), and acetyl-11-keto-β-boswellic acid (AKBA) [35]. These
secondary metabolites could be responsible for the therapeutic activity, particularly
BA that reaches relatively high concentration in the human plasma. BA, KBA, and
AKBA acted as inhibitors of mPGES-1 and, hence, PGE
2
synthesis. They reduced
the activity of cathepsin G [36], a serine protease whose relevance in OA has been
suggested in a recent study [37]. The suppressing effect of AKBA on production of
TNF-αin monocytes was also reported [36]. Crude Boswellia serrata extract
downregulated inflammatory cytokines (TNF-α, IL-1β, and IL-6) in peripheral blood
mononuclear cells [38]. Results of investigations using animal models of
inflammation and arthritis (e.g., adjuvant arthritis in Lewis rats, formaldehyde-
induced arthritis in rats, dextran-induced edema in rats, and carrageenan-induced
edema in rats and mice) are in accordance with the in vitro observed anti-
inflammatory activity [36]. Two randomized placebo-controlled clinical trials
conducted with Indian frankincense proprietary product 5-Loxin
®
(standardized
to contain at least 30% AKBA) indicated that oral application of this enriched extract
in a daily dose of 100 mg decreased pain and improved function in OA patients (n =
85) after 90 days treatment. The results of studies examining proprietary product
Aflapin
®
(enriched with non-volatile oil and standardized to contain at least 20%
AKBA) are consistent. New studies may change the estimations [10]. Concentration
of MMP-3 in synovial fluid of patients using 5-Loxin
®
decreased, suggesting that
therapeutic activity could be linked to the attenuation of cartilage destruction [39].
Pycnogenol
®
is standardized bark extract of French maritime pine (Pinus
pinaster Aiton) rich in polyphenolic compounds (procyanidins, taxifolin, catechin,
and phenolic acids) [40]. Pharmacokinetic studies demonstrated that certain anti-
inflammatory constituents of Pycnogenol
®
(ferulic acid and caffeic acid) and
procyanidins gut microbiota metabolite δ-(3,4-dihydroxy-phenyl)-γ-valerolactone
were able to reach synovial fluid [40, 41]. δ-(3,4-Dihydroxy-phenyl)-γ-
valerolactone concentration-dependently reduced nitrite production and iNOS
expression. Its affinity to accumulate in macrophages, monocytes, and endothelial
cells were demonstrated [42]. Investigation conducted in patients with severe OA
showed that expression of matrix metalloproteinases (MMP-3 and MMP-13) and
IL-1βin chondrocytes was decreased after intake of Pycnogenol
®
, as well as level of
ADAMTS-5 in serum [43]. Plasma obtained from volunteers taking Pycnogenol
®
orally for 5 days decreased activation of transcription factor NF-κB in macrophages
and inhibited COX-1 and COX-2 [44, 45]. Additionally, gene expression of COX-2
and 5-LOX, leukotriene biosynthesis, and phospholipase A
2
activity in polymor-
phonuclear leukocytes (isolated from the blood of volunteers) were reduced [46].
Moderate-quality evidence obtained from three randomized controlled clinical
trials indicated that Pycnogenol
®
(daily doses 100 or 150 mg) decreased pain and
improved physical function in patients with OA of knee and that it probably
reduced consumption of NSAIDs. The effect size after three-month treatment was
estimated to be large and clinically important. However, quality of evidence is
insufficient to make any firm conclusion. It should be noted that the content of
marker compound (procyanidins) differed in the investigated products [3, 10].
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Herbal Medicinal Products in the Treatment of Osteoarthritis
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Rosehip (Rosae pseudofructus cum fructibus)is obtained from Rosa canina L. It
represents pseudofruit, composed of achenes enclosed in a fleshy receptacle or
hypanthium. Phytochemical investigations revealed that rosehip contains sugars,
organic acids, pectins, procyanidins, catechins, flavonoids, carotenoids, triterpene
acids, unsaturated fatty acids, and a galactolipid [7, 35]. R. canina hip preparations
inhibited activation of transcription factor NF-κB, decreased expression of matrix
metalloproteinases (MMP-1, MMP-3, MMP-9, and MMP-13) in chondrocytes,
suppressed expression of COX-2 in human monocytes and chondrocytes, decreased
generation of PGE
2
and NO in murine macrophages, and reduced levels of pro-
inflammatory cytokines (IL-1β, TNF-α, and IL-6) and chemokine CCL5 in various
assays. Dried powder of R. canina hips given to animals during 3 weeks exerted
activity in rat arthritis model (monoiodoacetate-induced) and suppressed produc-
tion of MMP-3 and MMP-13. Rosehip preparations also displayed activity in animal
models of acute inflammation [47]. Active constituents belong to different groups
of compounds; e.g., galactolipid was able to modulate chemokines (CCL5 and IL-8),
matrix metalloproteinases (MMP-1, MMP-3, and MMP-13) and aggrecanase
ADAMTS-4 expression, whereas fatty acids (linoleic and linolenic) inhibited
cyclooxygenases [47, 48]. It seems that reputed antirheumatic effect of rosehip is
a sum of actions of several individual constituents. Data obtained from three
clinical trials examining effects of rosehip powder provided modest and somewhat
conflicting evidence that orally administered product (daily dose 5 g) is superior
to placebo in the treatment of osteoarthritic pain [10].
Turmeric rhizome (Curcumae longae rhizoma)consists of whole, peeled,
shortly boiled or steamed and dried rhizome of Curcuma longa L. (syn. C. domestica
Valeton) [4]. Characteristic constituents are curcuminoids (phenolic
diarylheptanoids), essential oil rich in turmerones (sesquiterpene ketones), and
polysaccharides. It is popular in Ayurveda and Chinese medicine as an anti-
inflammatory agent [7]. Curcumin in vitro prevented the apoptosis of chondrocytes
and decreased the production of matrix metalloproteinases and monocyte
chemoattractant protein. It also suppressed expression of pro-inflammatory cyto-
kines, cyclooxygenase, and PGE
2
in chondrocytes. These effects were probably
mediated by inhibition of IkB phosphorylation and thus transcription factor NF-κB
activation. Regulation of AP-1 and protein kinase C was described as well. In vivo
curcumin suppressed carrageenan-induced edema and formaldehyde-induced
arthritis [49, 50]. Meta-analyses of randomized controlled trials indicated that
curcumin was able to decrease circulating levels of pro-inflammatory cytokines
TNF-αand IL-6 [51, 52]. Curcuminoids and Curcuma longa extract decreased oxi-
dative stress in patients with OA, which suggested that antioxidant activity partic-
ipated in turmeric beneficial action [53, 54]. A four-week multicenter randomized
double-blind controlled clinical study showed that ethanol extract of turmeric rhi-
zome (daily dose 1500 mg, 7585% curcuminoids) was not inferior compared to
ibuprofen (daily dose 1200 mg) in the management of knee OA. The number of side
effects was similar in both groups, but incidence of gastrointestinal side effects was
significantly higher in patients treated with ibuprofen [55]. Authors of a systematic
review and meta-analysis concluded that a short-term treatment with curcumin and
extract of Curcuma longa produced significant and clinically meaningful reduction
of pain and improvement of physical function in patients with OA of knee. The
quality of evidence was estimated to be very low to moderate. Characteristics of
available studies limit possibility to make firm conclusion on the efficacy of tur-
meric rhizome preparations [3].
Ginger (Zingiberis rhizoma)is dried, whole or cut rhizome of Zingiber officinale
Roscoe, with the cork removed, either completely or from wide, flat surfaces only
[4]. It is characterized by the presence of essential oil and a mixture of pungent
6
Osteoarthritis
tasting phenolic compounds (gingerols, gingerdiols, gingerdiones, dihydrogin-
gerdiones, and shogaols) [7]. In a recent in vitro study, it has been shown that ginger
extract was able to attenuate oxidative stress and reduce succeeding cell death of
chondrocytes resulting from a mitochondrial apoptosis [56]. Ginger preparations
also inhibited LPS-induced PGE
2
formation in U937 cells and decreased levels of
TNF-αand IL-1βin murine peritoneal macrophages [57]. In vivo, they suppressed
carrageenan- and fresh egg albumin-induced edema in rats and exhibited analgesic
action in models of chemically and thermally induced pain in mice [58, 59]. Ginger
essential oil reduced acetic acid-induced writhing response in animals [57]. Intra-
peritoneally administered 6-gingerol exhibited analgesic and anti-inflammatory
action, i.e., decreased formalin-induced licking time in late phase and suppressed
carrageenan-induced edema and acetic acid-induced writing response [60].
In vitro assay showed considerable potential of 6-gingerol to inhibit prostaglandin
biosynthesis [61]. Therapeutic effect of ginger in patients with OA was investigated
in two randomized controlled cross-over clinical studies. In one trial, ibuprofen
treatment was reported to be more effective than acetone extract of ginger root
(DER 20:1, daily dose 510 mg) in terms of pain reduction and consumption of
NSAIDs. Available data did not allow reanalysis. Another trial showed that CO
2
extract of ginger root (daily dose: 1000 mg of extract, 40 mg of gingerol) signifi-
cantly differed from placebo after a six-month study [10]. Although clinical trials
investigating ginger were performed, its clinical benefit at this moment cannot be
assessed with confidence.
Cats claw (Uncaria tomentosa and U. guianensis), South American vines that
share the same common name, are used traditionally to treat inflammatory condi-
tions (e.g., arthritis) [62]. Active constituents of these medicinal plants are consid-
ered to be oxindole alkaloids (isorhynchophylline, rhynchophylline and their
N-oxides, mitraphylline) and the quinovic acid glycosides [63]. According to the
monograph of the World Health Organization, cats claw bark (Uncariae cortex)
consists of the dried stem bark of Uncaria tomentosa (Willd.) DC. (Rubiaceae) [64].
In vitro studies in murine macrophages showed that U. tomentosa and U. guianensis
preparations suppressed TNF-αand PGE
2
formation [62] and that aqueous bark
extract of U. tomentosa inhibited activation of transcription factor NF-κB [65]. The
observed anti-inflammatory activity was further supported by in vivo experiments.
U. tomentosa bark extracts (spray-dried hydroalcoholic and aqueous freeze-dried)
suppressed carrageenan-induced paw edema in mice [66]. Using in vivo model of
acute inflammation, fractions of U. tomentosa bark extract yielded quinovic acid
glycoside as one of pharmacologically active compounds [67]. Mitraphylline,
pentacyclic oxindole alkaloid, decreased blood levels of pro-inflammatory cytokines
(IL-1βand TNF-α) in the LPS-challenged mice [68]. Double-blind placebo-
controlled study in 45 patients within 4 weeks compared pain-relieving property of
freeze-dried aqueous extract of U. guianensis bark (daily dose 100 mg) to placebo. A
significant decrease in activity-related OA knee pain occurred in a group receiving
U. guianensis preparation in the first week of trial. On the other hand, U. guianensis
preparation did not reduce the pain at rest or at night. Serious side effects were not
observed [62]. Clinical data were insufficiently reported for reanalysis [10].
Preclinical studies suggested that U. tomentosa (especially pentacyclic chemotype)
could exert immunostimulatory action; therefore, patients under risk of
transplanted organ rejection should be advised not to use cats claw products [63].
Bromelain is a mixture of proteolytic enzymes obtained from the fruit and stem
of pineapple (Ananas comosus L.) and other species of Bromeliaceae family [7].
Experimental evidence suggests that bromelain anti-inflammatory properties may
be mediated by its ability to decrease levels of bradykinin and PGE
2
and to modulate
cell surface adhesion molecule implicated in arthritis. Investigations in animals
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DOI: http://dx.doi.org/10.5772/intechopen.80593
confirmed that bromelain acted as an analgesic agent [69]. Anti-osteoarthritic
property of orally administered bromelain (daily dose 500 mg) was compared with
therapeutic activity of diclofenac (daily dose 100 mg) in a randomized single-blind
active-controlled pilot study in 40 patients with mild-to-moderate knee OA. After a
four-week treatment, there was no difference in symptoms relief between
bromelain-treated and diclofenac-treated groups [70]. Bromelain (800 mg/day)
was also compared with placebo in a randomized double-blind three-month long
pilot study that included patients with moderate-to-severe OA of knee. The authors
suggested that bromelain was not efficacious as an adjunctive treatment, but, due to
the trial limitations, proposed that new studies should be performed [71]. Recent
systematic review of clinical trials, examining dietary supplements used in the
management of OA, has shown that the short-term treatment with bromelain was
not effective in alleviation of pain and function improvement. Evidence quality was
low [3].
Purified purple passion fruit peel extract, obtained from South American
climbing vine Passiflora edulis, contains considerable amounts of flavonoids and
anthocyanins. Its therapeutic effects (daily dose 150 mg) in patients with OA of
knee were examined in a randomized double-blind placebo-controlled short-term
study. The observed reduction of pain and improvement of physical function were
significant and clinically meaningful. The quality of provided evidence was
moderate [3, 72].
3. Herbal medicinal products for topical use in the treatment of
osteoarthritis
Capsicum (Capsici fructus)is a dried ripe fruit of Capsicum annuum L. var.
minimum (Miller) Heiser and small-fruited varieties of Capsicum frutescens L. [4].
With respect to its medicinal properties, the most important compounds are
capsaicinoids (capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homodihydro-
capsaicins I and II, caprylic acid vanillylamide, etc.). Triglycerides, carotenoids,
ascorbic acid, flavonoids, and a complex mixture of volatile compounds are also
present [35]. Standardized products of capsicum (semisolid or liquid dosage forms,
medicated plasters) are intended for the relief of muscle (e.g., low back pain) and
osteoarthritic pain. They should be used continuously until relief of pain is
achieved, but not longer than 3 weeks and with a subsequent, at least two-week
break period. Its use is contraindicated in cases of broken skin, wounds, eczema,
and hypersensitivity to herbal substance or capsaicinoids. The plasters and semi-
solid dosage forms are not intended for concomitant use with other products for
external administration. Topical application of capsicum HMPs initially causes skin
irritation that is manifested by erythema and warmth sensation. Next stage is
characterized by prolonged (hours to weeks) desensitization to pain stimuli. Side
effects include skin hypersensitivity and allergic reactions [35, 73]. Capsaicin acts as
an agonist of vanilloid receptors on C-type nerve fibers and thus it leads to deple-
tion of neuropeptide substance P and consequent antinociception [7]. Standardized
product containing capsicum tincture (Capsica gel
®
, 0.0125% of capsaicin) was
investigated in a cross-over, randomized, placebo-controlled trial recruiting 99
patients with the OA of knee, within 9 weeks. Gel (2 inches) was applied topically
three times per day. The conducted study provided moderate-quality evidence that
the product probably did not decrease pain and improve function. Adverse events
were common and included skin irritation and burning sensation [74, 75]. Creams
containing higher concentration of capsaicin (0.0250.075%) are indicated in the
treatment of OA symptoms [1].
8
Osteoarthritis
Arnica flower (Arnicae flos)is, whole or partially broken, dried flower-head of
Arnica montana L. [4]. This herbal drug is employed traditionally for relief of
bruises, sprains, and localized muscular pain. Semisolid and liquid dosage forms
based on arnica preparations (tinctures or ethanolic liquid extract) are applied
cutaneously. The use of arnica HMPs is contraindicated in patients with known
hypersensitivity to arnica and other plants belonging to Asteraceae family. They
should not be applied on broken skin. Reported side effects include allergic skin
reactions [76]. Main constituents of arnica flower-heads are pseudoguianolide-type
sesquiterpene lactones helenalin and 11α,13-dihydrohelenalin [7]. Contribution of
these secondary metabolites to the anti-inflammatory effect is likely as it was shown
that helenalin and 11α,13-dihydrohelenalin had the ability to interfere with the
activation of transcription factor NF-κB [77]. In vitro experiments conducted on the
pig skin indicated that sesquiterpene lactones can penetrate into it, and thus further
support this assumption [78, 79]. Better permeation through stratum corneum (the
outermost layer of the skin) was achieved when sesquiterpene lactones were
applied in the form of arnica tinctures than as pure compounds [78]. Arnica flower
preparations at low concentration/s were able to reduce levels of pro-inflammatory
cytokines (IL-1 and TNF-α) in human mononuclear cells and of mRNA of matrix
metalloproteinases (MMP-1 and MMP-13) in human and bovine articular
chondrocytes [80, 81]. Whole plant methanolic extract suppressed expression of
iNOS and COX-2 in LPS-stimulated murine macrophages [82]. Presented literature
data may help to rationalize the use of arnica in management of diseases with
underlying inflammation. Moderate evidence from a single, double-blind
randomized controlled clinical trial showed that topical application of arnica gel
(A. Vogel Arnica Gel
®
, 50 g herbal tincture/100 g gel, extraction solvent 50%
ethanol, and DER 1:20) three times per day probably decreased pain and improved
function related to hand OA as ibuprofen gel (5%), with a similar number of
adverse events [74, 83].
Rosemary leaf (Rosmarini folium)is whole, dried leaf of Rosmarinus officinalis
L. [4]. Its chemistry is characterized by the presence of essential oil, phenolic
diterpenes (e.g., carnosol, carnosolic acid, and rosmanol), hydroxycinnamic
derivatives, flavonoids, and triterpenoids [6]. Rosemary leaf bath additive is applied
as an adjuvant to relieve minor muscular and articular pain, exclusively based upon
long-standing traditional use [84]. Several rosemary compounds exhibited anti-
inflammatory action in vitro. Rosmarinic acid decreased levels of PGE
2
and NO in
rat chondrocytes [85]. Phenolic diterpene carnosol decreased concentrations of
PGE
2
and NO, and reduced gene expression of iNOS, IL-1α, IL-6, and CCL5 in LPS-
stimulated macrophages. In addition, it interfered with transcription factor NF-κB
activation and influenced expression of anabolic and catabolic genes in
chondrosarcoma cell line SW1353 and in primary human chondrocytes [86].
Comfrey root (Symphyti radix)is obtained from Symphytum officinale L., a
traditional medicinal plant that can be found throughout Europe, parts of Asia, and
as a naturalized plant in North America. It contains allantoin, mucilage polysaccha-
rides, phenolic acids (e.g., rosmarinic acid), glycopeptides, amino acids, triterpene
saponins, and pyrrolizidine alkaloids with 1,2-unsaturated necine ring structures.
Identity of active principles is not sufficiently known although it is assumed that
allantoin and rosmarinic acid play an important role in biological activity [87].
Taking into account considerable hepatotoxic and carcinogenic potential of
pyrrolizidine alkaloids, their content in comfrey products has to be specified, as
daily exposure has to be below 0.35 μg [88]. Anti-inflammatory action of comfrey
preparations was demonstrated in preclinical studies when they dose-dependently
inhibited complement activation and suppressed carrageenan-induced rat paw
edema [87]. Moderate evidence from a double-blind, randomized, bicenter,
9
Herbal Medicinal Products in the Treatment of Osteoarthritis
DOI: http://dx.doi.org/10.5772/intechopen.80593
placebo-controlled trial with 220 participants indicated that comfrey root gel Kytta-
Salbe
®
f probably reduced pain related to knee OA after 3 weeks of external appli-
cation (6 g daily, 3 2 g) [74, 89]. Investigated proprietary product contained 35%
of liquid extract (DER 1:2, ethanol 60% V/V, allantoin 0.20.5%) and <0.35 ppm of
pyrrolizidine alkaloids [89].
Essential oils such as juniper oil, Juniperi aetheroleum; rosemary oil, Rosmarini
aetheroleum; eucalyptus oil, Eucalypti aetheroleum; peppermint oil, Menthae piperitae
aetheroleum; sweet birch oil, Betulae lentae aetheroleum; and wintergreen oil,
Gaultheriae aetheroleum are employed for external treatment of articular pain and
rheumatism. They are used in the form of bath additives and semisolid and liquid
dosage forms. When applied to skin, essential oils act as irritants, which cause local
increase of blood flow, reddening of the skin, and sensation of warmth thus antag-
onizing pain. Juniper oil must be avoided in the case of severe renal diseases [6, 7,
90, 91].
4. Conclusion
Osteoarthritis (OA) is a slowly developing degeneration disease affecting joint
cartilage and adjacent tissues. It is one of the most prevalent diseases and most
common causes of disability in the elderly, associated with worsening symptoms of
joint pain, stiffness, and limitation of articular movement. Therefore, it imposes a
significant functional and economic burden not only on affected patients but also
on health-care systems.
Contemporary therapy protocols involve an array of non-pharmacological,
pharmacological, and surgical measures. Although non-pharmacological treatments
represent a basis for OA treatment, pharmacotherapy is considered to be an impor-
tant adjunct. Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently a
cornerstone in OA pharmacotherapy. None of the therapeutic options are curative,
but the aim of treatment is to relieve the pain, improve quality of life, and reduce
the loss of physical functionality.
NSAIDs often have serious adverse effects, with gastrointestinal complications
as the most frequently reported. Some patients do not respond well to conventional
medical therapy. Facing unsatisfactory efficacy and adverse effects of conventional
therapy, they try to overcome current treatment deficiencies by using herbal
medicinal products.
Preclinical studies showed that a number of herbal extracts and respective con-
stituents exhibited pharmacological properties that could be relevant for their ben-
eficial effect in OA. They interfered with cytokine (IL-1β, TNF-α, and IL-6), PGE
2
,
and NO production, modulated biosynthesis and activity of collagenases and
aggrecanases, stimulated formation of extracellular matrix, and inhibited activation
of transcription factor NF-κB. Active constituents are not often defined satisfacto-
rily, but it could be said that they belong to various groups of secondary metabolites
such as sesquiterpene lactones, triterpenic acids, galactolipids, diarylheptanoids,
iridoid glycosides, phenolic glycosides, procyanidins, and alkaloids. Trials in
humans support observations from in vitro and animal studies.
Unfortunately, this area is still far under-researched and needs further and
better attention. Existing studies were frequently based on flawed research design,
unclear and incomplete selection criteria, inadequate definition of the herbal inter-
ventions, or post hoc manipulation of data to support the authorspreferred
conclusions [10]. The same authors urge on high quality and adequately powered
clinical studies, advising future researchers that particular attention should be given
to the detail of study design, which would ensure that participant samples are well
10
Osteoarthritis
defined according to American College of Rheumatology (ACR) criteria and that
participants are recruited without bias [10]. Furthermore, herbal preparations should
be reported in detail, including dose, extraction method, and chemical characteriza-
tion of active principle(s). Finally, study results should be recorded using reliable,
valid outcome measures that combine pain and functional impairments in the identi-
fication of treatment response (as proposed by OMERACT-OARSI initiative) for
comparing the efficacy of different medicinal plant products [10].
Herbal medicines that have been shown to be effective in the treatment of pain
associated with OA could help lowering or ceasing the consumption of NSAIDs,
reducing at the same time the incidence and severity of their adverse effects. This
would also produce necessary long-term safety data, which are needed for most of
the herbal medicinal products.
Currently available data are insufficient to acknowledge their use in OA treatment
as clinically proven (i.e., with demonstrated efficacy and safety). However, it could
be stated that the body of evidence is growing and that expectations on arrival of
reliable, efficient, and safe herbal products, fulfilling the criteria of modern medicine
in the near future, seem reasonable.
Acknowledgements
This work was supported by the Ministry of Education, Science and Technolog-
ical Development of the Republic of Serbia (grant no. 173021).
Conflict of interest
The authors declare no conflict of interest.
Author details
Zoran Maksimović* and Stevan Samardžić
Department of Pharmacognosy, Faculty of Pharmacy, University of Belgrade,
Belgrade, Serbia
*Address all correspondence to: zoran.maksimovic@pharmacy.bg.ac.rs
© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License (http://creativecommons.org/licenses/
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.
11
Herbal Medicinal Products in the Treatment of Osteoarthritis
DOI: http://dx.doi.org/10.5772/intechopen.80593
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18
Osteoarthritis
... Reduced OA associated pain [42,43] Inhibits lipoxygenase (LOX-5), modulates the corresponding pro-and anti-inflammatory cytokines (interleukin 1, 6, 8, 10) and nuclear factors (TNF-α, NF-κB) [44] Supplements Aloe vera -Protects the gastrointestinal tract from NSAIDs -Avocado/soy unsaponifiables -Reduced pain in OA patients and reduced consumption of NSAIDs [45,46] Reduces levels of iNOS and MMP-13 [47]. Suppresses TNF-α, IL-1β, COX-2, and iNOS in LPS-activated chondrocytes [48] Calcium fructoborate -Suppresses IL-1β, IL-6, iNOS in vivo Collagen hydrolysates Relieves pain associated with OA [49] Stimulates the regeneration of collagen type 2 and increases the biosynthesis of proteoglycans ...
Article
Full-text available
Osteoarthritis (OA) is a degenerative joint disease and an important cause of incapacitation. There is a lack of drugs and effective treatments that stop or slow the OA progression. Modern pharmacological treatments, such as analgesics, have analgesic effects but do not affect the course of OA. Long-term use of these drugs can lead to serious side effects. Given the OA nature, it is likely that lifelong treatment will be required to stop or slow its progression. Therefore, there is an urgent need for disease-modifying OA treatments that are also safe for clinical use over long periods. Phytonutraceuticals are herbal products that provide a therapeutic effect, including disease prevention, which not only have favorable safety characteristics but may have an alleviating effect on the OA and its symptoms. An estimated 47% of OA patients use alternative drugs, including phytonutraceuticals. The review studies the efficacy and action mechanism of widely used phytonutraceuticals, analyzes the available experimental and clinical data on the effect of some phytonutraceuticals (phytoflavonoids, polyphenols, and bioflavonoids) on OA, and examines the known molecular effect and the possibility of their use for chondroprotection.
... However, available scientific data are still insufficient to support the use of these products in the clinical management of OA. However, the growth of studies in this sense brings expectations regarding the arrival of reliable, efficient, and safe herbal products that meet the criteria of modern medicine [35]. ...
Article
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The aim of this study was to analyze the analgesic potential of Arrabidaea chica extract (EHA) as an alternative to osteoarthritis (OA) treatment. Thus, the extract was initially evaluated by the cyclooxygenase inhibition test. The analgesic effect of the extract, in vivo, was also verified in a model of OA induced by sodium monoiodoacetate (2 mg). EHA was administered to rats at doses of 50, 150, and 450 mg/kg between 3 and 25 days after OA induction. The animals were clinically evaluated every 7 days, euthanized at 29 days, and the liver, spleen, kidney and knee collected for histopathological analysis. The chemical composition of EHA was identified by HPLC-MS and the identified compounds submitted to molecular docking study. The results showed that the extract promoted cyclooxygenase inhibition and produced significant improvements in disability, motor activity, hyperalgesia, and OA-induced allodynia parameters, in addition to improvements in the radiological condition of the knees (but not observed in the histopathological study). Chemically the extract is rich in flavonoids. Among them, we evidence that amentoflavone showed very favorable interactions with the enzyme COX-2 in the in silico analysis. Thus, it is concluded that A. chica has important analgesic properties for the treatment of OA.
Article
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Rheumatoid arthritis (RA) is an autoimmune disease associated with advanced joint dysfunction. Madhuca indica J. F. Gmel, from the family Sapotaceae, is an Indian medicinal plant reported to have an array of pharmacological properties. The aim of present investigation was to determine the anti-arthritic potential of an isolated phytoconstituent from methanolic leaf extract of Madhuca indica (MI-ALC) against FCA-induced experimental arthritis. Polyarthritis was induced in female rats (strain: Wistar) via an intradermal injection of FCA (0.1 mL) into the tail. Polyarthritis developed after 32 days of FCA administration. Then rats were treated orally with an isolated phytoconstituent from MI-ALC at doses of 5, 10, and 20 mg/kg. Findings suggested that High-Performance Thin-Layer Chromatography, Fourier-Transform Infrared Spectroscopy, and Liquid Chromatography-Mass Spectrometry spectral analyses of the phytoconstituent isolated from MI-ALC confirmed the structure as 3,5,7,3′,4′-Pentahydroxy flavone (i.e., QTN). Treatment with QTN (10 and 20 mg/kg) showed significant (p < 0.05) inhibition of increased joint diameter, paw volume, paw withdrawal threshold, and latency. The elevated synovial oxidative stress (Superoxide dismutase, reduced glutathione, and malondialdehyde) and protein levels of Tumor necrosis factor-α (TNF-α) and Interleukin (ILs) were markedly (p < 0.05) reduced by QTN. It also effectively (p < 0.05) ameliorated cyclooxygenase-2 (COX-2), Nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-kβ) and its inhibitor-α (Ikβα), and ATP-activated P2 purinergic receptors (P2X7) protein expressions as determined by western blot analysis. In conclusion, QTN ameliorates FCA-induced hyperalgesia through modulation of elevated inflammatory release (NF-kβ, Ikβα, P2X7, and COX-2), oxido-nitrosative stress, and pro-inflammatory cytokines (ILs and TNF-α) in experimental rats.
Article
Osteoarthritis (OA) is a leading cause of musculoskeletal disorders that mainly affects the elderly population. Some herbal medicines have the potential to alleviate the pain associated with OA and improve physical activity mostly through anti-inflammatory and anti-oxidative properties. The aim of this study was to investigate the effects of herbal medicines, especially topical types, on osteoarthritis. In this systematic review, the keywords “osteoarthritis”, “herbal compounds”, “herbal medicine”, “topical drug”, “hydrogels”, “cream” and “treatment” were used to search publications published from 2010 to 2019 and indexed in databases including PubMed, SCOPUS, Web of Science and Google Scholar. After screening of titles and abstracts and detection of duplicate publications, 38 eligible articles were included in the main review. We also included herbal formulations in vivo. Bioactive fractions of herbal medicines mostly worked on OA through suppression of interleukin-1β (IL-1β), inducing nuclear factor-κB (NF-κB) activation by inhibition of inhibitor of NF-κB (IκBα) phosphorylation, IκBα degradation, p65 phosphorylation, and p65 nuclear translocation, downregulation of NF-κB targets including COX-2 and MMPs, upregulation of collagen type II, cartilage-specific proteoglycans (CSPGs), β1-integrin, and expression of cartilage-specific transcription factor SOX-9 protein. Noticeably, herbal medicines do not produce desirable effects, thereby using their combinations with other therapeutic agents seem to exert substantial clinical outcomes. Herbal gels have demonstrated robustly significant healing effects on knee pain, stiffness and mobility. It is worth considering that because OA is a chronic disease, longer duration of the studies/trials would even lead to obtaining more reliable judgments regarding topical treatment tolerability, safety and efficacy and clarify local or systemic adverse effects. Stability and standardization of a defined amount or concentrations of herbal gels would give promising effects on OA treatment and pain relief.
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Background: The standardized maritime pine bark extract (Pycnogenol®) has previously shown symptom alleviating effects in patients suffering from moderate forms of knee osteoarthritis (OA). The cellular mechanisms for this positive impact are so far unknown. The purpose of the present randomized pilot controlled study was to span the knowledge gap between the reported clinical effects of Pycnogenol® and its in vivo mechanism of action in OA patients. Methods: Thirty three patients with severe OA scheduled for a knee arthroplasty either received 100 mg of Pycnogenol® twice daily or no treatment (control group) three weeks before surgery. Cartilage, synovial fluid and serum samples were collected during surgical intervention. Relative gene expression of cartilage homeostasis markers were analyzed in the patients' chondrocytes. Inflammatory and cartilage metabolism mediators were investigated in serum and synovial fluid samples. Results: The oral intake of Pycnogenol® downregulated the gene expression of various cartilage degradation markers in the patients' chondrocytes, the decrease of MMP3, MMP13 and the pro-inflammatory cytokine IL1B were statistically significant (p ≤ 0.05). Additionally, protein concentrations of ADAMTS-5 in serum were reduced significantly (p ≤ 0.05) after three weeks intake of the pine bark extract. Conclusions: This is the first report about positive cellular effects of a dietary supplement on key catabolic and inflammatory markers in patients with severe OA. The results provide a rational basis for understanding previously reported clinical effects of Pycnogenol® on symptom scores of patients suffering from OA. Trial registration: ISRCTN10754119 . Retrospectively registered 08/10/2015.
Article
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Objective To investigate the efficacy and safety of dietary supplements for patients with osteoarthritis. Design An intervention systematic review with random effects meta-analysis and meta-regression. Data sources MEDLINE, EMBASE, Cochrane Register of Controlled Trials, Allied and Complementary Medicine and Cumulative Index to Nursing and Allied Health Literature were searched from inception to April 2017. Study eligibility criteria Randomised controlled trials comparing oral supplements with placebo for hand, hip or knee osteoarthritis. Results Of 20 supplements investigated in 69 eligible studies, 7 (collagen hydrolysate, passion fruit peel extract, Curcuma longa extract, Boswellia serrata extract, curcumin, pycnogenol and L-carnitine) demonstrated large (effect size >0.80) and clinically important effects for pain reduction at short term. Another six (undenatured type II collagen, avocado soybean unsaponifiables, methylsulfonylmethane, diacerein, glucosamine and chondroitin) revealed statistically significant improvements on pain, but were of unclear clinical importance. Only green-lipped mussel extract and undenatured type II collagen had clinically important effects on pain at medium term. No supplements were identified with clinically important effects on pain reduction at long term. Similar results were found for physical function. Chondroitin demonstrated statistically significant, but not clinically important structural improvement (effect size −0.30, –0.42 to −0.17). There were no differences between supplements and placebo for safety outcomes, except for diacerein. The Grading of Recommendations Assessment, Development and Evaluation suggested a wide range of quality evidence from very low to high. Conclusions The overall analysis including all trials showed that supplements provided moderate and clinically meaningful treatment effects on pain and function in patients with hand, hip or knee osteoarthritis at short term, although the quality of evidence was very low. Some supplements with a limited number of studies and participants suggested large treatment effects, while widely used supplements such as glucosamine and chondroitin were either ineffective or showed small and arguably clinically unimportant treatment effects. Supplements had no clinically important effects on pain and function at medium-term and long-term follow-ups.
Article
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Rosmarinic acid (RosA) is a water-soluble polyphenol, which can be isolated from many herbs such as orthosiphon diffuses and rosmarinus officinalis. Previous studies have shown that RosA possesses various biological properties. In this study, we investigate the anti-osteoarthritic effects of RosA in rat articular chondrocytes. Chondrocytes were pre-treated with RosA, followed by the stimulation of IL-1β. Real-time PCR and Western blot were performed to detect the expression of matrix metalloproteinase (MMP)-1, MMP-3 and MMP-13. Nitric oxide and PGE2 production were measured by Griess reagent and enzyme-linked immunosorbent assay (ELISA). The expression of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) was also investigated by Western blot analysis. We found that RosA down-regulated the MMPs expression as well as nitric oxide and PGE2 production in IL-1β-induced chondrocytes. In addition, RosA inhibited p38 and JNK phosphorylation as well as p65 translocation. The results suggest that RosA may be considered a possible agent in the treatment of OA.
Article
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The present randomized controlled study aimed to investigate the in vivo distribution of constituents or metabolites of the standardized maritime pine bark extract Pycnogenol®. Thirty-three patients with severe osteoarthritis scheduled for a knee arthroplasty were randomized to receive either 200 mg per day Pycnogenol® (P+) or no treatment (Co) over three weeks before surgery. Serum, blood cells, and synovial fluid samples were analyzed using liquid chromatography coupled to tandem mass spectrometry with electrospray ionization (LC-ESI/MS/MS). Considerable interindividual differences were observed indicating pronounced variability of the polyphenol pharmacokinetics. Notably, the highest polyphenol concentrations were not detected in serum. Catechin and taxifolin primarily resided within the blood cells while the microbial catechin metabolite δ-(3,4-dihydroxy-phenyl)-γ-valerolactone, ferulic, and caffeic acid were mainly present in synovial fluid samples. Taxifolin was detected in serum and synovial fluid exclusively in the P+ group. Likewise, no ferulic acid was found in serum samples of the Co group. Calculating ratios of analyte distribution in individual patients revealed a simultaneous presence of some polyphenols in serum, blood cells, and/or synovial fluid only in the P+ group. This is the first evidence that polyphenols distribute into the synovial fluid of patients with osteoarthritis which supports rationalizing the results of clinical efficacy studies.
Book
Does Echinacea fight the common cold? Does St. John's Wort (SJW) really counteract depression? What about chondroitin for joint health? Today's healthcare professionals are increasingly confronted with questions from patients who want to use herbal supplements to treat various conditions. A critical and scientific assessment of medicinal plant research by an internationally recognized researcher and writer in the field, Tyler's Herbs of Choice: The Therapeutic Use of Phytomedicinals, Third Edition combines the scientific aspects of herbal medicine, phytomedicine, and pharmacognosy with the modern clinical trials that support the rationale for using plant products in healthcare. A Decade's Worth of Updates The original edition of this volume was authored by the late Professor Varro E. Tyler, a true giant in the field of pharmacognosy and pharmacy education. Following in Tyler's footsteps, Dennis V.C. Awang, co-editor of the journal Phytomedicine, recognized the need for a revised third edition, in light of how quickly the clinical literature surrounding the dietary supplement market is growing. Millions of consumers are demanding natural treatment options from their doctors and pharmacies in a variety of forms, from herbal teas to tinctures and capsules. Tyler's Herbs of Choice: The Therapeutic Use of Phytomedicinals, Third Edition effectively fosters understanding in patients and practitioners of the role that herbs and phytomedicinal products can play in both self-care and healthcare.
Article
Ethnopharmacological relevance: Meadowsweet (Filipendula ulmaria (L.) Maxim.) and dropwort (Filipendula vulgaris Moench) are herbaceous perennials employed in folk medicine for their antirheumatic, antipyretic and anti-ulcer properties. Aim of the study: To assess ethnomedicinal claims through investigation of antioxidant, anti-inflammatory and gastroprotective effects of F. ulmaria and F. vulgaris lyophilized flower infusions (LFIs) as well as the F. vulgaris isolated flavonoids spiraeoside, kaempferol 4'-O-glucoside, astragalin 2''-O-gallate, mixture of hyperoside 2''-O-gallate and isoquercitrin 2''-O-gallate, and a tannin tellimagrandin II. Materials and methods: Free radical scavenging activity of the tested samples was determined by examining their ability to neutralize DPPH and OH radicals in vitro, whereas reducing properties were assessed in Ferric Reducing Antioxidant Power (FRAP) assay. Anti-inflammatory activity was studied ex vivo in human platelets by monitoring the effect on eicosanoid biosynthesis. Gastroprotective action was estimated in animal model of acute gastric injury induced by ethanol. Results: LFIs and spiraeoside exerted activities comparable to those of positive control in DPPH-radical scavenging and FRAP antioxidant assays, whereas notable hydroxyl radical scavenging ability was demonstrated only for spiraeoside (IC50 =5.1μg/mL). Among tested samples, astragalin 2″-O-gallate (IC50 =141.1μg/mL) and spiraeoside (IC50 =4.69μg/mL) the most markedly inhibited production of pro-inflammatory prostaglandin E2 and 12(S)-hydroxy-(5Z,8Z,10E,14Z)-eicosatetraenoic acid in human platelets, respectively. Examination of LFIs (100-300mg/kg, p.o.) gastroprotective action in rats revealed their capacity to preserve mucosal integrity. In addition, spiraeoside (50mg/kg, p.o.) and tellimagrandin II (40mg/kg, p.o.) showed ulcer preventive ability. Conclusion: Current study supports documented traditional use of investigated herbs and indicates that flavonoid and tannin components are partially responsible for the demonstrated pharmacological activities.
Article
Aims: The protective effects of ginger (Zingiber officinale Roscoe) extract on IL-1β-mediated oxidative stress and mitochondrial apoptosis were investigated in C28I2 human chondrocytes. Methods: The effects of various concentrations of ginger extract on C28I2 human chondrocyte viability were evaluated in order to obtain noncytotoxic concentrations of the drug by methylthiotetrazole assay. The cells were pretreated with 5 and 25 μg/mL ginger extract for 24 h, followed by incubation with IL-1β (10 ng/mL) for 24 h. The effects of ginger extract on IL-1β-induced intracellular reactive oxygen species (ROS) production and lipid peroxidation were examined. The mRNA expressions of antioxidant enzymes including catalase, superoxide dismutase-1, glutathione peroxidase-1, glutathione peroxidase-3, and glutathione peroxidase-4 were evaluated by reverse transcription polymerase chain reaction. The protein expressions of Bax, Bcl-2, and caspase-3 were analyzed by Western blotting. Results: No cytotoxicity was observed at any concentration of ginger extract in C28I2 cells. Ginger extract pretreatment remarkably increased the gene expression of antioxidant enzymes and reduced the IL-1β-induced elevation of ROS, lipid peroxidation, the Bax/Bcl-2 ratio, and caspase-3 activity. Conclusions: Ginger extract could considerably reduce IL-1β-induced oxidative stress and consequent mitochondrial apoptosis as the major mechanisms of chondrocyte cell death. These beneficial effects of ginger extract may be due to its antioxidant properties. It may be considered as a natural herbal product to prevent OA-induced cartilage destruction in the clinical setting.
Article
The review summarizes the effects of the standardized proprietary bark extract of the French maritime pine (Pycnogenol(®)) in mild osteoarthritis (OA), stage 1 and 2. The extract exerts antioxidative, anti-inflammatory, and chondroprotective effects in vitro and in vivo. Its phenolic acids as well as catechin and taxifolin are quickly absorbed. Active metabolites, produced by gut microbiota in the intestinal tract from oligomeric procyanidins, appear in blood 6 h following ingestion and remain for at least 14 h, providing a long-lasting flow of anti-inflammatory substances for relief of OA symptoms. These constituents of Pycnogenol could be detected in serum, blood cells, and synovial fluid of OA patients. The resulting inhibition of cartilage-destructing proteases and pain-producing cyclo-oxygenases provides the basis for relief from pain, improvement of stiffness, enhanced mobility, and well-being in three clinical studies with the pine bark extract as an adjunct supplement. Sparing the use of nonsteroidal anti-inflammatory drugs, supplementation with the pine bark extract reduced gastric complications and hospital admissions of OA patients. Because of its favorable safety profile and sustained anti-inflammatory action, Pycnogenol represents an option as an add-on supplement for OA patients.