Current nutraceuticals in the management of osteoarthritis ... 16.pdfchondrocytes [Shukla et al. 2008a]. We showed the inhibitory effects of PFE on IL1βinduced proteoglycan breakdown

7/26/2015 Current nutraceuticals in the management of osteoarthritis: a review

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Ther Adv Musculoskelet Dis. 2012 Jun; 4(3): 181–207.doi: 10.1177/1759720X11436238

PMCID: PMC3400101

Current nutraceuticals in the management of osteoarthritis: a reviewNahid Akhtar and Tariq M. Haqqi

Nahid Akhtar, Department of Medicine/Rheumatology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA;Contributor Information.Corresponding author.

Email: [email protected]

Copyright © The Author(s), 2012

This article has been cited by other articles in PMC.

Abstract

Osteoarthritis (OA) is a progressive degenerative joint disease that has a major impact on joint function and qualityof life. Nutraceuticals and dietary supplements derived from herbs have long been used in traditional medicine andthere is considerable evidence that nutraceuticals may play an important role in inflammation and joint destructionin OA. We review the biological effects of some medicinal fruits and herbs – pomegranate, green tea, cat’s claw,devil’s claw, ginger, Indian olibaum, turmeric and ananas – in an attempt to understand the pivotal moleculartargets involved in inflammation and the joint destruction process and to summarize their toxicities and efficacy forOA management. So far there is insufficient reliable evidence on the effectiveness of ginger, turmeric and ananas.Pomegranate and green tea only have preclinical evidence of efficacy due to the lack of clinical data. In vivo andclinical studies are required to understand their targets and efficacy in OA. Limited in vitro and in vivo evidence isavailable for cat’s claw and Indian olibaum. More extensive studies are required before longterm controlled trialsof whole cat’s claw and Indian olibaum extracts, or isolated active compounds, are carried out in patients with OAto determine their longterm efficacy and safety. Devil’s claw has not been rigorously tested to determine itsantiarthritic potential in in vitro and in vivo models. There is strong clinical evidence of the effectiveness of devil’sclaw in pain reduction. However, highquality clinical trials are needed to determine its effectiveness. No seriousside effects have been reported for any fruits and herbs. Overall, these studies identify and support the use ofnutraceuticals to provide symptomatic relief to patients with OA and to be used as adjunct therapy for OAmanagement. More highquality trials are needed to provide definitive answers to questions related to their efficacyand safety for OA prevention and/or treatment.

Keywords: cat’s claw, green tea, inflammation, osteoarthritis, pomegranate

Introduction

Osteoarthritis (OA) is one of the most prevalent and disabling chronic diseases affecting older people. A highprevalence of OA among older people and women and the moderate to severe impact on daily life pose asignificant public health problem [Malemud et al. 2003; Yelin, 2003]. OA involves the erosion of articularcartilage, inflammation of synovial membrane, and resorption of the underlying subchondral bone [van der Kraanand van den Berg, 2000]. These pathological changes are associated with an excessive production ofproinflammatory molecules such as interleukin 1β (IL1β) and tumor necrosis factor α (TNFα), which shift thebalance between the synthesis and degradation of matrix components resulting in progressive destruction of the

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joint tissue [van der Kraan and van den Berg, 2000]. Today, a cure for OA remains elusive. Nonpharmacologicalmanagement includes physical therapy, aerobic exercises, muscle strengthening, weight reduction, walking aids,knee braces, footwear and insoles, electromagnets, thermal modalities and acupuncture. For OA treatment andprevention, glucosamine and chondroitin sulfate, two of the molecular building blocks found in articular cartilage,are the most commonly used dietary supplements. In randomized trials of variable quality, these compounds showefficacy in reducing symptoms, but neither has been shown to arrest progression of the disease or regeneratedamaged cartilage [reviewed in Häuselmann, 2001; Morelli et al. 2003; McAlindon, 2006; Gregory et al. 2008].Pharmacological management of OA has targeted symptoms of the disease rather than the underlying cause;analgesics and nonsteroidal antiinflammatory drugs (NSAIDs) represent the mainstay of treatment [Altman, 2009].These drugs generally decrease pain and stiffness and improve function. Although, any beneficial effects to theunderlying cartilage and bone associated with the use of these drugs have not been demonstrated, they remainamong the most widely prescribed drugs for OA therapy [Abramson, 2003]. Other treatment options are selectivecyclooxygenase 2 (COX2) inhibitors (rofecoxib) for pain management but these drugs are reported to beassociated with gastrointestinal [Chan et al. 2010] and cardiovascular [Hsiao et al. 2009] adverse events. Matrixmetalloproteinase (MMP) inhibitors have been studied for prevention of cartilage degradation but their clinical usehas been limited by severe side effects [Nuti et al. 2009]. Intraarticular therapies like glucocorticoid andhyaluronan injections have been used for pain relief but recent observations suggest that they may acceleratecartilage breakdown [GonzalezFuentes et al. 2010]. Basically, longterm use of available pharmacological agentsto relieve OA symptoms is associated with serious adverse events and highlights the importance of developing saferalternative and prevention strategies. Such prevention and alternative/adjunct therapies could come fromnutraceuticals. The term ‘nutraceutical’ was coined from ‘nutrition’ and ‘pharmaceutical’ in 1989 by DeFelice andwas originally defined as ‘a food (or part of the food) that provides medical or health benefits, including theprevention and/or treatment of a disease’ [Kalra, 2003]. Zeisel distinguished whole foods from the bioactivechemical compounds derived from them and available in a nonfood matrix by using the terms ‘functional foods’and ‘nutraceuticals’ respectively [Zeisel, 1999]. However, the term nutraceuticals has no regulatory definition andis not recognized by the US Food and Drug Administration (FDA), which uses the term ‘dietary supplements’instead [Halsted, 2003]. OA as a chronic disease is a perfect paradigm of pathology of treatment, which could beaddressed by nutraceuticals and dietary supplements. First, because nutraceuticals only have limited effects on theirbiological target and significant differences can be reached over time through a buildup effect in which dailybenefits add up and the time window for intervention is longer in chronic diseases. Second, nutraceuticals couldprovide a safer alternative because generally their use is devoid of adverse effects, although this is not universal.Public interest in the benefits provided by nutraceuticals such as medicinal herbs for OA is high and 47% of olderadults use nonprescribed alternative medications (dietary supplements) for OA management [Ramsey et al. 2001].The objective of this review is to discuss the scientific evidence supporting the efficacy of Punica granatum(pomegranate fruit), Camellia sinensis (green tea), Uncaria tomentosa/Uncaria guianensis (cat’s claw),Harpagophytum procumbens (devil’s claw), Zingiber officinale (ginger), Boswellia serrata, Curcuma longa(turmeric) and Ananas comosus in an attempt to understand the pivotal molecular targets involved in inflammationand the joint destruction process and to summarize their toxicities and efficacies for OA management. We havepurposely not considered use of glucosamine sulphate and chondroitin sulphate because these compounds havebeen the main topic of numerous recent reviews [e.g. Häuselmann, 2001; Morelli et al. 2003; McAlindon 2006;Gregory et al. 2008]. For this review a literature search was performed of the Pubmed database and the scientificdata with a direct link to OA were selected. We tried to include all the relevant references but the list may not becomplete. If some published work is not included, the omission is unintentional.

Punica granatum (pomegranate)

Pomegranate fruit [PF, Figure 1(A)] has been used for centuries to confer health benefits in many cultures. It isnative to semitropical Asia and is now being cultivated in Afghanistan, India, China, Russia, Japan and the United

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States [Palaniswamy, 2003]. Modern use of PFderived products includes treatment of AIDS [Lee and Watson,1998], cancer [Kim et al. 2002], cosmetic use [Moayadi, 2004], allergic symptoms [Watanabe and Hatakoshi,2002], cardiovascular conditions [Aviram and Dornfeld, 2003], oral hygiene [Kim and Kim, 2002] and asophthalmic ointment [Bruijn et al. 2003]. Edible parts of the PF are composed of 80% juice and 20% seed [Singh etal. 2002b]. PF itself is a rich source of two types of polyphenolic compounds: anthocyanins (such as delphinidin,cyanidin, and pelargonidin) and hydrolyzable tannins (such as punicalin, pedunculagin, punicalagin, gallagic, andellagic acid esters of glucose), which account for 92% of the antioxidant activity of the whole fruit [Singh et al.2002b]. Anthocyanins are potent antioxidants, provide the brilliant color of the pomegranate juice, and theiradministration is reported to significantly decrease the malondialdehyde, hydroperoxide levels, lipid peroxidationand also enhance the activities of catalase, superoxide dismutase, glutathione peroxidase and glutathione reductasein the liver [Sudheesh and Vijayalakshmi, 2005; Gil et al. 2000; Seeram and Nair, 2002]. Punicalagin has beenshown to downregulate the expression of IL2 from antiCD3/antiCD28stimulated murine splenic CD4+ T cellsand suppress mixed leukocyte reaction without exhibiting cytotoxicity to the cells via inhibition of nuclear factor ofactivated T cells [Lee et al. 2008]. This suggests that PF could be a potential candidate for the therapeutics ofimmune pathologies. We reported that pomegranate fruit extract (PFE)derived bioavailable compounds suppressCOX2 enzyme activity and IL1βinduced prostaglandin E (PGE ) and nitric oxide (NO) production in OAchondrocytes [Shukla et al. 2008a]. We showed the inhibitory effects of PFE on IL1βinduced proteoglycanbreakdown in cartilage explants in vitro [Ahmed et al. 2005]. We also studied the efficacy of PFE in suppressingjoint inflammation and damage using a collageninduced arthritis mouse model. Consumption of PFE potentlydelayed the onset and reduced the incidence of collageninduced arthritis in mice. Histopathology of the arthriticjoints from PFEfed mice demonstrated reduced joint infiltration by the inflammatory cells, and the destruction ofbone and cartilage was alleviated with the decrease level of IL6 [Shukla et al. 2008b]. Activation of mitogenactivated protein kinases (MAPKs) and nuclear factor (NF)κB is intimately associated with the increasedexpression of critical mediators of inflammation involved in OA pathogenesis, including the expression of IL6 andIL8 [Marcu et al. 2010; Firestein and Manning, 1999]. We recently showed that inhibition of IL6 and IL8 byPFE in PMACI (phorbol12myristate 13acetate plus calcium inophore A23187)stimulated KU812 cells wasmediated by inhibition of NFκB, cJunNterminal kinases (JNKs) and the extracellular regulated kinase (ERK)–MAPK pathway [Rasheed et al. 2009a]. We also showed that PFE (6.25–25 mg/liter) inhibits the IL1βinducedexpression of MMP1, MMP3 and MMP13 mRNA and proteins in OA chondrocytes, which was mediated byinhibiting the activation of p38MAPK and JNK, thereby reducing the available pool of activated cJun andactivating transcription factor 2 [Ahmed et al. 2005]. Our recent study showed that PFE inhibits the IL1βinducedactivation of MKK3 and the p38αMAPK isoform and DNA binding activity of the runtrelated transcription factor2 in human chondrocytes [Rasheed et al. 2010]. These results provide an important insight into the molecular basisof the reported cartilage protective and arthritis inhibitory effects of pomegranate [Rasheed et al. 2010].

Figure 1.Medicinal fruits and herbs commonly used as dietary supplements for thetreatment of osteoarthritis.

Repeated administration of high doses of PFE or its constituents ellagitannin and punicalagin to rats resulted in notoxicity in the dosages commonly used in traditional medicine systems [Cerdá et al. 2003]. An acutesupplementation with PFE containing 330 mg of punicalagins and 22 mg of ellagic acid in 11 healthy volunteersled to the detection of ellagitannin metabolites, including ellagic acid, urolithin A, hydroxyl urolithin A, urolithin B,urolithin A glucuronideet and dimethyl ellagic acid glucuronide in plasma after 2–24 h [MertensTalcott et al.

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2006]. In healthy human volunteers who consumed 180 ml of a commercially available pomegranate juicecontaining 25 mg of ellagic acid, ellagic acid was detected at a maximum concentration of 32 ng/ml in the plasmaafter 1 h [Seeram et al. 2004]. We also showed that ellagic acid becomes bioavailable 2 h after oral ingestion ofPFE [Shukla et al. 2008b]. Ellagic acid has been reported to inhibit the activation of NFκB and the production ofinflammatory mediators [Choi and Yan, 2009].

Overall, these data indicate that consumption of PF may be beneficial and of value in developing adjunctpreventive and/or therapeutic approaches to the prevention and treatment of OA. However, clinical trials showingthe benefit of pomegranate fruit or its extracts on inflammation and OA are lacking. Based on published evidence,further in vivo evaluation and clinical testing for the efficacy of PF in OA are needed [Khalifé and Zafarullah,2011].

Camellia sinensis (green tea)

Tea is a widely consumed beverage throughout the world and is reported to possess significant healthpromotingeffects (reviewed by Cabrera and colleagues and reference therein) [Cabrera et al. 2006]. Green tea [Figure 1(B)]contains proteins (15%), amino acids (4%), fiber (26%), other carbohydrates (7%), lipids (7%), pigments (2%),minerals (5%), and phenolic compounds (catechins; 30%). The principal catechins found in green tea areepicatechin (6.4%), epicatechin3gallate (13.6%), epigallocatechin (19%) and epigallocatechin3gallate (EGCG;59%), and account for 30–40% of its dry weight [Cabrera et al. 2006]. Green tea catechins, especially EGCG, havebeen reported to have antimutagenic [Cheng et al. 2009], anticancer [Johnson et al. 2010], antidiabetic [Zhang etal. 2010], antiinflammatory [Danesi et al. 2010], antibacterial [Osterburg et al. 2009], antiviral [Xiao et al. 2008],antiobesity [Moon et al. 2007] and neuroprotective effects [Smith et al. 2010]. The strong antioxidant activity ofgreen tea catechins has been widely demonstrated in vitro and in vivo [reviewed in Cabrera et al. 2003, 2006; Freiand Higdon, 2003]. Several studies have shown that EGCG blunts reactive oxygen species (ROS)mediatedcytotoxicity in human chondrocytes [Lo et al. 1996]. EGCG has been reported to increase the activities of catalase,superoxide dismutase, and glutathione peroxidase, which are essential components of a robust antioxidant defensesystem [Meng et al. 2001]. The potential diseasemodifying effects of green tea on arthritis came to light throughour study, when in a mouse model of rheumatoid arthritis (RA) induction and severity of arthritis was amelioratedby the prophylactic administration of green tea polyphenols in drinking water [Haqqi et al. 1999]. The antiinflammatory and antiarthritic effects of EGCG are supported by several studies, indicating that green tea or itscomponent EGCG can regulate the expression of cytokines, chemokines, MMPs, aggrecanase, ROS, NO, COX2,and PGE in cell types relevant to the pathogenesis of OA [reviewed in Singh et al. 2010; Akhtar and Haqqi,2011]. We recently studied the global effect of EGCG on IL1βinduced expression of cytokines and chemokinesassociated with OA pathogenesis in human chondrocytes. Our results suggest that the potential of EGCG in OAtreatment and prevention may be related to its ability to globally suppress the IL1βinduced inflammatory responsein human chondrocytes [Akhtar and Haqqi, 2011]. Similarly, others have shown the inhibitory effects of EGCG onIL1β, TNFα, IL6, regulated upon activation normal Tcell expressed and secreted (RANTES), monocytechemotactic protein 1, epithelial neutrophil activating peptide78, and growthrelated oncogene α expression in RAsynovial fibroblasts and other cell types [Shen et al. 2009; Shin et al. 2006; Ahmed et al. 2006]. NFκB andMAPKs are involved in the regulation of genes important in high expression of several mediators of inflammationin OA [Marcu et al. 2010; Firestein and Manning, 1999]. EGCG has been reported to downregulate IL6expression by inducing alternative splicing of gp130 mRNA resulting in enhanced sgp130 production in RAsynovial fibroblasts [Ahmed et al. 2008]. High levels of nitrates/nitrites have been found in the synovial fluid andserum of patients with OA [Farrell et al. 1992]. Studies from our laboratory have shown that EGCG inhibits NOproduction in IL1βstimulated human OA chondrocytes by suppressing the expression of inducible nitric oxidesynthase (iNOS) mRNA, which was mediated in part by inhibition of NFκB/p65 [Singh et al. 2002a, 2003].COX2 is the rate limiting enzyme in the production of PGE and we reported that EGCG inhibited the PGEproduction via inhibition of COX2 expression in IL1βstimulated human OA chondrocytes [Ahmed et al. 2002].

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However, Koeberle and colleagues reported that microsomal prostaglandinE synthase 1 (mPGES1) is a moleculartarget of EGCG, and inhibition of mPGES1 is seemingly the predominant mechanism underlying suppression ofcellular PGE biosynthesis by EGCG in vitro [Koeberle et al. 2009]. Agerelated accumulation of advanceglycation end products (AGEs) produced by the nonenzymatic glycation of macromolecules could be an importantcontributing factor for the development of OA. We recently reported that EGCG inhibited AGEstimulatedexpression and production of TNFα and MMP13 and this inhibitory effect was mediated at least in part viasuppression of p38MAPK, JNK, and NFκB activation in human OA chondrocytes [Rasheed et al. 2009b].EGCG has also been reported to inhibit the degradation of human cartilage proteoglycan and type II collagen andselectively inhibit the expression of ADAMTS1,4 and 5 (A Disintegrin And Metalloproteinase withThrombospondin Motifs), which are known to cleave aggrecan [Vankemmelbeke et al. 2003]. Previously weshowed that EGCG significantly inhibited the expression and activities of MMP1 and MMP13 in OAchondrocytes at physiologically achievable doses [Ahmed et al. 2004]. We and others have also shown that EGCGinhibits NFκB activation by inhibition of proteosome activity, inhibition of IκBα phosphorylation or inhibition ofIKKβ kinase activity in human OA chondrocytes [Singh et al. 2002a; Andriamanalijaona et al. 2005; Rasheed etal. 2009b]. We have also shown that EGCG selectively inhibited IL1βinduced activation of JNK, withoutsignificantly inhibiting the phosphorylation of p38MAPK or ERK p44/ p42 in human OA chondrocytes [Singh etal. 2003]. Activator protein (AP)1 transcription factor is a heterodimer of Jun and Fos proteins and plays animportant role in the inflammatory response [Okamoto et al. 2008]. EGCG was found to inhibit the activation andDNA binding activity of AP1 in human OA chondrocytes [Andriamanalijaona et al. 2005; Ahmed et al. 2002].

Tea consumption in general has not displayed any acute or chronic toxic effects, and in fact, it is health promoting.Schwarz and colleagues described regular tea drinkers as people with a generally healthy lifestyle [Schwarz etal.1994]. However, harmful effects of ‘overconsumption’ of green tea cannot be ruled out and could be due to twomain factors: caffeine content, and the presence of aluminum [Bruneton, 2001; Minoia et al. 1994]. Due to theirrelatively low absorption, rapid metabolism and elimination from the body, consumption of large amounts offlavonols is well tolerated by humans. At present the safe upper limit for chronic ingestion is about 1 g offlavonols/day [de Mejia et al. 2009]. The health benefits of tea consumption in preventing cancer have beenintensively investigated [Khan and Mukhtar, 2008]. However, limited information is available about the protectiveeffect of consumption of green tea or its bioactive components in OA. The bioavailability of EGCG or othercatechins is relatively low and this may be due to the short half life, which ranges from 1.87 to 4.58 h for a 50–1600mg dose (approximately 0.7–23 mg/kg body weight, based on 70 kg body weight) [Ullmann et al. 2003].This might be overcome by repeated administration of EGCG because of its reported low toxicity and hightolerance by humans, even when given in doses as high as 1600 mg [van het Hof et al. 1999], which can achieve amaximum human plasma level of 7.6 μmol/liter [Ullmann et al. 2003]. These studies point out that apharmaceutically prepared formulation of green tea catechins could reach plasma levels equivalent to effective invitro doses and can be used as adjunct therapy for the treatment and prevention of OA [Katiyar and Raman, 2011].Currently, there is sufficient in vitro and in vivo data available showing the antiinflammatory and antiarthriticpotential of green tea and its constituent EGCG. Hence, more in vivo and clinical studies are required to evaluate itsefficacy for OA.

Uncaria tomentosa and Uncaria guianensis (cat’s claw)

Cat’s claw is a vine from the basin of the Amazon River. There are two species, U. tomentosa [Figure 1(C)] and U.guianensis [Figure 1(D)] that are traditionally used in South America for their antiinflammatory properties. Cat’sclaw bark contains oxindole alkaloids (virtually absent in U. guianensis), polyphenols (flavonoids,proanthocyanidins, and tannins), quinovic acid αglycosides, pentacyclic alkaloids, and sterols [Ganzera et al.2001]. Traditionally, the bark of cat’s claw is prepared as a decoction, said to be beneficial in the treatment ofarthritis, bursitis, lupus, chronic fatigue syndrome, and for stomach and intestine disorders [Foster, 1996; reviewedin Williams, 2001]. The most investigated of the active constituents in U. tomentosa extract for immunemodulating

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and antiinflammatory effects are pentacyclic oxindole alkaloids [Williams, 2001]. However, the antioxidant andantiinflammatory effects of the extracts of U. tomentosa and U. guianensis appear to be independent of theiralkaloid content as in several assays both species of Uncaria were reported to be a strong free radical scavenger[Sandoval et al. 2000, 2002; reviewed in Rosenbaum et al. 2010]. We reported that U. guianensis in combinationwith Lepidium meyenii had chondroprotective properties in human cartilage. This action was mediated in partthrough upregulation of gene expression of the anabolic insulinlike growth factor 1 in IL1βstimulatedchondrocytes [Miller et al. 2006]. Pretreatment with a hydroalcholic extract (500 μg/ml) of U. tomentosa inhibitedCOX1 and COX2 via inhibition of the activation of NFκB in Jurkat T cells [Aguilar et al. 2002]. Uncaria hasbeen found to inhibit lipopolysaccharide (LPS)induced iNOS gene expression, TNFα, PGE and NO production,and cell death via inhibiting the activation of NFκB [SandovalChacón et al. 1998; AllenHall et al. 2010].

Recent studies support the use of Uncaria alone or in combination with other medicinal herbs for OA management[Piscoya et al. 2001; Miller et al. 2005; Mehta et al. 2007]. The available animal toxicological data did not indicateany severe toxicity by the oral intake of Uncaria [Piscoya et al. 2001; Valerio and Gonzales, 2005]. In some cases,mild nausea and diarrhea may occur upon ingestion of crude extracts [Piscoya et al. 2001; Santa Maria et al. 1997].Several other groups have documented the safety and pharmacological profile of cat’s claw in animal models andalso showed that cat’s claw was nontoxic in vitro [Williams, 2001; Sandoval et al. 2002; Fetrow and Avila, 1999and references therein]. Although in recommended dosages use of cat’s claw is considered nontoxic, this aspect hasnot been rigorously investigated. Piscoya and colleagues evaluated the safety and side effects of U. guianensisextract in patients with OA of the knee [Piscoya et al. 2001]. Pain associated with activities of daily living wassignificantly reduced, however pain at rest or at night was not reduced during this 4week trial period. In anotherstudy, a combination of a natural mineral supplement (Sierrasil, Sierra Mountain Minerals Inc., Bozeman, MT,USA) with a cat’s claw extract (Vincaria, Rainforest Nutritionals Inc., Raleigh, NC, USA) showed therapeuticpotential in mild to moderate knee OA [Miller et al. 2005]. The Western Ontario and McMaster UniversitiesArthritis Index (WOMAC) and visual analog scale (VAS) scores were improved after 8 weeks compared withplacebo. Rescue medication use was 28–23% lower in the herbomineral combination. Comparison of Reparagen(Rainforest Nutritionals, Inc., Raleigh, NC, USA) (1800 mg/day), a mixture of U. guianensis and L. meyenii withglucosamine sulfate (1500 mg/day) was also studied in patients with OA in a multicenter, randomized, doubleblindtrial. Reparagen and glucosamine sulfate produced substantial improvements in pain, stiffness and function inpatients with mild to moderate OA as evidenced by improved WOMAC and VAS scores [Mehta et al. 2007].More extensive studies employing animals and in vitro models are required before longterm controlled trials ofUncaria extracts (Table 1), or active compounds therein, can be initiated in a large number of human subjects todetermine their longterm efficacy and safety profile.

Table 1.Summary of clinical trials on neutraceuticals and evidence of their safety andefficacy.

Harpagophytum procumbens (devil’s claw)

For more than 50 years preparations of H. procumbens [devil’s claw, Figure 1(E)] have been used in Europe forthe treatment of rheumatic entities. Devil’s claw is native to the southern part of the African continent and may befound in Namibia, Botswana, South Africa, Angola, Zambia, and Zimbabwe [Anonymous, 2008; Qi et al. 2006].Historically, devil’s claw has been used as an analgesic, for fevers and allergies, appetite stimulation, wounds andskin rashes, dyspepsia, liver and kidney disorders, as diuretic and sedative, and to treat degenerative disorders of themusculoskeletal system [Blumenthal, 1998; Stewart and Cole, 2005; Qi et al. 2006; Ragusa et al. 1984]. The majorchemical constituents of devil’s claw are iridoid glycosides (primarily harpagoside, harpagide, and procumbide),sugars (mainly the tetrasaccharide, stachyose), triterpenoids (oleanolic and ursolic acid), phytosterols (primarily βsitosterol), aromatic acids (caffeic, cinnamic, and chlorogenic acids), and flavonoids such as luteolin and

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kaempferol [Bradley, 1992]. Harpagoside, harpagide, and procumbide, found in the tubers of the plant, appear tobe the most therapeutically important constituents. Wholeplant extracts appear to have a better therapeutic effectthan those prepared from isolated parts [Qi et al. 2006]. A large body of evidence indicates that devil’s claw maybe an effective treatment for OA because of its painrelieving and antiinflammatory actions. Higher concentrationsof serum oxygenfree radicals prevalent with arthritis may alter the oxidant/antioxidant balance, thus facilitatinglipid peroxidation and leading to tissue damage [Jaswal et al. 2003]. Devil’s claw extract has been shown toincrease superoxide dismutase, catalase, glutathione peroxidase enzyme activities in a dosedependent manner anda reduction in lipid peroxidation was also noted in vivo, which contribute to its antioxidant effects [Bhattacharyaand Bhattacharya, 1998]. The flavonoids and plant phenols present in devil’s claw extracts may be the constituentsresponsible for the observed antioxidant activity [Dugas et al. 2000; Sawa et al. 1999]. Devil’s claw has beenfound to scavenge both superoxide and peroxyl radicals [Langmead et al. 2002]. A recent study also showed thatboth root tuber extract of devil’s claw and tincture are effective as free radical scavengers and inhibit LPSinducednitrite levels in RAW 264.6 macrophages [Grant et al. 2009]. Significant antioxidant effects by an aqueous extractof devil’s claw and by the flavonoid constituents lutteolin and kaempferol have also been noted [BetancorFernández et al. 2003]. A dried aqueous extract (5 and 10 mg/kg) of devil’s claw has been shown to exert asignificant dosedependent analgesic and antiinflammatory effect in rats. However, carrageenaninduced pawedema was not affected by harpagoside, suggesting harpagoside may not have an antiinflammatory effect at leastin the doses used in vivo [Lanhers et al. 1992]. In vitro data also demonstrated that the active principle (sum ofcoactive constituents) of devil’s claw inhibits not only inflammatory mediators such as iNOS and COX2 mediatedPGE production [Fiebich et al. 2001; Jang et al. 2003; Huang et al. 2005] or leukotriene release [Loew et al.2001] but also mediators of cartilage destruction, such as TNFα, IL1β, IL6, MMPs, NO [Fiebich et al. 2001;Huang et al. 2005; SchulzeTanzil et al. 2004a], and elastase [Boje et al. 2003]. Reported chondroprotective effectsof devil’s claw may be due to suppression of NFκB activation, thereby inhibiting inflammation [Huang et al.2005].

Devil’s claw extract appears to be safe when used in appropriate dosages. The side effects are few, usually limitedto gastrointestinal upset, dyspepsia and loss of taste; no longterm toxicities or druginteractions are known[Vlachojannis et al. 2008]. Devil’s claw extract exerts a peripheral analgesic effect as it has been demonstrated todecrease pain in knee and hip OA [reviewed in Ameye and Chee, 2006; Chrubasik et al. 2002; Chantre et al.2000]. The effectiveness of certain devil’s claw preparations has been tested with a daily dose of 360 mg ofharpagoside (a coactive ingredient) in the treatment of painful OA of the hip, knee and nonspecific low back pain.Multivariate analysis confirmed that in all groups, both the generic and diseasespecific outcome measuresimproved by week 4 and further by week 8 [Chrubasik et al. 2002]. H. procumbens powder was equally effectiveas diacerhein in reducing pain as measured using a 100 mm VAS. This study constitutes moderate evidence that 4months’ daily use of 2610 mg H. procumbens powder is not significantly different from 100 mg diacerhein,producing comparable improvements in pain [Leblan et al. 2000]. Studies on devil’s claw extracts, containing 50–100 mg harpagoside daily, have shown the best results [Brien et al. 2006]. In a clinical study, 89 patients with OAwere randomized to receive placebo or devil’s claw at a total daily dose of 2010 mg/day for 8 weeks. The studyidentified that after 30 and 60 days of treatment, patients who received devil’s claw had a significant reduction inpain (p = 0.018 after 30 days and p = 0.012 after 60 days of treatment) compared with placebo [Lecomte andCosta, 1992]. Effectiveness, safety and tolerability of Harpagophytum was studied in rheumatic disorders includingOA for 8 weeks (259 patients). There were statistically significant (p < 0.0001) improvements in patient assessmentof global pain, stiffness, function and quality of life. There were also statistically significant reductions in mean painscores for hand, wrist, elbow, shoulder, hip, knee and back pain [Warnock et al. 2007]. Numerous trials have beenconducted using several devil’s claw extracts for OA (Table 1 and rheumatism [Rutten and Schafer, 2000;Bélaiche,1982; Lecomte and Costa, 1992; Schmelz et al.1997; Frerick et al. 2001; Chrubasik et al. 2002; Chantreet al. 2000; Leblan et al. 2000; Warnock et al. 2007]. Unfortunately, the results of many of the studies are ofquestionable value because of methodological flaws. However, devil’s claw appears to be effective in the reduction

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of pain. More highquality trials are needed to assess the effectiveness and efficacy of devil’s claw to determinewhether this is a beneficial remedy for the treatment of OA.

Zingiber officinale (ginger)

Ginger, the rhizome of Z. officinale [Figure 1(F)], is one of the most widely used species of the ginger family(Zingiberaceae) and is a common condiment for various foods and beverages. Ginger has a long history ofmedicinal use dating back 2,500 years in China and India for conditions such as headaches, motion sickness,nausea, vomiting, vascular conditions, cold and arthritis, and as a antimicrobial and antifungal [reviewed in White,2007; Afzal et al. 2001]. Characterized in traditional Chinese medicine as spicy and hot, ginger is claimed to warmthe body and treat cold extremities, improve a weak and tardy pulse, address a pale complexion, and strengthen thebody after blood loss [Chang et al. 1995]. The major constituents of ginger include volatile oils, oleoresin(gingerol), linoleic acid and trace elements such as magnesium, phosphorus, and potassium. The pungent phenolicconstituent of ginger, [6]gingerol, inhibited LPSinduced iNOS expression and production of NO and otherreactive nitrogen species in macrophages and blocked peroxynitriteinduced oxidation and nitration reactions invitro [Ippoushi et al. 2003]. These results suggest that [6]gingerol is a potent inhibitor of NO synthesis and also aneffective protector against peroxynitritemediated damage. Another in vitro study showed that ginger extract waseffective in inhibiting the production of PGE , TNFα, and COX2 expression in human synoviocytes by regulatingNFκB activation and degradation of its inhibitor IkBα [Thomson et al. 2002]. Similarly, ginger extract decreasedthe IL1β and LPSinduced production of NO and PGE in OA cartilage [Shen et al. 2003]. It has also beenreported to decrease the IL1βinduced expression of TNFα expression and TNFαinduced production of COX2and activation of NFκB in synoviocytes [Frondoza et al. 2004]. Use of ginger extract also decreased carrageenaninduced edema in rats [Jana et al. 1999].

Ginger is on the US FDA’s generally recognized as safe (GRAS) list. The British Herbal Compendium documentsno adverse effects of ginger consumption [Bradley, 1990]. Ginger extract has been studied as an alternative toNSAID therapy for arthritic conditions and had moderately positive results (Table 1) [Altman and Marcussen,2001; reviewed in Ameye and Chee, 2006]. A randomized, placebocontrolled, crossover study comparing gingerextracts and ibuprofen was performed and included 75 people with OA of the hip or knee [Bliddal et al. 2000].Patients received 170 mg ginger extract, 400 mg ibuprofen, or placebo three times per day and were followed for 3weeks. The study revealed significant improvement in symptoms for both groups before crossover; however, at thestudy’s end there was no difference between ginger and placebo. No side effects were noted in the ginger group[Bliddal et al. 2000]. A randomized, doubleblind, placebocontrolled trial studied the effects of ginger in thetreatment of knee OA in 261 patients. During the treatment period patients ingested 255 mg of EV.EXT 77, apatented ginger and galangal, a spice that is closely related to ginger and is of the ginger extract, which contained500–4000 mg of dried ginger rhizomes and 500–1500 mg of dried galangal rhizomes and was given twice daily.The primary endpoint of the study was pain on standing after 6 weeks. In the ginger extract group 63% versus 50%in the placebo group showed improvement (p < 0.048). The study failed to show improvement in quality of life,decrease in the consumption of the rescue analgesic (acetaminophen). The dosage of medications used in this studywas based empirically on what is typically consumed in Europe. Those receiving the ginger extract experiencedmore gastrointestinal side effects (116 events in 59 patients, 45%) than those who received placebo (28 events in 21patients, 16%) [Altman and Marcussen, 2001]. While a significant number of patients experienced side effects, theywere mild and mostly gastrointestinal conditions, dyspepsia, and nausea. In some studies, consumption of gingerextract was found to alleviate pain and associated symptoms in patients with OA. At present, ginger extract appearsto be of limited efficacy for OA and current evidence is weak. However, these results are strong enough toadvocate and support further studies using different doses and duration of treatment to assess the efficacy of gingerextract alone or in combination with other drugs for the treatment of OA.

Boswellia serrata (Indian olibaum)

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The Boswellia spp., which is native to India, Ethiopia, Somalia, and the Arabic peninsula, produce a gum resin thatis known as olibanum (frankincense). The resin of B. carteri and B. serrata [Figure 1(G)] is used for the treatmentof arthritis and other inflammatory diseases in the traditional medicine system in many countries [Safayhi andAmmon, 1997; Chevrier et al. 2005]. Besides their renowned antiinflammatory activity, boswellic acids have beenextensively investigated for their chemopreventive effects [Glaser et al. 1999; Zhao et al. 2003]. B. frereanaextracts have also been reported to inhibit IL1β and oncostatin M induced MMP9 and MMP13 expression incartilage explants culture [Blain et al. 2010]. Further, boswellic acids have been reported as inhibitors of 5lipoxygenase, the key enzyme for leukotriene biosynthesis in inflammatory disorders [Safayhi et al. 1992; Gupta etal. 1997] and human leukocyte elastase a member of serine proteases subfamily, which can hydrolyze collagen IVand elastin of the extracellular matrix [Safayhi and Ammon, 1997]. Thus, its use may be beneficial in inhibiting theprogression of OA. Recently, we studied the efficacy of a herballeucine mix (HLM) containing B. serrata as oneof the constituents. HLM was found to be an effective antiinflammatory agent, as evidenced by strong inhibition ofiNOS, MMP9 and MMP13 expression and NO production in IL1βstimulated OA chondrocytes in vitro. IL1βinduced cartilage matrix breakdown was also inhibited by HLM, as evidenced by inhibition of glycosaminoglycan(GAG) release from human cartilage explants in vitro. These inhibitory effects of HLM on the inflammatory andcartilage catabolic factors were mediated by inhibiting the activation of NFκB in human OA chondrocytes [Akhtaret al. 2011]. A novel composition of B. serrata extract (Aflapin, Indian Patent Application No. 2229/CHE/2008)showed antiinflammatory and antiarthritic potential in a rat model. Aflapin showed significant protection from IL1βinduced death of human primary chondrocytes, improved glycosaminoglycans production and inhibited MMP3production [Sengupta et al. 2011].

Toxicity studies of Boswellia in rats and primates showed no pathological changes in hematological, biochemical,or histological parameters at doses up to 1000 mg/kg and the LD50 was established at >2 g/kg [Singh and Atal,1986]. A trial of a herbomineral formulation containing B. serrata as one of the components also showedsignificant reduction in severity of pain and disability score in OA [Kulkarni et al. 1991]. A randomized clinicaltrial of multiplant ayurvedic drugs containing B. serrata demonstrated the potential efficacy and safety in thesymptomatic treatment of knee OA over 32 weeks of therapy [Chopra et al. 2004]. A B. serrata extract (5Loxin,US Patent publication no.: 2004/0073060A1) alone with Oacetyl11ketoβboswellic acid (AKBA) (Aflapin) orAKBA (30%; Loxin) alone was tested in patients with knee OA . Both treatments were effective in reducing painand significantly improved physical functioning and stiffness scores. However, Aflapin was more effective thanLoxin [Sengupta et al. 2010]. In a doubleblind, placebocontrolled trial, Boswellia demonstrated a beneficial effecton knee OA [Kimmatkar et al. 2003]. Thirty patients were given either 1000 mg Boswellia daily or placebo inthree divided doses for 8 weeks. Patients in the Boswellia group experienced a significant decrease in pain andswelling and increase in range of motion compared with placebo [Kimmatkar et al. 2003]. B. serrata extractcontaining 5Loxin with 3Oacetyl11ketoβboswellic acid (30%) inhibited the 5lipoxygenase enzyme. A 90day, placebocontrolled study was conducted to evaluate the efficacy and safety of 5Loxin in the treatment of OAof the knee with 75 patients. The patients received either 100 mg (n = 25) or 250 mg (n = 25) of 5Loxin daily or aplacebo (n = 25) for 90 days. Both doses of 5Loxin conferred clinically and statistically significant improvementsin pain scores and physical function scores in patients with OA. A significant reduction in synovial fluid MMP3was also noted. In comparison with placebo, the safety parameters were almost unchanged in the treatment groupsand it was concluded that 5Loxin reduces pain and improves physical functioning significantly in patients withOA; and it is safe for human consumption [Sengupta et al. 2008]. So far the in vitro, in vivo and clinical evidence (Table 1) for the effectiveness of Boswellia is encouraging but existing data do warrant further investigations[Moussaieff and Mechoulam, 2009].

Curcuma longa (turmeric)

Turmeric is a widely used spice and coloring/ flavoring agent that comes from the root of C. longa [Figure 1(H)]






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[Aggarwal and Shishodia, 2004]. Turmeric is on the GRAS substance list of the US FDA. In Ayurveda, turmerichas been used for various medicinal conditions including rhinitis, wound healing, common cold, skin infections,liver and urinary tract diseases, and as a ‘blood purifier’ [Aggarwal and Shishodia, 2004; ChainaniWu, 2003].Turmeric was found to be effective even when given by different routes, including topical, oral or by inhalation,dependent on the intended use. The major constituent of turmeric is curcumin (diferuloylmethane), whichconstitutes up to 90% of total the curcuminoid content, with demethoxycurcumin and bisdemethoxycurcumincomprising the remainder [Aggarwal and Shishodia, 2004]. Curcumin has been extensively investigated due to itsantitumor, antioxidant, antiinflammatory, and analgesic properties [reviewed in Henrotin et al. 2010]. The antiarthritic potential of curcumin has been widely studied in vitro. Curcumin was found to downregulate the catabolicand degradative effects in cartilage explants or chondrocytes stimulated with IL1β, LPS, and TNFα and inhibitedthe production of MMP3, MMP9, and MMP13 [Liacini et al. 2003; SchulzeTanzil et al. 2004b; Shakibaei et al.2007; MathyHartert et al. 2009] and restored type II collagen and GAG synthesis [Shakibaei et al. 2005; Toegel etal. 2008]. In human chondrocytes, curcumin significantly inhibited MMP3 and MMP13 gene expression byinhibiting the JNK, AP1 and NFκB pathways [Liacini et al. 2002]. Other studies have shown that curcuminblocks LPS and interferoninduced production of NO and TNFα in vitro by inhibiting the activation of NFκB andAP1 [reviewed in Aggarwal and Shishodia, 2004]. Curcumin also inhibited the incorporation of arachidonic acidinto membrane lipids, PGE production, leukotriene B4 and leukotriene C4 synthesis, as well as the secretion ofcollagenase, elastase, and hyaluronidase by macrophages [Wallace, 2002].

Curcumin has also demonstrated antiapoptotic activity in chondrocytes [Shakibaei et al. 2005]. However, toxiceffects of curcumin have been reported at high dosage (50 mM) without any beneficial effect on cartilage matrix[Toegel et al. 2008]. This study was performed using immortalized human OA chondrocytes, which can explainthe discordance with previous studies. No clinical data are available for the effect of pure curcumin in OA.However, one study tested the clinical efficacy of a herbomineral formulation containing a component rich incurcumin in people with OA in a randomized, doubleblind, placebocontrolled, crossover study [Kulkarni et al.1991]. Positive results in pain management and mobility were obtained in the treated group. Use of curcumin forthe treatment of OA is of significant current research interest but more studies are needed before coming to anyconclusion on its antiarthritis potential.

Ananas comosus

Bromelain [Figure 1(I)] is a crude, aqueous extract obtained from the stems and immature fruits of the pineappleplant (A. comosus Merr, from the family of bromeliaceae), which contains a number of proteolytic enzymes. Thereare some in vitro and in vivo reports of antiedematous, antiinflammatory, antithrombotic, and fibrinolytic effects ofbromelain [Maurer, 2001; Brien et al. 2004]. Experimental evidence suggests that bromelain’s action as an antiinflammatory is mediated via decreasing levels of PGE , thromboxane A2 and through modulation of certainimmune cell surface adhesion molecules, which play a role in the pathogenesis of arthritis [Hale et al. 2002;Kumakura et al. 1988]. Pretreatment of SpragueDawley rats with bromelains (10 mg/kg intravenously) completelyprevented the potentiation of inflammation by ramipril [Caspritz et al. 1986]. Due to its efficacy after oraladministration, its safety and lack of undesired side effects, bromelain has earned growing acceptance andcompliance among patients as a phytotherapeutical drug. The majority of studies assessing bromelain for OA havebeen either open studies or equivalence studies designed to assess comparative effectiveness and safety againststandard NSAID treatment (Table 1). The majority of the studies have methodological issues that make it difficultto draw definite conclusions. Three different preparations containing bromelain mixed with diverse enzymes havebeen tested in knee OA: Phlogenzyme (Mucos Parma, Geretsried, Germany), which contains the proteolyticbromelain (90 mg/tablet), trypsin, and rutin; Wobenzym (Mucos Parma, Geretsried, Germany), which containsbromelain (45 mg/tablet), papain, trypsin, chymotrypsin, pancreatin, lipase, and amylase; and Wobenzym N(Mucos Parma, Geretsried, Germany), which contains bromelain (45 mg/tablet), trypsin, papain, chymotrypsin,pancreatin and rutin [reviewed in Brien et al. 2004]. In a doubleblind, randomized, controlled trial of 73 patients

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with knee OA commercial proteolytic enzyme preparation (Phlogenzym) containing bromelain was compared witha dose of diclofenac (100–150 mg/day). An equivalent reduction in pain indices (80%) for the two treatmentsduring 3 weeks of therapy and 4 weeks of follow up with few adverse reactions to either treatment has beenreported [Klein and Kullich, 2000]. In contrast, efficacy of bromelain (800 mg/day) in treating knee OA wasstudied in a randomized, doubleblind placebocontrolled 12week trial. No statistically significant differences wereobserved between groups for the primary outcome, nor the WOMAC subscales. This study suggests that bromelainis not efficacious as an adjunctive treatment of moderate to severe OA, but its limitations support the need for afollowup study [Brien et al. 2006]. Two more published studies reported trials to assess the effectiveness ofbromelain for knee OA [Singer et al. 2001; Tilwe et al. 2001]. These studies used 3 or 4weeks period and dosesof a standard treatment, diclofenac (150–100 mg/day); however, different doses of bromelain were tested (rangefrom 540 to 1890 mg/day). Tilwe and colleagues compared a daily bromelain dose of 1890 mg/day (Phlogenzym)with the diclofenac comparative group [Tilwe et al. 2001]. Both groups showed reduced symptoms of pain,swelling and joint tenderness but the improvement was significantly better in the phlogenzym group. Singer andcolleagues compared bromelain (Phlogenzym) at a dose of 540 mg/day with diclofenac [Singer et al. 2001]. Thisstudy demonstrated that bromelain showed significantly better improvement in both the primary outcome andsummary pain scores compared with diclofenac. In conclusion, bromelain appears to have potential for thetreatment of knee OA. However, there is not enough evidence to support recommending bromelain for thetreatment of OA at this stage. It is important to note that there are a number of methodological issues that arecommon to the studies reported, including the possibility of inadequate power, duration of the study, inadequatetreatment periods, inadequate or nonexistent followup to monitor possible adverse drug reactions. Furthermore,the optimum dosage for this condition remains unclear. More trials of higher quality are needed to confirm theefficacy of bromelain in OA.

Conclusion

At present, the current modalities for treating OA are symptomatic and have not been shown to block or reverse thecartilage degradation and joint destruction. This has resulted in heightened interest in the use of nutraceuticals forOA management. Many studies have been carried out to highlight the potency of several nutraceuticals and dietarysupplements for the treatment of OA. Nutraceuticals offer a large variety of products with a wide range of effects.They open new and large horizons for the treatment of degenerative joint diseases. Many nutraceuticals and dietarysupplements are claimed to provide pain relief in OA and they have a great potential but there is a need for moresubstantial data. We have gathered studies and clinical trials of selected neutraceuticals and some results are reallypromising and encouraging. However, there is a need for serious, well designed, good quality clinical trials that canaddress most of the questions about the safety and efficacy of such fruit and plantderived products. This could helpin recommending them for OA treatment either alone or in combination with NSAIDs.

Footnotes

This work was supported in part by grants from the National Institute of Health/National Centre for Complimentary andAlternative Medicine (RO1 AT003267, RO1AT005520, R21AT504615) and funds from the Metro Health Medical Centre.

The authors declare that there is no conflict of interest.

Contributor Information

Nahid Akhtar, Department of Medicine/Rheumatology, MetroHealth Medical Center, Case Western ReserveUniversity, Cleveland, OH, USA.

Tariq M. Haqqi, Department of Medicine/Rheumatology, Rammelkamp327, MetroHealth Medical Center/CaseWestern Reserve University, 2500 Metro Health Drive, Cleveland, OH 44109, USA.

References



Abramson S.B. (2003) The role of NSAIDs in the treatment of osteoarthritis. In Brandt K.D., Doherty M.,Lohmander L.S., editors. (eds), Osteoarthritis. Oxford: Oxford University Press, pp. 251–258

Afzal M., AlHadidi D., Menon M., Pesek J., Dhami M.S. (2001) Ginger: an ethnomedical, chemical andpharmacological review. Drug Metabol Drug Interact 18: 159–190 [PubMed]

Aggarwal B.B., Shishodia S. (2004) Suppression of the nuclear factorκB activation pathway by spicederivedphytochemicals: reasoning for seasoning. Ann N Y Acad Sci 1030: 434–441 [PubMed]

Aguilar J.L., Rojas P., Marcelo A., Plaza A., Bauer R., Reininger E., et al. (2002) Antiinflammatory activity oftwo different extracts of Uncaria tomentosa (Rubiaceae). J Ethnopharmacol 81: 271–276 [PubMed]

Ahmed S., Marotte H., Kwan K., Ruth J.H., Campbell P.L., Rabquer B.J., et al. (2008) Epigallocatechin3gallateinhibits IL6 synthesis and suppresses trans signaling by enhancing soluble gp130 production. Proc Natl AcadSci U S A 105: 14692–14697 [PMC free article] [PubMed]

Ahmed S., Pakozdi A., Koch A.E. (2006) Regulation of interleukin1betainduced chemokine production andmatrix metalloproteinase 2 activation by epigallocatechin3gallate in rheumatoid arthritis synovial fibroblasts.Arthritis Rheum 54: 2393–2401 [PubMed]

Ahmed S., Rahman A., Hasnain A., Lalonde M., Goldberg V.M., Haqqi T.M. (2002) Green tea polyphenolepigallocatechin3gallate inhibits the IL1 betainduced activity and expression of cyclooxygenase2 and nitricoxide synthase2 in human chondrocytes. Free Radical Biol Med 33: 1097–1105 [PubMed]

Ahmed S., Wang N., Hafeez B.B., Cheruvu V.K., Haqqi T.M. (2005) Punica granatum L. extract inhibits IL1betainduced expression of matrix metalloproteinases by inhibiting the activation of MAP kinases and NFkappaB in human chondrocytes in vitro. J Nutr 135: 2096–2102 [PMC free article] [PubMed]

Ahmed S., Wang N., Lalonde M., Goldberg V.M., Haqqi T.M. (2004) Green tea polyphenol epigallocatechin3gallate (EGCG) differentially inhibits interleukin1 betainduced expression of matrix metalloproteinase1 and13 in human chondrocytes. J Pharmacol Exp Ther 308: 767–773 [PubMed]

Akhtar N., Haqqi T.M. (2011) Epigallocatechin3gallate suppresses the global interleukin1betainducedinflammatory response in human chondrocytes. Arthritis Res Ther 13: R93. [PMC free article] [PubMed]

Akhtar N., Mark J.S.M., Haqqi T.M. (2011) Effect of a HerbalLeucine mix on the IL1βinduced cartilagedegradation and inflammatory gene expression in human chondrocytes. BMC Complement Altern Med 11: 66.[PMC free article] [PubMed]

AllenHall L., Arnason J.T., Cano P., Lafrenie R.M. (2010) Uncaria tomentosa acts as a potent TNFalphainhibitor through NFkappaB. J Ethnopharmacol 127: 685–693 [PubMed]

Altman R.D. (2009) Practical considerations for the pharmacologic management of osteoarthritis. Am J ManagCare 15 (8 Suppl.): S236–S243 [PubMed]

Altman R.D., Marcussen K.C. (2001) Effects of a ginger extract on knee pain in patients with osteoarthritis.Arthritis Rheum 44: 2531–2538 [PubMed]

Ameye L.G., Chee W.S. (2006) Osteoarthritis and nutrition from nutraceuticals to functional foods: a systematicreview of the scientific evidence. Arthritis Res Ther 8: R127. [PMC free article] [PubMed]

Andriamanalijaona R., Kypriotou M., Baugé C., Renard E., Legendre F., Raoudi M., et al. (2005) Comparativeeffects of 2 antioxidants, selenomethionine and epigallocatechingallate, on catabolic and anabolic geneexpression of articular chondrocytes. J Rheumatol 32: 1958–1967 [PubMed]

Anonymous (2008) Devil’s claw tuber. http://www.altcancer.com/phyto/devils_claw.htm (Accessed 6 January2012).

Aviram M., Dornfeld L. (2003) Methods of using pomegranate extracts for causing regression in lesions due toarteriosclerosis in humans. US Patent 6: 641

Bélaiche P. (1982) Clinical study of 630 patients with arthritis treated with the herbal remedy Harpagophytumprocumbens [in French]. Phytothérapy 1: 22–28

BetancorFernández A., PérezGálvez A., Sies H., Stahl W. (2003) Screening pharmaceutical preparationscontaining extracts of turmeric rhizome, artichoke leaf, devil’s claw root and garlic or salmon oil for antioxidant

http://www.ncbi.nlm.nih.gov/pubmed/14600251













http://www.altcancer.com/phyto/devils_claw.htm


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2567200/








capacity. J Pharm Pharmacol 55: 981–986 [PubMed]Bhattacharya A., Bhattacharya S. (1998) Antioxidant activity of Harpagophytum procumbens. Br J Phytother 5:

68Blain E.J., Ali A.Y., Duance V.C. (2010) Boswellia frereana (frankincense) suppresses cytokineinduced matrix

metalloproteinase expression and production of proinflammatory molecules in articular cartilage. Phytother Res24: 905–912 [PubMed]

Bliddal H., Rosetzsky A., Schlichting P., Weidner M.S., Andersen L.A., Ibfelt H.H. (2000) A randomized,placebocontrolled, crossover study of ginger extracts and ibuprofen in osteoarthritis. Osteoarthritis Cartilage 8:9–12 [PubMed]

Blumenthal M. (1998) The Complete German Commission E Monographs. Austin, TX: American BotanicalCouncil, pp. 120–121

Boje K., Lechtenberg M., Nahrstedt A. (2003) New and known iridoid and phenylethanoid glycosides fromHarpagophytum procumbens and their in vitro inhibition of human leukocyte elastase. Planta Med 69: 820–825[PubMed]

Bradley P., editor. (ed) (1990) British Herbal Compendium. Bournemouth, UK: British Herbal MedicalAssociation

Bradley P.R., editor. (ed) (1992) British Herbal Compendium. Dorset, UK: British Herbal Medicine AssociationBrien S., Lewith G.T., McGregor G. (2006) Devil’s claw (Harpagophytum procumbens) as a treatment for

osteoarthritis: a review of efficacy and safety. J Altern Complement Med 12: 981–993 [PubMed]Brien S., Lewith G., Walker A., Hicks S.M., Middleton D. (2004) Bromelain as a treatment for osteoarthritis: a

review of clinical studies. Evid Based Complement Alternat Med 1: 251–257 [PMC free article] [PubMed]Brien S., Lewith G., Walker A.F., Middleton R., Prescott P., Bundy R. (2006) Bromelain as an adjunctive

treatment for moderatetosevere osteoarthritis of the knee: a randomized placebocontrolled pilot study. QJM99: 841–850 [PubMed]

Bruijn C.D., Christ F.R., Dziabo A.J. (2003) Ophthalmic, pharmaceutical and other healthcare preparations withnaturally occurring plant compounds, extracts and derivatives. US Patent Application 20030086986

Bruneton J. (2001) Pharmacognosie, Phytochimie, Plantes Medicinales. Paris: Technique et DocumentationLavoisier

Cabrera C., Artacho R., Gimenez R. (2006) Beneficial effects of green tea – a review. J Am Coll Nutr 25: 79–99[PubMed]

Cabrera C., Giménez R., López M.C. (2003) Determination of tea components with antioxidant activity. J AgricFd Chem 51: 4427–4435 [PubMed]

Caspritz G., Alpermann H.G., Schleyerbach R. (1986) Influence of the new angiotensin converting enzymeinhibitor ramipril on several models of acute inflammation and the adjuvant arthritis in the rat.Arzneimittelforschung 36: 1605–1608 [PubMed]

Cerdá B., Cerón J.J., TomásBarberán F.A., Espín J.C. (2003) Repeated oral administration of high doses of thepomegranate ellagitannin punicalagin to rats for 37 days is not toxic. J Agric Fd Chem 51: 3493–3501[PubMed]

ChainaniWu N. (2003) Safety and antiinflammatory activity of curcumin: a component of turmeric (Curcumalonga). J Altern Complement Med 9: 161–168 [PubMed]

Chan F.K., Cryer B., Goldstein J.L., Lanas A., Peura D.A., Scheiman J.M., et al. (2010) A novel compositeendpoint to evaluate the gastrointestinal (GI) effects of nonsteroidal antiinflammatory drugs through the entireGI tract. J Rheumtol 37: 167–174 [PubMed]

Chang C.P., Chang J.Y., Wang F.Y., Chang J.G. (1995) The effect of Chinese medicinal herb Zingiberis rhizomaextract on cytokine secretion by human peripheral blood mononuclear cells. J Ethnopharmacol 48: 13–19[PubMed]

Chantre P., Cappelaere A., Leblan D., Guedon D., Vandermander J., Fournie B. (2000) Efficacy and tolerance ofHarpagophytum procumbens versus diacerhein in treatment of osteoarthritis. Phytomedicine 7: 177–183


















[PubMed]Cheng K.W., Wong C.C., Chao J., Lo C., Chen F., Chu I.K., et al. (2009) Inhibition of mutagenic PhIP formation

by epigallocatechin gallate via scavenging of phenylacetaldehyde. Mol Nutr Food Res 53: 716–725 [PubMed]Chevrier M.R., Ryan A.E., Lee D.Y., Zhongze M., WuYan Z., Via C.S. (2005) Boswellia carterii extract inhibits

TH1 cytokines and promotes TH2 cytokines in vitro. Clin Diagn Lab Immunol 12: 575–580 [PMC free article][PubMed]

Choi Y.H., Yan G.H. (2009) Ellagic acid attenuates immunoglobulin Emediated allergic response in mast cells.Biol Pharm Bull 32: 1118–1121 [PubMed]

Chopra A., Lavin P., Patwardhan B., Chitre D. (2004) A 32week randomized, placebocontrolled clinicalevaluation of RA11, an Ayurvedic drug, on osteoarthritis of the knees. J Clin Rheumatol 10: 236–245[PubMed]

Chrubasik S., Thanner J., Künzel O., Conradt C., Black A., Pollak S. (2002) Comparison of outcome measuresduring treatment with the proprietary Harpagophytum extract Doloteffin in patients with pain in the lower back,knee, or hip. Phytomedicine 9: 181–194 [PubMed]

Danesi F., Philpott M., Huebner C., Bordoni A., Ferguson L.R. (2010) Foodderived bioactives as polyphenolepigallocatechin3gallate inhibits advanced glycation end product induced potential regulators of the IL12/IL23 pathway implicated in inflammatory bowel diseases. Mutat Res 690: 139–144 [PubMed]

de Mejia E.G., RamirezMares M.V., Puangpraphant S. (2009) Bioactive components of tea: cancer, inflammationand behavior. Brain Behav Immun 23: 721–731 [PubMed]

Dugas A.J., Jr, CastañedaAcosta J., Bonin G.C., Price K.L., Fischer N.H., Winston G.W. (2000) Evaluation ofthe total peroxyl radicalscavenging capacity of flavonoids: structure–activity relationships. J Nat Prod 63: 327–331 [PubMed]

Farrell A.J., Blake D.R., Palmer R.M., Moncada S. (1992) Increased concentrations of nitrite in synovial fluid andserum samples suggest increased nitric oxide synthesis in rheumatic diseases. Ann Rheum Dis 51: 1219–1222[PMC free article] [PubMed]

Fetrow C.W., Avila J.R. (1999) Professional’s Handbook of Complementary and Alternative Medicines.Springhouse, PA: Springhouse

Fiebich B.L., Heinrich M., Hiller K.O., Kammerer N. (2001) Inhibition of TNFalpha synthesis in LPSstimulatedprimary human monocytes by Harpagophytum extract SteiHap 69. Phytomedicine 8: 28–30 [PubMed]

Firestein G.S., Manning A.M. (1999) Signal transduction and transcription factors in rheumatic disease. ArthritisRheum 42: 609–621 [PubMed]

Foster S. (1996) Herbs for your health. Loveland, CO: Interweave PressFrei B., Higdon J.V. (2003) Antioxidant activity of tea polyphenols in vivo: evidence from animal studies. J Nutr

133: 3275S–3284S [PubMed]Frerick H., Biller A., Schmidt U. (2001) Hip osteoarthritis: double blind study with devil claw [in German]. Der

Kassenarzt 5: 34–41Frondoza C.G., Sohrabi A., Polotsky A., Phan P.V., Hungerford D.S., Lindmark L. (2004) An in vitro screening

assay for inhibitors of proinflammatory mediators in herbal extracts using human synoviocyte cultures. In VitroCell Dev Biol Anim 40: 95–101 [PubMed]

Ganzera M., Muhammad I., Khan R.A., Khan I.A. (2001) Improved method for the determination of oxindolealkaloids in Uncaria tomentosa by high performance liquid chromatography. Planta Med 67: 447–450[PubMed]

Gil M.I., TomásBarberán F.A., HessPierce B., Holcroft D.M., Kader A.A. (2000) Antioxidant activity ofpomegranate juice and its relationship with phenolic composition and processing. J Agric Fd Chem 48: 4581–4589 [PubMed]

Glaser T., Winter S., Groscurth P., Safayhi H., Sailer E.R., Ammon H.P., et al. (1999) Boswellic acids andmalignant glioma: induction of apoptosis but no modulation of drug sensitivity. Br J Cancer 80: 756–765[PMC free article] [PubMed]























GonzalezFuentes A.M., Green D.M., Rossen R.D., Ng B. (2010) Intraarticular hyaluronic acid increases cartilagebreakdown biomarker in patients with knee osteoarthritis. Clin Rheumatol 29: 619–624 [PubMed]

Grant L., McBean D.E., Fyfe L., Warnock A.M. (2009) The inhibition of free radical generation by preparations ofHarpagophytum procumbens in vitro. Phytother Res 23: 104–110 [PubMed]

Gregory P.J., Sperry M., Wilson A.F. (2008) Dietary supplements for osteoarthritis. Am Fam Physician 77: 177–184 [PubMed]

Gupta I., Parihar A., Malhotra P., Singh G.B., Lüdtke R., Safayhi H., et al. (1997) Effects of Boswellia serratagum resin in patients with ulcerative colitis. Eur J Med Res 2: 37–43 [PubMed]

Hale L.P., Greer P.K., Sempowski G.D. (2002) Bromelain treatment alters leukocyte expression of cell surfacemolecules involved in cellular adhesion and activation. Clin Immunol 104: 183–190 [PubMed]

Halsted C.H. (2003) Dietary supplements and functional foods: 2 sides of a coin? Am J Clin Nutr 77: 1001S–1007S [PubMed]

Haqqi T.M., Anthony D.D., Gupta S., Ahmad N., Lee M.S., Kumar G.K., et al. (1999) Prevention of collageninduced arthritis in mice by a polyphenolic fraction from green tea. Proc Natl Acad Sci U S A 96: 4524–4529[PMC free article] [PubMed]

Häuselmann H.J. (2001) Nutripharmaceuticals for osteoarthritis. Best Pract Res Clin Rheumatol 15: 595–607[PubMed]

Henrotin Y., Clutterbuck A.L., Allaway D., Lodwig E.M., Harris P., MathyHartert M., et al. (2010) Biologicalactions of curcumin on articular chondrocytes. Osteoarthritis Cartilage 18: 141–149 [PubMed]

Hsiao F.Y., Tsai Y.W., Huang W.F. (2009) Changes in physicians’ practice of prescribing cyclooxygenase2inhibitor after market withdrawal of rofecoxib: a retrospective study of physician–patient pairs in Taiwan. ClinTher 31: 2618–2627 [PubMed]

Huang T.H., Tran V.H., Duke R.K., Tan S., Chrubasik S., Roufogalis B.D. (2005) Harpagoside suppresseslipopolysaccharideinduced iNOS and COX2 expression through inhibition of NFkB activation. JEthnopharmacol 13: 11–15 [PubMed]

Ippoushi K., Azuma K., Ito H., Horie H., Higashio H. (2003) [6]Gingerol inhibits nitric oxide synthesis inactivated J774.1 mouse macrophages and prevents peroxynitriteinduced oxidation and nitration reactions. LifeSci 73: 3427–3437 [PubMed]

Jana U., Chattopadhayay R.N., Shaw B.P. (1999) Preliminary studies on antiinflammatory activity of Zingiberofficinale Rosc., Vitex negundo Linn. and Tinospora cordifolia (Willid) miers in albino rats. Indian J Pharmacol31: 232–233

Jang M.H., Lim S., Han S.M., Park H.J., Shin I., Kim J.W., et al. (2003) Harpagophytum procumbens suppresseslipopolysaccharidestimulated expressions of cyclooxygenase2 and inducible nitric oxide synthase in fibroblastcell line L929. J Pharmacol Sci 93: 367–371 [PubMed]

Jaswal S., Mehta H., Sood A., Kaur J. (2003) Antioxidant status in rheumatoid arthritis and role of antioxidanttherapy. Clinica Chimica Acta 338: 123–129 [PubMed]

Johnson J.J., Bailey H.H., Mukhtar H. (2010) Green tea polyphenols for prostate cancer chemoprevention: atranslational perspective. Phytomedicine 17: 3–13 [PMC free article] [PubMed]

Kalra E.K. (2003) Nutraceutical – definition and introduction. AAPS PharmSci 5: E25. [PMC free article][PubMed]

Katiyar S.K., Raman C. (2011) Green tea: a new option for the prevention or control of osteoarthritis. Arthritis ResTher 13: 121. [PMC free article] [PubMed]

Khalifé S., Zafarullah M. (2011) Molecular targets of natural health products in arthritis. Arthritis Res Ther 13: 102.[PMC free article] [PubMed]

Khan N., Mukhtar H. (2008) Multitargeted therapy of cancer by green tea polyphenols. Cancer Lett 269: 269–280[PMC free article] [PubMed]

Kim M.M., Kim S. (2002) Composition for improving oral hygiene containing Punica granatum L. extract.Korean Patent: KR 2002066042




























Kim N.D., Mehta R., Yu W., Neeman I., Livney T., Amichay A., et al. (2002) Chemopreventive and adjuvanttherapeutic potential of pomegranate (Punica granatum) for human breast cancer. Breast Cancer Res Treat 71:203–217 [PubMed]

Kimmatkar N., Thawani V., Hingorani L., Khiyani R. (2003) Efficacy and tolerability of Boswellia serrata extractin treatment of osteoarthritis of knee – a randomized double blind placebo controlled trial. Phytomedicine 10:3–7 [PubMed]

Klein G., Kullich W. (2000) Shortterm treatment of painful osteoarthritis of the knee with oral enzymes: arandomised, doubleblind study versus Diclofenac. Clin Drug Invest 19:15–23

Koeberle A., Bauer J., Verhoff M., Hoffmann M., Northoff H., Werz O. (2009) Green tea epigallocatechin3gallate inhibits microsomal prostaglandin E(2) synthase1. Biochem Biophy Res Commun 388: 350–354[PubMed]

Kulkarni R.R., Patki P.S., Jog V.P., Gandage S.G., Patwardhan B. (1991) Treatment of osteoarthritis with aherbomineral formulation: a doubleblind, placebocontrolled, crossover study. J Ethnopharmacol 33: 91–95[PubMed]

Kumakura S., Yamashita M., Tsurufuji S. (1988) Effect of bromelain or kaolin induced inflammation in rats. Eur JPharmacol 150: 295–301 [PubMed]

Langmead L., Dawson C., Hawkins C., Banna N., Loo S., Rampton D. (2002) Antioxidant effects of herbaltherapies used by patients with inflammatory bowel disease: an in vitro study. Aliment Pharmacologic Ther 16:197–205 [PubMed]

Lanhers M.C., Fleurentin J., Mortier F., Vinche A., Younos C. (1992) Antiinflammatory and analgesic effects ofan aqueous extract of Harpagophytum procumbens. Planta Med 58: 117–123 [PubMed]

Leblan D., Chantre P., Fournié B. (2000) Harpagophytum procumbens in the treatment of knee and hiposteoarthritis. Fourmonth results of a prospective, multicenter, doubleblind trial versus diacerhein. Joint BoneSpine 67: 462–467 [PubMed]

Lecomte A., Costa J.P. (1992) Harpagophytum in osteoarthritis. Doubleblind, placebocontrolled study. LeMagazine 37: 27–30

Lee S.I., Kim B.S., Kim K.S., Lee S., Shin K.S., Lim J.S. (2008) Immunesuppressive activity of punicalagin viainhibition of NFAT activation. Biochem Biophys Res Commun 371: 799–803 [PubMed]

Lee J., Watson R.R. (1998) Pomegranate: a role in health promotion and AIDS? In Watson R.R., editor. (ed.),Nutrients and Foods in AIDS. Boca Raton, FL: CRC Press, p. 179

Liacini A., Sylvester J., Li W.Q., Huang W., Dehnade F., Ahmad M., et al. (2003) Induction of matrixmetalloproteinase13 gene expression by TNFalpha is mediated by MAP kinases, AP1, and NFkappaBtranscription factors in articular chondrocytes. Exp Cell Res 288: 208–217 [PubMed]

Liacini A., Sylvester J., Li W.Q., Zafarullah M. (2002) Inhibition of interleukin1stimulated MAP kinases,activating protein1 (AP1) and nuclear factor kappa B (NFkB) transcription factors downregulates matrixmetalloproteinase gene expression in articular chondrocytes. Matrix Biol 21: 251–262 [PubMed]

Lo Y.Y., Wong J.M., Cruz T.F. (1996) Reactive oxygen species mediate cytokine activation of cJun NH2terminal kinases. J Biol Chem 271: 15703–15707 [PubMed]

Loew D., Mollerfeld J., Schrodter A., Puttkammer S., Kaszkin M. (2001) Investigations on the pharmacokineticproperties of Harpagophytum extracts and their effects on eicosanoid biosynthesis in vitro and ex vivo. ClinPharmacol Ther 69: 356–364 [PubMed]

Malemud C.J., Islam N., Haqqi T.M. (2003) Pathophysiological mechanisms in osteoarthritis lead to noveltherapeutic strategies. Cells Tissues Organs 174: 34–48 [PubMed]

Marcu K.B., Otero M., Olivotto E., Borzi R.M., Goldring M.B. (2010) NFkappaB signaling: multiple angles totarget OA. Curr Drug Targets 11: 599–613 [PMC free article] [PubMed]

MathyHartert M., JacquemondCollet I., Priem F., Sanchez C., Lambert C., Henrotin Y. (2009) Curcumin inhibitsproinflammatory mediators and metalloproteinase3 production by chondrocytes. Inflamm Res 58: 899–908[PubMed]




















Maurer H.R. (2001) Bromelain: biochemistry, pharmacology and medical use. Cell Mol Life Sci 58: 1234–1245[PubMed]

McAlindon T.E. (2006) Nutraceuticals: do they work and when should we use them? Best Pract Res ClinRheumatol 20: 99–115 [PubMed]

Mehta K., Gala J., Bhasale S., Naik S., Modak M., Thakur H. (2007) Comparison of glucosamine sulfate and apolyherbal supplement for the relief of osteoarthritis of the knee: a randomized controlled trial[ISRCTN25438351]. BMC Complement Altern Med 7: 34. [PMC free article] [PubMed]

Meng Q., Velalar C.N., Ruan R. (2001) Effects of epigallocatechin3gallate on mitochondrial integrity andantioxidative enzyme activity in the aging process of human fibroblast. Free Radic Biol Med 44: 1032–1041[PubMed]

MertensTalcott S.U., JilmaStohlawetz P., Rios J., Hingorani L., Derendorf H. (2006) Absorption, metabolism,and antioxidant effects of pomegranate (Punica granatum L.) polyphenols after ingestion of a standardizedextract in healthy human volunteers. J Agric Fd Chem 54: 8956–8961 [PubMed]

Miller M.J., Ahmed S., Bobrowski P., Haqqi T.M. (2006) The chrondoprotective actions of a natural product areassociated with the activation of IGF1 production by human chondrocytes despite the presence of IL1beta.BMC Complement Altern Med 6: 13. [PMC free article] [PubMed]

Miller M.J., Mehta K., Kunte S., Raut V., Gala J., Dhumale R., et al. (2005) Early relief of osteoarthritis symptomswith a natural mineral supplement and a herbomineral combination: a randomized controlled trial[ISRCTN38432711]. Inflamm (Lond) 2: 11 [PMC free article] [PubMed]

Minoia C., Sabbioni E., Ronchi A., Gatti A. (1994) Trace element reference values in tissues from inhabitants ofthe European Community. IV. Influence of dietary factors. Sci Total Environ 141: 181–195

Moayadi A. (2004) Mixtures of pomegranate seed oils for cosmetics. Japanese Patent: JP 2004083544 A220040318

Moon H.S., Lee H.G., Choi Y.J., Kim T.G., Cho C.S. (2007) Proposed mechanisms of (−)epigallocatechin3gallate for antiobesity. Chem Biol Interac 167: 85–98 [PubMed]

Morelli V., Naquin C., Weaver V. (2003) Alternative therapies for traditional disease states: osteoarthritis. Am FamPhysician 67: 339–344 [PubMed]

Moussaieff A., Mechoulam R. (2009) Boswellia resin: from religious ceremonies to medical uses: a review of invitro, invivo and clinical trials. J Pharm Pharmacol 61: 1281–1293 [PubMed]

Nuti E., Casalini F., Avramova S.I., Santamaria S., Cercignani G., Marinelli L., et al. (2009) NOisopropylsulfonamidobased hydroxamates: design, synthesis and biological evaluation of selective matrixmetalloproteinase13 inhibitors as potential therapeutic agents for osteoarthritis. J Med Chem 52: 4757–4773[PubMed]

Okamoto H., Cujec T.P., Yamanaka H., Kamatani N. (2008) Molecular aspects of rheumatoid arthritis: Role oftranscription factors. FEBS J 275: 4463–4470 [PubMed]

Osterburg A., Gardner J., Hyon S.H., Neely A., Babcock G. (2009) Highly antibioticresistant Acinetobacterbaumannii clinical isolates are killed by the green tea polyphenol (−)epigallocatechin3gallate (EGCG). ClinMicrobiol Infect 15: 341–346 [PubMed]

Palaniswamy R. (2003) A Guide to Medicinal Plants of Asian Origin and Culture. Newbury, UK: CPL PressPiscoya J., Rodriguez Z., Bustamante S.A., Okuhama N.N., Miller M.J., Sandoval M. (2001) Efficacy and safety

of freezedried cat’s claw in osteoarthritis of the knee: mechanisms of action of the species Uncaria guianensis.Inflamm Res 50: 442–448 [PubMed]

Qi J., Chen J., Cheng Z., Zhou J., Yu B., Qui S. (2006) Iridoid glycosides from Harpagophytum procumbensD.C. (devil’s claw). Phytochemistry 67: 1372–1377 [PubMed]

Ragusa S., Circosta C., Galati E.M., Tumino G. (1984) A drug used in traditional medicine. Harpagophytumprocumbens DC. I. Scanning electron microscope observations. J Ethnopharmcol 11: 245–257 [PubMed]

Ramsey S.D., Spencer A.C., Topolski T.D., Belza B., Patrick D.L. (2001) Use of alternative therapies by olderadults with osteoarthritis. Arthritis Rheum 45: 222–227 [PubMed]























Rasheed Z., Akhtar N., Anbazhagan A.N., Ramamurthy S., Shukla M., Haqqi T.M. (2009a) Polyphenolrichpomegranate fruit extract (POMx) suppresses PMACIinduced expression of proinflammatory cytokines byinhibiting the activation of MAP Kinases and NFkappaB in human KU812 cells. J Inflamm (Lond) 8: 6[PMC free article] [PubMed]

Rasheed Z., Akhtar N., Haqqi T.M. (2010) Pomegranate extract inhibits the interleukin1βinduced activation ofMKK3, p38αMAPK and transcription factor RUNX2 in human osteoarthritis chondrocytes. Arthritis ResTher 12: R195. [PMC free article] [PubMed]

Rasheed Z., Anbazhagan A.N., Akhtar N., Ramamurthy S., Voss F.R., Haqqi T.M. (2009b) Green tea expressionof tumor necrosis factoralpha and matrix metalloproteinase13 in human chondrocytes. Arthritis Res Ther 11:R71. [PMC free article] [PubMed]

Rosenbaum C.C., O’Mathúna D.P., Chavez M., Shields K. (2010) Antioxidants and antiinflammatory dietarysupplements for osteoarthritis and rheumatoid arthritis. Altern Ther Health Med 16: 32–40 [PubMed]

Rutten S., Schafer I. (2000) Einsatz der afrikanischen Teufelskralle [Allya] bei Erkrankungen des Stutz undeBewegungsapparates. Ergebnisse einer Anwendungscbeobachtung Acta Biol 2: 5–20

Safayhi H., Ammon H.P.T. (1997) Pharmakologische Aspecte von Weihrauch und Boswelliasäuren.Pharmazeutisch Zeitung 142: 3277–3280

Safayhi H., Mack T., Sabieraj J., Anazodo M.I., Subramanian L.R., Ammon H.P. (1992) Boswellic acids: novel,specific, nonredox inhibitors of 5lipoxygenase. J Pharmacol Exp Ther 261: 1143–1146 [PubMed]

Sandoval M., Chaarbonnett R.M., Okuhama N.N., Roberts J., Krenova Z., Trentacosti A.M. (2000) Cat’s clawinhibits TNFa production and scavenges free radicals: role in cytoprotection. Free Rad Biol Med 29: 71–78[PubMed]

Sandoval M., Okuhama N.N., Zhang X.J., Condezo L.A., Lao J., Angeles F.M. (2002) Antiinflammatory andantioxidant activities of cat’s claw (Uncaria tomentosa and Uncaria guianensis) are independent of their alkaloidcontent. Phytomedicine 9: 325–337 [PubMed]

SandovalChacón M., Thompson J.H., Zhang X.J., Liu X., Mannick E.E., SadowskaKrowicka H., et al. (1998)Antiinflammatory actions of cat’s claw: the role of NFkappaB. Aliment Pharmacol Ther 12: 1279–1289[PubMed]

Santa Maria A., Lopez A., Diaz M.M., Alban J., Galan de Mera. A., Vicente Orellana J.A., et al. (1997)Evaluation of the toxicity of Uncaria tomentosa by bioassays in vitro. J Ethnopharmacol 57: 183–187[PubMed]

Sawa T., Nakao M., Akaike T., Ono K., Maeda H. (1999) Alkylperoxyl radicalscavenging activity of variousflavonoids and other phenolic compounds: implications for the antitumor promoter effect of vegetables. J AgricFood Chem 47: 397–402 [PubMed]

Schmelz H., Haemmerle H.D., Springorum H.W. (1997) Analgesic effectiveness of Devil claw root excerpt indifferent chronicdegenerative joint illnesses [in German]. In: Chrubasik S., Wink M., editors. (eds),Rheumatherapie mit Phytopharmaka. Stuttgart: Hippokrates

SchulzeTanzil G., Hansen C., Shakibaei M. (2004a) Effect of a Harpagophytum procumbens DC extract onmatrix metalloproteinases in human chondrocytes in vitro. ArzneimittelForsch 54: 213–220 [PubMed]

SchulzeTanzil G., Mobasheri A., Sendzik J., John T., Shakibaei M. (2004b) Effects of curcumin(diferuloylmethane) on nuclear factor kappaB signaling in interleukin1betastimulated chondrocytes. Ann N YAcad Sci 1030: 578–586 [PubMed]

Schwarz B., Bischof H.P., Kunze M. (1994) Coffee, tea and lifestyle. Prev Med 23: 377–384 [PubMed]Seeram N.P., Lee R., Heber D. (2004) Bioavailability of ellagic acid in human plasma after consumption of

ellagitannins from pomegranate (Punica granatum L.) juice. Clin Chim Acta 348: 63–68 [PubMed]Seeram N.P., Nair M.G. (2002) Inhibition of lipid peroxidation and structure–activityrelated studies of the dietary

constituents anthocyanins, anthocyanidins, and catechins. J Agric Fd Chem 50: 5308–5312 [PubMed]Sengupta K., Alluri K.V., Satish A.R., Mishra S., Golakoti T., Sarma K.V., et al. (2008) A double blind,

randomized, placebo controlled study of the efficacy and safety of 5Loxin for treatment of osteoarthritis of the





















knee. Arthritis Res Ther 10: R85. [PMC free article] [PubMed]Sengupta K., Kolla J.N., Krishnaraju A.V., Yalamanchili N., Rao C.V., Golakoti T., et al. (2011) Cellular and

molecular mechanisms of antiinflammatory effect of Aflapin: a novel Boswellia serrata extract. Mol CellBiochem 354: 189–197 [PubMed]

Sengupta K., Krishnaraju A.V., Vishal A.A., Mishra A., Trimurtulu G., Sarma K.V., et al. (2010) Comparativeefficacy and tolerability of 5Loxin® and Aflapin® against osteoarthritis of the knee: a double blind,randomized, placebo controlled clinical study. Int J Med Sci 7: 366–377 [PMC free article] [PubMed]

Shakibaei M., John T., SchulzeTanzil G., Lehmann I., Mobasheri A. (2007) Suppression of NFkappaB activationby curcumin leads to inhibition of expression of cyclooxygenase2 and matrix metalloproteinase9 in humanarticular chondrocytes: implications for the treatment of osteoarthritis. Biochem Pharmacol 73: 1434–1445[PubMed]

Shakibaei M., SchulzeTanzil G., John T., Mobasheri A. (2005) Curcumin protects human chondrocytes from ILl1betainduced inhibition of collagen type II and beta1integrin expression and activation of caspase3: animmunomorphological study. Ann Anat 187: 487–497 [PubMed]

Shen C.L., Hong K.J., Kim S.W. (2003) Effects of ginger (Zingiber officinale Rosc.) on decreasing the productionof inflammatory mediators in sow osteoarthrotic cartilage explants. J Med Fd 6: 323–328 [PubMed]

Shen Y.J., Li W.G., Zhang H., Li B., Yuan H.X., Zhang J.J. (2009) Effects of (−)epigallocatechin3gallate oninterleukin1beta expression in mouse wound healing. Fen Zi Xi Bao Sheng Wu Xue Bao 42: 179–185[PubMed]

Shin H.Y., Kim S.H., Jeong H.J., Kim S.Y., Shin T.Y., Um J.Y., et al. (2006) Epigallocatechin 3gallate inhibitssecretion of TNFalpha, IL6 and IL8 through the attenuation of ERK and NFkappaB in HMC1 cells. IntArch Allergy Immunol 142: 335–344 [PubMed]

Shukla M., Gupta K., Rasheed Z., Khan K.A., Haqqi T.M. (2008a) Bioavailable constituents/metabolites ofpomegranate (Punica granatum L) preferentially inhibit COX2 activity ex vivo and IL1betainduced PGEproduction in human chondrocytes in vitro. J Inflamm (Lond) 5: 9. [PMC free article] [PubMed]

Shukla M., Gupta K., Rasheed Z., Khan K.A., Haqqi T.M. (2008b) Consumption of hydrolyzable tanninsrichpomegranate extract suppresses inflammation and joint damage in rheumatoid arthritis. Nutrition 24: 733–743[PMC free article] [PubMed]

Singer F., Singer C., Oberleitner H. (2001) Phlyoenzym versus diclofenac in the treatment of activatedosteoarthritis of the knee. Int J Immunother 17: 135–141

Singh G.B., Atal C.K. (1986) Pharmacology of an extract of salai guggal exBoswellia serrata, a new nonsteroidalantiinflammatory agent. Agents Actions 18: 407–412 [PubMed]

Singh R., Ahmed S., Islam N., Goldberg V.M., Haqqi T.M. (2003) Epigallocatechin3gallate inhibits selectivelyinhibits interleukin1betainduced activation of mitogen activated protein kinase subgroup cJun Nterminalkinase in human osteoarthritis chondrocytes. J Orthop Res 21: 102–109 [PubMed]

Singh R., Ahmed S., Malemud C.J., Goldberg V.M., Haqqi T.M. (2002a) Epigallocatechin3gallate interleukin1betainduced expression of nitric oxide synthase and production of nitric oxide in human chondrocytes:suppression of nuclear factor kappaB activation by degradation of the inhibitor of nuclear factor kappaB.Arthritis Rheum 46: 2079–2086 [PubMed]

Singh R., Akhtar N., Haqqi T.M. (2010) Green tea polyphenol epigallocatechi3gallate: Inflammation and arthritis.Life Sci 86: 907–918 [PMC free article] [PubMed]

Singh R.P., ChidambaraMurthy K.N., Jayaprakasha G.K. (2002b) Studies on the antioxidant activity ofpomegranate (Punica granatum) peel and seed extracts using in vitro models. J Agric Fd Chem 50: 81–86[PubMed]

Smith A., Giunta B., Bickford P.C., Fountain M., Tan J., Shytle R.D. (2010) Nanolipidic particles improve thebioavailability and alphasecretase inducing ability of epigallocatechin3gallate (EGCG) for the treatment ofAlzheimer’s disease. Int J Pharm 389: 207–212 [PubMed]

Stewart K., Cole D. (2005) The commercial harvest of devil’s claw ( Harpagophytum spp.) in southern Africa: the

2
























devil’s in the details; J Ethnopharmacol 100: 225–236 [PubMed]Sudheesh S., Vijayalakshmi N.R. (2005) Flavonoids from punica granatumpotential antiperoxidative agents.

Fitoterapia 76: 181–186 [PubMed]Thomson M., AlQattan K.K., AlSawan S.M., Alnaqeeb M.A., Khan I., Ali M. (2002) The use of ginger

(Zingiber officinale Rosc.) as a potential antiinflammatory and antithrombotic agent. Prostaglandins LeukotEssent Fatty Acids 67: 475–478 [PubMed]

Tilwe G.H., Beria S., Turakhia N.H., Daftary G.V., Schiess W. (2001) Efficacy and tolerability of oral enzymetherapy as compared to diclofenac in active osteoarthritis of the knee joint: an open randomised controlledclinical trial. J Assoc Physicians India 49: 621–626 [PubMed]

Toegel S., Wu S.Q., Piana C., Unger F.M., Wirth M., Goldring M.B., et al. (2008) Comparison betweenchondroprotective effects of glucosamine, curcumin, and diacerein in IL1betastimulated C28/I2chondrocytes. Osteoarthritis Cartilage 16: 1205–1212 [PubMed]

Ullmann U., Haller J., Decourt J.P., Girault N., Girault J., RichardCaudron A.S. (2003) A single ascending dosestudy of epigallocatechin gallate in healthy volunteers. J Int Med Res 31: 88–101 [PubMed]

Valerio L.G., Jr, Gonzales G.F. (2005) Toxicological aspects of the South American herbs cat’s claw (Uncariatomentosa) and Maca (Lepidium meyenii): a critical synopsis. Toxicol Rev 24: 11–35 [PubMed]

van der Kraan W.B., van den Berg P.M. (2000) Anabolic and destructive mediators in osteoarthritis. Curr OpinClin Nutr Metab Care 3: 205–211 [PubMed]

Vankemmelbeke M.N., Jones G.C., Fowles C., Ilic M.Z., Handley C.J., Day A.J., et al. (2003) Selective inhibitionof ADAMTS1,4 and 5 by catechin gallate esters. Eur J Biochem 270: 2394–2403 [PubMed]

van het Hof K.H., Wiseman S.A., Yang C.S., Tijburg L.B. (1999) Plasma and lipoprotein levels of tea catechinsfollowing repeated tea consumption. Proc Soc Exp Biol Med 220: 203–209 [PubMed]

Vlachojannis J., Roufogalis B.D., Chrubasik S. (2008) Systematic review on the safety of Harpagophytumpreparations for osteoarthritic and low back pain. Phytother Res 22: 149–152 [PubMed]

Wallace J.M. (2002) Nutritional and botanical modulation of the inflammatory cascade eicosanoids,cyclooxygenases, and lipoxygenases – as an adjunct in cancer therapy. Integr Cancer Ther 1: 7–37 [PubMed]

Warnock M., McBean D., Suter A., Tan J., Whittaker P. (2007) Effectiveness and safety of devil’s claw tablets inpatients with general rheumatic disorders. Phytother Res 21: 1228–1233 [PubMed]

Watanabe K., Hatakoshi M. (2002) Punica granatum leaf extracts for inactivation of allergen. Japanese patent JP2002370996, A2 20021224, 5

White B. (2007) Ginger: an overview. Am Fam Physician 75: 1689–1691 [PubMed]Williams J.E. (2001) Review of antiviral and immunomodulating properties of plants of the Peruvian rainforest

with a particular emphasis on unade Gato and Sangre de Grado. Altern Med Rev 6: 567–579 [PubMed]Xiao X., Yang Z.Q., Shi L.Q., Liu J., Chen W. (2008) Antiviral effect of epigallocatechin gallate (EGCG) on

influenza A virus. Zhongguo Zhong Yao Za Zhi 3: 2678–2682 [PubMed]Yelin E. (2003) The economics of osteoarthritis. In Brandt K.D., Doherty M., Lohmander L.S., editors. (ed),

Osteoarthritis. Oxford: Oxford University Press, pp. 17–21Zeisel S.H. (1999) Regulation of ‘nutraceuticals’. Science 285: 1853–1855 [PubMed]Zhang Z.F., Li Q., Liang J., Dai X.Q., Ding Y., Wang J.B., et al. (2010) Epigallocatechin3Ogallate(EGCG)

protects the insulin sensitivity in rat L6 muscle cells exposed to dexamethasone condition. Phytomedicine 17:14–18 [PubMed]

Zhao W., Entschladen F., Liu H., Niggemann B., Fang Q., Zenker K.S., et al. (2003) Boswellic acid acetateinduced differentiation and apoptosis in highly metastatic [PubMed]

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Current nutraceuticals in the management of osteoarthritis ... 16.pdfchondrocytes [Shukla et al. 2008a]. We showed the inhibitory effects of PFE on IL1βinduced proteoglycan breakdown