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Avocado/soybean unsaponifiable (ASU) to treat osteoarthritis: a clarification

2008; Elsevier BV; Volume: 16; Issue: 9 Linguagem: Inglês

10.1016/j.joca.2008.01.010

1522-9653

Yves Henrotin,

Osteoarthritis Treatment and Mechanisms

Today, a cure for osteoarthritis (OA) remains elusive and the management of OA is largely palliative focussing on the alleviation of symptoms. Current recommendations for the management of OA include a combination of non-pharmacological interventions and pharmacological treatments1Zhang W. Doherty M. Arden N. Bannwarth B. Bijlsma J. Gunther K.P. et al.EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).Ann Rheum Dis. 2005; 64: 669-681Crossref PubMed Scopus (748) Google Scholar, 2Jordan K.M. Arden N.K. Doherty M. Bannwarth B. Bijlsma J.W. Dieppe P. et al.EULAR recommendations 2003: an evidence based approach to the management of knee osteoarthritis. Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT).Ann Rheum Dis. 2003; 62: 1145-1155Crossref PubMed Scopus (1645) Google Scholar, 3Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update.Arthritis Rheum. 2000; 43 (American College of Rheumatology Subcommittee on Osteoarthritis Guidelines): 1905-1915Crossref PubMed Scopus (1982) Google Scholar. Until now, the pharmacological management of OA is dominated by non-steroidal anti-inflammatory drugs and analgesic (mainly paracetamol). Beside these conventional drugs, some new compounds classified as Symptomatic Slow Acting Disease Modifying drugs (SYSADOAs) have shown symptomatic efficacy in human hip and knee OA. The term SYSADOA covers a range of agents, including glucosamine sulphate, chondroitin sulphate, diacerhein, hyaluronic acid and avocado/soybean (A/S) unsaponifiables (ASUs), components of PIASCLEDINE®300 (Laboratories Expansciences, Courbevoie, France). The original ASUs are recommended for the treatment of OA symptoms by the American College of Rheumatology (ACR) and by European League Against Rheumatism (EULAR). These recommendations have been elaborated on the basis of clinical, animal and in vitro studies performed with PIASCLEDINE®300 (Laboratories Expansciences, Courbevoie, France). PIASCLEDINE®300 has been used in France as a prescription treatment for OA, subsidized by the government and meticulously tracked for safety for over 15 years. PIASCLEDINE®300 pill is composed by 100 mg of avocado unsaponifiables and 200 mg of soybean unsaponifiables. The originality is based on the A/S ratio and avocado specific modified unsaponifiables obtained by a patented process. In other countries, ASUs are delivered as over-the-counter products. At this time, there are three well-conducted, randomized, placebo-controlled, trials demonstrating a beneficial symptomatic effect of PIASCLEDINE®300 in the treatment of hip and/or knee OA4Appelboom T. Schuermans J. Verbruggen G. Henrotin Y. Reginster J.Y. Symptoms modifying effect of avocado/soybean unsaponifiables (ASU) in knee osteoarthritis. A double blind, prospective, placebo-controlled study.Scand J Rheumatol. 2001; 30: 242-247Crossref PubMed Scopus (114) Google Scholar, 5Maheu E. Mazieres B. Valat J.P. Loyau G. Leloet X. Bourgeois P. et al.Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the knee and hip: a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with a six-month treatment period and a two-month followup demonstrating a persistent effect.Arthritis Rheum. 1998; 41: 81-91Crossref PubMed Scopus (171) Google Scholar, 6Blotman F. Maheu E. Wulwik A. Caspard H. Lopez A. Efficacy and safety of avocado/soybean unsaponifiables in the treatment of symptomatic osteoarthritis of the knee and hip. A prospective, multicenter, three-month, randomized, double-blind, placebo-controlled trial.Rev Rhum Engl Ed. 1997; 64: 825-834PubMed Google Scholar. Until now, only the ASUs found in PIASCLEDINE®300 have demonstrated their clinical efficiency. Further, we have demonstrated that in vitro, PIASCLEDINE®300 displayed anabolic, anti-catabolic and anti-inflammatory effects on human chondrocytes. It increased the basal synthesis of aggrecan and reversed the interleukin (IL)-1β-induced reduction of aggrecan synthesis by human chondrocytes in alginate beads7Henrotin Y.E. Sanchez C. Deberg M.A. Piccardi N. Guillou G.B. Msika P. et al.Avocado/soybean unsaponifiables increase aggrecan synthesis and reduce catabolic and proinflammatory mediator production by human osteoarthritic chondrocytes.J Rheumatol. 2003; 30: 1825-1834PubMed Google Scholar. It decreased the spontaneous and IL-1β-induced production of stromelysin-1 [matrix metalloproteinase (MMP-3)], IL-6 and -8, and prostaglandin E2 (PGE2) while it weakly reversed the IL-1-induced decrease of tissue inhibitor of metalloprotease's (TIMP)-1 production7Henrotin Y.E. Sanchez C. Deberg M.A. Piccardi N. Guillou G.B. Msika P. et al.Avocado/soybean unsaponifiables increase aggrecan synthesis and reduce catabolic and proinflammatory mediator production by human osteoarthritic chondrocytes.J Rheumatol. 2003; 30: 1825-1834PubMed Google Scholar, 8Henrotin Y.E. Labasse A.H. Jaspar J.M. De Groote D.D. Zheng S.X. Guillou G.B. et al.Effects of three avocado/soybean unsaponifiable mixtures on metalloproteinases, cytokines and prostaglandin E2 production by human articular chondrocytes.Clin Rheumatol. 1998; 17: 31-39Crossref PubMed Scopus (91) Google Scholar. It also decreased the spontaneous production of the macrophage inflammatory protein (MIP)-1β but stimulated the production of transforming growth factor (TGF)-β17Henrotin Y.E. Sanchez C. Deberg M.A. Piccardi N. Guillou G.B. Msika P. et al.Avocado/soybean unsaponifiables increase aggrecan synthesis and reduce catabolic and proinflammatory mediator production by human osteoarthritic chondrocytes.J Rheumatol. 2003; 30: 1825-1834PubMed Google Scholar. Finally, this drug fully prevented the inhibitory effect of OA osteoblasts on cartilage matrix protein production by human chondrocytes9Henrotin Y.E. Deberg M.A. Crielaard J.M. Piccardi N. Msika P. Sanchez C. Avocado/soybean unsaponifiables prevent the inhibitory effect of osteoarthritic subchondral osteoblasts on aggrecan and type II collagen synthesis by chondrocytes.J Rheumatol. 2006; 33: 1668-1678PubMed Google Scholar. All of this clearly demonstrates the therapeutic and biological effects of the ASU from PIASCLEDINE®300. Recently, Au et al.10Au R.Y. Al-Talib T.K. Au R.Y. Phan P.V. Frondoza C.G. Avocado soybean unsaponifiables (ASU) suppress TNF-alpha, IL-1beta, COX-2, iNOS gene expression, and prostaglandin E(2) and nitric oxide production in articular chondrocytes and monocyte/macrophages.Osteoarthritis Cartilage. 2007; 15: 1249-1255Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar have demonstrated that an ASU extract, named ASU-NMX 1000™ (Nutramax Laboratories Inc, Edgewood, MD, USA) suppressed tumour necrosis factor (TNF)-α, IL-1β, cyclooxygenase (COX)-2 and inducible nitric oxide (iNOS) gene expression, and PGE2 and nitric oxide production in articular chondrocytes and monocyte/macrophages. They conclude that these observations provide a scientific rationale for the pain-reducing and anti-inflammatory effects of ASU observed in OA patients. In other terms, the authors attempt to explain the therapeutic effect of PIASCLEDINE®300 by in vitro effects obtained with another ASU extract which shows a different chromatographic spectrum. Lippielo et al. (Nutramax Laboratories) have recently demonstrated that, compared to ASU-NMX 1000™, PIASCLEDINE®300 contains three major additional peaks11Lippiello L, Nardo JV, Harlan R, Chiou T, Metabolic effects of avocado/soy unsaponifiables on articular chondrocytes. Evid Based Complement Alternat Med (In press).Google Scholar. These peaks result of the particular extraction process used to prepare PIASCLEDINE®300. In comparison with PIASCLEDINE®300, other ASU formulations showed almost the complete absence of specific molecules which are patented. Therefore, while the ability of ASU-NMX 1000™ and PIASCLEDINE®300 to reduce PGE2 production or MMP activity or to stimulate glycosaminoglycans seems to be comparable11Lippiello L, Nardo JV, Harlan R, Chiou T, Metabolic effects of avocado/soy unsaponifiables on articular chondrocytes. Evid Based Complement Alternat Med (In press).Google Scholar, different effects of these two formulations on other aspects of the chondrocyte metabolism can not be excluded. Therefore, to extrapolate the data obtained with one ASU formulation to another one remains fully speculative. Further, clinical studies are required before concluding on the safety and the clinical efficacy of ASU-NMX 1000™. To use the in vitro and clinical data obtained with PIASCLEDINE®300 to support a potential effect of ASU-NMX 1000™ must be done with a great caution.