533 CHRONIC ADMINISTRATION OF CHONDROITIN SULFATE DOES NOT AFFECT CYTOCHROME P450 AND NADPH P450 REDUCTASE IN THE RABBIT

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  • S226 Osteoarthritis and Cartilage Vol. 16 Supplement 4

    Results: Progressive histopathologic changes characteristic of devel-oping OA were observed concomitantly with aging. This change wasinitiated by the disruption of the weight-bearing regions of articularcartilage at 6 months of age, and subsequent changes such as cloningof chondrocytes or loss of Safranin-O staining were recognized from8 months of age onward. The gure shows the Mankin scores obtainedfrom sections stained with Safranin-O. As shown in this gure, the scoreswere increased with aging in both groups. Statistical signicance wasrecognized between two groups only in the early phase at 6 months(p = 0.032). This data was consistent with the data of gross appearance.Conclusions: The present study demonstrated that menaquinones coulddelay the progression of osteoarthritis. To our knowledge, this is the rstreport to discuss the effect of menaquinones on the pathological featureof OA.

    531 EFFECT OF HYALURONIC ACID IN SYMPTOMATIC HIPOA: A MULTICENTRE, RANDOMISED, DOUBLE-BLIND,PLACEBO-CONTROLLED STUDY

    P. Richette1, P. Ravaud2, T. Conrozier3, L. Euller-Ziegler4, B. Mazie`res5,Y. Maugars6, D. Mulleman7, P. Clerson8, X. Chevalier9. 1HopitalLariboisie`re, Rhumatologie, Paris, FRANCE, 2Hopital Bichat.,Epidemiologie, Biostatistique et Recherche Clinique, Paris, FRANCE,3Centre Hospitalier Lyon sud, Rhumatologie, Lyon, FRANCE, 4Hopitalde lArchet, Rhumatologie, Nice, FRANCE, 5Hopital Rangeuil,Rhumatologie, Toulouse, FRANCE, 6Hopital Hotel-Dieu, Rhumatologie,Nantes, FRANCE, 7CHU de tours, Rhumatologie, Tour, FRANCE,8Orgametrie, Roubaix, FRANCE, 9Hopital Henri-Mondor, Rhumatologie,Creteil, FRANCE

    Purpose: To evaluate the efcacy and tolerability of one single hyaluronicacid (Adant) intra articular (IA) injection for hip osteoarthritis (OA).Methods: A randomised, double-blind (investigator blinded to the proce-dure), placebo-controlled trial. Patients (age over 30) with symptomatichip OA (pain level on VAS >40mm), Kellgren Lawrence grade II or III, wererandomly allocated to receive one uoroscopically guided IA injection ofhyaluronic acid (2.5ml) or placebo (2.5ml). Patients were followed upevery month for 3 months. The mean outcome measure was the levelof pain recorded on a VAS (0100mm) at month 3 and compared withbaseline. Secondary outcomes included the percentage of respondersaccording to the OMERACT-OARSI criteria, the Western Ontario andMcMaster Universities (WOMAC) OA index subscores on pain, stiffnessand disability, the patients and physicians global assessments. Safetywas assessed at each visit. Statistical analysis was performed on theinter-group difference in the intent-to-treat population (ITT) and in the perprotocol (PP) population. Missing data were replaced by carrying forwardthe last outcome.Results: Eighty-ve patients were included, and were randomized in thehyaluronic acid group (n = 42) or in the placebo group (n = 43). Baselinecharacteristics were similar between the two groups. The number of dropsout was 5% (n=4). At end point, the decrease in pain was 7.8 (24.95)and 9.12 (27.37) in the hyaluronic acid and placebo groups respectively,in the ITT population (p = 0.98). Same result was found in PP analysis.The OMERACT-OARSI responder rate was 33.3% in the hyaluronic acidgroup and 32.5% in the placebo group (p = 0.94). There was no signicant

    difference, both in ITT and in PP analysis, in secondary end points as wellas in the consumption of rescue medication between placebo and verum.There was no difference in the frequency of adverse events betweengroups.Conclusions: This study failed to show a superior symptomatic effectof a single IA hyaluronic acid injection (Adant) over placebo in patientswith hip OA. Further studies are required to explore the potential efcacyof more than one single intra articular injection in hip OA.

    532 HYALURONIC ACID INTERACTION WITH BUPIVACAINE ININTRAARTICULAR ADMINISTRATION

    J.A. Sanchez Lazaro1, L. Gonzalez Lobato2, G.M. Mendoza Cantos2,A.I. Alvarez de Felipe2, G. Merino Pelaez2, R. Real Fernandez2,J.G. Prieto Fernandez2. 1Hospital of Leon, Leon, SPAIN, 2University ofLeon, Leon, SPAIN

    Purpose: Elucidate if a daily common clinical administration of twointraarticular drugs as Hyaluronic Acid (H.A.) used to treat osteoarthrosisand Bupivacaine used as local anaesthesia, cause increase degradationof Hyaluronic Acid.Methods: In vitro studies with ve commercial H.A. have been used forthis study, (Synvisc, Coxarthrum, Go-on, Hyalgan and Durolane)with Bupivacaine at three different concentrations (0.25%, 0.50% and0.75%) with/without adrenaline (1/200,000), with 24 hours incubation at4C and 37C. Cromatography procedures (molecular exclusion HPLC)have been used for determination of molecular weight and degradationpercentage of H.A. Anova-Manova and Kendalls correlation have beenused to determinate statistiscal signicance.Results: Synvisc and Durolane have shown less degradation anddifferent behavior than Coxarthrum, Hyalgan and Go-on (Kendallscorrelation p< 0.05). Temperature of incubation modied the degradationof H.A. Durolane and Synvisc at 4C showed higher degradationthan at 37C (p< 0.05), otherwise happens for Coxarthrum, Go-on

    and Hyalgan that increased degradation at 37C (p< 0.05). Higherconcentration of Bupivacaine increased the degradation of H.A. in allcases (p< 0.05) and the concomitant use of adrenaline increased thedegradation in the three concentrations used at the present study forSynvisc, 0.25 and 0.75 for Coxarthrum, only at 0.75 for Durolane and0.25 for Go-on (p< 0.05). Adrenaline seems not to increase degradationover Hyalgan.Conclusions: Bupivacaine administration (with/without adrenaline) withH.A. must be valued before concomitant intraarticular administrationbecause Bupivacaine increased H.A degradation of all the H.A. studied.Durolane and Synvisc have shown less degradation (6 to 20%) anddifferent behavior than Coxarthrum, Hyalgan, Go-on (12 to 20%, 27to 29% and 28 to 39% respectively). Higher concentration of Bupivacaineand the concomitant use of adrenaline increased the degradation of H.A.in all cases except the concomitant use of adrenaline that seems not toaffect Durolane degradation except at highest Bupivacaine concentra-tion.

    533 CHRONIC ADMINISTRATION OF CHONDROITIN SULFATEDOES NOT AFFECT CYTOCHROME P450 AND NADPH P450REDUCTASE IN THE RABBIT

    E. Montell1, M-O. Iovu2, L. Heroux2, J. Verges1, P. du Souich2.1Scientic Medical Department, Bioiberica, Barcelona, SPAIN,2Departement de pharmacologie, Faculte de medecine, Universite deMontreal, Montreal, QC, CANADA

    Purpose: Chondroitin sulfate (CS) is a SYSADOA eliciting an anti-inammatory effect. Since patients take CS over long periods, it wasof interest to assess whether CS modulates the activity of cytochromeP450 isoforms (P450).Methods: Two models were used, chronic intake of CS in control rabbitsand in rabbits with a down-regulated P450 by an inammatory reaction(IR). Six groups of 5 rabbits were used; three were used to assess theeffect of CS on P450, one without CS and two receiving orally around20mg/kg/day CS for 20 and 30 days; three groups received turpentines.c. generating an aseptic IR (AIR) 48 h before their sacrice, e.g. days2, 18 and 28, exposed to CS for 0, 20 or 30 days, respectively. CYP3A6,CYP1A2 and NADPH P450 reductase (NADPH) activity, expression andRNAm were assessed in the hepatocytes.Results: Compared with control rabbits, 20 and 30 days CS did not affectthe activity of CYP3A6, e.g. 155821330, 134803052 and 14701841,and of CYP1A2, e.g. 65321203, 116122403 and 7494746, arbitrary

  • Poster Presentations Therapy Pharmacologic S227

    units. The AIR increased seromucoids to 95.15.7 vs 8.41.6mg/dlin controls (p< 0.05). The AIR reduced CYP3A6 activity to 5972464,5415541 and 2639747, and CYP1A2 activity, 3026113, 38561151,3805753 for control, 20 and 30 days of CS, respectively (p< 0.05compared without AIR). CS did not affect NADPH activity or expression.Conclusions: It is concluded that CS does not affect activity or expres-sion of CYP3A6 and CYP1A2, nor prevents AIR-induced down-regulation.These results are in agreement with the absence of CS-drug interactionsin humans.

    534 SIX-MONTH EFFICACY OF INTRA-ARTICULAR HYALURONICACID FOR CARPOMETACARPAL JOINT OSTEOARTHRITIS

    M. Massarotti, F. Uboldi, E. Valcamonica, L. Belloli, B. Marasini.Rheumatology Unit, IRCCS Humanitas Clinical Institute, University ofMilan, Rozzano (Milan), ITALY

    Purpose: To investigate the six-month efcacy of a three intra-articularhyaluronic acid (HA) injection course on pain relief in osteoarthritis (OA)of the carpometacarpal joint (CMC).Methods: Thirty-nine female patients affected by symptomatic CMC OA(aged 668 years, meanSD) were treated with three once-weekly intra-articular injections of HA (Hyalgan 1ml). All subjects met ACR criteriafor hand OA and had CMC OA grade 14 according to Kellgren andLawrence on standard X-ray performed within 6 months before theinclusion. Fifty-nine CMC joints were treated and evaluated (twenty-threepatients underwent to bilateral injections, thirteen patients had only onehand treated). Patients were followed for a 6-month period after the lastinjection. Treatment efcacy was assessed through visual analogue scale(VAS) pain quantication (baseline; 2nd and 3rd injection; one, three andsix months after the last injection). Side effects were recorded.Results: VAS was signicantly reduced after the rst injection (2ndinjection vs baseline, p< 0.01; 3rd injection vs baseline, p< 0.0001;3rd injection vs 2nd injection, p< 0.05) and reached the slowest scoreone month after the last injection. The efcacy was maintained for allthe 6-month follow-up period (one month vs baseline, p< 0.0001;threemonths vs baseline, p< 0.0001; six months vs baseline, p = 0.0001 onemonth vs 3rd injection, p = n.s.;three months vs 3rd injection, p = n.s.; sixmonths vs 3rd injection, p = n.s.). Only minor side effects were observed(mild pain and/or ecchymosis in injection site).Conclusions: Our study supports viscosupplementation with HA as asafe and efcacious approach for symptomatic CMC OA. Our schedulebased on three weekly intra-articular injections supplies pain relief lastingas long as 6 months with negligible side-effects.Further studies are needed to determine the long-term efcacy and theoptimal treatment schedule.

    535 TWELVE WEEKS MULTIMODAL CONSERVATIVE TREATMENTOF KNEE OSTEOARTHRITIS USING A NEWLY DEVELOPEDTREATMENT PROTOCOL IN THE NETHERLANDS:PRELIMINAIRY RESULTS

    G.F. Snijders, A.A. den Broeder, C.H. van den Ende, F.H. van denHoogen. Sint Maartenskliniek, Nijmegen, NETHERLANDS

    Purpose: Recently extensive evidence based recommendations havebeen made in the Netherlands for diagnosis and treatment of knee and hiposteoarthritis (OA). Based on this a three months standardized treatmentprotocol was developed including education, advice about weight lossand lifestyle measures, use of analgetics, referral for physical therapyand when necessary other interventions like intra-articular injections. Toimplement this protocol an outpatient clinic was initiated for conservativetreatment of primary osteoarthritis of the knee. The aim of this study wasto assess the results of a standardized conservative treatment protocolfor knee OA.Methods: Patients with symptomatic clinical knee OA according to theACR classication criteria referred to the rheumatology department bygeneral practitioners were treated at the outpatient clinic of the SintMaartenskliniek. In addition to patient education, treatment consisted ofthree main modalities: stepwise analgesia, referral to exercise therapyusing graded activity principle and weight reduction advises if necessary.Visits took place at the outpatient clinic at intake and after 12 weeks;patients were contacted by telephone at 4 and 8 weeks. Pain and ADLfunction were measured using a Likert scale (010) for pain and patientglobal assessment (PGA) and using WOMAC compatible subscales ofthe Knee injury and Osteoarthritis Outcome Score (WKOOS) (Likertscale version). WKOOS based OMERACT-OARSI responder criteria were

    measured in all patients after twelve weeks. Finally kinesiophobia wasmeasured using the Tampa Scale of Kinesiophobia (TSK).Results: Fifteen patients (13 females, mean age (SD) 6212) werethus far included. At intake the following values were found (meanSD):pain and PGA 6.11.9 and 6.12.5 respectively, WOMAC compatiblesubscales for pain, stiffness and function 114.4, 4.51.5 and 3814respectively, BMI 34.44.8 and TSK scores 406 (cut-off for irrationalkinesiophobia >37). After twelve weeks pain, PGA, BMI and TSK didnot change signicantly: scores were 6.43.2 (p = 0.8), 6.22.7 (p = 0.9),33.75.0 (p = 0.09) and 395 (p = 0.3) respectively. WKOOS basedOMERACT-OARSI responder criteria were however met in 40% of thepatients.Conclusions: Although 40% of patients met the OMERACT-OARSI re-sponder criteria using this protocol, mean pain and ADL function did notchange, indicating that a subgroup of patient worsened. However, thissample probably reects a highly selected population. Future researchshould be directed at identifying prognostic factors for non-response suchas body weight and kinesiophobia.

    536 EFFECTS OF EXOGENOUSLY INJECTED HYALURONAN ONTHE ARTICULAR CARTILAGE IN A RAT IMMOBILIZED KNEEMODEL

    A. Ando, Y. Hagiwara, E. Chimoto, Y. Onoda, H. Suda, E. Itoi. TohokuUniversity, Sendai, JAPAN

    Purpose: Joint immobilization is an essential treatment in daily exami-nations but it also causes degeneration of the articular cartilage. Intra-articular hyaluronan (HA) injection is widely used as a treatment ofosteoarthritis (OA) due to its physical and biological activities. Thougha large number of studies regarding chondroprotective effects of HA onOA animal models have been reported, most of these are based on jointinstability models by resection of ligaments or meniscus. There were fewreports of the effects of HA regarding immobilized joints. In this study, weexamined the chondroprotective effects of exogenously administered HAin a rat immobilized knee model.Methods: Animals: A total of 84 adult male Sprague-Dawley rats weigh-ing from 380400 g were used. Their unilateral knee joints were immo-bilized rigidly at 150 in exion with a plastic plate and metal screwsplaced internal but extra-articularly for various periods (1, 2, 4, 6, 8,12, and 16 weeks). 50 ml of HA (molecular weight = 1.9106) wasadministered intra-articularly for HA group on the day after surgeryand once a week until euthanasia. The same amount of saline wasadministered for control group. Tissue Preparation: The specimens werexed with 4% paraformaldehyde. After decalcication and dehydration,the specimens were embedded in parafn. The embedded tissue wascut into 5mm sagittal sections. Standardized serial sections were createdin the medial midcondylar region of the knee. Histological Evaluation:We chose 3 areas (non-contact, transitional, and contact area) from thearticular surface of the femur and tibia. A degr...

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