Cartilage supplements:glucosamine and chondroitin. Alexandrina Ferreira Mendes

8/6/2019 Cartilage supplements:glucosamine and chondroitin. Alexandrina Ferreira Mendes

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Cartilage supplements:

glucosamine and chondroitin

Curia, April 23rd 2010

Alexandrina Ferreira Mendes

Laboratory of Pharmacology, Faculty of Pharmacy

And Center for Neuroscience and Cell Biology

University of CoimbraCoimbra, Portugal


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synthesis of:

ECM components (aggrecan, collagen II)

Anti-inflammatory mediators (HO-1)

catabolic and pro-inflammatory responses to IL-1:

activation of NF-B, iNOS, COX-2, MMPs,

ADAMTS

expression of HO-1, proteoglycans, collagen II

Glucosamine salts:

sulfate and hydrochloride

In vitro: chondrocyte, synoviocyte and cartilage explant cultures

Concentration range: 1-25000 M

Largo et al. Osteoarthritis Cartilage. 2003;11:290-8

Toegel et al. Osteoarthritis Cartilage. 2008; 16:1205-12



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Chondroitin Sulfate

catabolic and pro-inflammatory responses to IL-1:

activation of NF-B, p38, ERK1/2, iNOS, COX-2, PLA2,

MMPs

In vitro: chondrocyte, synoviocyte and cartilage explant cultures

Chondroitin-4-sulfate Chondroitin-6-sulfate

n= 20-40 disaccharide units Alexandrina Ferreira Mendes

Glucuronic ac. N-acetylgalactosamine Glucuronic ac. N-acetylgalactosamine


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Common mechanism of action:

NF-B inhibition

TNFTNF--ILIL--11,,,,,,,, ILIL--1818

ILIL--6, IL6, IL--88

MMPsMMPsADAMTSADAMTS

iNOSiNOS

COXCOX--22


Matrix degradation

Inflammation

Pro-inflammatory

pro-catabolic

cytokines

Excellent efficacy in vitro and in vivo (animal models)


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Some recently completed clinical trials

Reference Sponsor Total daily

dose, mg

Size/duration Outcome (JSN,

WOMAC, Lequesne)

Glucosamine

Lancet.

2001;357:251-6

Rottapharm 1500 N=106/arm; 3 yr significant from

placebo

sulfate (GS) Arch Intern Med.2002;162:2113-23

Rottapharm 1500 N=101/arm; 3 yr significant fromplacebo

Glucosamine

hydrochloride

(G.HCl)

Arthritis Rheum.

2008; 58:3183-91

GAIT (NIH) 1500 N300/arm; 2 yr no significant from

placebo

Chondroitin

Arthritis Rheum.

2008; 58:3183-91

GAIT (NIH) 1200 N300/arm; 2 yr no significant from

placebo

sulfate (CS) Arthritis Rheum.

2009;60:524-33

STOPP 800 N300/arm; 2 yr significant from

placebo

G.HCl+CS Arthritis Rheum.

2008; 58:3183-91

GAIT (NIH) 1500 + 1200 N300/arm; 2 yr no significant from

placebo

Reference Sponsor Total daily

dose, mg

Size/duration Outcome (Pain)

G.HCl, CS,

G.HCl+CS

N Engl J Med.

2006;354:795-808

GAIT (NIH) 1500, 1200,

1500+1200

N300/arm;

24 weeks

no significant from

placebo

(significant improvement with

combination in moderate-severe pain)



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Glucosamine salts and chondroitin

sulfate

Black et al. Health Technol Assess. 2009; 13:1-148Block et al. Osteoarthritis Cartilage. 2010; 18:5-11

Rosa et al., Arthritis Res Ther. 2009; 11:R80 Alexandrina Ferreira Mendes

Sulfate seemingly more effective than hydrochloride

Large discrepancy between efficacy in vitro and in vivo vs clinical

trials

Cmax

(~10 M)


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Patient selection

Early stage OA late stage

Bay-Jensen et al. Rheumatol Int. 2010; 30:435-42

Ng et al. Arthritis Res Ther. 2010;12:R25

Aggrecanases MMPs

Aggrecan degradation

Collagen degradation

IrreversibleReversible

Glucosamine sulphate, 1500 mg/day + walking, N=36, ages 40-73, no daily

medication (analgesics included), 6 weeks:

Improvement in WOMAC scores, physical activity and function



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Endpoints/outcome

measures

Slow changes in JSN low sensitivity

Low reproducibility (improved w/ MRI)

Earlier and quantifiable endpoints/outcome measures

and biomarkers

sensitive, specific, reproducible

disease staging

discriminate fast and slow progressorsAlexandrina Ferreira Mendes


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Dosage regimen

Source of drug/compound

Single dose vs multidosingImplications on Cmax

Drugs vs nutritional supplements

EC: drugs and/or nutritional supplements

USA: nutritional supplements less stringentrequirements (purity, composition, dosage,

pharmacokinetics, pharmacodynamics)

Block et al. Osteoarthritis Cartilage. 2010; 18:5-11

Reginster et al. Rheumatology (Oxford). 2007;46:731-5. Alexandrina Ferreira Mendes


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Glucosamine and

Chondroitin sulphate

Positive effects on symptomatic andstructural outcomes of knee OA (still

debated)

Trend to combination more effective

than either alone

Symptomatic and structure modifying properties

enhanced in early OA?Alexandrina Ferreira Mendes


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Hyaluronic acid:

viscosupplement or drug?

Viscoelastic propertieslubrication

load absorption

Marshall et al. J Orthop Res. 2000; 18:416-25


MW Sodium hyaluronate 400-500 kDa

MW Crosslinked hyaluronan 6000 kDaGlucuronic ac. N-acetylglucosamine


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Hyaluronic acid:

viscosupplement or drug?In vitro: chondrocyte and synoviocyte cultures

p38 activation, NO production, mitochondrial DNA damage,

apoptosis,

mitochondrial DNA repair capacity, ATP levels

Hylan better than HA in improving growth factor expression

profile in synoviocytes

Grishko et al. J Biol Chem. 2009; 284:9132-9

Kaplan et al. Am J Sports Med. 2009;37:2323-7Lee et al. J Orthop Res. 2010; 28:492-6

Takahashi et al. Int J Mol Med. 2004;14:139-44 Alexandrina Ferreira Mendes

In vitro: animal models

GAG content after acute injury


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Clinical trials (mainly retrospective or pilotprospective studies)

Pain reduction

Functional improvement

Excellent tolerability

Hyaluronic acid:

viscosupplement or drug?

Castellacci & Polieri. Drugs Exp Clin Res. 2004;30:67-73

Migliori et al. Arthritis Res Ther. 2009;11:R183Alexandrina Ferreira Mendes


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Main features

Delayed effects

Reduce NSAID use

Carry-over effects


SYmptomatic Slow Acting Drugs for

OsteoArthritis SYSADOA

Current Drugs

Glucosamine sulphate

Chondroitin sulfate

Diacerhein

Hyaluronic acid


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Cellular Immunology and Oncobiology Group:

Chondrocyte Biology and Osteoarthritis Research

Documents

Cartilage supplements:glucosamine and chondroitin. Alexandrina Ferreira Mendes