Glucosamine sulfate and osteoarthritis

Pharm.D., BCPS

Ph.D.

(Osteoarthritis, OA

marginal

(articular cartilage)

subchondral bone

degenerative joint disease)

overgrowth

modifiable risk factors

1-3

integrity

proteoglycans

cartilage

proteolytic enzymes
bone exposure

fibrillation

collagen

(synovitis)
MRI

osteocytes

bony sclerosis

capsule

inflammatory mediators

prostaglandins

periarticular muscle weakness

proteoglycan

chondrocytes

callus

chondrocyte

microfractures

cartilage

X-ray

joint stiffness

fatique

systemic

joints
1

metatarsophalangeal joint of the great toe, DIP

carpometacarpal

OA

of Rheumatology

2000

OA

OA

nonpharmacological

OA

nonpharmacological treatments

program, weight reduction,

joint load

acetaminophen
NSAIDs

improve joint

pharmacological

nonpharmacological management

NSAIDs

ergonomic

drug of choice

therapeutic exercise

assistive devices

OA

topical

corticosteroid injection

osteoarthritic drugs

constituent

cartilage

NSAIDs

OA

disease modifying
DMOADs

major nonstructural

cartilage extracellular fluid

intra-articular

hyaluronic acid

topical capsaicin cream,

hyaluronic acid-like products

(DMOADs)

tramadol

systemic pharmacological treatments

topical methylsalicylate, topical NSAIDs

maintain

management

American College

PIP

mobility

synovial fluid

6,7

cartilage degeneration

chondroprotective agents
1 , glucosamine

proteolytic activity

glycosaminoglycan sulfate

proteoglycans

Diacerhein

cartilage matrix

incorporate

IL-

Glucosamine and chondroitin sulfate

Glucosamine

repair

chondroitin

maintenance

supplement

fructose-6-phosphate

ligament glucosamine

precursor

glycosaminoglycans matrix
core (proteoglycan)

cartilage tissue

hyaluronate

disaccharide unit

form

cartilage

glucosamine-6-

nutritional

aminosaccharide

fructose-6 phosphate amide transferase

glucosamine

prescription drugs glucosamine

phosphate

cartilage

cartilage

OA

tendon

protein

hydrophilic aggregate

chondroitin sulfate

GAG

hydrophobicity

8,9

aggregan structure

Glucosamine

glucosamine

glucosamine

mucopolysaccharide

cartilage

glucosamine-6-phosphate

Pharmacology
Glucosamine

glycosaminoglycans

in vitro

in vivo

cartilage

synovial fluid

cartilage matrix

glucosamine sulfate (GS)

in vitro

human articular chondrocyte

culture media
Noyszewski

galactosamine moiety
glucosamine
collagen

proteoglycans

aggrecanase

cartilage matrix

cartilage

chondrocytes

13

glucosamine

GS

colagenase

retinoic acid

chondrocytes

14

proteoglycan

11

glucosamine

12

cellular

aggrecan proteolysis

degeneration

bovine cartilage

fibrillated osteoarthritic

fibronectin

cartilage-specific type II

fibrillated cartilage

adhesion

incubate GS

cell proliferation

rat chondrosarcoma cell line

normal cartilage

intact articular cartilage explants

proteinase

interleukin-1

fibronectin

10

human osteoarthritic chondrocytes

collagenase

adhesion

phospholipase A2 activator

explants

C-labelled glucosamine

preferential incorporation

human fetal chondrocyte

GS

chondrocyte clusters

14

adhesion

15

fibronectin

GS

proteoglycan

IL-1

pathway

17

IL-1

glucosamine
glucosamine

GS

PGE2

prostaglandins
glucosamine

20,21

glucosamine

22

lysosomal enzymes

chondroitin sulfate

COX-2

elastase

19

antireactive effects

formalin

cartilage matrix

degenerative joint disease

18

N-acetyl

flexion scores

prostaglandin metabolism

rabbit instability model

1 Pharmacodynamic properties of GS
Pharmacodynamic

NF B

glycosaminoglycans

prostaglandin

free radical scavengers

chondroitin sulfate

NF B

expression

glucosamine

carageenan dextran acetic acid

superoxide

translocation

human osteoarthritic chondrocytes

chondrocytes

IL-1

N-acetyl galactosamine

proteoglycans

NF B

human PMNs

leukocytes

IL-1

16

B degradation

enzyme

NF B

down regulate glucuronyltransferase I

glycosaminoglycans

macrophages

proinflammatory cytokines

chondrocytes

glucosamine

properties
Anabolic effects

Anti-catabolic
effects

Anti-inflammatory
effects

Principal findings
Preferred and essential substrate for the synthesis of
glycosaminoglycans
and
consequently
of
10
proteoglycans by the chondrocyte.
Stimulates
cultured
human
chondrocytes
to
11
synthesize proteoglycans.
Increases gene expression of the proteoglycans
23
aggrecan and perlecan in human chondrocytes.
Inhibits the action of catabolic enzymes such as
stromelysin, collagenase, phospholipase A2 and
23-25, 14
aggrecanase.
15
Promotes adhesion of chondrocytes to fibronectin.
20,21
Inhibits the generation of superoxide radicals.
20,21
Inhibits the activity of lysosomal enzymes.
26
Inhibits inducible nitric oxide synthesis.
20,21
Does not inhibit the synthesis of prostaglandins.
15
Increases PKC production.

Pharmacokinetics
GS

14

IV

first pass metabolism

radioactivity

elimination half life 70

radioactivity

IV

(oral AUC = 26%

cartilage ground substance

Glucosamine

feces

14

CO2

28%

500

27

IV)

30%

glucosamine

N-acetyl-galactosamine sulfate

glycosaminoglycans

initial half life = 0.28

cartilage

glucosamine

uptake

90-98%

chitins

(1500

. )

glucosamine sulfate

stabilize matrix

cartilage

sulfur

Adverse Side Effects:

GS

diarrhea

cases of nausea, vomiting,

glucosamine sulfate (Clinical studies of GS)

modifying drugs)

29

1)

acetaminophen (paracetamol)

steroidal anti-inflammatory drugs (NSAIDs)

(structure-modifying drugs)

30

proteoglycan

8,31

GS

2)

proteoglycan
30,8

30,8

( 2)

glucosamine

non-

(symptom-

chondroprotective

5,29

30,8

glucosamine

10

5,28

29

 Western Ontario and

McMaster Universities

4-12

(WOMAC) osteoarthritis

index
Western Ontario and
McMaster Universities

(WOMAC) osteoarthritis

6-12

index

Lequesne index
Joint space width

Noack et al

32

symptom-modifying drugs

Osteoarthritis and Cartilage

..

GS

1994 (.. 2537)

multicenter, randomized, double-blind, placebo-controlled, parallel-group

500

60%

(n=126)

(p < 0.05)

parallel-group

(> 30%

(n=126)

et

al

33

GS

GS

65

( Lequesnes index)

1994 (.. 2537)

Mller-Fabender
ibuprofen

55

252

Osteoarthritis and Cartilage

GS

..

randomized, controlled, double-blind,

200

GS

ibuprofen

54

90%

400

48%

(n=100)

GS

ibuprofen

GS

(n=100)
4

(p < 0.001)

ibuprofen

500

34

Hughes et al

mild-moderate

2545)

GS

34

Hughes et al

GS

Rheumatology

randomized, double-blind, placebo-controlled

62

80

GS

500

(95% CI, -0.87 to 9.07)

2002 (..

68%

..

GS

McAlindon et al

35

symptom-modifying drugs

Controlled

JAMA

..

..

Trials

osteoarthrosis,

structure-modifying drugs
glucosamine

meta-analysis

2000 (.. 2543)

MEDLINE

1966

..

Register

degenerative

1999

arthritis,

glucosamine,

Cochrane

osteoarthritis,
chondroitin,

glycosaminoglycans

(95% CI, 0.24-0.64)

meta-analysis

glucosamine

glucosamine

heterogeneity

McAlindon et al

asymmetry; p 0.01)

glucosamine

aggregated effect size = 0.44

( funnel plots

glucosamine

glucosamine

36

Reginster et al

controlled

Lancet

GS

212

width

2001 (.. 2544)

1500

(95% CI, -0.48 to 0.13)

osteoarthritis index

(n=106)

(DMOADs)

GS

GS

GS

+9.8%

76%

-0.31

joint-space

joint-space width

(p = 0.043)

intention-to-treat

66

crystalline GS (powder

(95% CI, -0.22 to 0.09)

index 11.7%
36

al

-0.06

(3

for oral solution)

(n=106)

..

randomized, double-blind placebo

GS

WOMAC

WOMAC osteoarthritis

(p = 0.02) Reginster et

disease-modifying osteoarthritis drugs

Reginster

et

36

al

Halbekath et al

37

GS

36

Reginster et al
3

38

36

baseline

Swinburne LM

Reginster et al

Halbekath et al

glucosamine

36

Reginster et al

Pavelk et al

40

Archives Internal Medicine

GS

..

crystalline GS (powder for oral solution)

78%

+0.04

baseline
0.05,

(n=101)

intention-to-treat

GS

Lequesne index

GS

glucosamine

1500

62

mild-moderate

GS

p = 0.001

(-0.19

WOMAC total index)

(p = 0.02)

(p <

(p = 0.04)

(p =

0.047)

39

35

McAlindon et al

2002 (.. 2545)

(n=101)

202

glucosamine

randomized, double-blind, placebo-controlled

37

GS

GS

GS

glucosamine sulfate

glucosamine

glucosamine

glucosamine hydroiodide

glucosamine

GS

GS

8,34

1500

8,31

//

glucosamine

31

29

GS

31

bioavailability

GS

8,31

GS

8,31

4-6

GS

( 500

GS

20

GS

31

glucosamine

aminosaccharide

glucosamine

NSAIDs

GS

GS

DMOADs

GS

-GS -GS

GS

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