jointsaver - LONG

[flemmerl@rcbhsc.wvu.edu (Flemmer, Linda)]

jtaylor@pyramid.net wrote:
> 
> I missed some of the post on Adequan. Where can you get it and can it be
> used on humans? 

Your vet has to prescribe Adequan injectable.  Similar results can be
obtained from oral CS and GAG's in combination, but it take longer. 
These are avaiable thru most feed/horse supply catalogs.

There IS a human version of Adequan, but again it is prescription only. 
Check w/ your doctor.  Humans do have the option to take the oral
supplements as well.  Here is a snippet of an article on this for
humans.  Sorry for the length.  Further info on the referenced articles
may be traced through any Medline server.

Linda Flemmer


Viscosupplementation for the Treatment of Osteoarthritis

                                      Peter Barland, M.D.
Introduction

The FDA has recently approved the use of hyaluronan for the treatment of
osteoarthritis of the knee for patients who have
failed treatment with acetaminophen, nonsteroidal anti-inflammatory
agents and physical therapy. Hyaluronan is given as a
series of weekly intra-articular injections (viscosupplementation) over
three to five weeks and the beneficial results -- relief
of pain, improved joint mobility and improved ambulation -- appear to
last for several months to one year. 

Role of hyaluronan in normal and osteoarthritic joints

Hyaluronan (hyaluronic acid, hylan) is a high molecular polysaccharide
consisting of repeating units of the disaccharide
glucuronic acid and glucosamine. It is produced by the type B lining
cells of the synovial membrane. There is a constant
turnover of hyaluronan in the joint -- the half-life of hyaluronan
injected into the joint is in the order of 24 to 48 hours. In
normal synovial fluid, hyaluronan, because of its high molecular weight
and negative charge, occupies a very large volume,
with the molecules of hyaluronan overlapping to form a continuous mesh.
It is this property of hyaluronan that gives normal
synovial fluid its high viscosity at low shear forces which contributes
to joint stability.1,2 

Hyaluronan can also dampen the response of the pain fibers in the
synovial membrane by coating the nociceptors.3 In
osteoarthritis, the hyaluronan concentration in the synovial fluid is
decreased, as is the molecular weight of the hyaluronan
molecules. It is believed that these changes contribute to the decrease
in joint function, as well as the pain, which are
characteristic features of the disease. Hyaluronan is also synthesized
by the articular choncrocytes where it forms the
backbone of the macromolecular aggregates of proteoglycans that make up
the matrix of all but the superficial layer of
articular cartilage.4 These aggregates are largely responsible for the
elasticity and compressibility of articular cartilage.
Chondrocytes appear to have a receptor for hyaluronan on their surface
membranes (CD44) which, when linked to
hyaluronan, inhibits the synthesis and secretion of an enzyme
aggrecanase that leads to the dissolution of the articular
matrix.5

Osteoarthritis is characterized by the degeneration of the articular
cartilage leading to fissuring and eventual loss of the
articular cartilage, followed by sclerosis of the subchondral bone,
osteophyte formation and a mild synovitis.6 The causes of
the cartilage degeneration appear to include physical stresses, such as
repeated trauma to the joint or sclerosis of the
underlying bone, and biochemical changes, such as calcium pyrophosphate
deposition in the articular cartilage. It appears
that both decreased synthesis, as well as increased degradation,
contribute to the changes in hyaluronan seen in
osteoarthritis.

History of hyaluronan for the treatment of osteoarthritis

A highly purified, noninflammatory form of hyaluronan can be purified
from rooster combs. In 1970, Rydell and coworkers
reported that, when this material was injected into arthritic equine
knee joints, there was a clinical improvement.7 In the
early 1980s there were several uncontrolled studies of the benefit of
intra-articular hyaluronan in the knees and hips of
patients with osteoarthritis which reported beneficial effects in the
majority of the patients often lasting six to twelve months.
Very few or no adverse side effects were reported. With the advent and
availability of total joint replacement, interest in
intra articular hyaluronan waned for several years.

More recently, there has been renewed interest in hyaluronan as a result
of controlled trials reported from Europe8 and
Canada.9 In some of these studies, the group receiving hyaluronan was
statistically improved for up to twelve months after
the intra-articular injections. The most consistent clinical parameter
to show improvement has been the patient's pain scores.
As in the earlier studies, there were very few adverse reactions and no
deaths have ever been reported after hyaluronan
therapy. While some authors have referred to this form of therapy as
chondroprotective, they have not presented evidence
to support this claim. However, a recent study of intra-articular
hyaluronan in a rabbit model of osteoarthritis reported that
there was less macroscopic and less microscopic damage to the articular
cartilage in the treated animals.10


Mechanism of action

It is not at all clear how hyaluronan relieves the symptoms of
osteoarthritis for such a long period of time since it is cleared
from the joints within a few days after intra-articular injection. It
has been proposed that the hyaluronan promotes long
lasting changes in the homeostasis of the joint by stimulating the
synovial lining cells to synthesize more hyaluronan, while, at
the same time, inhibiting the production of aggrecanase by chondrocytes,
thereby establishing a new homeostasis in the joint
more closely resembling the condition in the normal joint.

 Practical considerations

Hyaluronan treatment is indicated in patients with osteoarthritis of the
knee that is symptomatic despite treatment with
conservative measures which include acetaminophen, physical therapy and
nonsteroidal antiinflammatory drugs. Flares of
synovitis (swelling and tenderness) probably will do better with
intra-articular steroids than with hyaluronan. Hyaluronan,
like most therapies, is more effective in patients who have some
remaining range of motion and some remaining articular
cartilage, as judged by X-ray or MRI imaging. While total joint
replacement is probably the treatment of choice for patients
with advanced disease, intra-articular hyaluronan may provide
symptomatic relief in patients who are not surgical candidates
or refuse surgery.

There are currently two hyaluronan preparations approved for use in
osteoarthritis of the knee. One is Synvisc. (hylan G-F
20, distributed by Wyeth Laboratories), manufactured by the crosslinking
of hyaluronan purified from rooster combs to a
higher molecular weight form, known as hylan, which has a viscosity
similar to the hyaluronan found in the joint. Synvisc. is
retained in the joint for seven to fourteen days after intra-articular
injection. Clinical trials have shown that three weekly
injections of 16 mg. of this product into the knee results in an optimal
response. The other preparation, Hyalgan. (sodium
hyaluronate, distributed by Sanofi Pharmaceuticals), is a
non-crosslinked hyaluronan purified from rooster combs. It has a
viscosity considerably less than normal hyaluronan and has a biological
half-life in the joint considerably shorter than hylan
but may have wider distribution after intra-articular injection. The
optimal dosing for Hyalgan. appears to be five weekly
injections of 20 mg. each.

There are no comparative studies of the two agents in humans and the
very low adverse reaction rates and costs appear to
be comparable. Neither agent should be mixed with quaternary ammonium
anesthetics either in the syringe or in the joint
coprecipitation. Care should be taken not to inject the hyaluronan
subcutaneously or intravenously. Patients who are allergic
to chicken products should not receive these agents. The safety of the
agents in pregnancy or for nursing mothers has not
been established, though animal studies have not shown teratogenecity.
Patients on anticoagulant therapy should be treated
with caution, if at all. Repeat courses of hyaluronan have not been
studied or approved by the FDA although, theoretically,
they should be equally efficacious.

Other forms of therapy for osteoarthritis

Recently, there have been additional treatments advocated for
osteoarthritis in addition to those listed above. These include
the use of oral glucosamine with and without chondroitin sulfate.11
While the mechanism of action of these agents is
unknown and the original enthusiasm was based mainly on testimonials and
anecdotal experience, there is now at least one
prospective controlled trial indicating some mild clinical benefit for
the combination form of therapy. Experimentally, the use
of autologous cartilage implants12 and orthopedic procedures to
stimulate new cartilage growth and to change the weight
bearing surfaces of joints are attracting increasing interest. It
appears that osteoarthritis is no longer considered an inevitable
accompaniment of aging but rather a dynamic and largely treatable
disease.

References

1. Balazs EA, Denlinger JL: Sodium hyaluronate and joint function. J
Equine Vet Sci 1985; 5: 217-28. return

2. Balazs EA: The physical properties of synovial fluid and the special
role of hyaluronic acid. In: Helfet A, editor. Disorders
of the knee. Philadelphia: Lippincott; 1974: 61-74. return

3. Kitoh Y, Katsuramaki T, Tanaka H, et al: Effect of SL-1010 (sodium
hyaluronate with high molecular weight) on
experimental osteoarthritis induced by intra-articularly applied papain
in rabbits. Folia Pharmaco Jpn 1992; 100:67-76.
return

4. Hascall VC, Hascall GK: Proteoglycans. In; Hay ED, editor: Cell
biology of the extracellular matrix. New York: Plenum
Press 1981: p 39-63. return

5. Chow G, Nietfeld JJ, Knudson CB, Knudson W: Antisense inhibition of
chondrocyte CD44 expression leading to
cartilage chondrolysis. Arthritis Rheum 1998; 41:1411-1419. return

6. Kuettner KE: Osteoarhtritis: cartilage integrity and homeostasis. In:
Klippel JH, Dieppe PA, editors; Rheumatology, St.
Louis: Mosby - Year Book Europe Limited, 1994: p 6.1 - 6.16. return

7. Rydell NW, Butler J, Balazs EA. Hyaluronic acid in synovial fluid.
IV. Effect of intra-articular injection of hyaluronic acid
on the clinical symptoms of arthritis in track horses. Acta Vet Scand
1970; 11: 139-155. return 

8. Leardini G, Mattara L, Franceschini M, Perbellini A. Intra-articular
threatment of knee osteoarhtritis. A comparative
study between hyaluronic acid and 6-mehtylprednisolone acetate. Clin Exp
Rheumatol 1991; 9:375-381. return

9. Adams ME, Atkinson MH, Lussieri AJ, et al. The role of
viscosupplementation with hylan G-F20 (Synvisc) in the
treatment of osteoarthritis of the knee: a Canadian multicenter trial
comparing hylan G-F 20 alone, hylan G-F 20 with
non-steroidal anti-inflammatory drugs (NSAIDs) and NSAIDs alone.
Osteoarthritis Cartilage 1995; 3:213-225. return

10. Shimizu C, Kubo T, Hirasawa Y, et al. Histomorphometric and
biochemical effect of various hyaluronans on early
osteoarthritis. J Rheumatol 1998; 25:1813-1819. return

11. Muller-Fabender H, Bach GI, Haase W, et al. Glucosamine sulfate
compared to ibuprofen in osteoarthritis of the knee.
Osteoarthritis Cartilage 1994; 2:61-69. return

12. Brittberg M, Lindahl A, Nilsson A, et al. Treatment of deep
cartilage defect in the knee with autologous chondrocyte
transplantation. N Engl J Med 1994; 331:889-895. return