The active ingredient in Adequan® Canine is polysulfated glycosaminoglycan
(PSGAG). Polysulfated glycosaminoglycan is a semi-synthetic glycosaminoglycan
prepared by extracting glycosaminoglycans (GAGs) from bovine tracheal
cartilage. GAGs are polysaccharides composed of repeating disaccharide
units. The GAG present in PSGAG is principally chondroitin sulfate
containing 3 to 4 sulfate esters per disaccharide unit. The molecular
weight for PSGAG used in the manufacture of Adequan® is 3,000
to 15,000 daltons. Each mL of Adequan® Canine contains 100 mg
of PSGAG, 0.9% v/v benzyl alcohol as a preservative, and water for
injection q.s. to 1 mL. Sodium hydroxide and/or hydrochloric acid
added when necessary to adjust pH.
The specific mechanism of action of Adequan® in canine joints
is not known. PSGAG is characterized as a "disease modifying
osteoarthritis drug." Experiments conducted in vitro have shown
PSGAG to inhibit certain catabolic enzymes which have increased
activity in inflamed joints, and to enhance the activity of some
anabolic enzymes. For example, PSGAG has been shown to significantly
inhibit serine proteinases. Serine proteinases have been demonstrated
to play a role in the Interleukin-1 mediated degradation of cartilage
proteoglycans and collagen. PSGAG is reported to be an inhibitor
of Prostaglandin E2 (PGE2) synthesis. PGE2 has been shown to increase
the loss of proteoglycan from cartilage. PSGAG has been reported
to inhibit some catabolic enzymes such as elastase, stromelysin,
metalloproteases, cathepsin B1, and hyaluronidases, which degrade
collagen, proteoglycans, and hyaluronic acid in degenerative joint
disease. Anabolic effects studied include ability to stimulate the
synthesis of protein, collagen, proteoglycans, and hyaluronic acid
in various cells and tissues in vitro. Cultured human and rabbit
chondrocytes have shown increased synthesis of proteoglycan and
hyaluronic acid in the presence of PSGAG. PSGAGs have shown a specific
potentiating effect on hyaluronic acid synthesis by synovial membrane
cells in vitro.
distribution, metabolism, and excretion of PSGAG following intramuscular
injection have been studied in several species, including rats,
rabbits, humans, horses and dogs.
Studies in rabbits
showed maximum blood concentrations of PSGAG following IM injection
were reached between 20 to 40 minutes following injection, and that
the drug was distributed to all tissues studied, including articular
cartilage, synovial fluid, adrenals, thyroid, peritoneal fluid,
lungs, eyes, spinal cord, kidneys, brain, liver, spleen, bone marrow,
skin, and heart.
injection of PSGAG in humans, the drug was found to be bound to
serum proteins. PSGAG binds to both albumin and chi- and beta-globulins
and the extent of the binding is suggested to be 30 to 40%. Therefore,
the drug may be present in both bound and free form in the bloodstream.
Because of its relatively low molecular weight, the synovial membrane
is not a significant barrier to distribution of PSGAG from the bloodstream
to the synovial fluid. Distribution from the synovial fluid to the
cartilage takes place by diffusion. In the articular cartilage the
drug is deposited into the cartilage matrix.
Serum and synovial
fluid distribution curves of PSGAG have been studied in dogs and
appear similar to those found in humans and rabbits.
metabolism of PSGAG is reported to take place in the liver, spleen,
and bone marrow. Metabolism may also occur in the kidneys. PSGAG
administered intramuscularly and not protein bound or bound to other
tissues is excreted primarily via the kidneys, with a small proportion
excreted in the feces.
Efficacy of Adequan® Canine was demonstrated in two studies.
A laboratory study using radiolabeled PSGAG established distribution
of PSGAG into canine serum and synovial fluid following a single
intramuscular injection of 2 mg/lb. A clinical field trial was conducted
in dogs diagnosed with radiographically-confirmed traumatic and/or
degenerative joint disease of 1 or 2 joints. Joints evaluated included
hips, stifles, shoulders, hocks and elbows. Fifty-one dogs were
randomly assigned to receive either Adequan® Canine at 2 mg/lb
of body weight or 0.9% saline. Both treatments were administered
by intramuscular injection twice weekly for 4 weeks (8 injections
total). Investigators administering treatment and evaluating the
dogs were unaware of the treatment assignment. A total of 71 limbs
in 51 dogs were evaluated. Of these, 35 limbs in 24 dogs were in
the Adequan® Canine treated group. Each lame limb was scored
for lameness at a walk, lameness at a trot, pain, range of motion,
and functional disability. The scores for the individual parameters
were combined to determine a total orthopedic score. At the end
of the treatment period, dogs treated with Adequan® Canine showed
a statistically significant improvement in range of motion and total
orthopedic score over placebo treated control dogs.
and Usage: Adequan® Canine is recommended for intramuscular
injection for the control of signs associated with non-infectious
degenerative and/or traumatic arthritis of canine synovial joints.